The Pauson-Khand reaction in synthesis of bicyclic rigid α-amino acids

Article abstract of DOI:10.1081/SCC-100103996

The combination of intramolecular Pauson-Khand methodology for Co₂(CO)₈ mediated cyclization, and the Schoellkopf chiral auxiliary for stereoselective preparation of appropriate 1,6-heptenynes constitutes a powerful method for the preparation of rigidified bicyclic α-amino acids.

Full text of DOI:10.1081/SCC-100103996

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THE PAUSON-KHAND
REACTION IN SYNTHESIS OF
BICYCLIC RIGID α-AMINO
ACIDS
Jing Wang a , Mette Lene Falck-Pedersen a ,
Christian Rømming a & Kjell Undheim b
a Department of Chemistry , University of Oslo ,
Oslo, N-0315, Norway
b Department of Chemistry , University of Oslo ,
Oslo, N-0315, Norway
Published online: 09 Nov 2006.
To cite this article: Jing Wang , Mette Lene Falck-Pedersen , Christian Rømming
& Kjell Undheim (2001) THE PAUSON-KHAND REACTION IN SYNTHESIS OF BICYCLIC
RIGID α-AMINO ACIDS, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:8, 1141-1148, DOI:
10.1081/SCC-100103996
To link to this article: http://dx.doi.org/10.1081/SCC-100103996
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SYNTHETIC COMMUNICATIONS, 31(8), 1141–1148 (2001)
THE PAUSON-KHAND REACTION IN
SYNTHESIS OF BICYCLIC RIGID
a-AMINO ACIDS
Jing Wang, Mette Lene Falck-Pedersen,
Christian Rømming, and Kjell Undheim*
Department of Chemistry, University of Oslo,
N-0315 Oslo, Norway
ABSTRACT
The combination of intramolecular Pauson-Khand
methodology for Co2(CO)8 mediated cyclization, and the
Schollkopf chiral auxiliary for stereoselective preparation of
appropriate 1,6-heptenynes constitutes a powerful method for
the preparation of rigidified bicyclic a-amino acids.
INTRODUCTION
a-Substituted a-amino acids are conformationally constrained and
will constitute a powerful approach for generating structurally defined
peptides as conformational probes and bioactive agents when incorporated
into peptides.1–5 Such findings have stimulated a search for ways to prepare
conformationally constrained amino acids. Our efforts have largely been
directed toward the development of stereoselective methodology for the
preparation of rigid cyclic amino acids where the a-carbon of the amino
acid is imbedded in the ring.6–10 The chiral information required for the
* Corresponding author.
1141
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1142
WANG ET AL.
preparation of these structures is available in the Schollkopf bislactim aux-
iliary 1 as a substrate for stereoselective alkenylation and alkynylation. The
bislactim ether 1 is derived from an enantiomerically pure diketopiperazine
of valine and glycine.11 Subsequent cyclization reactions by Pd(0)-catalysis
or Ru(II)-RCM reactions have been found compatible with the bislactim
moiety and have been highly useful for the construction of rigid cyclic
a-amino acids.6–10 In this report we show that cobalt complexes under the
Pauson-Khand conditions are also compatible with the bislactim moiety and
can become highly useful for the construction of bicyclic a-amino acids. The
cyclopentenone ring moiety in the pentalene system 3 and 4 is inherently
functionalized for further chemical transformations if desired. In the family
of pentalenes, a recent report describes related structures in the form of a
racemic synthesis of 3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids as
conformationally constrained glutamic acid. The products were enatiomeri-
cally resolved as diastereomeric salts.12
RESULTS AND DISCUSSION
In the preparation of the substrate 2 for the Pauson-Khand transfor-
mation, the stereoselectivity in the first alkylation step of the auxiliary 1,
which generates a new stereogenic center at C-5, is of little significance
because the stereochemistry is lost when the first product is remetalated
with nBuLi. In general, the second alkylation has been found to be highly
stereoselective with the new substituent entering trans with respect to the
isopropyl group.6–9 In substrate 2, the stereochemistry at C-5 has been
formed by an initial allylation, which is followed by alkynylation. The
stereochemistry at C-5 is conveniently changed by altering the order of
the alkylation reactions. In this manner the other enantiomers of the
amino acids 5 and 6 would be available without having to change the
chiral auxiliary 1 to its enantiomeric structure (Scheme 1).
The Pauson-Khand reaction, a formal [2þ2þ1]cyclization, in its intra-
molecular form is a powerful method for the construction of bicyclic
annulated cyclopentenone derivatives.13,14 In the present case, the
intramolecular Pauson-Khand reaction with the 4,4-disubstituted 1,6-
enyneheptane 2 was to be effected under conditions with stoichiometric
amounts of dicobaltoctacarbonyl in the presence of an N-oxide to promote
the reaction at low temperature to avoid decomposition of the bislactim
moiety.15 As intended, the enyne complex with dicobalthexacarbonyl
was formed from the substrate 2 and dicobaltoctacarbonyl in hexane
at ambient temperature. Evaporation of the solvent and redissolution of
the complex in dichloromethane and subsequent addition of an excess of

BICYCLIC RIGID a-AMINO ACIDS
1143
Scheme 1. (i) a: hexane, 20ꢀC, 1 h, b: MeN(O)(CH2CH2)2OÁH2O, CH2Cl2, 20ꢀC,
0.5 H; (ii) 0.25 M HCl, dioxane, 208C, 5 h.
N-methylmorpholine N-oxide furnished the spiroannulated Pauson-Khand
products 3 and 4.The stereogenic centers in the bislactim ring did not exert
any significant diastereoselective control on the cyclopentenone annulation
reaction. The overall yield was 56% of the pentalene spiranes 3 and 4 as a
1:1 mixture. A similar finding has been reported for a simpler related struc-
ture, viz. a 4,4-disubstituted 1,6-heptenyne by a methyl and an ethoxy-
carbonyl group.16 In this case it was proposed that the almost complete lack
of stereoselectivity was caused by low steric differentiation between the
4,4-geminal substituents. Substituents on the allylic or propargylic carbons,
however, may influence the sterical course. Thus it has been found that high
stereoselectivity may be achieved in 3,4- and 4,5-disubstituted 1,6-
heptenynes, and that the selectivity is influenced by the nature and relative
stereochemistry of the substituents.17,18
The stereoisomers 3 and 4 were readily separated by flash chromato-
graphy and were obtained in crystalline state. Their structures and relative
stereochemistry at C-50 in the bicyclo[3,3,0]octane moiety have been estab-
lished by single crystal x-ray analysis, as given in formulae 3 and 4. The
ORTEP diagrams of the x-ray structures are presented in Fig. 1.
Both isomers 3 and 4 were hydrolyzed separately under mild acid con-
ditions to the target amino acids 5 and 6. The latter, as well as the Pauson-
Khand spiranes 3 and 4, can also be regarded as functionalized building
blocks suitable for further chemical transformations.
In conclusion, we have shown that the Pauson-Khand reaction is com-
patible with the bislactim ether auxiliary (2R)-2,5-dihydro-3,6-dimethoxy-
2-isopropyl-5-pyrazine and can be used in stereoselective constructions of
bicyclic a-amino acid where the ring carbon of the amino acid is imbedded
in the pentalene ring system.

1144
WANG ET AL.
Figure 1. The ORTEP plot of the x-ray structure of compounds 3 and 4. Ellipsoids
are shown at 50% probability. For clarity only hydrogens at stereogenic centers are
shown. The absolute configurations at the stereogenic centers were established rela-
tive to the known chirality (2R) at (C3) (1).
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 at 300 MHz or 500 MHz
using a Bruker DPX 300 or DPX 500. 13C NMR spectra were recorded in
CDCl3 at 75 MHz or 125 MHz using the above instruments. Chemical shifts
are reported in ppm using residual CHCl3 (7.24 ppm) and CDCl3 (77 ppm)
as references. J values are given in Hz. Mass spectra were recorded under
electron impact conditions at 70 eV (EI) using a VG Prospect instrument.
The spectra are presented as m/z (% rel. int.). IR spectra were recorded on a
Perkin-Elmer 1310 infrared spectrophotometer or a Nicolet Magna FT-IR
550 spectrometer with Attenuated Total Reflectance (ATR spectra). Hexane
and dichloromethane were dried over a molecular sieve. Silica gel for flash
chromatography was Merck Kiselgel 60 (F254).
(2R,5S,50R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-
spiro(30-oxobicyclo[3,3,0]oct-10-en-70-yl) (3) and (2R,5S,50S)-2,5-
Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro
(30-oxobicyclo[3,3,0]oct-10-en-70-yl) (4)
A solution of (2R,5S)-5-allyl-2,5-dihydro-3,6-dimethoxy-2-isopropyl-
5-(2-propynyl)pyrazine (2)8 (578 mg, 2.21 mmol) in dry hexane (5 mL)
was added dropwise with stirring to a suspension of octacarbonyldicobalt
(840 mg, 2.21 mmol, 90–95%) in dry hexane (15 mL) under argon at ambient
temperature. The reaction mixture was evaporated to dryness at reduced

BICYCLIC RIGID a-AMINO ACIDS
1145
pressure after stirring for 1 h. Dichloromethane (15 mL) added to the
residual material followed by solid N-methylmorpholine N-oxide monohy-
drate (1.79 g, 13.26 mmol). The mixture was stirred at ambient temperature
for 0.5 h before the reaction was quenched by addition of 1 M phosphate
buffer (pH 7, 15 mL). The aqueous phase was extracted with diethyl ether
(3Â20 mL), the combined organic solution dried (MgSO4), evaporated at
reduced pressure, and the residual material subjected to flash chromato-
graphy using Et2O:hexane 1:1. The isomeric products 3 and 4 were obtained
as white solids in yields 179 mg (28%) and 181 mg (28%), respectively.
Compound 3
M.p. 58–59ꢀC. (Found: C, 66.10; H, 7.85. C16H22N2O3 requires C,
66.19; H, 7.64%). HRMS: M 290.1630. C16H22N2O3 requires 290.1630;
ꢀ
max(ATR)/cmÀ1 2964, 1713, 1690, 1634, 1237; ꢁH(500 MHz) 0.65 (3 H, d,
J 6.8, CH3), 1.02 (3 H, d, J 6.8, CH3), 1.78–1.90 (2 H, m, CH2), 2.08 (1 H,
dd, J 17.8, 3.6, CHH), 2.21 (ds, J 3.2, 6.8, 1 H, (CH3)2CH), 2.57–2.62 (m, 2 H,
2ÂCHH), 3.11–3.15 (1 H, m, CHH), 3.52–3.57 (1 H, m, CH), 3.59 (3 H, s,
OCH3), 3.62 (3 H, s, OCH3,), 3.96 (1 H, d, J 4, 0 H-2), 5.87 (1 H, t,
J 1.1, CH¼); ꢁC (125 MHz) 16.8 (CH3), 19.2 (CH3), 31.1 (Me2CH-), 42.1
(CH2), 43.1 (CH2), 44.7 (CH), 45.9 (CH2), 52.2 (OCH3), 52.5 (OCH3), 60.85
(C-2), 65.4 (C-5), 124.7 (CH¼), 161.3 (C), 163.65 (C), 188.24 (C¼), 210.4
(CO); m/z 290 (Mþ, 63), 259 (58), 247 (100), 219 (18), 217 (30), 195 (50),
196 (61), 154 (94).
Compound 4
M.p. 82–83ꢀC. (Found: C, 65.84; H 7.73. C16H22N2O3 requires C,
66.19; H, 7.64%). HRMS: M 290.1629. C16H22N2O3 requires 290.1630;
ꢀ
max(ATR)/cmÀ1 2960, 1712, 1690, 1635, 1234; ꢁH (500 MHz) 0.63 (3 H, d,
J 6.8, CH3), 1.03 (3 H, d, J 6.8, CH3), 1.46 (1 H, t, J 12.3, CHH), 2.08 (1 H,
dd, J 17.8, 3.3, CHH), 2.18 (1H, ds, J 6.8, 3.2, (Me2CH), 2.23 (1 H, J 12.7,
8.6, CHH), 2.56–2.61 (2 H, m, 2ÂCHH), 3.19 (1 H, d, J 12.7, CHH), 3.39–
3.45 (1 H, m, CH), 3.57 (3 H, s, OCH3), 3.68 (3 H, s, OCH3), 3.95 (1 H, d, J
4,0, H-2), 5.89 (1 H, s, CH¼); ꢁC (125 MHz) 16.8 (CH3), 19.3 (CH3), 31.0
(Me2CH-), 42.8 (CH2), 43.4 (CH2), 45.9 (CH), 47.3 (CH2), 52.35 (OCH3),
52.6 (OCH3), 61.0 (C-2), 64.7 (C-5), 125.1 (CH¼), 162.0 (C), 165.0 (C),
188.3 (C¼), 210.5 (CO); m/z 290 (Mþ, 49), 259 (68), 247 (88), 219 (17),
217 (33), 195 (64), 196 (85), 154 (100).

1146
WANG ET AL.
Methyl (3S,5R)-3-amino-7-oxobicyclo[3,3,0]oct-8(1)-ene-3-carboxylate
(5)
1 M HCl (8 mL) was added to a solution of (2R,5S,50R)-2,5-dihydro-
3,6-dimethoxy-2-isopropylpyrazine-5-spiro(30-oxobicyclo[3,3,0]oct-10-en-70-
yl) (3) (566 mg, 1.95 mmol) in dioxane (16 mL) and water (8 mL) at ambient
temperature. The mixture was stirred for 5 h, pH adjusted to 10 by addition
of conc. aq. ammonia, and the mixture extracted with dichloromethane
(3Â20 mL). The combined organic phases were dried (MgSO4), the solvent
distilled off at reduced pressure, and the residual material subjected to flash
chromatography using 3% methanol in dichloromethane; yield 195 mg (51%)
as a colorless oil. HRMS: M 195.0890. C10H13NO3 requies 195.0895;
ꢀ
max(film)/cmÀ1 3369(b), 2955, 1704, 1633, 1299, 1036; ꢁH (300 MHz)
1.61 (1 H, app.t, J 12.3, CHH), 1.77 (2 H, br.s, NH2), 1.87–2.12 (2 H, m,
2ÂCHH), 2.32–2.60 (2 H, m, 2ÂCHH), 3.11 (1 H, d, J 18.0, CHH), 3.40–
3.43 (1 H, m, CH), 3.65 (3 H, s, OCH3), 5.82 (1 H, s, CH¼); ꢁC (75 MHz)
40.5 (CH2), 41.9 (CH2), 43.8 (CH2), 44.5 (CH), 52.5 (OCH3), 65.7 (C-3),
125.4 (CH¼), 176.6 (CO), 187.21 (C¼), 209.7 (CO); m/z 195 (Mþ, 20), 178
(5), 136 (100), 119 (6), 108 (13), 102 (54), 94 (31), 91 (9).
Methyl (3S,5S)-3-amino-7-oxobicyclo[3,3,0]oct-8(1)-ene-3-carboxylate
(6)
Was prepared as above from (2R,5S,50S)-2,5-dihydro-3,6-dimethoxy-
2-isopropylpyrazine-5-spiro(30-oxobicyclo[3,3,0]oct-10-en-70-yl) (4) (785 mg,
2.71 mmol) and was isolated as an oily material after flash chromato-
graphy; yield 211 mg (40%). HRMS: Found:
M
195.0886.
C10H13NO3:requires 195.0895; ꢀmax(film)/cmÀ1 3371(b), 2955, 1703, 1630,
1260, 1043 cmÀ1; ꢁH (300 MHz) 1.17 (1 H, app.t. J 12.3, CHH), 1.79 (2
H, br.s, NH2), 1.94 (1 H, dd, J 12.0, 3.1, CHH), 2.34–2.63 (3 H, m,
3ÂCHH), 3.06–3.16 (2 H, m, CH and CHH), 3.61 (3 H, s, OCH3), 5.75 (1
H, br.s, CH¼); ꢁC (75 MHz) 41.4 (CH2), 42.2 (CH2), 44.6 (CH2), 45.0 (CH),
52.4 (OCH3), 65.3 (C-3), 125.2 (CH¼), 176.6 (CO), 186.2 (C¼), 209.4 (CO);
m/z195(Mþ,10%),178(4),136(100),119(3),108(23),102(51),94(39),91(15).
X-Ray CrystallographicAnalysis Data for Compounds 3 and 4
The crystal structures have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition numbers
CCDC 145874/CCDC 145875.

BICYCLIC RIGID a-AMINO ACIDS
1147
Data for Compound 3
C16H22N2O3 (290.36); orthorhombic; space group P212121: a¼8.642 (1),
b¼12.110(1), c¼14.897(1) A; V¼1559.05(6) A3, Z¼4; Dc¼1.237 Mg/m3;
F(000)¼624. Data were collected on a Siemens SMART CCD diffract-
ometer19 using graphite monochromated MoKa radiation (ꢂ¼0.71073 A,
m¼0.086 mmÀ1). Data collection method: o-scan, range 0.6ꢀ, crystal to
detector distance 5 cm, temperature 150(2) K. 21630 reflections were meas-
ured, of which 4736 were independent reflections with 2y in the range of
5.4ꢀ–61.2ꢀ, Rint¼0.058. The structure was determined and refined using the
SHELXTL program package.20 The non-hydrogen atoms were refined ani-
sotropically, hydrogen positions were calculated from geometrical criteria
and refined with isotropic thermal parameters. 278 parameter refined
against 4736 F2. Final R indices were R1¼0.054 for Io>2s(Io) and 0.065
for all data (residual ꢁr < 0.43 e.AÀ3).
Data for Compound 4
C16H22N2O3
(290.36);
orthorhombic;
space
group
P212121: a ¼ 8.894(1), b ¼ 11.369(1), c ¼ 15.058(1) A; V ¼ 1522.44(6) A3,
Z ¼ 4; Dc ¼ 1.267 Mg/m3; F(000) ¼ 624. Data collection as above. 24452
reflections were measured, of which 5781 were independent reflections
with 2y in the range of 5.3ꢀ–66.3ꢀ, Rint¼0.062. The structure was determined
and refined using the SHELXTL program package.13 The nonhydrogen
atoms were refined anisotropically, hydrogen positions were calculated
from geometrical criteria and refined with isotropic thermal parameters.
278 parameter refined against 5781 F2. Final R indices were R1¼0.042 for
Io>2r(Io) and 0.053 for all data (residual ꢁr<0.35 e.AÀ3).
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Received April 17, 2000