Enantioselective synthesis of tricyclic amino acid derivatives based on a rigid 4-azatricyclo[5.2.1.02,6]decane skeleton

Article abstract of DOI:10.3762/bjoc.5.81

An enantioselective route to four tricyclic amino acids and N-tosylamides, composed of a central norbornane framework with a 2-endo,3-endo-annelated pyrrolidine ring and a 5-endo-C₁ or -C₂ side chain, has been developed. A key intermediate was the chiral, N-Boc-protected ketone (1R,2S,6S,7R)-4-azatricyclo[5.2.1.0^2,6]decan-8-one, available from inexpensive endo-carbic anhydride in five steps and 47% yield. The rigid scaffold makes these amino acid derivatives promising candidates for β-turn-inducing building blocks in peptidomimetics and for chiral auxiliaries in asymmetric organocatalysis.

Full text of DOI:10.3762/bjoc.5.81

Enantioselective synthesis of tricyclic
amino acid derivatives based on a rigid
4-azatricyclo[5.2.1.02,6]decane skeleton
Matthias Breuning*1, Tobias Häuser1, Christian Mehler1,
Christian Däschlein2, Carsten Strohmann2, Andreas Oechsner3
and Holger Braunschweig3
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 81.
1Institut für Organische Chemie, Universität Würzburg, Am Hubland,
97074 Würzburg, Germany, 2Anorganische Chemie, Universität
Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany and 3Institut
für Anorganische Chemie, Universität Würzburg, Am Hubland, 97074
Würzburg, Germany
doi:10.3762/bjoc.5.81
Received: 20 August 2009
Accepted: 26 October 2009
Published: 21 December 2009
Email:
Associate Editor: N. Sewald
Matthias Breuning* - breuning@chemie.uni-wuerzburg.de
© 2009 Breuning et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
amino acid; enantioselective synthesis; norbornane; polycyclic
compounds; pyrrolidine
Abstract
An enantioselective route to four tricyclic amino acids and N-tosylamides, composed of a central norbornane framework with a
2-endo,3-endo-annelated pyrrolidine ring and a 5-endo-C1 or -C2 side chain, has been developed. A key intermediate was the chiral,
N-Boc-protected ketone (1R,2S,6S,7R)-4-azatricyclo[5.2.1.02,6]decan-8-one, available from inexpensive endo-carbic anhydride in
five steps and 47% yield. The rigid scaffold makes these amino acid derivatives promising candidates for β-turn-inducing building
blocks in peptidomimetics and for chiral auxiliaries in asymmetric organocatalysis.
Introduction
Unnatural amino acids with a rigid bowl-shaped backbone have conformationally rigid amino acid derivatives. In this context,
received considerable interest in recent years. Incorporated in focus was also put on derivatives in which the activating acidic
peptides or proteins, they may increase the metabolic stability group is anchored at a more remote position of the molecule,
and allow the introduction of novel structural motifs [1-4]. but still in close spatial proximity to the amino function.
ß-Turns, for example, result if conformationally constrained Examples are β-proline (4) [18,19], the bispidinium salt 5 [20],
spiro- or bicyclic amino acids such as 1 [5], 2 [6], and 3 [7,8] and the binaphthyl-derived amino acid 6 [21-23], which
are embedded in peptidomimetics (Figure 1). Enantioselective provided excellent enantioselectivities in several aldol and
organocatalysis [9-17] is another field of application for Mannich reactions.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 81.
Scheme 1: Synthesis of the racemic ketone rac-9. i) NH4OAc, HOAc,
Δ, 4 d, 100%; ii) LiAlH4, THF, Δ, 1 d, 87% [24]; iii) Boc2O, CH2Cl2, rt,
16 h, 85%; iv) NaBH4, Me2SO4, THF, rt, 6 h, then NaOH, H2O2, Δ, 90
min, 75%; v) PCC, Celite®, CH2Cl2, rt, 16 h, 79%.
Figure 1: The conformationally rigid amino acid derivatives 1–3
(β-turn-inducing building blocks) and 4–6 (successful organocatalysts).
Our studies targeted the chiral, tricyclic amino acid derivatives trichlorosilane in the presence of a catalytic amount of
7 and 8 (Figure 2), which possess a central norbornane frame- [Pd(C3H5)Cl]2 and (R)-MOP [(R)-2-diphenylphosphino-2′-
work equipped with a 2-endo,3-endo-annelated pyrrolidine ring. methoxy-1,1′-binaphthyl], followed by SiCl3/OH exchange,
Due to the constrained, bowl-shaped backbone, these com- delivered the exo-alcohol 12 in 81% yield and 85% ee, as deter-
pounds may possess high potential as β-turn-inducing peptide mined from the (S)- and (R)-Mosher esters of 12. After oxida-
building blocks and as bifunctional organocatalysts. In this tion (see Scheme 1), the chiral ketone 9 was thus available in
paper we report on the first enantioselective synthesis of 7 and overall five steps and 47% yield from 10. The X-ray crystal
8, which was achieved via the chiral ketone 9 as the key inter- structure of 9 is shown in Figure 3.
mediate.
Scheme 2: Enantioselective hydrosilylation/oxidation of 11. i) HSiCl3,
[Pd(C3H5)Cl]2 (0.06 mol %), (R)-MOP (0.25 mol %), toluene, rt, 3 d,
then evaporate, then KF, KHCO3, H2O2, THF/MeOH, rt, 1 d, 81%.
Figure 2: The targeted tricyclic amino acid derivatives 7 and 8, and the
key intermediate 9.
Initial studies on the installation of the functionalized C1 side
chain, as required for the amino acid derivatives 7, were done
Results and Discussion
on racemic material and aimed at an oxidation of the alkene
The key intermediate, the tricyclic amino ketone 9, was first rac-13 (Scheme 3), which was available from the ketone rac-9
prepared in racemic form starting from inexpensive endo-carbic either by Wittig reaction or by a Tebbe-type olefination [31]
anhydride (10, Scheme 1). Conversion of the succinyl anhy- using Mg, TiCl4, and CH2Cl2. Hydroboration/oxidation of rac-
dride moiety in 10 into the pyrrolidine ring in 11 was accom- 13 occurred highly diastereoselectively on the exo-side
plished in three steps and 74% yield by imide formation, reduc- providing the desired endo-alcohol rac-14, as determined by
tion [24], and N-protection. Hydroboration/oxidation of the NOE measurements. Further oxidation with PCC gave the alde-
alkene function of 11 delivered the exo-configured alcohol rac- hyde rac-15, albeit in low 13% overall yield from rac-9. As an
12, which was oxidized with PCC furnishing rac-9 in 79% alternative, the epoxidation of rac-13 with MCPBA was investi-
yield.
gated, which delivered the spirocyclic exo-configured epoxide
rac-16 in 46% overall yield from rac-9 as the sole diastereomer.
The asymmetric synthesis of the ketone 9 was realized by enan- Lewis acid-catalyzed rearrangement of rac-16 with BF3
tioselective hydration of the meso-alkene 11 using Hayashi’s etherate [32] furnished the desired aldehyde rac-15 in 26%
method (Scheme 2) [25-30]: Hydrosilylation with yield (12% overall yield from rac-9) and the tetracyclic
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Beilstein Journal of Organic Chemistry 2009, 5, No. 81.
selective hydrolysis of the enol ether moiety in 18 in the pres-
ence of the N-Boc-protective group was achieved by using
trichloroacetic acid. The desired endo-configured aldehyde 15
was thus available in only two steps in good 64% overall yield
from 9. After oxidation of 15 to the acid 19, the target amino
acid 7a•HCl was obtained by N-deprotection with aqueous HCl
in overall four steps and 38% yield from 9. The N-tosylamide
7b•HCl was accessed from 19 by condensation with TsNH2
under Steglich conditions followed by N-deprotection with
ethereal HCl (overall five steps and 12% yield from 9).
Figure 3: X-ray crystal structure of 9. X-ray data have been deposited
with the Cambridge Crystallographic Data Centre (CCDC 743050).
Scheme 4: Assembly of the amino acid 7a•HCl and the N-tosylamide
7b•HCl. i) MeOCH2PPh3+Cl−, t-BuOK, toluene/THF, rt, 1 d, 84%; ii)
Cl3CCO2H, H2O, CH2Cl2, rt, 1.5 h, 76%; iii) NaClO2, H2O2, KH2PO4,
H2O/MeCN, rt, 6 h, 75%; iv) HCl, H2O, Δ, 1 d, 79%; v) TsNH2, DCC,
DMAP, CH2Cl2, rt, 1 d, 64%; vi) HCl, Et2O, MeOH, rt, 3 h, 38%.
N,O-acetal rac-17 in 35% yield. The latter compound is
presumably formed from rac-15 by a Lewis acid-catalyzed,
intramolecular, and thus proximity-facilitated tandem hydride
transfer/cyclization sequence [33].
The preparation of the amino acid 8a•HCl and the N-tosyl-
Since the yields of rac-15 from the alkene rac-13 were low, we amide 8b•HCl required the attachment of an endo-oriented
turned our attention to an alternative approach via the enol ether acetic acid substituent at the position of the keto group in 9
18, which was available from 9 as a 1:1 mixture of E/Z-isomers (Scheme 5). Initial attempts to introduce such a side chain by
by Wittig reaction with MeOCH=PPh3 (Scheme 4). The Wittig or Horner-Wadsworth-Emmons reactions, for example
Scheme 3: Initial route to the aldehyde rac-15. i) MePPh3+Br−, t-BuOK, toluene, Δ, 7 h, 77% or Mg, TiCl4, CH2Cl2, 0 °C → rt, 2 h, 55%; ii) NaBH4,
Me2SO4, THF, 0 °C → rt, 18 h, then NaOH, H2O2, rt, 3 h, 34%; iii) PCC, CH2Cl2, rt, 6 h, 51%; iv) MCPBA, CH2Cl2, rt, 3 h, 60%; v) BF3•OEt2, toluene,
0 °C, 5 min, 35% (rac-17) and 26% (rac-15).
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Beilstein Journal of Organic Chemistry 2009, 5, No. 81.
with MeO2CCH=PPh3 or MeO2CCH2P(O)(OEt)2/n-BuLi, A first evaluation of the bowl-shaped amino acid derivatives 7
failed. By contrast, Peterson-type olefination using and 8 in standard organocatalytic aldol and Mannich reactions
TMSCH2CO2Et/LDA cleanly afforded the α,β-unsaturated ester showed that these compounds are capable of promoting these
20 as a 77:23 mixture of the E/Z-isomers in 50% yield. The reactions, albeit with low yields and enantioselectivities.
reduction of the conjugated double bond with Mg in methanol Further investigations on this issue and on the use of 7 and 8 as
furnished, after saponification, the endo-configured acid 21 as a β-turns are in progress.
single diastereomer. The further conversion of 21 into the target
molecules was carried out in analogy to the preparation of Conclusion
7a/b•HCl from 19 (see Scheme 4), giving 8a•HCl in overall The enantioselective syntheses of the bowl-shaped, tricyclic
24% yield from 9 (four steps) and 8b•HCl in overall 10% yield amino acids and N-tosylamides 7 and 8 were successfully
(five steps). The required endo-orientation of the acetic acid accomplished in 9–10 steps starting with inexpensive endo-
moiety in 8a•HCl was confirmed by the X-ray structure of the carbic anhydride (10). The key stereochemical step was the
corresponding free base 8a•MeOH (Figure 4).
desymmetrization of the meso-alkene 11 using Hayashi’s
hydrosilylation/oxidation procedure, which provided the endo-
alcohol 12 in 85% ee. The target molecules are promising
candidates as ß-turn-inducing building blocks in peptidomi-
metics and as chiral auxiliaries in organocatalysis.
Supporting Information
Supporting Information File 1
Full experimental details and characterization data for all
new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-81-S1.pdf]
Supporting Information File 2
NMR spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-81-S2.pdf]
Scheme 5: Preparation of the amino acid 8a•HCl and the N-tosyl-
amide 8b•HCl. i) TMSCH2CO2Et, LDA, THF, −78 °C → rt, 19 h, 50%;
ii) Mg, MeOH, rt, 16 h, 76%; iii) KOH, EtOH/H2O, Δ, 1 d, 90%; iv) HCl,
H2O, Δ, 1 d, 71%; v) TsNH2, DCC, DMAP, CH2Cl2, rt, 4 d, 72%; vi)
HCl, Et2O, rt, 20 h, 42%.
Supporting Information File 3
Crystallographic data of the compounds 8a•MeOH and 9.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-81-S3.pdf]
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