Sequential [6+2], [2+2], and [3+2] annulations for rapid assembly of multiple fragments

Article abstract of DOI:10.1039/c2cc38854e

Assembly of four components through sequential [6+2], [2+2], and [3+2] annulations on an azulenone manifold allows for five-step access to a natural product-inspired scaffold with exquisite control of the ten consecutive stereocenters. X-ray analysis was used to define the spatial arrangement of the three fragments and functional groups on this rigid scaffold. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2cc38854e

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ARTICLE TYPE
Sequential [6+2], [2+2], [3+2] Annulations for Rapid Assembly of
Multiple Fragments
a
a
a
Velisoju Mahendar, Hideaki Oikawa and Hiroki Oguri*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Assembly of four components through sequential [6+2], [2+2],
and [3+2] annulations on an azulenone manifold allows for
The threeꢀdimensional (3ꢀD) array of the key components is
defined accurately by seven stereogenic centers on the framework
6
five-step access to a natural product-inspired scaffold with 30 leading to tight and specific interactions. A series of biologically
7
8
intriguing terpenoids, exemplified as 1, 2 and 3, share the
bicyclo[5.3.0]decane frameworks that often have additional ring
fusions and display dense arrays of functional groups and
acyl/aromatic sidechains. This implies that attachments of
exquisite control of the ten consecutive stereocenters. X-ray
analysis was used to define the spatial arrangement of the
three fragments and functional groups on this rigid scaffold.
1
0
Fragmentꢀbased drug design (FBDD) represents a rational 35 different fragments on terpenoidꢀrelated scaffolds could generate
method for drug discovery as an alternative to highꢀthroughput
screening (HTS). Despite recent advancements, tactics for
a collection of small molecule modulators specific for biological
receptors.
1
1
5
fragment linking remain limited and usually rely on click
chemistry or costꢀeffective medicinal transformations employing
2
heteroꢀaromatic manifolds or flexible alkyl/peptidyl linkers. The
2
linear assemblies of several fragments typically produce sp ꢀrich
flat molecules with limited threeꢀdimensionality and complexity
3
,4
2
0
compared to those of natural products. A structurally elaborated
2+
sesquiterpene, thapsigargin is a subꢀnanomolar inhibitor of Ca ꢀ
ATPase that interacts through multipoint recognitions exploiting
four acyl sideꢀchains and a fiveꢀmembered lactone displayed on a
5
bicyclo[5.3.0]decane framework (Figure 1).
2
5
Figure 1. Structures of naturally occurring terpenoids 1ꢀ3 containing a
bicyclo[5.3.0]decane framework.
Scheme 1. (a) A hypothetical biosynthetic route to 1; (b) Outline of
sequential annulations for fragment assembly on the hexacyclic scaffold
40
7
.
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According to a hypothetical biosynthetic proposal, the tricyclic 25 maleimide derivative having “FG-2” might occur at the sterically
skeleton of 1 could be formed through intramolecular cyclizations
less hindered double bond to afford 6. Subsequent [3+2]
annulation of the enone unit with azomethine ylide bearing “FG-
3” and the glycine unit would produce a hexacyclic scaffold 7
of farnesyl diphosphate concomitant with several oxidations and
9
a lactone formation (Scheme 1a). Further oxidations and
2
5
0
5
0
condensations would occur to install the distinct acyl chains on
with installation of a substituted proline moiety. The six sp ꢀ
the framework in a stepwise fashion. The biosynthetic approach 30 carbons of the cycloheptatriene unit in manifold 4 could
requires multistep transformations to access the pharmacophore
displaying various fragments. With intentions to develop a
concise and universal platform for FBDD employing the
bicyclo[5.3.0]decane framework, we conceived of a rapid and
participate in the intermolecular annulations for displaying
multiple fragments on 7, in which the 3Dꢀarrays of three
fragments, a substituted proline unit, a cyclopentanone moiety,
1
1
2
and a triꢀsubstituted olefin group, are regulated by ten
dense integration of intended fragments and functional groups 35 consecutive stereocenters on the rigid skeleton. In addition, the
within fiveꢀsteps. We thus designed azulenone manifold 4 to
assemble multiple fragments through sequential annulations by
exploiting versatile reactivity of the 6πꢀunit of cycloheptatriene
linkages of fragments to the core skeleton are expected to be
resistant to biological degradations.
With this strategic planning in mind, the azulenone 4 was
10
12
merged with a cyclopentenone moiety (Scheme 1b). Dieneꢀ
readily prepared in 5ꢀ10 g batches. First, cobaltꢀcatalyzed
transmissive [4+2]ꢀcycloadditions employing a 6πꢀunit of a crossꢀ 40 formal [6+2] annulation of 4 with phenyl acetylene 8 was
conjugated triene system have been developed to efficiently
generate molecular complexity through appendages of
examined by applying Buono’s conditions for the cycloaddition
13
of cycloheptatriene (Scheme 2). Upon treatment of 4 with 8 in
the presence of 10 mol% CoI (dppe), Zn and ZnI , tricyclic 10
11
dienophiles. In this study, a distinct strategy was devised for
sequential annulations on without employing [4+2]
cycloadditions. A cobaltꢀcatalyzed formal [6+2] cycloaddition of 45 isomer (10%). Although it was difficult to control the
2
2
4
was obtained as the major isomer (55%) along with a regioꢀ
4
with an alkyne containing a fragment designated as “FG-1”
regioselectivity of 8, the expected formal [6+2] cycloadditions
would produce 5 with transpositions of double bonds. A regioꢀ
proceeded siteꢀselectively with installation of a quaternary center.
and stereoꢀcontrolled [2+2] photoꢀcycloaddition with the
Scheme 2. Sequential annulations leading to 22 in 5 steps.
50
55
60
The next task was the critical [2+2] photoꢀcycloaddition of 10
vicinity of the conjugated system (C7ꢀC9a). Cobaltꢀcatalyzed
with Nꢀphenyl maleimide 12. While photoꢀcycloadditions of 65 formal [6+2] reaction of 4 with trimethylsilyl acetylene 9 gave 11
1
4
cyclopentenones have been well investigated, little is known
as the major product (53%). Fortuitously, irradiation of 11 with
12 (3 equiv.) using a 500ꢀW lamp in refluxing THF cleanly
effected the desired [2+2] cycloaddition to afford 13 in 82% yield
with high regioꢀ and stereoꢀselectivities. Note that irradiation of
70 11 in the absence of 12 afforded homoꢀdimer 14 in 75% yield. Xꢀ
ray analysis revealed formation of headꢀtoꢀhead dimer 14 and
established the relative configuration of 14 having cisꢀantiꢀcis
about substrates with extended conjugated systems, such as 10
1
5
containing an α, β, γ, δꢀunsaturated ketone system. Moreover,
photoꢀactivation of the cycloheptenone unit often generates a
16
highly reactive transꢀisomer leading to transꢀfused adducts,
which poses a particularly difficult challenge for controlling the
homo/cross as well as regioꢀ and stereoꢀselectivities. In fact,
attempted cycloadditions of 10 with 12 gave a complex mixture
under several irradiation conditions. After unsuccessful attempts,
17
relationship, which indicates that the intermolecular [2+2]ꢀ
cycloaddition proceeded with retention of geometry at the C7ꢀC8
the substrates (10→11) were modified by replacing the phenyl 75 double bond of both monomeric units.
substituent on C5 with a trimethylsilyl group to suppress
With 13 in hand, assembly of “FG-3” and the glycine unit
photochemical activation of the styryl group in 10 located in the
through the [3+2] cycloaddition was then performed.
2
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congested quaternary center. The Xꢀray analysis unambiguously
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stereogenic centers. It confirmed exquisite controls of the regioꢀ
and stereoꢀselectivities for both the [2+2] and the subsequent
[3+2] cycloadditions. Next, the task of installing the “FG-1” by
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5
65
7
7
8
8
0
5
0
5
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1
9
produced 19 in 86% yield. Thus, iodination was performed
before the [3+2] cycloaddition. The [3+2] cycloaddition of the
resulting 19 with 17 also occurred stereoselectively to furnish 20
in 90% yield. SuzukiꢀMiyaura crossꢀcoupling of 20 with
phenylbronic acid 21 proceeded efficiently without protection of
the substituted proline moiety, giving rise to targeted 22 in 60%
yield.
8
9
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In summary, assemblies of four components through sequential
[6+2], [2+2], and [3+2] annulations on azulenone manifold 4
1
0
Y. Ishigaki, V. Mahendar, H. Oguri and H. Oikawa, Chem. Commun.,
allows fiveꢀstep access to the densely functionalized hexacyclic
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2
010, 46, 3304ꢀ3305.
11 O. Kwon, S. B. Park and S. L. Schreiber, J. Am. Chem. Soc., 2002,
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pharmacophoric groups in FBDD, this synthetic process is
expected to provide a general platform for developing screening
1
1
2
3
3
collections displaying spatially diverse sets of fragments on a sp ꢀ
rich scaffold. Xꢀray analysis of 18 was used to elucidate spatial
arrangement of the three sites for installing the fragments as well
as the neighboring functional groups (Figure S25), which would
spur a rational design of small molecules bearing improved
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siteꢀvariable installations of intended fragments onto the multiple 100 16 H. Dorr and V. H. Rawal, J. Am. Chem. Soc. 1999, 121, 10229ꢀ
sites in 7 and biological evaluations will be reported in due
course.
We thank Ms. Yuko Fujimura (Shionogi & Co., Ltd.) for
performing the Xꢀray analyses. This work was financially 105
supported by JSPS KAKENHI Grant Number (24651253) and
Science and Technology Research Partnership for Sustainable
Development Program (SATREPS) of the Japan Science and
Technology Agency (JST).
95
14 D. I. Schuster, G. Lem and N. A. Kaprinidis, Chem. Rev., 1993, 93,
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1
7
Crystal data for 14. C30
H
40
O
2
Si
2
; M = 488.80; monoclinic; a =
= 90.756(2)⁰; V
/c; Z = 4; 33007
reflections measured, 5205 unique (Rint = 0.072), R = 0.1148 and
wR = 0.3826 (observed data). CCDCꢀ910960. Crystal data for 18.
Si•0.5(C O); M = 624.81; triclinic; a = 10.06519(18)
Ǻ, b = 11.1789(2) Ǻ, c = 16.4195(3) Ǻ, = 82.6410(10)⁰;
81.6980(7)⁰; = 64.6870(7)⁰; V = 1648.04(5) Ǻ ; T = 173(2) K;
space group Pꢀ1; Z = 2; 19565 reflections measured, 5910 unique
1
3.2625(5) Ǻ, b = 13.3817(6) Ǻ, c = 16.1422(7) Ǻ; β
3
= 2864.6(2) Ǻ ; T = 173(2) K; space group P2
1
1
2
C
35
H
38
N
2
O
5
3 8
H
α
β =
3
1
10
γ
(
9
R
1
int = 0.015), R = 0.0475 and wR2 = 0.1473 (oberved data). CCDCꢀ
Notes and references
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a
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Electronic Supplementary Information (ESI) available: Experimental
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procedure, spectral data, Figure S1ꢀS25. See DOI: 10.1039/b000000x/
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