Synthesis of skeletally diverse alkaloid-like molecules: Exploitation of metathesis substrates assembled from triplets of building blocks

Article abstract of DOI:10.3762/bjoc.9.88

A range of metathesis substrates was assembled from triplets of unsaturated building blocks. The approach involved the iterative attachment of a propagating and a terminating building block to a fluorous-tagged initiating building block. Metathesis cascade chemistry was used to "reprogram" the molecular scaffolds. Remarkably, in one case, a cyclopropanation reaction competed with the expected metathesis cascade process. Finally, it was demonstrated that the metathesis products could be derivatised to yield the final products. At each stage, purification was facilitated by the presence of a fluorous-tagged protecting group.

Full text of DOI:10.3762/bjoc.9.88

Synthesis of skeletally diverse alkaloid-like
molecules: exploitation of metathesis substrates
assembled from triplets of building blocks
Sushil K. Maurya1,2, Mark Dow1,2, Stuart Warriner1,2 and Adam Nelson*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 775–785.
1School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK and
2Astbury Centre for Structural Molecular Biology, University of Leeds,
Leeds, LS2 9JT, UK
doi:10.3762/bjoc.9.88
Received: 10 January 2013
Accepted: 18 March 2013
Published: 22 April 2013
Email:
Adam Nelson* - a.s.nelson@leeds.ac.uk
This article is part of the Thematic Series "Creating complexity".
Guest Editor: D. Craig
* Corresponding author
Keywords:
alkaloids; cyclopropanes; diversity-oriented synthesis; metathesis
© 2013 Maurya et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A range of metathesis substrates was assembled from triplets of unsaturated building blocks. The approach involved the iterative
attachment of a propagating and a terminating building block to a fluorous-tagged initiating building block. Metathesis cascade
chemistry was used to “reprogram” the molecular scaffolds. Remarkably, in one case, a cyclopropanation reaction competed with
the expected metathesis cascade process. Finally, it was demonstrated that the metathesis products could be derivatised to yield the
final products. At each stage, purification was facilitated by the presence of a fluorous-tagged protecting group.
Introduction
Our collective understanding of the biological relevance of pounds are based on only 0.25% of the known molecular scaf-
chemical space has been shaped, in large part, by the historic folds [9]! This uneven coverage of chemical space is also
exploration of chemical space by chemical synthesis (and typical of small-molecule screening collections [7,10]. Conse-
biosynthesis) [1]. The scaffolds of known bioactive small mol- quently, the biological relevance of most known scaffolds has
ecules, in particular, play a key role in guiding the navigation of been poorly explored. The field of diversity-oriented synthesis
chemical space [2-4]. The field of biology-oriented synthesis [11-13] has emerged with the specific aim of populating
(BIOS) [5], for example, uses biologically validated scaffolds screening collections with diverse and novel small molecules.
[6-8] to inspire library design.
We have previously developed a robust approach for the syn-
Known organic molecules populate chemical space unevenly thesis of skeletally diverse small molecules (Scheme 1) [14].
and unsystematically. Around half of all known organic com- The approach relied on the synthesis of metathesis substrates by
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Scheme 1: Illustrative examples of a synthetic approach to natural-product-like molecules with over eighty molecular scaffolds.
Results and Discussion
iterative attachment of simple unsaturated building blocks to a
fluorous-tagged linker 1 (e.g., → 2 or 3). Subsequently, meta- Library design
thesis cascade reactions were used to “reprogram” the An overview of the proposed approach to the synthesis of
molecular scaffolds, concomitantly releasing the products from diverse scaffolds is shown in Scheme 2. The building blocks
the linker (e.g., → 4 or 5) [14-17]. The approach enabled the used in this study are shown in Figure 1. It was planned to start
combinatorial variation of molecular scaffolds, and was with an “initiating” building block (e.g., 6a or 7) bearing a
exploited in the synthesis of natural-product-like small mol- fluorous tag to facilitate the purification of synthetic intermedi-
ecules with unprecedented scaffold diversity (over 80 distinct ates [18]. Iterative attachment of a propagating and a termin-
scaffolds).
ating building block would yield a metathesis substrate (such as
14 or 16). Finally, a metathesis cascade reaction would yield a
Although powerful, this general approach to skeletally diverse product scaffold (such as 15 and 17). It was planned that many
molecules had only been exemplified by varying pairs of unsat- of the product scaffolds would bear an o-nitrophenylsulfonyl
urated building blocks [14]. Thus, by exploiting the linker 1, protecting group. The combinations of building blocks were
which is an allyl alcohol or allyl amine equivalent, all of the carefully chosen to ensure that, after deprotection, selective
products were inevitably allylic alcohols or cyclic allylic derivatisation of the product scaffolds would be possible.
amines. Here, we demonstrate that the approach is considerably
more general, and that it is feasible to exploit triplets of building Synthesis of building blocks
blocks, extending the range of diverse molecular scaffolds that The initiating building blocks 6a and 6b were prepared by using
may be prepared.
the approach outlined in Scheme 3. The allylic alcohol 14 [19]
Scheme 2: Overview of the proposed synthetic approach. FDIPES = diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)silyl;
Ns = o-nitrophenylsulfonyl.
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Figure 1: Structures of building blocks used in this study. Panel A: fluorous-tagged initiating building blocks. Panel B: propagating building blocks.
Panel C: terminating building blocks.
Scheme 3: Synthesis of the initiating building blocks 6a and 6b. TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
was converted into the allylic carbonate 15 by treatment with building block 6b. Finally, desulfonylation (→ 19) and
methyl chloroformate and DMAP. The allylic carbonate 15 trifluoromethylsulfonylation yielded the alternative initiating
underwent efficient asymmetric allylic amination [20] with building block 6a.
o-nitrophenylsulfonamide as the nucleophile to give the allylic
sulfonamide 17 in 66% yield; in addition, the linear product 16
was also obtained in 7% yield. Desilylation of 17 (→ 18) and
reaction with diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecyl)silyl (FDIPES) bromide, generated in situ
from the corresponding silyl hydride, gave the fluorous-tagged
The initiating building block 7 was prepared from the sulfin-
imine 21 by adapting a synthesis previously reported by Ellman
(Scheme 4) [21]. Treatment of the sulfinimine 21 in dichloro-
methane with allylmagnesium bromide yielded the corres-
ponding sulfinimides as a 79:21 mixture of diastereoiomers;
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Scheme 4: Synthesis of the initiating building block 7.
following column chromatography, the major diastereomer 22 ponding diastereomeric O-methyl mandelate esters. The termin-
was obtained in 70% yield, and was converted into the corres- ating building blocks 12a and 13 were prepared by straightfor-
ponding amino alcohol 23. The configuration of the amino ward derivatisation of commercially available starting materials
alcohol 23 was determined by conversion into the corres- (see Supporting Information File 1).
ponding benzamide and comparison with racemic and enantio-
merically enriched samples (prepared from the commercially Synthesis of metathesis substrates
available amino acid). Analysis by chiral HPLC indicated that Initially, the propagating building blocks 8–11 were attached to
the amino alcohol 23 had (R)-configuration. It was concluded the fluorous-tagged initiating building blocks (6a, 6b or 7). In
that the sense of diastereoselectivity in the addition 21 → 22 each case, an excess of the propagating building block, DEAD
contrasted with that reported by Ellman [21]. However, the and triphenylphosphine was used. In general, the crude product
sense of diastereoselectivity was the same as that reported for was directly deacetylated. At each stage, the required fluorous-
the addition of allylmagnesium bromide in dichloromethane to a tagged product was isolated by fluorous-solid-phase extraction
similar sulfinimine [22]. The amino alcohol 23 was converted (F-SPE), and its purity determined by analysis by 500 MHz
into the corresponding o-nitrophenylsulfonamide 24 and, hence, 1H NMR spectroscopy. These results are summarised in
the fluorous-tagged building block 7.
Table 1.
The propagating building blocks 8–11, and the terminating The metathesis substrates were prepared by subsequent attach-
building block 12b, were prepared by using established ment of a terminating building block (12a, 12b or 13) (see
methods [14]. The enantiomeric excess (68% ee) of the hydroxy Table 2). In each case, an excess of the terminating building
alcohol 11 was determined by conversion into the corres- block, DEAD and triphenylphosphine was used; the required
Table 1: Attachment of propagating building blocks to the fluorous-tagged initiating building blocks.
Building blocks
Attachment
Deacetylationa
Product
Methoda (mass recovery / %)
{Purityb / %}
Mass recovery / %
(Purityb / %)
6a, 8
6a, 9
A1 (70) {>98}
A2 (97) {92}
92 (92)
87 (93)
25
26
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Table 1: Attachment of propagating building blocks to the fluorous-tagged initiating building blocks. (continued)
6a, 10c
A3 (85) {>98}
87 (98)
27
6b, 11d
A3 (85) {76}
85e (72)
28
29
7, 8
7, 9
A3 (92) {91}
A3 (74f)
94f
97 (98)
30
7, 10
A3 (97) {91}
80f
31
aMethods: A1: Initiating building block (1.0 equiv), propagating building block (4.0 equiv), DEAD (4.0 equiv), PPh3 (4.0 equiv), CH2Cl2, 0 °C → rt then
F–SPE; A2: Initiating building block (1.0 equiv), propagating building block (4.0 equiv), DEAD (2.0 equiv), PPh3 (2.0 equiv), CH2Cl2, 0 °C → rt then
F–SPE; A3: Initiating building block (1.0 equiv), propagating building block (4.0 equiv), DEAD (2.0 equiv), PPh3 (2.0 equiv), THF, 0 °C → rt then
F–SPE; Deacetylation: 0.025 M NH3 in MeOH. bDetermined by analysis of the 500 MHz 1H NMR spectrum. cThe building block had >98% ee. dThe
building block had 68% ee. eIsolated as a ca. 75:25 mixture of diastereoisomers. fIsolated yield of purified product (see Supporting Information File 1).
Table 2: Attachment of propagating building blocks to the fluorous-tagged initiating building blocks.
Terminating
building block
Substrate
Attachment
Product
Methoda (mass recovery / %)
{Purityb / %}
25
25
12b
13
A4 (89) {83}
A4 (89) {86}
32
33
26
12b
A4 (76) {93}]
34
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Table 2: Attachment of propagating building blocks to the fluorous-tagged initiating building blocks. (continued)
26
27
13
A4 (75) {97}
35
12b
A5 (62c)
36
27
13
A5 (54c)
37
38
28d
28d
12a
13
A5 (86c,e)
A5 (77c,e)
39
40
29
29
12a
A6 (86c)
A6 (77c)
13
41
42
30
30
12a
13
A6 (92c)
A6 (55c)
43
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Table 2: Attachment of propagating building blocks to the fluorous-tagged initiating building blocks. (continued)
31
12a
A6 (85c)
44
aMethods: A4: Substrate (1.0 equiv), propagating building block (4.0 equiv), DEAD (2.0 equiv), PPh3 (2.0 equiv), CH2Cl2, 0 °C → rt then F-SPE;
A5: Substrate (1.0 equiv), propagating building block (4.0 equiv), DEAD (4.0 equiv), PPh3 (4.0 equiv), THF, 0 °C → rt then F-SPE; A6: Substrate
(1.0 equiv), propagating building block (4.0 equiv), DEAD (2.0 equiv), PPh3 (2.0 equiv), THF, 0 °C → rt then F-SPE. bDetermined by analysis of the
500 MHz 1H NMR spectrum. cIsolated yield of purified product. dThe starting material was a ca. 75:25 mixture of diastereoisomers. eIsolated as a ca.
75:25 mixture of diastereomers.
fluorous-tagged product was isolated by solid-fluorous phase tions were judged to be complete by TLC analysis. After
extraction (F-SPE), and its purity was determined by analysis removal [24] of the catalyst by using tris(hydroxymethyl)phos-
by 500 MHz 1H NMR spectroscopy.
phine, the metathesis products were generally purified by flash
column chromatography. Finally, the o-nitrophenylsulfonyl
groups were removed from the products. The results are
Metathesis cascade reactions
The scaffolds of the metathesis substrates were “repro- summarised in Table 3.
grammed” by treatment with Hoveyda–Grubbs second-genera-
tion catalyst in either dichloromethane or tert-butyl methyl ether In general, the metathesis reactions proceeded smoothly to give
[23] (TBME). Many of the metathesis reactions were rather the expected metathesis cascade products. In the case of 39,
sluggish, and the catalyst was added portionwise until the reac- however, the cyclopentene did not participate in the metathesis
Table 3: Application of cascade metathesis reactions in the synthesis of diverse scaffolds and subsequent desulfonylation.
Substrate
Methoda (mol %; time)
Product
Yield / %
32
B1 (5 + 2.5; 3 d) then C1
45, 37%b
45
46
47
46, 11%b
47, 5%b
33
34
B1 (2 × 5; 4 d) then C1 then D
B1 (5 + 5 + 2.5; 10 d) then C1
43%b
48
49
49%b (86%c)
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Table 3: Application of cascade metathesis reactions in the synthesis of diverse scaffolds and subsequent desulfonylation. (continued)
36
B1 (4 × 5; 20 d) then C1
B1 (3 × 5; 14 d) then C1
77 then 81 (93%c)
50
51
52
38d
63 then 85 (51)
29 then 94 (52)
39
B1 (4 × 5; 20 d) then C2
8%b
53
54
40
41
42
43
B2 (5; 24 h) then C1
B2 (5; 24 h) then C2
B2 (3 × 5; 7 d) then C1
B2 (2 × 5; 3 d) then C2
93 then 96 (87%c)
93 then 80 (93%c)
76 then 92 (92%c)
54 then 77 (86%c)
55
56
57
58
44
B2 (5; 24 h) then C1
53 then 99 (98%c)
aMethods: B1: Hoveyda–Grubbs second-generation catalyst, CH2Cl2, 50 °C then Et3N (86 equiv), P(CH2OH)3 (86 equiv) then silica; B2:
Hoveyda–Grubbs second-generation catalyst, MTBE, 50 °C then Et3N (86 equiv), P(CH2OH)3 (86 equiv) then silica; C1: PhSH (1.2 equiv), K2CO3
(3.0 equiv), DMF; C2: PhSH (2.4 equiv), K2CO3 (6.0 equiv), DMF; E: aq HF, MeCN–CH2Cl2. bYield over more than one step. cPurity of the product
determined by 500 MHz 1H NMR spectroscopy. dThe starting material was a ca. 75:25 mixture of diastereoisomers.
reaction, and the bridged macrocycle 53 was obtained in low byproducts in the metathesis cascade reaction of 32 was
yield. We have previously observed the formation of macro- remarkable [25]. Presumably, in this case, the metathesis
cyclic metathesis products in similar metathesis cascade reac- cascade leads to the generation of the intermediate 59
tions [14]. The formation of the cyclopropanes 46 and 47 as (Scheme 5); the intermediate could then react to conclude the
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Scheme 5: Fate of the metathesis reaction of the substrate 32.
metathesis cascade (to give 45 after deprotection), or cyclopro- Finally, a selection of fluorous-tagged products was derivatised
panate [25] the terminal alkene (to give 46 or 47 after deprotec- (typically on a 50 μmol scale) to yield a range of amides and
tion) (Scheme 5).
ureas (Table 4). The fluorous tag facilitated the purification of
Table 4: Derivatisation and deprotection of final products.
Substrate (puritya / %)
Productb
Methodc
Yield / %
60a
60b
60c
60d
D
51
E1 then D
E2 then D
E3 then D
81 then 60
67 then 98
94 then 81
45
46
47
61b
62b
E1 then D
E1 then D
39 then 70
43 then 63
63a
63b
63c
63d
D
83
E1 then D
E2 then D
E3 then D
32 then 64
83 then 58
84 then 79
49
(86)
64a
64b
64c
64d
D
87
E1 then D
E2 then D
E3 then D
29d
43d
34d
50
(93)
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Beilstein J. Org. Chem. 2013, 9, 775–785.
Table 4: Derivatisation and deprotection of final products. (continued)
65a
65b
65c
65d
D
70
E1 then D
E2 then D
E3 then D
40d
82d
74d
51
(85)
53
66a
D
52
67a
67b
67c
67d
D
91
E4 then D
E2 then D
E3 then D
77d
83d
42d
54
(87)
68a
68c
68d
D
94
E2 then D
E3 then D
67d
40d
55
(93)
69a
69b
69c
D
91
E4 then D
E2 then D
67d
67d
56
(92)
70a
70c
D
47
57
(86)
E2 then D
59d
71a
71b
71c
71d
D
91
E4 then D
E2 then D
E3 then D
64d
53d
29d
58
(98)
aDetermined by analysis of the product by 500 MHz 1H NMR spectroscopy. bThe suffix refers to the identity of the R substituent: a, R = H; b, R =
isoxazole-5-carbonyl; c, R = pyridine-3-carbonylamino; d, R = morpholine-4-carbonyl; cMethods: D: aq HF, MeCN–CH2Cl2; E1: isoxazole-5-carbonyl
chloride (2.0 equiv), Et3N (3.0 equiv), DMAP (1.0 equiv), CH2Cl2; E2: pyridine-3-isocyanate (2.0 equiv), Et3N (3.0 equiv), DMAP (1.0 equiv), CH2Cl2;
E3: morpholine-4-carbonyl chloride (2.0 equiv), Et3N (3.0 equiv), DMAP (1.0 equiv), CH2Cl2; E4: isoxazole-5-carbonyl chloride (2.0 equiv), pyridine;
dYield over two steps.
the derivitised products by F-SPE. The final products 60–71 diverse range of molecular scaffolds. The diversity of the
(Table 4) were obtained after removal of the fluorous tag by products was increased through variation of all three of the
desilylation.
building blocks used: the initiating, the propagating, and the
terminating building block.
Conclusion
Metathesis is an extremely powerful reaction for diversity- The overall approach was facilitated by fluorous tagging of the
oriented synthesis. It was demonstrated that metathesis initiating building block, allowing easy purification (by F-SPE)
substrates could be assembled efficiently from triplets of of synthetic intermediates and metathesis products. The pres-
building blocks. Thereafter, metathesis cascades yielded a ence of a fluorous tag also facilitated the purification of the
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Beilstein J. Org. Chem. 2013, 9, 775–785.
14.Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A.
functionalised products. Evaluation of the biological activity of
the final products will be reported in due course.
Angew. Chem., Int. Ed. 2009, 48, 104–109.
doi:10.1002/anie.200804486
15.Spandl, R. J.; Rudyk, H.; Spring, D. R. Chem. Commun. 2008,
3001–3003. doi:10.1039/b807278g
Supporting Information
See for other diversity-oriented approaches that exploit metathesis
chemistry.
Supporting Information File 1
16.Spiegel, D. A.; Schroeder, F. C.; Duvall, J. R.; Schreiber, S. L.
J. Am. Chem. Soc. 2006, 128, 14766–14767. doi:10.1021/ja065724a
See for other diversity-oriented approaches that exploit metathesis
chemistry.
Experimental and compound characterisation.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-88-S1.pdf]
17.O'Leary-Steele, C.; Pedersen, P. J.; James, T.; Lanyon-Hogg, T.;
Leach, S.; Hayes, J.; Nelson, A. Chem.–Eur. J. 2010, 16, 9563–9571.
doi:10.1002/chem.201000707
Acknowledgements
We thank the European Commission for a Marie Curie Interna-
tional Incoming Fellowship (to S.K.M.) and the EPSRC for
additional funding.
See for other diversity-oriented approaches that exploit metathesis
chemistry.
18.Gladysz, A.; Curran, D. P.; Horváth, I. T. Handbook of Fluorous
Chemistry; Wiley: New York, 2004. doi:10.1002/3527603905
19.Wuts, P. G. M.; Ashford, S. W.; Anderson, A. M.; Atkins, J. R. Org. Lett.
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