Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

Article abstract of DOI:10.3762/bjoc.8.11

Heating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde - which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions - or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.

Full text of DOI:10.3762/bjoc.8.11

Synthesis of fused tricyclic amines unsubstituted at
the ring-junction positions by a cascade
condensation, cyclization, cycloaddition
then decarbonylation strategy
Iain Coldham*1, Adam J. M. Burrell1, Hélène D. S. Guerrand1,
Luke Watson1, Nathaniel G. Martin2 and Niall Oram3
Full Research Paper
Open Access
Address:
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield
Beilstein J. Org. Chem. 2012, 8, 107–111.
1
doi:10.3762/bjoc.8.11
S3 7HF, United Kingdom, 2AstraZeneca, Mereside, Alderley Park,
Macclesfield, Cheshire SK10 4TG, United Kingdom and 3Eli Lilly and
Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United
Kingdom
Received: 01 November 2011
Accepted: 23 December 2011
Published: 18 January 2012
Email:
Associate Editor: J. N. Johnston
Iain Coldham* - i.coldham@sheffield.ac.uk
©
2012 Coldham et al; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
alkaloid; azomethine ylide; dipolar cycloaddition; heterocycle; tricyclic
Abstract
Heating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the
α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate
imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused
tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an
aldehyde – which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions – or
was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.
Introduction
Cascade reaction sequences [1] provide a rapid and efficient thesis [9-16] and were able to show that the azomethine ylide
means to build complexity in organic chemistry. One such could be prepared in situ by a cyclization step [17,18]; for
sequence involves a cyclization followed by in situ intra- example, by heating the aldehyde 1 (R = Et) with glycine ethyl
molecular cycloaddition to give three new rings in a single ester to give the tricyclic product 2 [19,20] (Scheme 1). In this
transformation [2-8]. We have been studying the intra- chemistry, the intermediate imine undergoes cyclization onto
molecular dipolar cycloaddition of azomethine ylides in syn- the tethered alkyl chloride to give an iminium ion which depro-
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Beilstein J. Org. Chem. 2012, 8, 107–111.
tonates to give an azomethine ylide that undergoes dipolar nitrile 3, we prepared three different aldehydes, as shown in
cycloaddition with the alkene. A single stereoisomer of product Scheme 2 and Scheme 3. Double deprotonation (of the alcohol
2
was formed. Alternatively, glycine could be used and led to a and alpha to the nitrile) of substrate 3 and C-alkylation occurred
tricyclic product via an intermediate azomethine ylide formed smoothly to give 4a or 4b (n = 1 or 2, respectively). A second
by decarboxylation. Unfortunately, when the substrate 1 double deprotonation and then an alkylation with bromochloro-
(
R = H) was used, heating with glycine or glycine ethyl ester propane gave 5a and 5b. Oxidation of the alcohol 5a (n = 1)
did not yield the desired tricyclic products due to competing gave the aldehyde 6. Alternatively, protection of 5a and 5b as
enamine formation [21].
their tert-butyldimethylsilyl ethers gave 7a and 7b. DIBAL-H
reduction of nitrile 7b (n = 2) gave aldehyde 8b. The same
reduction of nitrile 7a gave a low yield of the desired aldehyde
8
a; so, an alternative strategy to prepare the aldehyde with one
less methylene group in the side-chain was studied (Scheme 3).
Alkylation of the commercially available substituted malonate 9
gave product 10 together with diethyl cyclobutanedicarboxy-
late (formed by cyclization of the malonate anion onto the
internal alkyl chloride). This by-product was removed by
Scheme 1: Cascade chemistry for 2-ethyl-aldehydes.
For this cascade cyclization–cycloaddition chemistry to be
widely applicable (for example for the preparation of alkaloids),
we need to be able to access tricyclic products with no
substituents (only hydrogen atoms) at the ring junction posi-
tions (such as compound 2, R = H, or other ring sizes) [22].
This paper outlines an approach to such targets using a
substituent (to block side reactions) which can then be removed
by decarbonylation [23].
Results and Discussion
Preparation of the aldehyde substrates
Scheme 3: Preparation of aldehyde 8a. Step a: NaH, THF, 0 to 70 °C,
CH2=CHCH2CH2Br. Step b: DIBAL-H, CH2Cl2, 0 °C, 2 h then HCl(aq)
(2 M), 24% over two steps. Step c: TBSCl, imidazole, CH2Cl2, rt, 16 h,
We decided to incorporate a one-carbon substituent, alpha to the
aldehyde group, that could potentially be removed after the
cascade cyclization–cycloaddition chemistry. Starting from
86%. Step d: (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C to rt, 96%.
Scheme 2: Preparation of aldehydes 6 and 8b. Step a: LDA, THF, 0 °C, CH2=CHCH2(CH2)nBr (n = 1, 56%; n = 2, 76%). Step b: LDA, THF, −78 °C,
ClCH2CH2CH2Br (n = 1, 80%; n = 2, 89%). Step c: Using 5a, (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C to rt, 92%. Step d: TBSCl, imidazole, CH2Cl2, rt,
16 h (n = 1, 92%; n = 2, 94%). Step e: Using 7b, DIBAL-H, CH2Cl2, −78 °C, 2 h then HCl(aq) (2 M), 62%.
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Beilstein J. Org. Chem. 2012, 8, 107–111.
column chromatography after reduction of both esters to give ylation and this type of reaction is known using Wilkinson’s
diol 11. Mono-protection gave the alcohol 12 which was catalyst [25]. We were disappointed to find that attempts to con-
oxidized to aldehyde 8a.
duct this decarbonylation using aldehyde 16 and [Rh(PPh3)3Cl]
resulted only in decomposition.
Cascade condensation, cyclization, cyclo-
addition
The cascade tricyclic ring formation was then investigated with
the aldehydes 6, 8a and 8b. Heating aldehyde 6 with glycine
gave a mixture of unidentifiable products. However, heating
with glycine ethyl ester in toluene gave the desired tricyclic
product 13a as the major stereoisomer, together with a small
amount of the separable stereosiomer 13b (Scheme 4). The
major isomer 13a was assumed to have the all-cis configuration
based on related chemistry (compare with product 2 [19,20],
Scheme 1). The minor isomer was assigned by NOESY studies,
in which there was a strong enhancement between the ring junc-
tion protons and a strong enhancement between the proton
alpha to the ester and the ring junction proton alpha to the
nitrogen. The reaction is supposed to proceed by initial imine
formation, then cyclization with displacement of chloride to
Scheme 5: Cascade chemistry with aldehyde 8a and glycine.
give an iminium ion. Deprotonation of this iminium ion would As an aside, we were interested in using the products of this
give the azomethine ylide that undergoes intramolecular cyclo- chemistry for the construction of the core ring system found in
addition. The preference for the all-cis isomer 13a arises from a alkaloid natural products. Wittig reaction with aldehyde 16
preference for cycloaddition from the conformation shown in should be possible to provide the core ring system found in the
Scheme 4. Unfortunately, we were not able to remove the nitrile alkaloids meloscine and scandine [26-30]. However, we chose
substituent from the product 13a using lithium in ammonia [24], to investigate a shorter reaction sequence without the need for
which instead converted the ethyl ester to its primary carboxylic protecting groups and to carry out the Wittig reaction at an
amide, or using DIBAL-H, which gave a complex mixture of earlier stage, as shown in Scheme 6. Olefination of aldehyde 6
products.
with the anion formed from methyltriphenylphosphonium
bromide gave alkene 17, which was reduced with DIBAL-H to
Heating aldehyde 8a with glycine gave cycloadduct 14 as a give aldehyde 18. Heating this aldehyde with glycine in toluene
single diastereoisomer (Scheme 5). Deprotection of the silyl gave the desired tricyclic product 19 as a single stereoisomer.
ether with tetra-n-butylammonium fluoride (TBAF) gave the NOESY studies verified the stereochemistry as shown. Only
alcohol 15, then Swern oxidation yielded aldehyde 16. The one of the two alkene groups acts as the dienophile, as expected
stereochemistry of alcohol 15 was confirmed by single crystal for conformational reasons. This synthesis (six steps from
X-ray analysis. This stereochemistry was expected for these nitrile 3) represents an efficient entry to the core of the alka-
cascade reactions, in which the substituent alpha to the alde- loids meloscine and scandine, which contains the same fused
hyde (in this case the TBSOCH2 group) is located in the tran- tricyclic ring system.
sition state cis to the developing ring junction protons. The next
step, to remove the one-carbon unit to provide the desired The use of glycine to form a ‘non-stabilized’ ylide had led to
tricyclic product with all ring-junction protons, was a decarbon- the desired cycloadduct 14, although subsequent decarbon-
Scheme 4: Cascade chemistry with aldehyde 6 and preferred conformation of intermediate azomethine ylide during cycloaddition.
109

Beilstein J. Org. Chem. 2012, 8, 107–111.
entirely stereoselective and a (separable) mixture of two other
stereoisomers 22 and 23 was also formed (NOESY studies were
used to ascertain the relative stereochemistry).
Scheme 6: Synthesis of the core tricyclic ring system of meloscine and
scandine.
Scheme 7: Cascade chemistry with aldehydes 8a and 8b and glycine
ethyl ester.
ylation had not been successful using aldehyde 16 (Scheme 5).
Despite this, we chose to investigate the cascade chemistry
using glycine ethyl ester (to form a ‘stabilized’ ylide), followed
by possible later decarbonylation.
To complete the desired aim to provide a method to prepare
fused tricyclic products with all ring-junction protons, we
Heating aldehydes 8a or 8b with glycine ethyl ester in toluene carried out the transformations shown in Scheme 8. Desilyla-
gave the expected tricyclic products (Scheme 7). Using alde- tion of 20 and 21 gave the alcohols 24 and 27, respectively.
hyde 8a, a single stereoisomer was formed (assumed to have the Swern oxidation then gave the aldehydes 25 and 28. Finally,
all-cis configuration shown and confirmed by NOESY studies). using Wilkinson’s catalyst, we were pleased to find that both
Using aldehyde 8b, the major product was the stereoisomer 21, these aldehyde substrates were amenable to decarbonylation.
which was expected based on related chemistry [19] and veri- The optimum conditions were found to be a temperature of
fied by the large coupling constant in the 1H NMR spectrum for about 150 °C for about 2 h. The decarbonylation occurred with
the ring junction proton alpha to the nitrogen atom (2.20 ppm, overall retention of stereochemistry, as verified by NOESY
doublet, J = 11.5 Hz). However, this transformation was not studies. The presence of the ethyl ester substituent must be
Scheme 8: Decarbonylation reactions to give the products 26 and 29.
110

Beilstein J. Org. Chem. 2012, 8, 107–111.
1
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The chemistry described here provides a method to prepare
fused tricyclic products in which the ring junction positions are
unsubstituted. Problems with conducting the cascade
condensation, cyclisation, cycloaddition chemistry using azo-
methine ylides derived from enolisable aldehyde substrates [21]
has been circumvented by incorporating a one-carbon unit at the
alpha-position of the aldehyde. This one-carbon unit can be
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Supporting Information
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Org. Biomol. Chem. 2010, 8, 4530. doi:10.1039/c0ob00408a
3.Coldham, I.; Burrell, A. J. M.; Watson, L.; Oram, N.; Martin, N. G.
Heterocycles 2012, 84, 597. doi:10.3987/COM-11-S(P)29
Experimental procedures and spectroscopic data.
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We thank the EPSRC (grant EP/F06313X/1), the University of
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Harry Adams (University of Sheffield) is thanked for X-ray
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