Stereocontrolled construction of rigid tricyclic bis(α-amino acid) derivatives by RU(II)-catalyzed cascade and Diels-Alder reactions

Article abstract of DOI:10.1039/b103254m

In the preparation of rigid and annulated tricyclic bis(α-amino acid) derivatives the key construction was effected by a Ru(II)-catalyzed RCM cascade reaction of gem-dienynes. The substrates were available by stepwise and stereocontrolled alkynylations an

Full text of DOI:10.1039/b103254m

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Stereocontrolled construction of rigid tricyclic bis(ꢀ-amino acid)
derivatives by Ru(II)-catalyzed cascade and Diels–Alder reactions
Jon Efskind, Christian Römming and Kjell Undheim*
1
Department of Chemistry, University of Oslo, N-0315, Oslo, Norway
Received (in Cambridge, UK) 18th April 2001, Accepted 7th August 2001
First published as an Advance Article on the web 19th September 2001
In the preparation of rigid and annulated tricyclic bis(α-amino acid) derivatives the key construction was effected
by a Ru()-catalyzed RCM cascade reaction of gem-dienynes. The substrates were available by stepwise and
stereocontrolled alkynylations and alkenylations of (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine. The
cascade products were bis-heterospiranes or symmetrical or unsymmetrical bis(α-amino acid) derivatives. Tricyclic
Diels–Alder adducts were formed between diethyl acetylenedicarboxylate and the diene cascade products. Oxidative
aromatization provided rigid tricyclic bis(α-amino acid) derivatives. X-Ray analysis was used to verify configurational
assignments.
bridges in which the distance between the α-amino acid centers
can be varied by the ring sizes in the tricyclic bridge. Both sym-
metrical and unsymmetrical structures have been prepared. A
key step in our constructions is effected by Ru()-catalyzed
Introduction
Cystine is an important four-atom bridged bis(α-amino acid).
We have for some time been involved in the construction of
C4-bridged analogues where the disulfide moiety has been
ring-closing metathesis (RCM) cascade reactions of dienyne
replaced with a C2-unit.1,2 Conformational constraints may be
substrates (see Scheme 2 and 3) using Grubbs bis(tricyclohexyl-
introduced by a double or triple bond in the all-carbon
phosphine)benzylidene ruthenium dichloride as a catalyst.10,11
bridge,1,2 or by insertion of aryl or heteroaryl groups into the
The scope of the original methodology has been further
chain.3 C3-bridged bis(α-amino acids) have received wide atten-
extended by recent modifications of the precatalyst ligand
tion because of antimicrobial activity associated with some
system.12–15
members of this group.4 Simple C2-ethylene bridged as well as
constrained C2-bridged bis(α-amino acid) have been described.5
Bis(α-amino acids) with longer bridges have been constrained
Results and discussion
by insertion of more than one triple bond,6 by a heterocyclic
ring,3,7 or by ferrocene.8 The conformational constraints in
C4-bridged molecules have been additionally increased by
carbosubstitution at the α-carbon of the amino acid.9
Preparation of intermediate substrates for the RCM reaction,
viz. the C5-alkyne bridged bis(α-amino acid) derivative 4 and its
precursor 3 is shown in Scheme 1. The unsymmetrical alkyl-
ating reagent 1,5-dibromopent-2-yne 9 was prepared from
but-3-yn-1-ol by TBDMS-O-protection followed by lithiation
In this report we describe methodology which leads to highly
rigid bis(α-amino acid) structures in the form of tricyclic
Scheme 1 Reagents and conditions: (i) nBuLi, THF, Ϫ78 ЊC for 3 h and rt for 14 h; (ii) 0.1 M aq TFA–MeCN, rt, 4d; (iii) DMAP, CH2Cl2, rt, 5 h;
(iv) nBuLi, THF, Ϫ45 ЊC, (CH2O)n, rt, 1 h; (v) TBAF, THF, rt, 3 h; (vi) Br2, PPh3, MeCN, 0 ЊC rt, 1 h.
DOI: 10.1039/b103254m
J. Chem. Soc., Perkin Trans. 1, 2001, 2697–2703
This journal is © The Royal Society of Chemistry 2001
2697

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Scheme 2 Reagents and conditions: (i) Ph-CH᎐RuCl2(PCy3)2 2 × 5 mol%, toluene 85 ЊC, 2 × 5 h; (ii) PhCH᎐RuCl2(IMes)(PCy3) 3 × 10 mol%,
᎐
᎐
toluene, 85 ЊC, 3 × 3 h.
Fig. 1 The ORTEP plot of compound 10. Ellipsoids are shown at 50%
probability. For clarity only the hydrogens at stereogenic centers and at
the diene are shown. The double bonds of the diene are drawn in black.
The cascade reaction of the pentyne-bridged substrate 3
proceeded almost quantitatively with the standard Grubbs
Ru()-catalyst. After 5 hours at 85 ЊC about 60% conversion
was observed with 5 mol% catalyst. The same amount of
catalyst was added once more and the heating continued at this
temperature for another 5 hours when close to quantitative
yield of cascade product 10 was obtained (Scheme 2). Below
65 ЊC there was hardly any reaction. Low thermal stability
of the catalyst becomes an important problem in slow reac-
tions.15,20 Therefore the catalyst was added in two portions.
The product was a crystalline material. To verify the regio-
chemistry as well as the stereochemistry in the transformations
described, a single crystal X-ray analysis was carried out. The
ORTEP plot of the X-ray structure in Fig. 1 shows the product
to have the structure 10. The compound crystallizes with two
molecules in the asymmetric unit; the molecules are equal
within the accuracy of the determination, all bond lengths and
angles are as expected. The configuration of the molecule could
not be determined by the Flack parameter (0.5(5)) but is settled
by the known chirality at the positions of the isopropyl groups
(C3 and C21).
When the length of the bridge was reduced to a C4-chain as
in the analogue structure 12, the RCM reaction with the stand-
ard Grubbs catalyst failed.21 With new variations of the catalyst
system becoming available, this study was repeated in more
detail in the present work. Substrate 12 was prepared by
analogy to the above alkylations from the C4-alkyne 11.21 With
5% Ru()-catalyst below 60 ЊC no conversion of substrate 12
was seen. At 85 ЊC some 15–20% yield of the cascade product
13 could be obtained. Besides thermolytic reactions, the
catalytic activity may also reduce because the catalyst may
be consumed in formation of complexes with components in
the reaction medium.22 To elucidate any such problem simple
NMR studies were performed with the substrate 12 using 0.8
equivalents of the catalyst. There was no reaction at ambient
temperature and hardly any at 50 ЊC. Slow transformations
were seen at 85 ЊC but no complex formation between the
catalyst and the substrate was detected and hence this cannot
explain why the reaction did not proceed. We therefore applied
Scheme 3 Reagents and conditions: (i) PhCH᎐RuCl2(PCy3)2 2 × 8
᎐
mol%, toluene, 90 ЊC, 2 × 5 h.
and hydroxymethylation to furnish the propargyl alcohol
(prop-2-ynyl alcohol) 7. Tetrabutylammonium fluoride (TBAF)
was used to remove the silyl protecting group with formation
of the diol 8. The reactions proceeded well and this method
competes favourably with alternative preparations of the
diol.16,17 Br2ؒPPh3 was used for the conversion of the diol to
the dibromide 9 whereas previous workers have used PPh3 and
CBr4.16
For the preparation of the C5-alkyne bridged precursor for
the tricyclic bis(amino acid) derivatives the Schöllkopf method-
ology was used.18 The bislactim ether 1 was lithiated and
alkynylated with 1,5-dibromopent-2-yne to yield the unsym-
metrically bridged structure 2 in 73% yield. A minor product
was due to monoalkylation and a subsequent HBr elimination
in preference to a second alkylation. The product was identified
by NMR and was not further characterized. Lithiation and
alkylation with allyl bromide provided the dienyne 3 in 62%
yield after two alkylation steps. The reaction is stereoselective in
that the electrophile becomes attached trans to the isopropyl
group. The degree of stereoselectivity in the first alkylation pro-
viding intermediate 2, however, is not important because the
stereochemical information is lost when this product becomes
the substrate for a second lithiation and alkenylation reaction.
Only one stereoisomer was observed in the second alkenylation
reaction in accordance with previous experience in the stepwise
dialkylation of the bislactim ether substrate 1.19 It is thus
assumed that the new electrophile has entered trans to the iso-
propyl group in the metallated species of the bridged substrate
2 thereby providing the stereoisomer 3. Mild acid hydrolysis
with 0.1 M TFA, and protection of the amino group by
acetylation, gave the products 4 and 5 in 98 and 65% yield,
respectively.
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Scheme 4 Reagents and conditions: (i) anisole 145 ЊC, 14 h; (ii) dioxane, rt, 14 h; (ii) dioxane, rt, 14 h; (iii) dioxane, 100 ЊC, 5 h.
a slightly modified Grubbs catalyst with improved activity and
thermal stability.15 The catalyst was prepared from the Grubbs
benzylidene complex by replacement of one of the phosphine
ligands with the more nucleophilic 1,3-bis(2,4,6-trimethyl-
phenyl)imidazol-2-ylidene (IMes) ligand. The catalyst complex
diethyl acetylenedicarboxylate was used in the Diels–Alder
reactions. The reactions were run in anisole at 145 ЊC. From the
RCM products 10 and 13 (Scheme 2) containing the bulky bis-
lactim ether unit, no Diels–Alder adduct could be isolated. The
failure is attributed to the crowding in these substrates. In the
bis(amino acid) substrates 14–16, however, Diels–Alder reac-
tions proceeded satisfactorily (Scheme 4). In the bis(cyclo-
pentenyl)diene substrate 15 a mixture of the cycohexadiene
adduct 17 and its aromatized benzene analogue 18 was
obtained in a total yield of 63%. The products were difficult to
separate. The product mixture was therefore treated directly
with manganese dioxide for the conversion to the benzo deriv-
ative 18. The Diels–Alder product 19 from the bis(cyclohexene)
substrate 16 was obtained in 64% yield. The adduct 19 was
aromatized in almost quantitative yield to the benzo derivative
20 when reacted with manganese dioxide. The cyclopentenyl-
cyclohexenyl diene 14 with acetylene dicarboxylate also gave a
cyclohexadiene adduct 21 and its aromatized analogue 22 as a
mixture, about 1 : 1 in 68% overall yield. The mixture was fully
aromatized as above by the use of manganese dioxide. The
aromatizations could also be effected with DDQ.
In conclusion, we have described a methodology for the
preparation of rigid and enantiomerically pure tricyclic bis-
(α-amino acid) derivatives. The reaction sequence was initiated
by stereoselective alkynylations and alkenylations of (2R)-2,5-
dihydro-2-isopropyl-3,6-dimethoxypyrazine to provide dienyne
substrates for Ru()-catalyzed cascade RCM reactions. The
cascade products were substrates for Diels–Alder reactions in
the preparation of the tricyclic α-amino acids. Novel acyclic
and bicyclic α-amino acids were prepared which can be
formed was (PCy )(IMes)Cl Ru᎐CHPh. With this new catalyst
᎐
3
2
the cascade reaction could be effected at 85 ЊC in toluene.
The reaction was incomplete after 3 h with 10 mol% catalyst.
Addition of 10 mol% catalyst twice and heating for another two
3 hour periods furnished the cascade product 13 in very high
yield (92%).
The steric interactions in the bislactim substrates 3 and 12
are significantly reduced in the corresponding N-protected
bis(α-amino acid derivatives) such as the substrate 5 in Scheme
3. The cascade reaction in the latter case proceeded readily with
almost quantitative formation (in >95%) of the bicyclic product
14. Even with C4-yne bridged analogues of substrate 5 the
cascade reaction proceeded satisfactorily to furnish substrates
15 and 16 for the Diels–Alder in Scheme 4 in ca. 85% yield.21
The crude cascade products were slightly coloured due to
ruthenium and phosphine impurities. Addition of lead tetra-
acetate for oxidation,23 or tris(hydroxymethyl)phosphine for
providing water soluble ruthenium complexes, has been
recommended for removal of these impurities.24 We have used
the latter technique successfully.
With the cascade products in hand the conformational free-
dom due to the single carbon–carbon bond in the butadiene
moiety was to be prevented by the introduction of a third ring.
Thus the dienes were subjected to Diels–Alder reactions. For
simplicity the symmetrical and highly reactive dienophile
J. Chem. Soc., Perkin Trans. 1, 2001, 2697–2703
2699

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regarded as target amino acid molecules, or versatile inter-
mediates for the preparation of rigid tricyclic bis(α-amino acid)
derivatives.
CDCl3) 14.6 (CH2-CH2-CC), 16.5 (CHMe2), 16.7 (CHMe2),
19.05 (CHMe2), 19.1 (CHMe2), 25.5 (CH2), 31.5–31.8
(2 × CHMe2), 33.9 (2 × CH2 CH2-CC), 52.3 (OMe), 52.4
(2 × OMe), 52.5 (OMe), 54.2–54.8 (C-5 and C-5Ј), 60.8 (C-2
and C-2Ј), 76.1 (CC), 81.7 (CC), 162.1, 163.5, 164.6 (C-3, C-3Ј,
C-6 and C-6Ј); m/z (EI): 432 (Mϩ, 6%), 417 (5), 390 (24), 389
(100), 388, (5), 250 (24), 249 (57), 207 (11), 183 (20), 141 (81),
140 (10).
Experimental
1H NMR spectra were recorded in CDCl3 at 500, 300 or
200 MHz with Bruker DPX 500, DPX 300 or DPX 200
spectrometers. The 13C spectra were recorded in CDCl3 at 75 or
50 MHz. Chemical shifts are reported in ppm with residual
CHCl3 (7.24 ppm) and CDCl3 (77 ppm) as references. J values
are given in Hz. Mass spectra under electron-impact conditions
(EI) were recorded at 70 eV ionizing potential. The spectra are
presented as m/z (% rel. int.). IR spectra were measured on a
Nicolet Magna 550 spectrometer using ATR (attenuated total
reflectance). Optical rotations at 22 ЊC are given in 10Ϫ1 deg cm2
1-[(2R,5R)-5-Allyl-2,5-dihydro-2-isopropyl-3,6-dimethoxy-
pyrazin-5-yl]-5-[(2R,5S)-5-allyl-2,5-dihydro-2-isopropyl-3,6-
dimethoxypyrazin-5-yl]pent-2-yne 3
A
solution of 1,5-bis[(2R,5S)-2,5-dihydro-2-isopropyl-3,6-
dimethoxypyrazin-5-yl]pent-2-yne 2 (1.347 g, 3.12 mmol) in
anhydrous THF (16 ml) at Ϫ78 ЊC was lithiated by addition of
a solution of nBuLi in hexane (4.33 ml, 1.51 M, 6.55 mmol).
The solution was stirred at Ϫ78 ЊC for 1 h before a precooled
(Ϫ78 ЊC) solution of allyl bromide (0.792 g, 6.55 mmol) in THF
(8 ml) was added through a teflon tube. The reaction mixture
was stirred at Ϫ78 ЊC for 3 h, allowed to reach ambient tem-
perature overnight and quenched by addition of phosphate
buffer (pH 7) and water. The aqueous phase was extracted with
Et2O, the combined organic extracts dried (MgSO4), the solvent
removed in vacuo and the product isolated as a slightly yellow
oil after flash chromatography on silica gel using EtOAc–
hexane 7 : 93 with yield 0.989 g (62%); HRMS (electrospray):
M 512.3349. C29H44N4O4 requires 512.3362; νmax(film)/cmϪ1
2959 (m), 2870 (w), 1693 (s), 1436 (m), 1307 (m), 1239 (s), 1197
(m), 1143 (m), 1002 (m); δH(300 MHz, CDCl3) 0.58 (3 H, d,
J 6.8, CHMe2), 0.68 (3 H, d, J 6.8, CHMe2), 1.04 (3 H, d, J 6.8,
CHMe2), 1.07 (3 H, d, J 6.8, CHMe2), 1.69–2.05 (4 H, m,
4 × CHH), 2.14–2.47 (7 H, 5 × CHH, 2 × CHMe2), 2.63 (1 H,
m, CHH), 2.75 (1 H, m, CHH), 3.61 (3 H, s, OMe), 3.62 (3 H, s,
OMe), 3.66 (3 H, s, OMe), 3.67 (3 H, s, OMe), 3.78 (1 H, d,
J 3.2, H-2 or H-2Ј), 3.81 (1 H, d, J 3.2, H-2 or H-2Ј), 4.88–
5.02 (4 H, m, 2 × CH᎐CH ), 5.37–5.63 (2 H, m, 2 × CH᎐CH );
g
Ϫ1. Dry THF was distilled from sodium and benzophenone
under argon. Solvents were degassed by bubbling argon
through. Bis(tricyclohexylphosphine)benzylidene ruthenium
dichloride was purchased from Strem Chemicals Inc., 7
Mulliken Way, Newburyport, MA.
X-Ray crystallographic analysis data for compound 10†
X-Ray data were collected on a Siemens SMART CCD dif-
fractometer25 using graphite monochromated Mo-Kα radiation
(λ = 0.71073 Å). Data collection method: ω-scan, range 0.6Њ,
crystal to detector distance 5 cm. Data reduction and cell
determination were carried out with the SAINT and XPREP
programs.25 Absorption corrections were applied by the use of
the SADABS program.26 The structure was determined and
refined using the SHELXTL program package.27 The non-
hydrogen atoms were refined with anisotropic thermal param-
eters; hydrogen atoms were located from difference Fourier
maps and refined with isotropic thermal parameters.
Crystal data for C27H40N4O4 (10), M = 484.63, monoclinic,
P21, a = 15.094(1), b = 10.184(1), c = 17.828(1) Å, β = 96.19(1)Њ,
᎐
᎐
2
2
V = 2724.4(3) Å3, Z = 4, Dx = 1.182 Mg mϪ3, µ = 0.080 mmϪ1
,
δC(75 MHz, CDCl3) 14.7 (CH2CH2-CC), 16.8, 17.0, 19.5, 19.6
(2 × CHMe2), 30.4 (CHMe2), 30.6 (CHMe2), 30.9 (CH2), 39.1
(CH2), 44.6 (CH2), 45.0 (CH2), 52.1 (OMe), 52.3 (OMe), 52.3
(OMe), 52.4 (OMe), 60.6 (C-5 or C-5Ј), 60.8 (C-5 or C-5Ј), 61.5
(C-2 or C-2Ј), 61.8 (C-2 or C-2Ј), 76.5 (CC), 82.0 (CC), 118.3
(CH ᎐CH), 118.5 (CH ᎐CH), 133.1 (CH ᎐CH), 133.2 (CH ᎐
T = 150(2) K, measured 51259 reflections in 2θ range 11.8–
61.0Њ, Rint = 0.040. 951 parameters refined against 16207 F 2,
R = 0.042 for Io > 2σ(Io) and 0.065 for all data.
1,5-Bis[(2R,5S)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazin-
5-yl]pent-2-yne 2
᎐
᎐
᎐
᎐
2
2
2
2
CH), 162.7 (C-3 or C-3Ј or C-6 or C-6Ј), 163.0 (C-3 or C-3Ј or
C-6 or C-6Ј), 163.1 (C-3 or C-3Ј or C-6 or C-6Ј), 163.2 (C-3 or
C-3Ј or C-6 or C-6Ј); m/z (EI): 512 (Mϩ, 1%), 479 (15), 477 (11),
472 (30), 471 (100), 470 (17), 469 (54), 387 (12), 289 (29), 223
(29), 218 (14), 191 (17), 183 (13), 182 (11), 181 (84), 153 (14),
91 (15).
A
solution of (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxy-
pyrazine 1 (0.213 g, 1.06 mmol) in anhydrous THF (3 ml) at
Ϫ78 ЊC was lithiated by the addition of a solution of nBuLi in
hexane (0.69 ml, 1.53 M, 1.06 mmol). The solution was stirred
at Ϫ78 ЊC for 0.5 h before a solution of 1,5-dibromopent-2-yne
9 (0.14 g, 0.51 mmol) in THF (10 ml) was added through a
teflon tube. The reaction mixture was stirred at Ϫ78 ЊC for 3 h,
allowed to reach ambient temperature overnight and the reac-
tion was quenched by addition of phosphate buffer (pH 7) and
water. The aqueous phase was extracted with dichloromethane,
the combined organic extracts dried (MgSO4), the solvent
removed in vacuo and the product isolated after flash chrom-
atography on silica gel using EtOAc–hexane 20 : 80. The prod-
uct 0.168 g (73%) was an oil. HRMS: M 432.2744. C23H36N4O4
requires 432.2737; νmax(film)/cmϪ1 2959 (m), 2871 (w), 1697 (s),
1436 (m), 1238 (s), 1196 (m), 1017 (m); δH(300 MHz, CDCl3)
0.60 (3 H, d, J 6.8, CHMe2), 0.61 (3 H, d, J 6.8, CHMe2), 0.96
(3 H, d, J 6.8, CHMe2), 0.98 (3 H, d, J 6.8, CHMe2), 1.56–1.68
(1 H, m, CHH), 1.88–2.28 (5 H, m, 3 × CHH and 2 × CHMe2),
2.51–2.69 (2 H, m, 2 × CHH), 3.58–3.61 and 3.62–3.63 (12 H, s,
4 × OMe), 3.82–3.86 (1 H, m, H-2 or H-2Ј), 3.89–3.95 (2 H, m,
H-5 and H-5Ј), 3.98–4.02 (1 H, m, H-2 or H-2Ј); δC(75 MHz,
Dimethyl (2R,8S)-2,8-diallyl-2,8-diaminonon-4-yne-1,9-dioate 4
A solution of 1-[(2R,5R)-5-allyl-2,5-dihydro-2-isopropyl-3,6-
dimethoxypyrazin-5-yl]-5-[(2R,5S)-5-allyl-2,5-dihydro-2-iso-
propyl-3,6-dimethoxypyrazin-5-yl]pent-2-yne 3 (0.989 g, 1.93
mmol) in MeCN (96 ml) and aqueous TFA (96 ml, 0.2 M) was
stirred at ambient temperature for 4 d. The pH was adjusted
to 10 by addition of aqueous conc. ammonia, the mixture
extracted with dichloromethane, the combined organic extracts
dried (MgSO4), evaporated and the valine methyl ester removed
by distillation under high vacuum at ambient temperature. The
residual material was subjected to flash chromatography using
MeOH–CH2Cl2 5 : 95. The product 0.387 g (98%) was an oil.
HRMS: M 322.1894. C17H26N2O4 requires 322.1893; νmax(film)/
cmϪ1 3378 (w), 3321 (w), 2953 (m), 2926 (m), 1735 (s), 1672
(m), 1640 (m), 1437 (m), 1217 (s); δH(CDCl3) 1.52–2.18 (4 H,
m, 4 × CHH), 1.66 (4 H, s, 2 × NH2), 1.82–2.59 (6 H, m,
6 × CHH), 3.63 (3 H, s, OMe), 3.65 (3 H, s, OMe), 5.01–5.08
(4 H, m, 2 × CH᎐CH ), 5.47–5.71 (2 H, m, 2 × CH᎐CH );
δC(CDCl3) 13.8 (CH2), 29.9 (CH2), 38.6 (CH2), 43.4 (CH2), 44.2
(CH2), 52.1 (OMe), 52.2 (OMe), 60.3 (MeO-(CO)-C-NH2), 60.5
᎐
᎐
2
2
† CCDC reference number(s) 162724. See http://www.rsc.org/suppdata/
p1/b1/b103254m/ for crystallographic files in .cif or other electronic
format.
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(MeO-(CO)-C-NH ), 75.3 (CC), 82.6 (CC), 119.4 (CH ᎐CH),
CH2CH2O-Si), 4.21–4.24 (2 H, m, CCCH2O-H); δC(CDCl3)
᎐
2
2
119.6 (CH ᎐CH), 132.2 (2 × CH ᎐CH), 175.7 (CO-OMe),
Ϫ5.3 (2 × SiCH3), 18.3 (CMe3), 23.1 (CH2CCH), 25.8
(CMe3), 51.2 (CH2OH), 61.8 (CH2OSi), 79.5 (CCCH2OH),
83.2 (CCCH2OH).
᎐
᎐
2
2
176.4 (CO-OMe); m/z (EI): 322 (Mϩ, 0.6%), 282 (16), 281 (100),
264 (15), 249 (11), 221 (11), 195 (13), 194 (20), 189 (24), 138
(11), 134 (11), 128 (10), 120 (37).
Pent-2-yne-1,5-diol 8
Dimethyl (2R,8S)-2,8-diallyl-2,8-diacetamidonon-4-yne-1,9-
TBAF in THF (1.7 ml, 1.0 M, 1.70 mmol) was added to a
solution of the 5-(tert-butyldimethylsilyloxy)pent-2-yn-1-ol 7
(0.282 g, 1.31 mmol) in THF (8.5 ml) at 0 ЊC. The mixture was
stirred at 0 ЊC for 30 min, at ambient temperature for 3 h, and
the solvent was removed by distillation and the product isolated
after flash-chromatography using MeOH–CH2Cl2 1 : 10. The
product 0.106 g (81%) was a liquid. νmax(film)/cmϪ1 3332 (s),
2884 (m), 1423 (m), 1135 (m), 1034 (s), 1012 (s); δH(CDCl3) 1.65
(1 H, s, CH2OH), 2.16 (1 H, s CH2OH), 2.47 (2 H, tt, J 2.2, 6.1,
HOCH2CH2), 3.71 (1 H, t, J 6.1, HOCH2CH2), 4.24 (1 H, s,
CCH2OH); δC(CDCl3) 23.0 (HOCH2CH2), 50.9 (HOCH2CH2),
60.8 (HOCH2C), 80.2 (CC), 83.1 (CC); m/z (EI): 82 (Mϩ Ϫ 18,
30), 70 (10), 69 (9), 53 (20), 52 (100), 51 (13)(lit.16,17).
dioate 5
A solution of acetic acid anhydride (0.164 g, 1.61 mmol) in
dichloromethane (6 ml) was added dropwise to a solution of
dimethyl (2R,8S)-2,8-diallyl-2,8-diaminonon-4-yne-1,9-dioate
4 (0.140 g, 0.669 mmol) and DMAP (0.204 g, 1.67 mmol) in
dichloromethane (12 ml) at 0 ЊC and the solution stirred
at ambient temperature for 5 h. The reaction was stopped by
addition of saturated aqueous ammonium chloride, the mixture
extracted with dichloromethane and the combined organic
extracts dried (MgSO4), the solvent removed in vacuo and the
product purified by flash chromatography using MeOH–
CH2Cl2 5 : 95 to furnish a viscous oil, 176 mg (65%): HRMS:
M 406.2105. C21H30N2O6 requires 406.2104; νmax(film)/cmϪ1
3281 (m), 3075 (m), 2952 (m), 2926 (m), 1740 (s), 1653 (s),
1540 (m), 1436 (m), 1221 (m); δH(CDCl3) 1.83–2.11 (3 H, m,
3 × CHH), 1.96 (3 H, s, COMe), 1.98 (3 H, s, COMe), 2.42 (2 H,
dt, J 7.3, 14.6, CH2), 2.51–2.61 (1 H, m, CHH), 2.67 (1 H, d,
J 16.7, CHH), 2.95 (1 H, dd, J 7.3, 16.7, CHH), 3.05–3.17 (2 H,
m, 2 × CHH), 3.71 (6 H, s, 2 × OMe), 4.97–5.06 (4 H, m,
1,5-Dibromopent-2-yne 9
The reagent Br2PPh3 was prepared by the addition of Br2 (3.98
g, 1.28 ml, 24.90 mmol) to a solution of PPh3 (6.52 g, 24.90
mmol) in MeCN (53 ml) at 0 ЊC. Subsequently a solution of
pent-2-yne-1,5-diol 8 (1.132 g, 11.32 mmol) in MeCN (10 ml)
was added. The mixture was stirred at 0 ЊC for 15 min, at ambi-
ent temperature for 1 h, and the solvent was distilled off and the
residual material triturated with diethyl ether. The undissolved
and precipitated phosphine oxide was removed by filtration, the
filtrate evaporated and the residual material subjected to flash
chromatography using EtOAc–hexane; 1 : 10. The product was
isolated as an oil, yield 1.892 g (74%). HRMS: M 225.8826.
C5H10Br2 requires 225.8816; νmax(film)/cmϪ1 3002 (w), 2969 (w),
2237 (w), 1417 (w), 1271 (m), 1211 (m); δH(CDCl3) 2.80 (2 H, tt,
J 2.2, 7.2, CH2CH2Br), 3.40 (2 H, t, J 7.2, BrCH2CH2), 3.89
(2 H, t, J 2.2, BrCH2CC); δC(CDCl3) 14.8 (BrCH2CH2), 23.3
(BrCH2CH2), 29.0 (BrCH2C), 77.3 (CC), 84.2 (CC); m/z (EI):
228 (Mϩ, 10%), 226 (Mϩ, 17), 224 (Mϩ, 9), 147 (58), 145 (56), 81
(10), 79 (12), 66 (53), 65 (100), 63 (23), 62 (15) (lit.16).
2 × CH᎐CH ), 5.43–5.61 (2 H, m, 2 × CH᎐CH ), 6.32 (1 H, s,
NH), 6.37 (1 H, s, NH); δ (CDCl ) 13.9 (CH CH -CH᎐CH ),
23.6 (MeCO-), 23.9 (MeCO-), 25.3 (CH CH -CH᎐CH ), 33.6
(CH2), 38.9 (CH2), 39.2 (CH2), 52.7 (OMe), 52.7 (OMe), 62.8
(MeO-(CO)-C-NH), 63.8 (MeO-(CO)-C-NH), 75.4 (CC), 81.3
(CC), 119.0 (CH ᎐CH), 119.3 (CH ᎐CH), 131.6, (CH ᎐CH),
᎐
᎐
2
2
᎐
C
3
2
2
2
᎐
2
2
2
᎐
᎐
᎐
2
2
2
131.9 (CH ᎐CH), 169.2 (CONHR), 169.5 (-CONHR), 172.4
᎐
2
(CO2Me), 173.5 (CO2Me); m/z (CI): 406 (Mϩ, 6%), 366 (21),
365 (100), 361 (28), 347 (27), 323 (41), 305 (24), 283 (45), 281
(35), 263 (21), 237 (38), 236 (21), 221 (21), 204 (24), 194 (23),
171 (24), 128 (57), 91 (47).
1-(tert-Butyldimethylsilyloxy)but-3-yne 6
TBDSM-Cl (1.40 g, 9.32 mmol) was added to a solution of
triethylamine (1.03 g, 1.40 ml, 10.17 mmol), DMAP (0.103 g,
0.849 mmol) and but-3-yn-1-ol (0.594 g, 8.49 mmol) in
dichloromethane (27 ml). The mixture was stirred under argon
at ambient temperature for 3 h, diluted by addition of diethyl
ether, extracted with aq NH4Cl, and the organic solution was
dried (MgSO4), the solvent distilled off and the product isolated
after flash chromatography using EtOAc–hexane 1 : 10. The
product 1.470 g (93%) was a liquid. δH(CDCl3) 0.05 (6 H, s,
2 × SiCH3), 0.87 (9 H, s, 3 × CCH3), 1.93 (1 H, t, J 2.7, CCH),
2.38 (2 H, dt, J 2.7, 7.1, CH2CH2O-), 3.72 (2 H, t, J 7.1,
CH2CH2O-); δC(CDCl3) Ϫ5.3 (2 × SiCH3), 18.3 (CMe3), 22.8
(CH2CCH), 25.9 (CMe3), 61.7 (CH2O), 69.3 (CCH), 81.5
(CCH).
(2S,5R)-2,5-Dihydro-5-isopropyl-3,6-dimethoxy-4Ј-[(2R,5R)-
2,5-dihydro-5-isopropyl-3,6-dimethoxypyrazine-2-spiro-
(cyclopent-3Ј-en-3Ј-yl)]pyrazine-2-spiro(cyclohex-3Ј-ene) 10
Bis(tricyclohexylphosphine)benzylidene ruthenium dichloride
(50 mg, 0.0608 mmol) was added to a solution of 1-[(2R,5R)-
5-allyl-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazin-5-yl]-5-
[(2R,5S)-5-allyl-2,5-dihydro-2-isopropyl-3,6-dimethoxy-
pyrazin-5-yl]pent-2-yne 3 (0.623 g, 1.22 mmol) in dry degassed
toluene (50 ml) under argon. The reaction mixture was kept at
85 ЊC for 5 h when another portion of the catalyst (50 mg,
0.0603 mmol) was added and the heating continued for 5 h.
The cold mixture was filtered, the filtrate evaporated and dry
dichloromethane added. Any remaining catalyst was com-
plexed by addition of tri(hydroxymethyl)phosphine (50 mg,
0.304 mmol) and triethylamine (84 µl) and the product isolated
after flash chromatography using EtOAc–hexane 10 : 90. The
product 0.567 g (96%) was a white solid with mp 138 ЊC
(MeCN). HRMS: M 484.3033. C27H40N4O4 requires 484.3050
(Found: C, 66.92; H, 8.78. C27H40N4O4 requires: C, 66.91; H,
8.32%); νmax(ATR plate)/cmϪ1 2957 (m), 2944 (m), 2871 (w),
1690 (s), 1462 (m), 1436 (m), 1300 (m), 1232 (s), 1032 (m);
δH(300 MHz, CDCl3) 0.67 (3 H, d, J 6.9, CHMe2), 0.69 (3 H,
d, J 6.9, CHMe2), 1.05 (3 H, d, J 6.9, CHMe2), 1.07 (3 H, d,
J 6.9, CHMe2), 1.49–1.55 (1 H, m, CHH-CH2), 1.88 (1 H, dd,
5-(tert-Butyldimethylsilyloxy)pent-2-yn-1-ol 7
nBuLi in a hexane (20.30 ml, 1.50 M, 30.46 mmol) was added
dropwise to a solution of 1-(tert-butyldimethylsilyloxy)but-3-
yne 6 (5.63 g, 30.46 mmol) in THF (60 ml) at Ϫ40 ЊC and the
mixture stirred at this temperature for 15 min before the solu-
tion was transferred through a teflon tube to a suspension of
paraformaldehyde (2.92 g, 91.38 mmol) in THF (30 ml) at
Ϫ45 ЊC. The reaction mixture was stirred at ambient temper-
ature for 1 h, diethyl ether added, the organic phase washed
with brine, dried (MgSO4) and the solvent distilled off. The
product was isolated after flash chromatography using EtOAc–
hexane; 20 : 80 as an oil, yield 5.82 g (89%). δH(CDCl3) 0.05
(6 H, s, 2 × SiCH3), 0.88 (9 H, s, 3 × CCH3), 1.99 (1 H, t, J 3.8,
CH2OH), 2.44 (2 H, tt, J 1.4, 4.8, H2CH2O-), 3.73 (2 H, t, J 4.8,
J 4.1, 18.3, CHH-CH᎐C), 2.07 (1 H, dt, J 5.4, 12.4, CHH),
᎐
2.17–2.30 (3 H, m, CHH and 2 × CHMe2), 2.46–2.56 (3 H, m,
3 × CHH-CH᎐C), 2.72–2.79 (1 H, m, CHH-CH᎐C), 2.94–3.13
᎐
᎐
(2 H, m, 2 × CHH-CH᎐C), 3.58 (3 H, s, OMe), 3.62 (3 H, s,
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 2697–2703
2701

View Article Online
OMe), 3.64 (3 H, s, OMe), 3.68 (3 H, s, OMe), 3.93 (1 H, d,
J 3.4, H-2 or H-2Ј), 3.98 (1 H, d, J 3.4, H-2 or H-2Ј), 5.43–
319 (13), 261 (15), 260 (100), 245 (7), 213 (7), 201 (11), 200 (15),
169 (9), 141 (8).
5.51 (1 H, m, CH᎐C cyclopent.), 5.57–5.64 (1 H, m, CH᎐C
᎐
᎐
cyclohex); δC(75 MHz, CDCl3) 16.9 (CHMe2), 16.95 (CHMe2),
19.3 (CHMe2), 19.4 (CHMe2), 22.1 (CH2), 30.9 (CHMe2), 31.3
(CHMe2), 33.1 (CH2), 37.3 (CH2), 48.8 (CH2), 49.4 (CH2), 52.2
(OMe), 52.3 (OMe), 52.4 (OMe), 52.5 (OMe), 55.8 (C-2 or
C-2Ј), 60.6 (C-2 or C-2Ј), 61.1 (C-5 or C-5Ј), 62.2 (C-5 or C-5Ј),
Dimethyl (2R,7R)-2,7-diacetamido-4,5-bis(ethoxycarbonyl)-
1,2,3,3a,5a,6,7,8-octahydro-as-indacene-2,7-dicarboxylate 17
and dimethyl (2S,7S)-2,7-diacetamido-4,5-bis(ethoxycarbonyl)-
1,2,3,6,7,8-hexahydro-as-indacene-2,7-dicarboxylate 18
Dimethyl
(1R,1ЈR)-1,1Ј-diacetamido-3,3Ј-bicyclopenta-3,3Ј-
120.9 (C᎐CH), 121.4 (C᎐CH), 132.5 (C᎐CH), 141.2 (C᎐CH),
᎐
᎐
᎐
᎐
diene-1,1Ј-dicarboxylate 15 (0.172 g, 0.469 mmol) and diethyl
acetylenedicarboxylate (0.119 g, 0.705 mmol) were heated
together in anisole (6 ml) at 145 ЊC overnight. The solvent was
distilled off at reduced pressure and the products were isolated
by flash chromatography using MeOH–CH2Cl2 7 : 93. Separ-
ation of the aromatized product 18 and the dihydro product 17
was not effected under these conditions. The ratio between the
compounds was determined by 1H NMR and found to be 17–18
66 : 33; total yield 0.160 g (63%). This mixture was used directly.
Thus MnO2 (0.520 g, 6.0 mmol) was added to a solution of the
mixture (0.160 g, 0.300 mmol) in dioxane (15 ml), and the reac-
tion stirred at ambient temperature for 4 h. Filtration through
silica gel using CH2Cl2–MeOH 80 : 20 and evaporation of the
filtrate left a white solid, mp 248 ЊC (decomp.), yield 0.146 g
(91%) (Found: C, 58.64; H, 6.06. C26H32N2O10 requires: C,
58.77; H, 6.16%); MS (electrospray): M 533.2132. C26H33N2O10
requires: 533.2130; [α]D ϩ30.96 (c = 0.062, DMSO); νmax(film)/
cmϪ1 3271 (m), 3053 (m), 2983 (m), 2955 (m 2930 (m), 2849 (m),
2253 (w), 1716 (s), 1652 (s), 1538 (s), 1432 (m), 1372 (m), 1411
(s), 1198 (s), 1067 (m), 1040 (m); δH(CDCl3) 1.29 (6 H, t, J 7.1,
2 × Me), 1.92 (6 H, s, 2 × MeCO), 3.21 (2 H, d, J 16.8,
2 × CHH), 3.37 (2 H, d, J 17.0, 2 × CHH), 3.57 (2 H, d,
J 16.8, 2 × CHH), 3.61 (2 H, d, J 17.0, 2 × CHH), 3.67 (6 H,
s, 2 × OMe), 4.29 (4 H, q, J 7.1, 2 × CH2-Me), 6.25 (2 H, s,
2 × NH); δC(CDCl3) 14.1 (2 × Me), 23.1 (2 × MeCO-N), 41.5
(2 × CH2), 43.7 (2 × CH2), 61.6 (2 × OCH2Me), 61.6 (2 × MeO-
(CO)-C-NH), 67.1 (2 × OMe), 127.5 (2 × Ar), 139.5 (2 × Ar),
140.1 (2 × Ar), 167.3 (2 × CO), 170.2 (2 × CO), 173.1 (2 × CO);
m/z (EI): 550 (Mϩ ϩ 18, 18%), 521 (4), 519 (3), 518 (10), 493 (3),
487 (4), 486 (3).
161.0 (C-3 or C-3Ј or C-6 or C-6Ј), 161.4, (C-3 or C-3Ј or C-6 or
C-6Ј), 166.2 (C-3 or C-3Ј or C-6 or C-6Ј); m/z (EI): 484 (Mϩ,
100), 457 (21), 451 (13), 442 (20), 441 (73), 409 (14), 289 (11),
245 (39), 197 (12), 195 (11), 154 (13), 153 (28).
The structure has been verified by a single crystal X-ray
analysis (Fig. 1).
3Ј,3Љ-Bi[(2R,5R)-2,5-dihydro-5-isopropyl-3,6-dimethoxy-
pyrazine-2-spiro(cyclopent-3Ј-en-3Ј-yl)] 13
(IMes)(PCy )RuCl (᎐CHPh) (12 mg, 0.0144 mmol) was added
᎐
2
3
to
a solution of 1,4-bis[(2R,5R)-5-allyl-2,5-dihydro-2-iso-
propyl-3,6-dimethoxypyrazin-5-yl]but-3-yne21 12 (0.072 g,
0.144 mmol) in dry degassed toluene (6 ml) under argon and the
reaction heated at 85 ЊC for 3 h when more catalyst (12 mg,
0.0144 mmol) was added and the heating continued for 3 h.
Another portion (12 mg, 0.0144 mmol) of the catalyst was
added and the mixture heated for another 3 h. The solvent was
then distilled off and the product isolated after flash chrom-
atography using EtOAc–hexane 10 : 90. The product was a
white solid mp 141 ЊC, 0.062 g (92%). HRMS: M 471.2968.
C26H39N4O4 requires 471.2966; νmax(KBr)/cmϪ1 2940 (m), 1675
(s), 1455 (w), 1430 (w), 1295 (m), 1230 (s), 1215 (s), 1190 (m),
1132 (m), 1025 (m), 995 (m); δH(CDCl3) 0.69 (6 H, d, J 6.8,
CHMe2), 1.05 (6 H, d, J 6.8, CHMe2), 2.21 (2 H, dsept,
J 3.4, 6.8, 2 × CHMe2), 2.41–2.54 (4 H, m, 4 × CHH), 3.02–
3.12 (4 H, m, 4 × CHH), 3.61 (6 H, s, 2 × OMe), 3.68 (6 H, s,
2 × OMe), 3.97 (2 H, d, J 3.4, H-2 and H-2Ј), 5.47 (2 H, br s,
2 × CH᎐C); δ (CDCl ) 16.9 (2 × CHMe ), 19.3 (2 × CHMe ),
᎐
C
3
2
2
31.3 (2 × CHMe2), 49.1 (2 × CH2), 49.4 (2 × CH2), 51.3
(2 × OMe), 52.5 (2 × OMe), 61.1 (C-5 and C-5Ј), 62.7 (C-2
and C-2Ј), 124.2 (2 × C᎐CH), 136.9 (2 × C᎐CH), 161.3 (C-3,
᎐
᎐
Dimethyl (3R,6R)-3,6-diacetamido-9,10-bis(ethoxycarbonyl)-
1,2,3,4,5,6,7,8,8a,10a-decahydrophenanthrene-3,6-dicarboxylate
19
C-3Ј or C-6, C-6Ј), 165.8 (C-3, C-3Ј or C-6, C-6Ј); m/z (CI) 471
(Mϩ ϩ 1, 100%), 470 (Mϩ, 52%), 440 (11), 439 (37), 427 (37),
295 (50), 294 (19), 293 (16), 279 (18), 263 (21), 251 (22), 225
(12), 123 (31).
Dimethyl
(1R,1ЈR)-1,1Ј-diacetamido-3,3Ј-bicyclohexa-3,3Ј-
diene-1,1Ј-dicarboxylate21 16 (0.235 g, 0.645 mmol) and diethyl
acetylenedicarboxylate (0.204 g, 1.20 mmol) were heated
together in anisole (10 ml) at 145 ЊC overnight. The solvent
was distilled off at reduced pressure. The residual material was
subjected to flash chromatography using MeOH–CH2Cl2 4 : 96.
The product was a white solid, 0.220 g (64%); δH(CDCl3) 1.23
(3 H, t, J 7.1, OCH2CH3), 1.24 (3 H, t, J 7.1, OCH2CH3), 1.65
(1 H, d, J 14.3, CHH), 1.78 (1 H, dt, J 3.3, 13.3, CHH), 1.15–
1.37 (2 H, m, 2 × CHH), 1.88–2.24 (6 H, m, 6 × CHH), 1.92
(3 H, s, COMe), 2.01 (3 H, s, COMe), 2.51 (1 H, dd, J 1.5, 13.9,
Methyl (1R,3RЈ)-1-acetamido-3-(4-acetamido-4-methoxy-
carbonylcyclopent-1-en-1-yl)cyclohex-3-enecarboxylate 14
Compound 14 was prepared as above from (tricyclohexyl-
phosphine)benzylidene ruthenium dichloride (2 × 54 mg, 0.132
mmol) and dimethyl (2R,8S)-2,8-diacetamido-2,8-diallylnon-4-
yne-1,9-dioate 5 (0.321 g, 0.792 mmol). After removal of the
solvent, the residue was redissolved in dichloromethane and
tri(hydroxymethyl)phosphine (210 mg, 1.32 mmol) and tri-
ethylamine (0.36 ml) added. Evaporation and flash chrom-
atography using MeOH–CH2Cl2 7 : 93 gave the product as a
white solid 0.290 g (97%) with mp 270 ЊC. HRMS (electro-
spray): M 379.1871. C19H26N2O6 requires 379.1864; νmax(KBr)/
cmϪ1 3260 (m), 3020 (w), 1725 (s), 1645 (s), 1525 (s), 1425 (m),
1360 (m), 1290 (m), 1215 (m), 1075 (w); δH(CDCl3) 1.87–1.97
(1 H, m, CH2), 1.90 (3 H, s, COMe), 1.91 (3 H, s, COMe), 2.11–
CHH), 2.87–2.93 (2 H, m, C᎐C-CH), 3.01 (1 H, d, J 14.3,
᎐
CHH), 3.63 (3 H, s, OMe), 3.64 (3 H, s, OMe), 4.11–4.24
(4 H, m, OCH2CH3), 6.68 (1 H, s, NH-Ac), 8.16 (1 H, s,
NH-Ac); δC(CDCl3) 13.9 (2 × OCH2CH3), 22.3 (COMe), 22.7
(COMe), 28.1 (CH2), 28.4 (CH2), 29.6 (CH2), 34.9 (CH2), 36.0
(CH ), 36.5 (CH ), 40.6 (2 × CH-C᎐C), 52.2 (OCH ), 52.6
᎐
2
2
3
(OCH3), 59.1 (MeO-(CO)-C-NH), 59.4 (MeO-(CO)-C-NH),
61.1 (2 × OCH CH ), 123.8 (C᎐C), 127.1 (C᎐C), 133.1 (C᎐C),
2.22 (1 H, m, CH CH -C᎐CH), 2.28–2.39 (3 H, m, 3 × CHH),
᎐
2
2
᎐
᎐
᎐
2
3
2.59–2.81 (3 H, m, 3 × CHH), 3.03–3.16 (2 H, m, 2 × CHH),
3.66 (3 H, s, OMe), 3.68 (3 H, s, OMe), 5.25 (1 H, m, CH᎐C),
135.89 (C᎐C), 167.3 (CO), 169.9 (CO), 170.2 (2 × CO), 173.8
᎐
᎐
(CO), 174.3 (CO).
5.45 (1 H, m, CH᎐C), 5.66–5.74 (2 H, s, 2 × NH-Ac); δ (CDCl )
᎐
C
3
22.2 (CH CH -C᎐CH), 22.8 (MeCO-), 23.0 (MeCO-), 27.1
᎐
2
2
Dimethyl (3R,6R)-3,6-diacetamido-9,10-bis(ethoxycarbonyl)-
1,2,3,4,5,6,7,8-octahydrophenanthrene-3,6-dicarboxylate 20
(CH CH -C᎐CH), 34.2 (CH -C᎐CH), 43.5 (CH CH᎐C), 44.5
᎐
᎐
᎐
2
2
2
2
(CH CH᎐C), 52.4 (OMe), 52.7 (OMe), 120.4 (CH᎐C), 121.2
᎐
᎐
2
(CH᎐C), 132.4 (CH᎐C), 140.4 (CH᎐C), 170.1 (CO), 170.2
MnO2 (0.231 g, 2.66 mmol) was added to a solution of dimethyl
(3R,6R)-3,6-diacetamido-9,10-bis(ethoxycarbonyl)-1,2,3,4,5,6,
᎐
᎐
᎐
(CO), 174.1 (CO), 174.2 (CO); m/z (EI): 378 (Mϩ, 0%), 333 (3),
2702 J. Chem. Soc., Perkin Trans. 1, 2001, 2697–2703

View Article Online
7,8,8a,10a-decahydrophenanthrene-3,6-dicarboxylate 19 (0.071
g, 0.126 mmol) in dioxane (5 ml) and the reaction mixture
stirred at ambient temperature for 4 h. The reaction mixture
was filtered through silica gel using CH2Cl2–MeOH 80 : 20,
and the filtrate evaporated. The remaining product was a white
solid mp 127–129 ЊC; yield 0.066 g (94%). HRMS (electro-
spray): M 561.2418. C28H37N2O10 requires 561.2443; [α]D
Ϫ46.81 (c = 0.045, DMSO); νmax(ATR plate)/cmϪ1 3357 (m),
3296 (m), 3060 (m), 2982 (m), 2953 (m), 1728 (s), 1655 (s),
1535 (s), 1435 (s), 1370 (s), 1271 (s), 1186 (s), 1043 (m),
1025 (m); δH(CDCl3) 1.30 (6 H, t, J 7.1, 2 × -CH2CH3), 1.89
(6 H, s, 2 × MeCO), 1.93–2.00 (2 H, m, 2 × CHH), 2.39–2.49
(2 H, m, 2 × CHH), 2.71–2.95 (4 H, m, 4 × CHH), 2.87 (2H,
d, J 17.3, 2 × CHH-Ar), 3.08 (2H, d, J 17.3, 2 × CHH-Ar),
3.70 (6 H, s, 2 × OMe), 4.21–4.31 (4 H, t, 2 × -CH2CH3), 6.03
(2 H, s, 2 × NH-Ac); δC(CDCl3) 14.0 (2 × CH3CH2O), 22.9
(2 × MeCO-N), 23.3 (2 × CH2CH2Ar), 27.5 (2 × CH2CH2Ar),
35.1 (2 × CH2Ar), 52.7 (2 × OMe), 58.2 (2 × MeO-(CO)-C-
NH), 61.6 (2 × OCH2CH3), 130.1 (2 × Ar), 131.1 (2 × Ar),
134.7 (2 × Ar), 167.9 (2 × CO), 170.4 (2 × CO), 173.7 (2 × CO);
m/z (EI): 560 (Mϩ, 0%), 514 (24), 396 (29), 395 (100), 366 (53),
349 (32), 323 (27), 308 (41), 290 (32), 191 (31), 178 (48), 177
(39), 176 (51), 165 (44), 152 (29).
167.7 (EtO2C), 169.6 (CONHAc), 169.7 (CONHAc), 173.3
(CO2Me), 173.6 (CO2Me).
References
1 (a) P. Kremminger and K. Undheim, Tetrahedron, 1997, 53, 6925;
(b) J. Efskind, T. Benneche and K. Undheim, Acta Chem. Scand.,
1997, 51, 942; (c) B. S. Möller, T. Benneche and K. Undheim,
Tetrahedron, 1996, 52, 8807.
2 K. Undheim and P. Kremminger, PCT Int. Appl. WO 93,24,523,
(Chem. Abstr., 1995,122, 10682a).
3 (a) M. L. Falck-Pedersen and K. Undheim, Tetrahedron, 1996, 52,
7761; (b) K. Hammer, T. Benneche, H. Hope and K. Undheim, Acta
Chem. Scand., 1997, 51, 392; (c) R. Fitzi and D. Seebach,
Tetrahedron, 1988, 44, 5277.
4 (a) G. Bold, T. Allmendinger, P. Herold, L. Moesch, H.-P. Schär and
R. O. Duthaler, Helv. Chim. Acta, 1992, 75, 865; (b) R. M. Williams
and C. Yuan, J. Org. Chem., 1992, 57, 6519; (c) J. E. Baldwin, V. Lee
and C. J. Schofield, Synlett, 1992, 249; (d ) A. R. Jurgens,
Tetrahedron Lett., 1992, 33, 4727; (e) M. H. Gelb, Y. Lin, M. A.
Pickard, Y. Song and J. C. Vederas, J. Am. Chem. Soc., 1990, 112,
4932; ( f ) C. Dugave and A. Ménez, Tetrahedron: Asymmetry, 1997,
8, 1453.
5 (a) S. D. Bull, A. N. Chernega, S. G. Davies, W. O. Moss and
R. M. Parkin, Tetrahedron, 1998, 54, 10379; (b) S. Neset, H. Hope
and K. Undheim, Tetrahedron, 1997, 53, 10459.
6 S. Rödbotten, T. Benneche and K. Undheim, Acta Chem. Scand.,
1997, 51, 873.
Dimethyl (2R,8R)-2,8-diacetamido-4,5-bis(ethoxycarbonyl)-
2,3,3a,5a,6,7,8,9-octahydro-1H-cyclopenta[a]naphthalene-2,8-
dicarboxylate 21 and dimethyl (2R,8S)-2,8-diacetamido-4,5-
bis(ethoxycarbonyl)-2,3,6,7,8,9-hexahydro-1H-cyclopenta[a]-
naphthalene-2,8-dicarboxylate 22
7 B. Basu and T. Frejd, Acta Chem. Scand., 1996, 50, 316.
8 A.-S. Carlström and T. Frejd, J. Org. Chem., 1990, 55, 4175.
9 M. Lange and K. Undheim, Tetrahedron, 1998, 54, 5337.
10 (a) R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413;
(b) R. H. Grubbs, S. J. Miller and G. C. Fu, Acc. Chem. Res., 1995,
28, 446.
Methyl (1R,3RЈ)-1-acetamido-3-(4-acetamido-4-methoxycarb-
onylcyclopent-1-en-1-yl)cyclohex-3-enecarboxylate 14 (0.290 g,
0.767 mmol) was heated together with diethyl acetylene-
dicarboxylate (0.26 g, 0.153 mmol) in anisole (7 ml) at 145 ЊC
overnight. The solvent was removed in vacuo and the prod-
ucts were isolated by flash chromatography using MeOH–
CH2Cl2 6 : 94. The adduct 21 and its aromatized product
22 were not separated under these conditions and were isolated
in the ratio 1 : 1, in all 0.287 g (68%). Part of the mixture
was aromatized either by treatment with DDQ or with
MnO2.
DDQ: The 1 : 1 product mixture (33 mg, 0.060 mmol) was
dissolved in dioxane (5 ml) and stirred with DDQ (20 mg, 0.090
mmol) at 100 ЊC for 5 h. The product was isolated as a white
solid after flash chromatography using MeOH–CH2Cl2 5 : 95.
Yield: 0.30 g (91%), mp 270 ЊC (CH2Cl2).
MnO2: The product mixture (22 mg, 0.040 mmol) was dis-
solved in dioxane (3 ml) and the solution stirred with MnO2
(70 mg, 0.80 mmol) at 100 ЊC for 5 h. The product was isolated
as a white solid after flash chromatography using MeOH–
CH2Cl2 5 : 95. Yield: 0.21 g (>95%) mp 270 ЊC (CH2Cl2).
HRMS: M 547.2304. C27H34N2O10 requires 547.2286; [α]D
ϩ19.91 (c = 0.024, DMSO); νmax(ATR plate)/cmϪ1 3350 (m),
3294 (m), 3065 (w), 2960 (m), 2927 (m), 1724 (s), 1656 (s), 1537
(m), 1434 (m), 1370 (m), 1298 (s), 1259 (s), 1201 (s), 1085 (m),
1020 (m); δH(CDCl3) 1.23 (3 H, t, J 7.1, OCH2CH3), 1.24 (3 H,
t, J 7.1, OCH2CH3), 1.75 (3 H, s, COMe), 1.77 (3 H, s, COMe),
1.86–1.99 (1 H, m, CHH), 2.21–2.25 (1 H, m, CHH), 2.58–2.76
(2 H, m, 2 × CHH), 2.90 (1 H, d, J 17.1, CHH), 3.11 (1 H, d,
J 17.2, CHH), 3.15 (1 H, d, J 17.1, CHH), 3.39–3.47 (2 H, m,
CHH), 3.53–3.61 (1 H, m, CHH), 3.58 (3 H, s, OMe), 3.61 (3 H,
s, 2 × OMe), 4.17–4.26 (4 H, m, OCH2CH3), 8.20 (1 H, s,
2 × NH-Ac), 8.57 (1 H, s, NH-Ac); δC(CDCl3) 13.8 (OCH2-
CH3), 13.9 (OCH2CH3), 22.2 (COMe), 22.2 (COMe), 23.0
(CH2), 27.6 (CH2), 33.8 (CH2), 41.3 (CH2), 43.7 (CH2), 52.1
(OCH3), 52.3 (OCH3), 56.3 (MeO2C-C-NH), 60.9 (OCH2CH3),
61.0 (OCH2CH3), 64.0 (MeO2C-C-NH), 123.5 (Ar), 130.4 (Ar),
132.9 (Ar), 135.7 (Ar), 137.8 (Ar), 141.2 (Ar), 166.0 (EtO2C),
11 (a) A. Fürstner, Angew. Chem., Int. Ed., 2000, 39, 3012; (b) K. S.
Armstrong, J. Chem. Soc., Perkin Trans. 1, 1998, 371; (c) M.
Schuster and S. Blechert, Angew. Chem., Int. Ed. Engl., 1997, 109,
2124.
12 T. Weskamp, F. J. Kohl, W. Hieringer, D. Gleich and W. A.
Herrmann, Angew. Chem., Int. Ed., 1999, 38, 2416.
13 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999,
1, 953; (b) A. K. Chatterjee and R. H. Grubbs, Org. Lett., 1999, 1,
1751; A. K. Chatterjee, J. P. Morgan, M. Scholl and R. H. Grubbs,
J. Am. Chem. Soc., 2000, 122, 3783.
14 (a) L. Ackermann, D. El Tom and A. Fürstner, Tetrahedron, 2000,
56, 2195; (b) R. Stragies, U. Voigtmann and S. Blechert, Tetrahedron
Lett., 2000, 41, 5465.
15 J. Huang, H.-J. Schanz, E. D. Stevens and S. P. Nolan,
Organometallics, 1999, 18, 5375.
16 J. G. Millar and E. W. Underhill, Can. J. Chem., 1986, 64, 2427.
17 S. C. Jain, D. E. Dussourd, W. E. Connor, T. Eisner, A. Guerrero and
J. Meinwald, J. Org. Chem., 1983, 48, 2266.
18 (a) U. Schöllkopf, H.-J. Neubauer and M. Hauptreif, Angew. Chem.,
1985, 97, 1065; (b) U. Schöllkopf, S. Grüttner, R. Anderskewitz,
E. Egert and M. Dyrbusch, Angew. Chem., Int. Ed. Engl., 1987, 26,
683.
19 (a) K. Hammer and K. Undheim, Tetrahedron, 1997, 53, 5925;
K. Hammer and K. Undheim, Tetrahedron, 1997, 53, 10603;
(b) K. Hammer, C. Røming and K. Undheim, Tetrahedron, 1998, 54,
10837.
20 (a) L. Ackermann, A. Fürstner, T. Weskamp, F. J. Kohl and
W. A. Hermann, Tetrahedron Lett., 1999, 40, 4787; (b) T. Weskamp,
W. C. Schatternmann, M. Spiegler and W. A. Herrmann, Angew.
Chem., Int. Ed., 1998, 37, 2490; (c) J. Huang, E. D. Stevens,
S. P. Nolan and J. L. Petersen, J. Am. Chem. Soc., 1999, 121, 2674.
21 K. Undheim and J. Efskind, Tetrahedron, 2000, 56, 4847.
22 (a) A. Tallaricao, P. J. Bonitatebus and M. L. Snapper, J. Am. Chem.
Soc., 1997, 119, 7157; (b) S. B. Garber, J. S. Kingsbury, B. L. Gray
and A. H. Hoveyda, J. Am. Chem. Soc., 2000, 122, 8168.
23 L. A. Paquette, J. D. Schloss, I. Efremov, F. Fabris, F. Gallou,
J. M.-A Andino and J. Yang, Org. Lett., 2000, 2, 1259.
24 H. D. Maynard and R. Grubbs, Tetrahedron Lett., 1999, 40, 4137.
25 SMART and SAINT Area-detector Control and Integration
Software, Siemens Analytical X-ray Instruments Inc., Madison,
Wisconsin, USA 1996.
26 G. M. Sheldrick, Private Communication, 1996.
27 G. M. Sheldrick, SHELXTL, Version 5.1 Siemens Analytical X-ray
Instruments Inc., Madison, Wisconsin, USA.
J. Chem. Soc., Perkin Trans. 1, 2001, 2697–2703
2703