Synthesis of small molecules with high scaffold diversity: Exploitation of metathesis cascades in combination with inter-and intramolecular diels-alder reactions

Article abstract of DOI:10.1002/chem.201000707

Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules.Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter- and intramolecular Diels-Alder reactions, when used in conjunction with metathesis cascades, can extendthe range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to reprogram the molecular scaffolds. In many cases, the metathesis products were 1,3-dienes, which were potential substrates for either inter- or intramolecular Diels-Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a safety-catch linker that we have developed. It was demonstrated that, incertain cases, Diels-Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.

Full text of DOI:10.1002/chem.201000707

FULL PAPER
DOI: 10.1002/chem.201000707
Synthesis of Small Molecules with High Scaffold Diversity: Exploitation
of Metathesis Cascades in Combination with Inter- and Intramolecular
Diels–Alder Reactions
Catherine OꢀLeary-Steele,[a] Palle J. Pedersen,[a] Thomas James,[a]
Thomas Lanyon-Hogg,[b] Stuart Leach,[a] Jerome Hayes,[c] and Adam Nelson*[a]
Abstract: Our knowledge of the bio-
logical relevance of regions of chemical
space is shaped, in large part, by the
synthetic accessibility of small mole-
cules. Historically, however, chemists
have explored chemical space in an ex-
ceptionally uneven and unsystematic
way. We have previously demonstrated
that metathesis cascade chemistry may
be harnessed to yield small molecule
collections with high scaffold diversity.
Here, we describe the extent to which
inter- and intramolecular Diels–Alder
reactions, when used in conjunction
with metathesis cascades, can extend
the range of molecular scaffolds that
are accessible. A range of metathesis
substrates was prepared from combina-
tions of two or three building blocks.
Metathesis cascades were exploited to
“reprogram” the molecular scaffolds.
In many cases, the metathesis products
were 1,3-dienes, which were potential
substrates for either inter- or intramo-
lecular Diels–Alder reactions. The syn-
thesis and functionalisation of the
products was often facilitated by fluo-
rous tagging, for example by using a
“safety-catch” linker that we have de-
veloped. It was demonstrated that, in
certain cases, Diels–Alder reactions
could extend the range of molecular
scaffolds that may be prepared by
using metathesis cascade reactions.
Keywords: cycloaddition · diversi-
ty-oriented synthesis
·
domino
reactions · metathesis · molecular
diversity
Introduction
folds[4b,5] that have been biologically validated. Historically,
however, chemists have explored chemical space in an ex-
ceptionally uneven and unsystematic manner, with half of
known compounds being based on just 0.25% of the known
molecular scaffolds![6]
Our knowledge of the biological relevance of regions of
chemical space is shaped, in large part, by the synthetic (and
biosynthetic) accessibility of small molecules.[1] The field of
biology-oriented synthesis,[2] for example, seeks to target
bioactivity “islands”[3,4] by designing libraries around scaf-
The development of synthetic methods that allow the sys-
tematic variation of molecular scaffolds has proved extreme-
ly challenging.[7] Synthetic strategies have been developed to
allow the scaffolds of small molecules to be varied. In the
“folding” pathway strategy,[8] the scaffolds of products are
determined by structural features in starting materials
(sometimes known as s elements[8]). In contrast, in the
“branching” pathway strategy,[9] complementary reaction
conditions are used to convert starting materials into a
range of skeletally diverse products. The scaffolds of small
molecules may also be varied by using the “build-couple-
pair” strategy in which building blocks are exploited judi-
ciously in combination:[7c,10] here, building blocks are pre-
pared (built), connected (coupled) and then reacted intra-
molecularly (paired), to yield alternative molecular scaf-
folds. Some examples of branching and folding pathways
[a] Dr. C. OꢀLeary-Steele, P. J. Pedersen, T. James, Dr. S. Leach,
Prof. A. Nelson
School of Chemistry, University of Leeds
Leeds, LS2 9JT (UK)
Fax : (+44)113-343-6565
E-mail: a.s.nelson@leeds.ac.uk
[b] T. Lanyon-Hogg
Astbury Centre for Structural Molecular Biology
University of Leeds, Leeds, LS2 9JT (UK)
[c] Dr. J. Hayes
Chemical Development, GlaxoSmithKline
Old Powder Mill, Leigh, Tonbridge
TN11 9AN (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000707.
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Scheme 1. Application of fluorous-tagged linkers in the synthesis of skeletally diverse small molecules. A) An approach to the combinatorial variation of
the scaffolds of natural product-like small molecules. Building blocks were iteratively attached to a fluorous-tagged linker 1 to yield metathesis sub-
strates, such as 3. Metathesis cascades were used to reprogram the molecular scaffolds (e.g., 3!4) to yield final products, such as 4 with over 80 distinct
scaffolds. The substituent RF was fluorous-tagged. B) A fluorous-tagged safety-catch linker for preparing functionalised heterocycles. The fluorous tag fa-
cilitates purification of each of the synthetic intermediates by fluorous solid-phase extraction (FSPE). Crucially, only the products of successful metathe-
sis cascades are ultimately released from the fluorous tag (8!9). Bn=benzyl, TBS=tert-butyldimethylsilyl, Ts=tosyl.
can also be considered to exemplify the build-couple-pair
strategy.[7c]
More recently, we described a fluorous-tagged “safety-
catch” linker that facilitated the functionalisation of meta-
thesis products (Scheme 1B).[13] After attachment of building
blocks to the linker (5!6), metathesis cascades were ex-
ploited to define the scaffolds of the final products (e.g., !
7). Crucially, however, the metathesis products (e.g., 7) were
still fluorous-tagged, facilitating purification of the products
after derivatisation (e.g., !8). Finally, acid-catalysed cleav-
age (e.g., !9) released only the products of successful meta-
thesis cascades from the fluorous-tagged linker.
Recently, we reported a general approach to the combina-
torial variation of molecular scaffolds (Scheme 1A).[11] The
approach adopted the build-couple-pair strategy and, essen-
tially, combined the virtues of both branching and folding
pathways. Building blocks were prepared (built) and then,
in a branching pathway, attached iteratively onto a fluorous-
tagged linker (coupled) (e.g., 1!2!3). Subsequently, meta-
thesis cascades (e.g., 3!4) were used to fold the substrates
(pair), and to release the products of successful cascades
from a fluorous tag. The approach yielded a library of un-
precedented scaffold diversity (>80 scaffolds, around two-
thirds of which were previously unknown).[3,11,12]
In this paper, we demonstrate that the scope of our diver-
sity-oriented approach may be extended by using metathesis
cascades to prepare substrates for both inter- and intramo-
lecular Diels–Alder reactions (Scheme 2). We envisaged
Scheme 2. An overview of the synthetic approaches described in this paper. Building blocks may be combined to yield metathesis substrates 10, which
may be folded to yield metathesis products 11; the products 11 may be further functionalised by deprotection and derivatisation. Three approaches that
exploit Diels–Alder chemistry may be envisaged to extend the range of scaffolds that may be prepared. A) Culmination with an intermolecular Diels–
Alder reaction to yield scaffolds, such as 12a. B) Formation of a dienophile and a diene (11b) in a metathesis cascade, followed by intramolecular Diels–
Alder reaction to yield scaffolds, such as 12b. C) Attachment of a dienophile to the diene, 11c, and intramolecular Diels–Alder reaction to yield scaf-
folds, such as 12c. Note that substituents, fluorous tags and stereochemistry are omitted for clarity.
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Synthesis of Small Molecules with High Scaffold Diversity
FULL PAPER
that metathesis substrates, for example 10a–10c, could be
easily assembled from combinations of the building blocks
shown in Scheme 3. To allow for purification of the synthetic
intermediates by fluorous solid-phase extraction (FSPE),[14]
Results and Discussion
A wide range of metathesis substrates was prepared from
combinations of two or three building blocks (see Table 1
and Table 2). The allylic acetate 17 was reacted with the
propargylic alcohol 26 in a Pd-catalysed allylic etherification
reaction (Table 1, entry 1).[16] Similarly, the hydroxy acetates
19–22 were reacted with the propargylic sulfonamide 30 by
using a Fukuyama–Mitsunobu[17] reaction to yield, after de-
protection, compounds 37–40 (Table 1, entries 2–5). The flu-
orous-tagged safety-catch linker[13] 16 was treated with the
hydroxy acetates 23, 18 and 21 to yield, after FSPE and de-
acetylation, compounds 41–43 (Table 1, entries 6–8); the al-
cohol 41 was subsequently converted into the corresponding
sulfonamide 44 (Table 1, entry 9). Finally, the building block
25 was attached to the fluorous-tagged building block 15a to
yield the silaketal 45.
The synthesis of 23 metathesis substrates (46–68) was
completed by the attachment of a “capping” building block
(Table 2) by using three different reactions: the Fukuyama–
Mitsunobu reaction,[17] unsymmetrical silaketal formation[18]
and esterification. In general, fluorous-tagged metathesis
substrates were purified by FSPE alone, with purities deter-
1
mined by 500 MHz H NMR spectroscopy.
The metathesis substrates 46–68 were each treated with a
catalyst (Scheme 4) in refluxing dichloromethane (Table 2).
Scheme 3. Structures of the building blocks.
one of the first building blocks may be fluorous-tagged. For
example, the building blocks 13–15 contain a fluorous-
tagged version (FDIPES) of the diisopropylethylsilyl
(DIPES) protecting group, and the safety-catch linker, 16,
that we have previously described,[13] is also fluorous-tagged.
A metathesis cascade may then be used to determine the
scaffolds of the final products (e.g., 11a–11c). At this stage,
removal of the o-nitrosulfonyl (Ns) protecting groups would
be possible to allow the functionalisation of the scaffolds.
For metathesis products with an embedded 1,3-diene
(e.g., 11a–11c), however, we envisage three distinct ap-
proaches that would extend the range of scaffolds that may
be prepared (Scheme 2). The approach shown in Scheme 2A
would involve an intermolecular Diels–Alder reaction to
yield polycyclic products (e.g., 11a!12a). In the approach
shown in Scheme 2B, the metathesis cascade would have re-
vealed both a diene and a dienophile allowing the possibility
of an intramolecular Diels–Alder reaction[15] (e.g., 11b!
12b). Finally, the approach shown in Scheme 2C would in-
volve the tethering of a dienophile to the metathesis product
(e.g., 11c), followed by subsequent intramolecular Diels–
Alder reaction (e.g. !12c). In this paper, we describe the
scope and limitations of each of these complementary ap-
proaches, and their application in the synthesis of a library
of skeletally and substitutionally diverse small molecules.
Scheme 4. Structures of metathesis catalysts. Ar=2,4,6-trimethylphenyl;
Cy=cyclohexyl.
The reactions were monitored, and additional catalyst was
added as needed. The phosphine, PACHTUNGTRNEUNG
(CH2OH)3,[19] and, for
fluorous-tagged products, FSPE, were used to remove the
catalyst. The metathesis products were generally purified by
column chromatography. All reactions yielded the expected
cascade products, although, for 47 (Table 2), cyclisation to
the tetrasubstituted alkene 70 was slow,[20] and the by-prod-
uct 92 was also observed (Scheme 5). With the first-genera-
tion Grubbsꢀ catalyst (I), compound (ꢀ)-76 (Table 2) under-
went partial isomerisation to the unconjugated product 93
(Scheme 5). Finally, trifluoroacetic acid (TFA) released the
metathesis products 81–91 (R=H; Table 2), but not any re-
maining substrate, from the fluorous-tagged safety-catch
Scheme 5. Structures of by-products of metathesis cascades.
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9565

A. Nelson et al.
Table 1. Building-block couplings.
acetal hydrolysis, followed by
FSPE, gave the final products
96 (R=H) and 97 (R=H)
(Table 3).
Building
blocks[a]
Method[b]
Product
Yield [%]
58 [90][c]
71[d]
1
2
17, 26
A, B1
C, D1
We next investigated the in-
tramolecular Diels–Alder reac-
tions of the metathesis products
74–78 (Table 2) (Scheme 2B);
for each of these compounds,
the 1,3-diene is tethered to a
potential butenolide dienophile.
Previously, a similar intramolec-
ular Diels–Alder reaction in-
volving a butenolide dienophile
was exploited in a total synthe-
sis of Forskolin.[21] After 3 days
in refluxing p-xylene, the bute-
nolide (ꢀ)-76 gave the pentacy-
clic adduct (ꢀ)-98 (Scheme 6)
the relative configuration of
which was determined through
the observation of diagnostic
NOE correlations; in addition,
35% of the starting material
was recovered. The stereochem-
ical outcome of the reaction is
rationalised in Scheme 7. The
tether between the dihydropyr-
role and the butenolide rings
determines which face of the
diene and the dienophile
reacts: thus, with the relative
configuration of (ꢀ)-76, the re-
action proceeds through an exo
transition state to yield the
product (ꢀ)-98.
(ꢀ)-19, 30
(ꢀ)-20, 30
21, 30
[e]
[e]
3
4
5
6
C, D1
C, D1
C, D1
C, D2
22, 30
77[d]
16, 23
>96[f] (86)[g] [83][c]
7
8
16, 18
16, 21
C, D2
C, D2
>98[f] (>95)[g] [93][c]
97 [96][c]
9
41, 24
C, E
86 [86][c]
78 [35][c]
10
15a, 25
F, D2
[a] The first building block specified was the limiting reagent. [b] Methods: A: building blocks (1 equiv),
Et2Zn, Pd(OAc)2 (5 mol%), 2-PhC6H4PtBu2 (7.5 mol%), NH4OAc (7.5 mol%), THF; B1: tetrabutylammoni-
Surprisingly, the diastereo-
ACHTUNGTRENNUNG
um fluoride (TBAF), THF; C: building block in excess (4 equiv), diethyl azodicarboxylate (DEAD) (4 equiv),
PPh3 (4 equiv), THF, 08C, 1 h; D1: NaOMe, MeOH; D2: NH3 in MeOH (sat.); E: DMSO, D; F: silyl ether
(5.5 equiv); N-bromosuccinimide (NBS) (5 equiv); CH2Cl2, 08C!RT. [c] Yield for the second step. [d] Yield
over 2 steps. [e] Isolated as the corresponding acrylate (see Table 2). [f] Purified by FSPE. [g] Purity deter-
meric
substrate
(ꢀ)-75
(Table 2) gave a low yield (5%)
of the same product (ꢀ)-98
under these reaction conditions.
1
mined by 500 MHz H NMR spectroscopy.
linker.[13] Unfortunately, the 2,4-pentadien-1-ols 81, 82, 90
and 91 (Table 2) were prone to epimerisation under these
reaction conditions.
For the 1,3-diene metathesis products, we investigated the
potential of the complementary approaches outlined in
Scheme 6. Intramolecular Diels–Alder reaction of the metathesis product
Scheme 2 to expand the range of accessible small molecule
scaffolds. For the approach shown in Scheme 2A, we studied
the Diels–Alder reactions of the 1,3-dienes 70, (ꢀ)-76, 81
(R=R’F) and 82 (R=R’F) with the reactive dienophile 4-
phenyl-[1,2,4]-triazole-3,5-dione (Table 3). The design of our
safety-catch linker[13] meant that the metathesis products 81–
82 (R=R’F; Table 3) were still fluorous-tagged, allowing
easy purification (by FSPE) of the corresponding Diels–
Alder adducts 96–97 (R=R’F; Table 3); TFA-catalysed
(ꢀ)-98.
Scheme 7. Rationalisation of the stereochemical outcome of the intramo-
lecular Diels–Alder reaction of (ꢀ)-76
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Synthesis of Small Molecules with High Scaffold Diversity
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Table 2. Synthesis and cascade reactions of metathesis substrates; with starting materials (SM) 13, 14, 15b, 15a, 36, (ꢀ)-37, (ꢀ)-38 and 39–45 and cap-
ping building blocks (CBB) 27–35.
SM
CBB Method[a] Metathesis
substrate[b]
Mass recovery[c] Method
Product[b]
Yield [%]
A
(mol% cat.)
1
2
13 28
C
C
95 (>85)
96 (>85)
G1 (5)
95[c] (>90)[d]
13 30
14 31
G2 (5)
57[e]
3
4
5
C
C
F
48[f]
55[f]
34
G2 (5!10)
G2 (5)
27
15b 30
15a 34
69
G2 (5), B2
G2 (3)
51 [62][g]
6
7
8
9
36
(ꢀ)-37
(ꢀ)-38
39
–
–
–
–
H
H
H
H
87[f]
95[f]
62[h]
37[h]
46
G1 (5)
G1 (5)
G2 (3)
70
72[i]
31
10
40
–
H
78[f]
G2 (3)
56
11
12
45 29
41 35
C
F
52[f]
G2 (2ꢂ5)
87
16
67 (82)
G1 (4ꢂ5), B3
13
14
15
41 27
41 29
42 27
C
C
C
98 (85)
68[f]
G2 (3ꢂ5), I
G2 (3ꢂ5), I
G2 (5), I
61 [59][g]
74 [60][g,j]
20[k]
80 (85)
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A. Nelson et al.
Table 2. (Continued)
SM
CBB Method[a] Metathesis
substrate[b]
Mass recovery[c] Method
Product[b]
Yield [%]
A
(mol% cat.)
16
17
42 28
C
C
53[f]
G2 (5), I
98[c] (94)[d] [85][g]
42 30
98 (84)
G2 (2ꢂ5)
48[c] (88)[d] [50][g]
18
19
43 27
43 28
C
C
74[f]
G2 (4ꢂ5), I
G2 (2ꢂ5), I
12[k]
66[k]
20
21
43 30
C
C
74[f]
G2 (2ꢂ5), I
G2 (2ꢂ5), I
35 [58][g]
44 32
93 (84)
50 [66][g,j]
22
23
44 33
C
C
93 (84)
G2 (2ꢂ5), I
G2 (2ꢂ5), I
17[j,k]
44 31
43[f]
10[j,k]
[a] Methods: B2: HF (50% aq) CH2Cl2–MeCN, 1 h, RT; B3: HF·pyridine, THF, RT then Me3SiOMe; C: building block (4 equiv), DEAD (4 equiv), PPh3
(4 equiv), THF, 08C, 1 h; F: building block (5.5 equiv); NBS (5 equiv); CH2Cl2, 08C!RT; G1: i) catalyst I, CH2Cl2, 458C; ii) Et3N, P(CH2OH)3 then
AHCTUNGTRENNUNG
silica then filter through Celite; G2: i) catalyst III, CH2Cl2, 458C; ii) Et3N, PACTHNUTRGNEUNG(CH2OH)3 then silica then filter through Celite; H: acryloyl chloride,
iPr2NEt, CH2Cl2, 08C; I: TFA (3%), CH2Cl2. [b] For the definitions of RF and R’F, see Scheme 1B. [c] Purified by FSPE unless otherwise indicated.
1
[d] Purity determined by 500 MHz H NMR spectroscopy. [e] The triene 92 was also obtained in 6% yield. [f] Yield of the purified product after column
chromatography. [g] Yield for the second step. [h] Yield over three steps from the corresponding hydroxy acetate ((ꢀ)-20 or 21). [i] The isomeric product
93 was also obtained in 13% yield. The yield of 76 was 34% and 36% with 5 mol% of the catalysts III and II respectively. [j] Obtained as diastereomeric
mixture. [k] Yield over two steps.
Presumably, the endo transition state that is required for
direct cycloaddition is disfavoured; instead, isomerisation to
(ꢀ)-76 via the unconjugated compound 93 was followed by
intramolecular Diels–Alder reaction to give the pentacycle
(ꢀ)-98. Intramolecular Diels–Alder reaction was not ob-
served in refluxing p-xylene with either shorter (i.e., 74 or
78) or longer (i.e., 77) tethers between the diene and the di-
enophile.
A dienophile was attached to both of the alcohols of 80
(Scheme 8); here, the fluorous-tagged safety-catch linker al-
lowed the purification of the product 99 by FSPE alone. The
intramolecular Diels–Alder reactions of fumarate esters of
2,4-pentadien-1-ols are well known.[22] Microwave irradia-
tion[22c] of 99 (at 1608C) yielded the tricyclic fused product
100. The stereochemical outcome of the reaction is rational-
ised in Scheme 9. The diastereoselectivity of intramolecular
Diels–Alder reactions of achiral fumarate esters of 2,4-pen-
tadien-1-ols has been studied previously and, with (E,E)-
dienes, selectivity in favour of the exo (with respect to the
tethering ester) product was observed. The reaction of 99 is
more complicated because the substrate is chiral. The out-
come of the reaction (!100) is consistent with reaction
through an exo (with respect to the tethering ester) transi-
tion state in which 1,3-allylic strain is minimised.
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Synthesis of Small Molecules with High Scaffold Diversity
FULL PAPER
Table 3. Intermolecular Diels–Alder reactions with 4-phenyl-[1,2,4]-tria-
zole-3,5-dione.
SM
Method[a]
Product
Yield [%]
1
2
3
4
70
J
84
Scheme 9. Rationalisation of the stereochemical outcome of the intramo-
lecular Diels–Alder reaction of 80.
tion by FSPE of the intermediates, both after removal of the
Ns protecting group and after derivatisation of the resulting
secondary amine. The final products 101–107 (Table 4) were
obtained after removal of the fluorous tag either by desilyla-
tion (!101–104 and 107) or acetal hydrolysis (!105 and
106). In addition, treatment of the butenolide (ꢀ)-76 with
aqueous methylamine triggered conjugate addition and
amide formation to yield the amino alcohol 108 (Table 4) as
a single diastereomer.
(ꢀ)-76
J
95
81[b]
J, I
J, I
88[c] (>95)[d] [58][e]
82[b]
88[c] (90)[d] [75][e]
Conclusion
Metathesis cascade chemistry is an exceptionally powerful
reaction for the synthesis of skeletally diverse small mole-
cules. Metathesis substrates were easily assembled from
combinations of two or three building blocks; thereafter,
metathesis cascades allowed the molecular scaffolds to be
reprogrammed. The overall approach was facilitated by fluo-
rous tagging of one of the building blocks, allowing easy pu-
rification (by FSPE) of synthetic intermediates and metathe-
sis products. The presence of a fluorous tag also facilitated
the subsequent functionalisation of the metathesis products.
A fluorous-tagged safety-catch linker[13] was particularly
useful since it facilitated purification at each stage of the
synthesis, whilst only allowing the products of successful
metathesis reactions to be released from the fluorous tag.
The use of Diels–Alder reactions extended the range of
scaffolds that were synthetically accessible. The products of
several metathesis cascades were 1,3-dienes that are poten-
tial substrates for inter- or intramolecular Diels–Alder reac-
tions. A challenge posed by diversity-oriented synthesis is
that structurally diverse products are likely to exhibit di-
verse reactivity. The scope of our approach is a testament to
the remarkable generality of ring-closing metathesis.[23] The
Diels–Alder reaction allowed more complex scaffolds to be
prepared in certain cases: however, the scope of the intra-
molecular Diels–Alder reaction limited the range of addi-
tional scaffolds that were accessible. Synthetic approaches
that yield skeletally diverse small molecules are rare: devel-
oping new diversity-oriented approaches, particularly those
that do not rely on metathesis chemistry, remains a very sig-
nificant challenge for synthetic chemists.
[a] Methods: I: 3% TFA, CH2Cl2; J: 4-phenyl-[1,2,4]-triazole-3,5-dione,
CH2Cl2. [b] R=R’F; for the definition of R’F, see Scheme 1B. [c] Deter-
mined by 500 MHz 1H NMR spectroscopy. [d] Yield of purified product
after column chromatography. [e] Yield for the second step.
Scheme 8. Attachment of a pendant dienophile to the metathesis product
80 and intramolecular Diels–Alder reaction; DCC=N,N-dicyclohexylcar-
bodiimide, DMAP=4-dimethylaminopyridine, MW=microwave.
Finally, a selection of fluorous-tagged products were deri-
vatised to yield a range of amides, sulfonamides, ureas and
thioureas (Table 4). The fluorous tag facilitated the purifica-
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9569

A. Nelson et al.
Table 4. Functionalisation of metathesis products.
Acknowledgements
SM
Method[a]
Product
Yield [%]
50
We thank the EPSRC, GSK and the University of Leeds for funding,
and Chris Cordier and Daniel Morton for helpful discussions.
69
K, L, B2
69
69
69
69
69
69
K, L, B2
K, L, B2
K, M, B2
K, M, B2
K, L, B2
K, L, B2
101 (R=2-thiophenecarbonyl)
101 (R=5-isoxazolecarbonyl)
101 (R=CONHPh)
101 (R=CSNHBn)
101 (R=SO2Ph)
77
70
69
38
84
61
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K, L, B2
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94
94
94
K, L, B2
K, M, B2
K, L, B2
(ꢀ)-102 (R=5-isoxazolecarbonyl)
(ꢀ)-102 (R=CONHPh)
(ꢀ)-102 (R=SO2Ph)
61
37
72
72
K, L, B2
81
72
72
72
72
K, L, B2
K, L, B2
K, L, B2
K, L, B2
103 (R=2-thiophenecarbonyl)
103 (R=5-isoxazolecarbonyl)
103 (R=SO2Ph)
94
56
75
60
103 (R=SO2Me)
71
K,[c] M, B2
38
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K, M, I
21
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85[b]
K, M, I
63
43
79
K, L, B2
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(ꢀ)-76
N
48
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[a] Methods: B2: HF (50% aq) CH2Cl2–MeCN, 1 h, RT then Me3SiOMe;
I: TFA (3%), CH2Cl2; K: K2CO3 (4 equiv), PhSH (3 equiv), DMF, RT;
L: acid chloride or sulfonyl chloride (4 equiv), DMAP, CH2Cl2; M: isocy-
anate or thioisocyanate (4 equiv), CH2Cl2, RT; N: MeNH2 (aq). [b] R=
R’F; for the definition of R’F, see Scheme 1B. [c] Performed in MeCN
with 1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) as base.
9570
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Chem. Eur. J. 2010, 16, 9563 – 9571

Synthesis of Small Molecules with High Scaffold Diversity
FULL PAPER
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Received: March 19, 2010
Published online: June 2, 2010
Chem. Eur. J. 2010, 16, 9563 – 9571
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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