Synthesis of the B-seco limonoid core scaffold

Article abstract of DOI:10.3762/bjoc.10.15

Synthetic investigations towards the structurally complex and highly decorated framework of B-seco limonoid natural products by means of a [3,3]-sigmatropic rearrangement are described. Detailed model studies reveal, that an Ireland-Claisen rearrangement can be employed to construct the central C9-C10 bond thereby giving access to the B-seco limonoid scaffold. However, application of the developed strategy ended up failing in more complex and sterically demanding systems.

Full text of DOI:10.3762/bjoc.10.15

Synthesis of the B-seco limonoid core scaffold
Hanna Bruss1,2, Hannah Schuster1,2, Rémi Martinez1, Markus Kaiser3,
Andrey P. Antonchick1,2 and Herbert Waldmann*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 194–208.
1Abteilung Chemische Biologie, Max-Planck-Institut für Molekulare
Physiologie, Otto-Hahn-Straße 11, 44227 Dortmund, Germany,
2Fakultät für Chemie und Chemische Biologie, Technische Universität
Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany and
3Chemical Biology, Zentrum für Medizinische Biotechnologie, Fakultät
für Biologie, Universität Duisburg-Essen, Universitätsstraße 2, 45117
Essen, Germany
doi:10.3762/bjoc.10.15
Received: 30 September 2013
Accepted: 10 December 2013
Published: 16 January 2014
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
Email:
Herbert Waldmann* - herbert.waldmann@mpi-dortmund.mpg.de
Guest Editor: J. S. Dickschat
* Corresponding author
© 2014 Bruss et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
B-seco limonoids; biology oriented synthesis; Ireland–Claisen
rearrangement; natural products; tetranortriterpenoids
Abstract
Synthetic investigations towards the structurally complex and highly decorated framework of B-seco limonoid natural products by
means of a [3,3]-sigmatropic rearrangement are described. Detailed model studies reveal, that an Ireland–Claisen rearrangement can
be employed to construct the central C9–C10 bond thereby giving access to the B-seco limonoid scaffold. However, application of
the developed strategy ended up failing in more complex and sterically demanding systems.
Introduction
B-seco limonoids are a family of more than 100 highly B-seco limonoids constitute exceptionally challenging syn-
oxygenated plant tetranortriterpenoids derived from the 4,4,8- thesis targets, as the characteristic structural features are a
trimethyl-17-furanylsteroid core structure I (Figure 1) [1-3]. compact, highly oxygenated as well as richly decorated frame-
Members of this natural product class, like 21-hydroxytoona- work and stereochemically dense functionalization. In all
cilide (1) [4,5] and prieurianin (2) [6-16] display antifeedant B-seco limonoids an A ring is linked by a C–C bond to a trans-
[6,7,17-21], antimalaria and anticancer [10,11,22-25] as well as fused bicyclic C–D ring having an exo-methylene moiety. The
diverse further bioactivities. Recently it was discovered crowded C9–C10 bond bridging the two domains is the main
that prieurianin (2) impairs the actin cytoskeleton by a mecha- synthetic obstacle.
nism that does not involve direct interaction with actin
suggesting that its mode of action differs from previously Taking into account the biology-oriented synthesis (BIOS)
known modulators [26].
concept [27-34], which employs the scaffolds of biologically
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Figure 1: Structures of the 4,4,8-trimethyl-17-furanylsteroid core structure I and the representative B-seco limonoids 21-hydroxytoonacilide (1) and
prieurianin (2).
relevant natural product classes to inspire the synthesis of genic centers including two contiguous asymmetric quaternary
probes and reagents for chemical biology and medicinal chem- centers at the ring junction. We decided to start the sequence
istry research, we aimed at the development of a synthetic with known enone 15 [39] and intended to construct the all-
strategy to get access to the B-seco limonoid scaffold by means carbon quaternary center at C13 by substrate controlled α-func-
of a [3,3]-sigmatropic rearrangement as key step enabling the tionalization. The second quaternary center at C14 might be
formation of the crucial C9–C10 bond (Scheme 1) [35]. In this established by 1,2-addition and finally, ring-closing metathesis
paper we present a full report on this synthesis [36] as well as would give rise to bicyclic system 12.
further synthetic studies towards the application of the devel-
oped strategy to the total synthesis of B-seco limonoid natural Model studies towards the Claisen rearrangement. As the
products.
stereochemical substitution on the C ring system will have a
major impact on the face selectivity of the planned Claisen rear-
rangement we defined precursors 19, 20 and 22 (Scheme 3) as
Results and Discussion
Retrosynthetic analysis: Claisen rearrangement. In planning suitable model systems, presenting appropriate stereogenic
the synthesis we were inspired by Ley’s synthesis of aza- substitution at the C ring system. After merging these alcohols
dirachtin in which a Claisen rearrangement has been success- with an undecorated A ring, the resulting allyl vinyl ethers
fully employed as key transformation [37,38]. Thus the allyl could serve as suitable rearrangement precursors.
vinyl ether rearrangement precursor 11 was thought to be
obtained from an O-alkylation between the thermodynamic The synthesis of 19 and 20 commenced with enone 15 [39],
enolate of 2-methylcyclohexanone (5) and the bicyclic elec- which was prepared from (−)-quinic acid (16) according to the
trophile 12 (Scheme 2). A challenging synthetic problem route reported by Arthurs et al. [40] with minor modifications.
appears to be the construction of the stereochemically dense After Baylis–Hillman reaction and subsequent silylation of the
trans-fused C–D ring system 12, which possesses four stereo- resulting free primary hydroxy group, substrate-controlled
Scheme 1: Retrosynthetic analysis of the B-seco limonoid framework employing a [3,3]-sigmatropic rearrangement for formation of the C9–C10 bond.
R = Me or CO2H, LG = leaving group.
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Scheme 2: Retrosynthetic analysis of the B-seco limonoid scaffold employing a Claisen rearrangement as key step for formation of the C9–C10 bond.
PG = protecting group, LG = leaving group.
Scheme 3: Synthesis of alcohols 19, 20 and 22. Reagents and conditions: a) CSA, 2,3-butanedione, trimethyl orthoformate, MeOH, reflux, 16 h, 93%;
b) NaBH4, MeOH, rt, 0.5 h, quant.; c) silica-gel supported NaIO4, CH2Cl2/MeOH (20:1), rt, 3 h, quant.; d) MsCl, NEt3, CH2Cl2, 0 °C to rt, 3 h, quant.;
e) paraformaldehyde, imidazole, THF/1 M NaHCO3 (1:1), rt, 2.5 h, 74%; f) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 15 min, quant.; g) LiHMDS, MeI,
THF/DMPU (5:1), −78 °C to −10 °C, 91%, de = 100%; h) NaBH4, CeCl3·7H2O, MeOH, 0 °C, 15 min, 90%, de = 100%; i) PPh3, p-nitrobenzoic acid,
DEAD, toluene, rt, 18 h; j) MeOH, Et2O, aqueous saturated K2CO3 solution, rt, 1 h, 64% (2 steps); for the synthesis of 19: k) DIPEA, MOMCl, CH2Cl2,
reflux, 16 h, 99%; l) TBAF, THF, rt, 20 min, 94%; for the synthesis of 20: k) TIPSOTf, 2,6-lutidine, DMF, 0 °C to rt, 3 h, quant.; l) PTSA, MeOH, THF,
rt, 30 h, 77%; m) PivCl, DMAP, pyridine, −15 °C to rt, 2 h, 77%; n) NaBH4, CeCl3·7H2O, MeOH, 0 °C to rt, 30 min, 96%, de = 100%; o) TFA, H2O, rt,
5 min, 72%; p) DIPEA, MOMCl, CH2Cl2, reflux, 15 h, 62%; q) DIBAL-H, CH2Cl2, −78 °C to rt, 2 h, quant.
α-methylation of the lithium enolate proceeded with full stereo- alcohol 18 and Mitsunobu reaction installed the required stereo-
control [41,42], which can be explained by the strong con- chemistry at C14. The free C14 hydroxy group was masked
formational rigidity of the butane-2,3-diacetal (BDA) protected with protecting groups (MOM and TIPS) of different size and
trans-diequatorial diols [43] and the stereoelectronic preference chemical nature to examine the face-selectivity of the [3,3]-
for axial attack on the electron-rich C13. Luche reduction with sigmatropic rearrangement. After selective desilylation, alco-
stereoelectronically preferred axial attack of the hydride gave hols 19 and 20 were obtained.
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Beilstein J. Org. Chem. 2014, 10, 194–208.
In order to synthesize a model substrate without the rigid BDA- Alternative strategy: Ireland–Claisen rearrangement. As the
protecting group, compound 21 was treated with aqueous TFA Claisen rearrangement precursor, the allyl vinyl ether, could not
to give a triol which was masked with three MOM-protecting be obtained under various conditions, we had to change the
groups (Scheme 3). Reductive cleavage of the pivaloyl group synthetic strategy and employed the Ireland variant of the
furnished alcohol 22.
Claisen rearrangement to construct the crucial C9–C10 bond
(Scheme 4). In this strategy the A-ring 25 could be merged with
Mesylation or tosylation of the primary alcohols in 19, 20 and the bicyclic C–D system 26 by esterification in order to obtain
22 gave suitable electrophiles for the planned O-alkylation with the allyl ester rearrangement precursor 24. Murai et al. [48]
the thermodynamic enolate of 2-methylcyclohexanone. showed the utility of an Ireland–Claisen rearrangement
However, under various conditions (NaH/15-crown-5/THF; in their model studies addressing the limonoid framework of
t-BuOK/18-crown-6/THF/DMPU; KHMDS/THF) [44,45], the azadirachtin.
intended O-alkylation to yield the allyl vinyl ether failed.
Equally, copper-catalyzed C–O couplings [46] of the alcohols Model studies towards the Ireland–Claisen rearrangement.
19, 20 and 22 with organotrifluoroborates failed or gave only To test the feasibility of this approach, model rearrangement
low yields. Likewise Buchwald’s procedure for the copper- precursor 27 was prepared from alcohol 19 (Scheme 5). Esteri-
catalyzed coupling of primary alcohols with vinyl iodides to fication with cyclohexanecarboxylic acid gave the desired allyl
yield the allyl vinyl ether or, depending on the reaction condi- ester 27. Furthermore, to investigate the influence of the
tions, directly the Claisen rearrangement products was not protecting groups at C11, C12 and C14 on the stereoselectivity
successful [47].
and reaction rate, the allyl esters 28, 29 and 30 were prepared.
Scheme 4: Retrosynthetic analysis of the B-seco limonoid scaffold employing an Ireland–Claisen rearrangement as the key step for the formation of
the C9–C10 bond. PG = protecting group.
Scheme 5: Synthesis and Ireland–Claisen rearrangement of the allyl esters 27, 28, 29 and 30. Reagents and conditions: a) DCC, DMAP, cyclo-
hexanecarboxylic acid, CH2Cl2, rt, 4 h; b) TFA/H2O (3:1), rt, 30 min, 73% (2 steps); for the synthesis of 29: c) DIPEA, MOMCl, CH2Cl2, 40 °C, 15 h,
86%; for the synthesis of 30: c) imidazole, TBSCl, CH2Cl2, rt, 21 h, 45%; d) KHMDS, TMSCl, toluene, −78 °C to 85 °C, 18 h. Results: see Table 1.
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The four rearrangement precursors 27, 28, 29 and 30 were
exposed to KHMDS and TMSCl in toluene, in order to induce
the Ireland–Claisen rearrangement (Scheme 5, Table 1). The
rigid BDA protecting group at C11 and C12 in 27 was not
compatible with these conditions, resulting in only cleavage of
the ester moiety (Table 1, entry 1). In case of the unprotected
rearrangement precursor 28 an excess of base and TMSCl was
used for in situ protection of the three free hydroxy groups as
TMS ether, but the desired [3,3]-sigmatropic rearrangement
could not be induced (Table 1, entry 2). However rearrange-
ment of tris-MOM ether 29 as well as tris-TBS ether 30 gave
the desired carboxylic acids 33 and 34 in high yield and excel-
lent diastereoselectivity (Table 1, entries 3 and 4).
Figure 2: Conformation of rearrangement precursor 30 and possible
transition state involved in the Ireland–Claisen rearrangement.
Table 1: Ireland–Claisen rearrangement of model compounds 27, 28,
29 and 30.
in aqueous CH2Cl2 to release triol 36, which was masked with
different protecting groups (MOM, TBS, Piv). After desilyla-
tion, the liberated alcohols 40, 41 and 42 could be esterified
with various cyclic and acyclic model A rings to give the
targeted rearrangement precursors A (Scheme 6, Table 2).
rearrangement
precursor
entry
result
1
2
3
4
27
28
29
30
cleavage of the ester moiety
no conversion
89% yield of 33 (de = 76%)
quant. yield of 34 (de = 100%)
The obtained rearrangement precursors were submitted to the
Ireland–Claisen rearrangement conditions and gave the desired
carboxylic acids B in excellent yield and diastereoselectivity
In view of the stereochemistry of the major diastereomers of the (Scheme 6, Table 2). The presence of the keto functionality in
products, the rearrangement would occur from the re-face (tran- 43 is compatible with the rearrangement conditions (Table 2,
sition state A, Figure 2). Thus, assuming the OTBS group in 30 entry 1). Intermediary, the silyl enol ether and the silyl ketene
at C14 is pseudo-axial to avoid allylic A1,2-strain, the sigma- acetal are formed. However, after the rearrangement, the keto-
tropic rearrangement occurred via a pseudo-axial attack of the functionality can be set free again during an acidic work-up. In
silyl ketene acetal on the double bond in the cyclohexene ring. terms of yield and diastereoselectivity there was no difference
These results are in accordance with the observations of Ireland observed between rearrangements with derivatives with a cyclic
et al. [49], who examined the propensity for axial versus equa- or acyclic model A ring. Rearrangement precursor 51 contain-
torial attack in the rearrangement of cyclohexenyl acetates and ing a free hydroxy group could not be converted into the desired
observed a strong preference for the stereochemically controlled carboxylic acid (Table 2, entry 5). Under the same conditions
axial approach. The size of the protecting groups had a strong but by using an excess of base and TMSCl for the in situ protec-
influence on the face-selectivity, furnishing in case of the TBS tion of the free hydroxy group, only the starting material could
derivative only one diastereomer. By substitution of C14 with a be reisolated.
bulky group (1,2-allylic strain) the ring inversion barrier of the
cyclohexene conformations might be increased, resulting in Encouraged by these findings we attempted to perform the
higher de values.
[3,3]-sigmatropic rearrangement with C1-substituted A rings, as
many B-seco limonoids are oxygenated at this position. For this
These model studies suggested that an Ireland–Claisen rear- purpose, both the anti- and syn-substituted β-alkoxy esters 56
rangement is a feasible strategy to construct the C9–C10 bond and 57 were synthesized (Scheme 7; for experimental proce-
in B-seco limonoids.
dure see Supporting Information File 1). In the literature [50]
not many examples are known in which β-alkoxy esters serve as
In order to perform further model studies, we established a rearrangement precursors as the β-elimination of the alkoxy
straight forward synthetic access to model substrates without group can easily occur under the rearrangement conditions.
the BDA group (Scheme 6). With the TBDPS- instead of the Indeed, under various conditions by using different bases (LDA,
TBS ether on the primary hydroxy group, the BDA group in LiHMDS, KHMDS) and solvents (THF, toluene, THF/DMPU)
alcohol 35 could be selectively cleaved by treatment with TFA and by carefully controlling the reaction conditions (deprotona-
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Scheme 6: Synthesis of model C rings 40, 41 and 42. Reagents and conditions: a) TBDPSCl, DMAP, NEt3, CH2Cl2, rt, 18 h, 93%; b) LiHMDS, MeI,
THF/DMPU (10:1), −78 °C to 0 °C, 1.5 h, 98%; c) CeCl3·7H2O, NaBH4, MeOH, 0 °C, 15 min, 86%; d) Ph3P, p-nitrobenzoic acid, DEAD, toluene, 15 h;
e) MeOH, Et2O, aqueous saturated K2CO3-solution, rt, 2 h, 85% (2 steps); f) CH2Cl2/TFA/H2O (2:1:0.1), rt, 10 min, 85%; for the synthesis of 37:
g) DIPEA, MOMCl, NaI, THF, 65 °C, 4.5 h, 98%; for the synthesis of 38 g) TBSCl, imidazole, DMF, rt, 18 h, 92%; for the synthesis of 39: PivCl,
DMAP, pyridine, rt, 4 d, 78%; for the synthesis of 40: h) 37, TBAF, THF, rt, 2 h, 95%; for the synthesis of 41: h) 38, 10% NaOH/MeOH, reflux, 6.5 h,
72%; for the synthesis of 42: h) 39, HF·pyridine, THF, rt, 24 h, 71%.
Table 2: Esterification of alcohols 40, 41 and 42 and Ireland–Claisen rearrangement. Reagents and conditions: a) EDC·HCl, DMAP, carboxylic acid,
CH2Cl2, rt, 15–22 h; for 52: silylation of the free hydroxy group at C14: imidazole, TBSCl, DMAP, DMF, rt, 40 h; b) KHMDS, TMSCl, toluene, −78 °C to
85 °C, ca. 18 h.
entry
alcohol
allyl ester A
carboxylic acid B
1
40
44 (75% yield, de = 80%)
43 (87% yield)
2
40
46 (93% yield, de = 78%)
45 (81% yield)
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Table 2: Esterification of alcohols 40, 41 and 42 and Ireland–Claisen rearrangement. Reagents and conditions: a) EDC·HCl, DMAP, carboxylic acid,
CH2Cl2, rt, 15–22 h; for 52: silylation of the free hydroxy group at C14: imidazole, TBSCl, DMAP, DMF, rt, 40 h; b) KHMDS, TMSCl, toluene, −78 °C to
85 °C, ca. 18 h. (continued)
3
4
5
6
7
40
40
41
41
42
48 (quant. yield, de = 72%)
47 (93% yield)
49 (quant. yield)
51 (79% yield)
50 (95% yield, de = 72%)
–
53 (quant. yield, de = 94%)
52 (78% yield, 2 steps)
55 (90% yield, de = 94%)
54 (95% yield)
tion at low temperature (−100 °C), gradual warming of the reac- substitution seems to have major impact on the success of the
tion mixture), only the elimination product 58 could be isolated. rearrangement.
Furthermore, a dianionic Ireland–Claisen rearrangement em- Synthesis of the B-seco limonoid scaffold. Encouraged by the
ploying β-hydroxy ester 59 was unsuccessful (Scheme 7). results of the rearrangements of the model substrates with an
Under various conditions, we observed only decomposition of undecorated A ring, we attempted to access the B-seco limonoid
the starting material by cleavage of the ester moiety. Likewise, scaffold by an analogous rearrangement of bicyclic precursor 66
cleavage of the ester moiety occurred in an attempt to perform a (Scheme 8).
Carroll rearrangement with β-keto ester 60.
The elaboration of the required bicyclic system commenced
These studies show that it might be necessary to oxygenate with enone 15 (Scheme 8). Initially, we envisaged an α-vinyla-
at C1 after the sigmatropic rearrangement because the C1 tion via Buchwald’s procedure for the catalytic asymmetric
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Scheme 7: β-Substituted allyl esters tested in the Ireland–Claisen and the Carroll rearrangement.
Scheme 8: Synthesis and Ireland–Claisen rearrangement of bicyclic allyl ester precursor 66. Reagents and conditions: a) LiHMDS, TMSCl, THF,
−78 °C to 0 °C, 90 min; b) NBS, THF, 0 °C, 90 min, 68% (2 steps); c) allyltributyltin, AIBN, toluene, 80 °C, 18 h, 81%, de = 80%; d) KHMDS, THF,
−78 °C, 1 h, then MeI, rt, 20 min, 74%, de = 100%; e) PdCl2(CH3CN)2, toluene, 65 °C, 2 days, 70% (81% brsm); f) paraformaldehyde, imidazole,
THF/1 M NaHCO3 (2:1), rt, 19 h, 74%; g) TFA/H2O (3:1), rt, 30 min, 84%; h) TBSCl, imidazole, DMF, rt, 18 h, 94%; i) tetraallyltin, BuLi, THF, −78 °C
to rt, 30 min, 72%, dr = ca. 2:1; j) Grubbs I, CH2Cl2, rt, 18 h, 80%; k) HF·pyridine, THF, 0 °C to rt, 20 h, 99%; l) EDC·HCl, 4-oxocyclohexanecarboxylic
acid (25), DMAP, CH2Cl2, rt, 16 h, 80%; m) DIPEA, MOMCl, NaI, THF, 50 °C, 21 h, 62%; n) LiHMDS, supernatant of a centrifuged mixture of
TMSCl/NEt3 (v/v = 1:1) and toluene, toluene, −78 °C to 65 °C in 6 h, 60 h at 65 °C, 88% yield, dr = 1:2 (67:68).
vinylation of enones [51]. However, the desired vinylated prod- alkylation of the lithium enolate of 15 with alkyl halides under
uct could not be obtained under the described conditions. An several conditions. They incorporated an α-allyl side chain via
alternative α-formylation/Wittig olefination sequence gave only an α-bromo-enone, which can be obtained from an initially
low yields. O’Brien et al. [41] described the failure of a direct formed silyl enol ether, and subsequent reaction with NBS.
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Keck allylation of the α-bromo-enone using allyltributyltin and Figure 3a). This might be explained by the rigidity of the
AIBN gave the desired α-allylated product 61. We used the high bicyclic system, such that transition states B and C can compete
substrate control to construct the first quaternary center at C13 without preference for a conformation that clearly favours axial
by trapping the potassium enolate of 61 with MeI, furnishing attack. Underscored by MM2 conformational calculations, it is
the desired product as a single diastereomer. Isomerization of furthermore plausible that the C11 oxygen can form an H-bond
the terminal double bond with cat. PdCl2(CH3CN)2 and to the terminal methyl C–H of the C14 MOM group, thus
Baylis–Hillman reaction proceeded uneventfully to afford com- blocking a pseudo-axial approach and leading to the observed
pound 62. Deprotection of the butane-2,3-diacetal under acidic reversal in selectivity.
conditions followed by selective silylation of the primary and
the allylic hydroxy groups gave alcohol 63.
The second quaternary center of the bicyclic C–D system 66
was envisaged to be constructed by 1,2-addition, using the free
β-hydroxy functionality in 63 as directing group. Several condi-
tions with allyl boronates, stannanes, silanes, indium, magne-
sium bromide, cerium, zinc bromide and other reagents have
been screened. Finally, the best result was achieved with tetra-
allyltin and BuLi affording a 2:1 mixture of diastereomers, with
the desired diastereomer being the minor product. The stereo-
chemistry was unambiguously confirmed by crystal structure
analysis of a derivative of the major diastereomer [36]. Thus,
the preference for the axial attack predominates the aimed
directing effect of the β-hydroxy group.
Bicyclic system 65 could be obtained by ring-closing metathesis
using Grubbs 1st generation catalyst and subsequent selective
deprotection of the primary silyl ether. After esterification with
4-oxocyclohexanecarboxylic acid (25) and protection of the
remaining two free hydroxy groups as MOM ethers, which was
accompanied by silyl migration, the synthesis of rearrangement
precursor 66 was completed.
Application of the developed reaction conditions for the rear-
rangement of the model systems was fruitless, resulting in only
cleavage of the ester moiety. Crucial for the success of the
envisaged Ireland–Claisen rearrangement was a gradual
warming of the reaction mixture from −78 °C to 65 °C over a
period of 6 h and the addition of the supernatant of a
centrifuged mixture of TMSCl, NEt3 and toluene instead of the
Figure 3: Conformations of rearrangement precursors 66 and 77 and
possible transition states involved in the Ireland–Claisen rearrange-
ments. R = MOM.
addition of unactivated TMSCl. When 66 was exposed to We hypothesized that the diastereoselectivity could be impro-
TMSCl/NEt3 and LiHMDS in toluene, the intended rearrange- ved by performing the rearrangement with the open-chain
ment occurred smoothly giving rise to 67 and 68 (ca. 1:2 ratio, precursor 70 (Scheme 9), which should be less rigid than the
88% combined yield) through the desired C9–C10 bond forma- bicyclic system 66 and therefore, in analogy to the results of the
tion (Scheme 8). The configuration of the diastereomers was rearrangements with the model substrates, probably preferably
determined based on the analysis of the coupling constants of rearrange via a pseudo-axial attack. The open-chain precursor
H9 and H11 and nOe signal enhancements.
70 was obtained by MOM protection of diol 64, selective
cleavage of the primary TBS group and subsequent esterifica-
In contrast to the high face-selectivity in the rearrangement of tion with 4-oxocyclohexanecarboxylic acid (25).
the model systems, the reaction seems to take place from both
sides of the bicyclic C–D system. However, in this case the However, in this case the [3,3]-sigmatropic rearrangement
si-face approach appears to be favoured (transition state C, proceeded exclusively via pseudo-equatorial attack, giving after
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Scheme 9: Synthesis and Ireland–Claisen rearrangement of allyl ester
70. Reagents and conditions: a) DIPEA, MOMCl, NaI, THF, 65 °C,
3 days, 35%; b) HF·pyridine, THF, 20 h, rt, 83%; c) EDC·HCl, DMAP,
CH2Cl2, 4-oxocyclohexanecarboxylic acid (25), rt, 24 h, 83%;
d) LiHMDS, TMSCl/NEt3, toluene, 1 h at −78 °C, then gradual warming
to 65 °C within 6 h and 40 h at 65 °C, yield n.d. dr = 1:0; e) Grubbs I,
CH2Cl2, rt, 20 h, yield n.d.
Scheme 10: Synthesis and Ireland–Claisen rearrangement of allyl
ester 72. Reagents and conditions: a) TIPSOTf, pyridine, DMAP, rt,
22 h, 60%; b) DIPEA, MOMCl, THF, 25 h, 50 °C, 29%; c) LiHMDS,
TMSCl/NEt3, toluene, 1 h at −78 °C, then gradual warming to 65 °C
within 6 h and stirred for 2 days at 65 °C.
RCM the C9-epi limonoid scaffold 68 as single diastereomer. Moreover, in order to allow the synthetic access to further
The sterically demanding rearrangement precursor 70 seems to B-seco limonoid analogues, the C14-epi B-seco limonoid scaf-
allow only the undesired pseudo-equatorial attack.
fold 78 and C14-epi/C9-epi scaffold 79 were accessed
(Scheme 11). Starting from diol 74, the C14-epi rearrangement
We envisaged that protecting the free secondary hydroxy group precursor 77 was synthesized employing a sequence of ring-
in 71 with a sterically demanding TIPS group might induce a closing metathesis, TBS deprotection, esterification and MOM
conformational change of the rearrangement precursor and protection. The Ireland–Claisen rearrangement proceeded
intended to investigate the influence of this conformational smoothly and gave a ca. 1.3:1 (78:79) mixture of diastereomers
change on the diastereoselectivity of the Ireland–Claisen rear- with the product resulting from the pseudo-axial attack of the
rangement (Scheme 10). However, the allyl ester 72 seems to be silyl ketene acetal being the major diastereomer.
too sterically hindered to allow the [3,3]-sigmatropic rearrange-
ment to proceed. After 2 days reaction time, only traces of rear- In analogy to the results above the transition states D and E
rangement product 73 could be observed.
seem to compete without any preference for a conformation that
Scheme 11: Synthesis of the C14-epi and C14/C9-epi B-seco limonoid scaffolds 78 and 79. Reagents and conditions: a) Grubbs I, CH2Cl2, rt, 18 h,
86%; b) DIPEA, MOMCl, NaI, THF, 20 h, 65 °C, 89%; c) HF·pyridine, THF, 0 °C to rt, 24 h, 76%; d) EDC·HCl, DMAP, CH2Cl2, 4-oxocyclohexane-
carboxylic acid (25), rt, 19 h, 92%; e) LiHMDS, TMSCl/NEt3, toluene, 1 h at −78 °C, then gradual warming to 65 °C within 6 h and stirred for 43 h at
65 °C, 78% yield, dr = 1.3:1 (78:79).
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Beilstein J. Org. Chem. 2014, 10, 194–208.
clearly favours axial attack (Figure 3b). Presumably because of to the primary alcohol and protected to give TBDPS ether 82.
the absence of electrostatic interactions in the pseudo-axial After selective cleavage of the acetal group by treatment with
attack of the silyl ketene acetal (compare transition state B in perchloric acid, installation of the double bond via Saegusa oxi-
Figure 3a: electrostatic interaction with -OMOM at C14), this dation [56,57] of the previously formed TMS ether furnished
approach is slightly favored.
enone 83 as the major regioisomer. Minor amounts of the unde-
sired regioisomer could be separated by column chromatog-
Synthesis of fully functionalized A ring. Having these exten- raphy. Hydroxymethylation of 83 using 1H-benzotriazole-1-
sive studies completed we then focused on the synthesis of a methanol proceeded diastereoselectively due to substrate
suitable fully functionalized A ring 87 (Scheme 12) that after control [58]. The configuration was determined by the high
connection to the bicyclic C–D system and subsequent coupling constant (JH4/H5 = 12.6 Hz) indicating the trans-
Ireland–Claisen rearrangement was supposed to give access to diaxial orientation of H4 and H5. Silylation of the primary
the entire framework of B-seco limonoids.
hydroxy group afforded compound 84 that was converted into
the epoxide with complete stereocontrol [59]. The epoxide
Explorations to access this fragment started from Hajos–Parrish underwent regioselective opening [60,61] leading to the
ketone 80 [52] (Scheme 12), as we were inspired by a reaction β-hydroxyketone that was temporarily masked as a TES ether.
sequence Arseniyadis et al. [53] used in their synthesis of a left-
half taxoid building block. Regioselective protection of the less Reduction of ketone 85 with NaBH4 resulted in the formation of
hindered ketone in 80 and diastereoselective hydrogenation of two diastereomeric alcohols in 2:1 ratio. To our delight flash
the double bond could be achieved in a known one-pot proce- chromatography permitted smooth separation of the two com-
dure [54,55] affording the cis-hydrindanone and providing the pounds. nOe studies revealed that the main product is
desired stereochemistry at C4 and C5. Ozonolytic cleavage of 1S-configurated as in most B-seco limonoids suggesting that an
the corresponding silyl enol ether 81 followed by esterification equatorial attack of the hydride is slightly preferred over the
with TMSCHN2 furnished the ester aldehyde that was reduced axial attack. However bearing in mind the elimination issues
Scheme 12: Synthesis of fully functionalized A ring 87. Reagents and conditions: a) HO(CH2)2OH, THF, Pd/C, H2, pH 5, rt, overnight, 97%,
de = 100%; b) LDA, TMSCl, THF, −78 °C to rt, 1.5 h, quant.; c) O3, CH2Cl2, −78 °C, then DMS, −78 °C to rt; d) TMSCHN2, CH2Cl2/MeOH (1:1), rt,
0.5 h, 59% (2 steps); e) NaBH4, MeOH, 0 °C, 0.5 h; f) TBDPSCl, imidazole, DMAP, CH2Cl2, 0.5 h, rt, 78% (2 steps); g) CH2Cl2/H2O/HClO4 (25:5:1),
rt, 6 h; h) LiHMDS, TMSCl, THF, −78 °C to rt, 1.5 h; i) Pd(OAc)2, DMSO, O2, overnight, 72% (3 steps); j) LDA, 1H-benzotriazole-1-methanol, THF,
−78 °C, 3 h, 67%, de = 100%; k) TBSCl, imidazole, DMF, rt, overnight, 90%; l) H2O2, NaOH, MeOH, 0 °C, 1 h, 80%, de = 100%; m) NaBH4, (PhSe)2,
EtOH, 0 °C to rt, 10 min, 93%; n) TESCl, imidazole, DMF, 40 °C, 2 h, 99%; o) NaBH4, MeOH, 0 °C, 3 h, 64%; p) LiBH4, THF, 65 °C, 4 days, 67%
(92% brsm); q) MOMCl, DIPEA, NaI, THF, 50 °C, 4 days, 96%, dr = 2:1; r) 5% TFA in CH2Cl2, rt, 0.5 h, 74%; s) DMP, NaHCO3, CH2Cl2, 0 °C, 3 h,
76%; t) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (4:1), rt, 3.5 h, 91%.
204

Beilstein J. Org. Chem. 2014, 10, 194–208.
with β-alkoxy esters during Ireland–Claisen rearrangements again unsuccessful. As expected, elimination of the OMOM
discussed above we decided to continue the synthesis with both group during the reaction was not detected due to the
diastereomers as this elimination is expected to proceed faster unfavoured orientation of the hydrogen and the leaving group.
in syn-substituted β-alkoxy esters since the hydrogen and the Subsequent acidic treatment did again lead to formation of
leaving group are in an antiperiplanar arrangement.
enone 90.
Continuing the synthesis with the 1S-isomer (Scheme 12),
reduction of the ester moiety could be initiated by LiBH4 but
proceeded sluggishly. For the protection of the corresponding
diol we were limited to small protecting groups as introduction
of the MOM-groups already occurred slowly and required high
excess of reagents. Selective deprotection of the TBS and the
TES ethers in 86 was achieved under acidic conditions. Oxi-
dation of the resulting diol with Dess–Martin periodinane and
subsequent Pinnick oxidation completed the synthesis.
Ireland–Claisen rearrangements with fully decorated A
ring. With the suitable substituted fragment 87 in hand, we
decided to initially perform the intended rearrangement with
one of the model C rings. Thus carboxylic acid 87 was esteri-
fied with allylic alcohol 40 to give allyl ester 88 (Scheme 13).
Scheme 14: Synthesis and attempted Ireland–Claisen rearrangement
of allyl ester 93. Reagents and conditions: a) LiBH4, THF, 65 °C,
overnight, 84%; b) MOMCl, DIPEA, NaI, THF, 50 °C, overnight, 89%;
c) 8% TFA in CH2Cl2, rt, 0.5 h, 52%; d) DMP, NaHCO3, CH2Cl2, 0 °C,
3 h, 86%; e) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (4:1),
rt, 2.5 h, 99%; f) EDC·HCl, 40, DMAP, CH2Cl2, rt, 2 d, 47%.
R1 = MOM, R2 = CO2H.
Unfortunately exposure of 88 to the optimized conditions devel-
oped for the synthesis of the B-seco limonoid scaffold did not
initiate the desired Ireland–Claisen rearrangement. Addition of
HMPA was also fruitless. Noteworthy elimination of the MOM-
protected hydroxy group at C1 occurred only to a minor extent
under these conditions, but was not observed at all when HMPA
was added. In situ formation of the TMS enol ether of 88 was We assume that the additional substituents as well as the inter-
detected, however as a consequence of the acidic work-up mediary formed TMS ether cause excessive steric bulk and
β-elimination of the OMOM group was induced resulting in rigidity that prevent the silyl ketene acetals from adopting the
α,β-unsaturated ketone 90.
required conformation. Hence, we considered enone 90 as an
alternative rearrangement precursor as many B-seco limonoids
Despite these unsatisfactory results we continued with the syn- exhibit a double bond in this position (see 21-hydroxytoona-
thesis of C1-epi allyl ester 93 starting from alcohol 91 employ- cilide (1)). However, despite the incapacity to form the silyl
ing the same reaction sequence of ester reduction, diol protec- enol ether as well as the lack of the C1-substituent allyl ester 90
tion, desilylation, oxidation and esterification (Scheme 14). failed to furnish the corresponding carboxylic acid using the
Attempts to rearrange 93 under the optimized conditions were general conditions.
Scheme 13: and Attempted Ireland–Claisen rearrangement of allyl ester 88. R1 = MOM, R2 = CO2H.
205

Beilstein J. Org. Chem. 2014, 10, 194–208.
In order to explore whether the whole system or whether the A
ring 87 itself is too crowded to allow the rearrangement to
proceed, we used a completely undecorated C ring. For this
purpose rearrangement precursors 95, 96, and 97 were synthe-
sized (see Supporting Information File 1) and investigated with
respect to their behavior in the [3,3]-sigmatropic rearrangement
(Scheme 15). Unfortunately all attempts to procure this trans-
formation using different bases (LiHMDS, KHMDS, LDA),
additives (Et3N, HMPA), solvents (THF, toluene) and tempera-
tures (up to 110 °C) completely failed. Indeed the results are in
accordance with those obtained earlier. All allyl esters were
converted to the corresponding TMS ethers under the rearrange-
ment conditions. Formation of the β-elimination product was
exclusively observed for the 1S-configurated allyl ester 95 in
the absence of HMPA. Replacing the sterically demanding
TBDPS group by the smaller TBS group in 97 could not initiate
the rearrangement either. Furthermore, α,β-unsaturated ketone
98, that was generated during the acidic work-up, did not show
any conversion (Scheme 15).
Supporting Information
Supporting Information File 1
Experimental procedures and characterisation data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-15-S1.pdf]
Acknowledgements
This research was supported by the European Research Council
(ERC European Advanced Investigator Grant to H.W.), the
Max Planck Society and the Fonds der Chemischen Industrie
(Kekulé-stipend to H.S.).
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