Stereoselective synthesis of novel chimerical amino acids via a photochemical key step

Article abstract of DOI:10.1055/s-1999-2843

The synthesis of novel chimerical amino acid derivatives 6-8 bearing the 6-azatricyclo[3.3.1.03^3,7]nonane (methanotropane) skeleton is described. Starting with one chirality centre in L-4-oxoprolines 2 we succeeded in the fully stereoselective introduction of four new chirality centres. The key step of our synthetic route is a photochemical cyclization of phenyl ketones, whose stereoselectivity has been explained by the different stability of the triplet biradical conformers.

Full text of DOI:10.1055/s-1999-2843

LETTER
1465
Stereoselective Synthesis of Novel Chimerical Amino Acids via a
Photochemical Key Step
Pablo Wessig
Institut für Chemie, Humboldt-Universität zu Berlin, Hessische Str. 1-2, D-10115 Berlin
Fax +49 (30) 2093 6940, E-mail: pablo.wessig@chemie.hu-berlin.de
Received 15 June 1999
The oxoprolines 2 were then subjected to an α,α-anella-
tion with 2-chloromethyl-3-chloropropiophenone 3 giv-
ing the 8-oxo-6-azabicyclo-[3.2.1]octane-7-carboxylic
esters 4 in good yields. This method was firstly described
Abstract: The synthesis of novel chimerical amino acid derivatives
6-8 bearing the 6-azatricyclo[3.3.1.03,7]nonane (methanotropane)
skeleton is described. Starting with one chirality centre in L-4-oxo-
prolines 2 we succeeded in the fully stereoselective introduction of
four new chirality centres. The key step of our synthetic route is a by Stetter7 and recently extended by us to heterocyclic ke-
tones.8 Noteworthy, the anellation 2 → 4 occurs fully dia-
stereoselectively affording only the products with endo-
photochemical cyclization of phenyl ketones, whose stereoselectiv-
ity has been explained by the different stability of the triplet biradi-
cal conformers.
benzoyl group in agreement with previous findings
(Scheme 2).7,8
Key words: amino acid, stereoselective synthesis, cyclizations,
photochemistry, radical reactions.
R2 COOR1
O
O
The investigation of the relationships between the chemi-
1. pyrrolidine
O
H
N
COOR1
cal structure and the biological activity of peptides and
proteins is one of the most challenging problems in cur-
rent chemical research. A particularly successful concept
is the incorporation of peptide mimetics, which influence
the peptide conformation in a foreseeable manner.1 Chi-
merical amino acids, which contain structural features of
several natural and unnatural amino acids, are of special
importance in this context.2,3
O
N
R2
2.
(3)
Cl
Ph
Ph
H
Cl
4a 84%
4b 56%
4c 80%
2a-c
Scheme 2
In continuation of our recent studies about the synthesis of
unnatural amino acids4 we now wish to report on an enan-
tioselective synthesis of tricyclic chimerical amino acids.
Starting with L-trans-4-hydroxyproline 1 we protected
the secondary amino group and the carboxyl group and
than oxidized the secondary OH group. Thus, we obtained
the N-,C-protected 4-oxoprolines 2a-c in good yields.
(Some derivatives were obtained according to literature
procedures, Scheme 1).
Irradiation of bicyclic compounds 4a-c at wavelengths ≥
300 nm results in a selective n,π* excitation of the benzoyl
group followed by an intramolecular hydrogen atom ab-
straction from position 7. After an intersystem crossing
(ISC) of the triplet biradicals 5 a C,C-bond formation
takes place and the tricyclic compounds 6 are obtained in
good yields and in a fully stereoselective manner.9 The
relative configuration of products 6 were established by
cleavage of the Cbz group in 6c and crystal structure anal-
ysis of the obtained t-Bu-ester 7 (Scheme 3).10
O
HO
The cyclization products 6 contain five chirality centres
which were formed completely stereoselectively starting
from one chirality centre at C(2) of 4-hydroxyproline 1.
The stereochemical information is conserved by the intro-
duction of the 2-benzoyl-1,3-propylidene handle (2 → 4).
In the course of the photocyclization this information is
lost due to the sp2-hybridization of the radical centre A in
the biradical 5 (see Scheme 3). The rigidity of the bicyclic
skeleton results inevitably in an attack of the radical cen-
tre B from the same side.
3 steps
COOR1
COOH
N
R2
N
H
2a R1=Bn, R2=Boc
2b R1=Bn, R2=Cbz
2c R1=t-Bu, R2=Cbz
1
Reagents and conditions: 2a: i) Boc2O, aq. NaOH, rt., 12 h, quant. ,
ii) BnBr, NaOH, EtOH, rfx., 15 h, 55%, iii) DM, CH2Cl2, rt., 16 h,
86%. 2b: i) CbzCl, NaHCO3, H2O, rt., 16 h, quant. 5 ii) BnBr, NaOH,
EtOH, rfx., 15 h, 88%, iii) DM, CH2Cl2, rt., 16 h, 88%. 2c: i) CbzCl,
However, it is more difficult to give an answer to the ques-
tion why the new C,C-bond is formed highly stereoselec-
6
NaHCO3, H2O, rt., 16 h, quant., ii) Jones-reagent, rt., 30 min, 60%
iii) CH2=C(CH3)2, CH2Cl2, H2SO4 cat., 76%. (DM = Dess Martin pe- tively. In general, two different approaches are discussed
riodinane).
concerning the simple diastereoselectivity of the Norrish-
Yang-reaction. The first concept postulates different ISC
Scheme 1
Synlett 1999, No. 9, 1465–1467 ISSN 0936-5214 © Thieme Stuttgart · New York

1466
P. Wessig
LETTER
R2 COOR1
H
showed a low diastereoselectivity indicating that polar ef-
fects play an important role whereas different ISC rates
should be of lower importance. To establish this assump-
tion we have performed a conformational analysis of a
simplified model of biradicals 5 and found, at high level
of theory, that a strong intramolecular hydrogen bond sta-
bilizes a conformation which corresponds to the observed
products. The two low energy conformers BR1 and BR2
which afford products 6 as well as the conformer BR3
which corresponds with the not observed diastereomer of
6 are depicted in Scheme 4.13 One can see that in BR1 a
strong hydrogen bond with a length of 1.97 Å appears be-
tween the OH-group and the N-protecting group. Admit-
tedly, this hydrogen bond cannot be the only reason for
the observed diastereoselectivity as realized by the struc-
ture and the energy of BR2. Although no hydrogen bond
occurs in BR2 its energy is still lower by 2.9 kcal/mol
compared with BR3 which is also stabilized by a hydro-
gen bond. Obviously, the diastereoselective ring closure is
a result of both steric and electronic factors.
R2
3
COOR1
OH
A
O
O
hν, ISC
N
N
O
~ H
B
Ph
Ph
H
H
4a-c
5
ISC
R2
COOR1
O
6a 60%
6b 57%
6c 67%
N
Ph
OH
H
Cbz
COOtBu
COOtBu
H
O
O
N
N
Ph
Ph
Pd/C
Compounds 6 bearing four different functional groups
possess a high synthetic potential and contain many bio-
logically interesting substructures. Thus, we succeeded in
the fully stereoselective reduction of the keto group in 6c
affording 8 in nearly quantitative yield (Scheme 5).
OH
OH
H
H
7
6c
Scheme 3
rates of the involved triplet biradical conformers and
points out the importance of geometries with high spin or-
bit coupling (SOC).11 The second concept discusses the
relative energies of different triplet biradical equilibrium
geometries and assumes similar ISC rates of these con-
formers.12 Of course, in most cases both concepts should
be of some importance but often it is possible to decide
which influence dominates. In the present case we wish to
compare the selectivity of the cyclization of 4 with recent-
ly published results of a carbocyclic analogue (cyclopen-
tanone was used instead of 2).8 The carbocyclic reactant
Cbz
Cbz
H
COOtBu
COOtBu
O
NaBH4
quant.
HO
N
N
Ph
Ph
OH
OH
H
H
8
6c
Scheme 5
Scheme 4
Synlett 1999, No. 9, 1465–1467 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Novel Chimerical Amino Acids via a Photochemical Key Step
1467
purified by flash chromatography. The given yields refer to
the purified products. Other diastereomers were not detectable
by NMR spectroscopy of the crude products.
The tricyclic dihydroxyamino acid derivative 8 contains
the structures of L-homoserine, D-serine, D-phenylalanine,
D-threonine, D-isoleucine, D-allo-isoleucine, L-valine and
L-hydroxyproline. Therefore it can rightly be called a chi-
merical amino acid. Furthermore, the methanotropane
skeleton of 6-8 is contained in many alkaloids such as ko-
busine and nominine.14
Analytical data of 6c: mp 55-56°C. [α]D24 = -51.96 ( c=1,
CHCl3). 1H-NMR (CDCl3): δ 1.28 (s, 9H), 1.48-1.61 (m, 1H),
1.68-1.73 (m, 1H), 2.19 (s, br, 1H), 2.38-2.42 (m, 1H), 2.81-
2.86 (m, 1H), 3.42-3.45 (m, 1H), 4.42 (s, 1H), 5.16 (s, 2H),
7.26-7.36 (m, 10H). 13C-NMR (CDCl3): δ 27.4 (CH3), 31.6
(CH2), 36.7 (CH2), 45.6 (CH), 55.4 (CH), 61.6 (CH), 67.4
(CH2), 74.1 (Cq), 83.0 (Cq), 84.0 (Cq), 126.5, 127.2, 127.5,
127.9, 128.2, 128.5, 136.1, 144.6, 154.4 (CO), 166.6 (CO),
203.8 (CO). IR (KBr): ν 3461, 2954, 1774, 1726, 1710, 1446,
1408, 1366, 1304, 1283, 1246, 1153, 1129, 1036, 753, 704.
EI-MS (70 eV): 407(5, M+ - (CH3)2C=CH2), 272 (20, M+ -
(CH3)2C=CH2, -Cbz), 244 (10), 171 (1), 144 (3), 122(7), 115
(3), 91 (100), 84 (33), 79 (11), 77 (19). C27H29NO6 calcd. C
69.96, H 6.31, N 3.02; found C 70.00, H 6.41, N 2.92.
(10) 2 g (4.32 mmol) 6c was dissolved in a mixture of 50 ml MeOH
and 4.3 ml cyclohexene and 0.5 g Pd/C (10% Pd). The mixture
was refluxed for 1.5 h, filtered through a pad celite and
evaporated giving 1.08 g (76%) 7. The crystallographic data
of 7 were deposited as "supplementary publication no. CCDC-
120118“ at the Cambridge Crystallographic Data Centre.
Copies of the data may be received free of charge at the
following address: CCDC, 12 Union Road, Cambridge
CB21EZ (Fax: (+44) 1223-336-033; E-mail:
In conclusion, we have synthesized highly functionalized
tricyclic amino acid derivatives via a photochemical key
step. Further investigations toward incorporation in pep-
tides are in progress.
Acknowledgement
We gratefully acknowledge the financial support by the Deutsche
Forschungsgemeinschaft. Furthermore, we thank Dr. Kurt Polborn
for performing the crystal structure analysis of 7.
References and Notes
(1) Hanessian, S.; G. McNaughton-Smith, G.; Lombart, H.;
Lubell, W. Tetrahedron 1997, 53, 12789 and the literature
cited therein.
(2) Obrecht, D.; Abrecht, C., Altorfer, M.; Bohdal, U.; Grieder,
A.; Kleber, M.; Pfyffer, P.; Müller, K. Helv. Chim. Acta 1996,
79, 829. Marshall, G. R. Tetrahedron 1993, 49, 3547.
(3) (a) Ramachandran, G. N.; Sasisekharan, V. Adv. Protein
Chem. 1968, 23, 283. (b) Marshall, G. R.; Beusen, D.D.;
Nikiforovich, G.V. Peptide Conformation: Stability and
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Diego 1995.
deposit@ccdc.cam.ac.uk).
(11) Griesbeck, A.G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res.
1994, 27, 70.
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Molder, D.; Wessig, P. J. Photochem. Photobiol. A:
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(4) (a) Wessig, P.; Wettstein, P.; Giese, B.; Neuburger, M.;
Zehnder, M. Helv. Chim. Acta 1994,77, 829. (b) Steiner, A.;
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(13) The Cbz group was replaced by a methoxycarbonyl group to
simplify the calculations. Low energy conformers were
selected by preliminary investigations on semiempirical level
(PM3). These geometries were optimized at UHF/3-21G level
and characterized by frequency analysis. Improved energies
were obtained at UB3PW91/6-31G* level. All calculations
were performed with the ab initio package Gaussian 98.
Energies and geometry data of these calculations are available
upon request. In Scheme 4 all hydrogen atoms are omitted
except that of the OH-group.
(7) Stetter, H.; Rämsch, K.-D.; Elfert, K. Liebigs Ann. Chem.
1974, 1322.
(8) Wessig, P.; Schwarz, J.; Wulff-Molder, D.; Reck, G. Monatsh.
Chem. 1997, 128, 849.
(14) Atta-ur-Rahman, Handbook of Natural Products Data,
Volume 1, Elsevier, Amsterdam 1990.
(9) The irradiation of compounds 4 was performed in
dichloromethane (300 ml) using a pyrex glas photoreactor and
a high pressure mercury arc lamp TQ-150 (Heraeus) at 25 °C.
Irradiation was continued until no reactant was detectable by
TLC (2-4 h). After removal of the solvent products 6 were
Article Identifier:
1437-2096,E;1999,0,09,1465,1467,ftx,en;G15999ST.pdf
Synlett 1999, No. 9, 1465–1467 ISSN 0936-5214 © Thieme Stuttgart · New York