X=Y=ZH Systems as potential 1,3-dipoles. Part 58: Cycloaddition route to chiral conformationally constrained (R)-pro-(S)-pro peptidomimetics

Article abstract of DOI:10.1016/j.tet.2003.09.032

Imines of (1S,9S)-t-butyl-9-amino-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2] diazepine-1-carboxylate undergo thermal (toluene, 110°C) or LiBr-DBU catalysed (MeCN, room temperature) regio- and stereo-specific cycloaddition to a range of chiral dipolarophiles giving enantiopure spiro-cycloadducts in excellent yield. The reactions proceed via intermediate NH azomethine ylides and litho azomethine ylides, respectively and results in the multiplication of chiral centres from 2 (one of which is lost in the process) to 5.

Full text of DOI:10.1016/j.tet.2003.09.032

Tetrahedron 59 (2003) 8481–8487
X5Y5ZH Systems as potential 1,3-dipoles. Part 58:
Cycloaddition route to chiral conformationally constrained
(R)-pro-(S)-pro peptidomimetics
a
H. Ali Dondas,a,b Ronald Grigga and Colin Kilner
,
*
aDepartment of Chemistry, Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry,
The University of Leeds, Leeds LS2 9JT, UK
bDepartment of Chemistry, Faculty of Pharmacy, Mersin University, 33342 Mersin, Turkey
Received 14 July 2003; revised 22 August 2003; accepted 11 September 2003
Abstract—Imines of (1S,9S)-t-butyl-9-amino-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate undergo thermal
(toluene, 1108C) or LiBr-DBU catalysed (MeCN, room temperature) regio- and stereo-specific cycloaddition to a range of chiral
dipolarophiles giving enantiopure spiro-cycloadducts in excellent yield. The reactions proceed via intermediate NH azomethine ylides and
litho azomethine ylides, respectively and results in the multiplication of chiral centres from 2 (one of which is lost in the process) to 5.
q 2003 Elsevier Ltd. All rights reserved.
The strong and continuing interest in peptidomimetics has
been given a substantial boost by the emerging importance
of the proteume.1 Special interest attaches to conformation-
ally constrained building blocks that mimic the b-turn
motif.2
conformationally restricted pro-pro peptidomimetics. To
explore this possibility we selected the ala-pro mimetic 4b,
a key intermediate in the synthesis of cilazapril 3. Elegant
1H NMR studies on 4a and 4b have shown the CO2H and
CO2But groups to be axial and the pyridazine to have a
locked chair conformation.10 Furthermore the conformation
of the diazepine ring is locked due to the two amide bonds in
conjunction with the chair locked pyridazine.
Drug discovery programs aimed at inhibitors of the zinc
metalloprotease, angiotensin-converting enzyme (ACE),
resulted in a range of drugs such as captopril 1, lisinopril
2 and cilazapril 3 that are effective in the treatment of
essential hypertension and other cardiovascular and renal
disorders.3,4 Recently, a novel human zinc metalloprotease,
ACE2, has been reported5 which in an essential regulator of
heart function.6 There is significant structural homology
between ACE and ACE2,7 and this has encouraged us to
explore peptidomimetics based on cilazapril.8
A substantial amount of novel chemistry, mainly targeted at
ACE inhibitors, has been developed from the parent
9-aminopyridazino diazepine carboxylic acid 4a, the
corresponding t-butyl ester 4b and related bicyclic
compounds.8–10
Our thermal and metal catalysed11–13 imine-azomethine
ylide-cycloaddition cascade chemistry has provided a series
of cephalosporin analogues14 and spirobenzodiazepines
related to MK-32913 and potentially offers a facile route
Thus a series of imines 6a–c (Scheme 1) was prepared from
4b which was liberated from its phthalimido t-butyl ester 515
by treatment with hydrazine hydrate. The imines were then
evaluated in thermal and metal catalysed cycloaddition
reactions with respect to regio-, diastereo- and enantio-
selectivity.
Keywords: cilazapril; ACE inhibitors; imines; azomethine ylide; 1,3-
dipolar cycloaddition; peptidomimetics; multiplication of chirality.
*
Corresponding author. Tel.: þ44-1133436501; fax: þ44-1133436530;
e-mail: r.grigg@chemistry.leeds.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.032

8482
H. A. Dondas et al. / Tetrahedron 59 (2003) 8481–8487
Scheme 1.
During these cycloadditions a pale green colour develops
and is then largely discharged suggesting it is associated
with the resonance stabilised azomethine ylide 7 which
arises via formal 1,2-prototropy of the C(9)–H. The cis-
stereochemistry of HA, HB and HC was readily established
from n.O.e data (see Section 4) and conforms to that
expected13,16–18 whilst the C(2)-stereochemistry is assigned
on the basis of previous studies14,16–18 and an X-ray crystal
structure of 8a (Fig. 1).
The formation of single stereoisomers in these kinetically
controlled cycloadditions indicates steric shielding of one
face of the azomethine ylide 7 (Scheme 2) by the puckered
dioxo-diazepine ring. This shielding effect is also apparent
in the crystal structure of 8a (Fig. 1) in which the dihedral
angle between the planes of two amide moieties N(1)–
C(7)–O(7) and N(2)–C(11)–O(11) is 63.28. This compares
with a predicted angle from 1H NMR and modelling of 608.
A further feature of the cycloaddition is that the new C–C
bond formed at C(9) replaces the C(9)–H with ‘retention’ of
configuration but the chiral descriptor for this site changes
to R due to stereochemical preference rules. Thus 8a–c
arise from endo-cycloaddition to the 9-Re, 10-Si face of the
anti-dipole 7 and in 8a–c the new stereocentres are 1S, 2R,
4S, and 5R.
1. Thermal cycloaddition
The imines 6a–c of t-butyl 1S,9S-9-amino-octahydro-6,10-
dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate
underwent thermal (toluene, 1108C) regio- and diastereo-
specific cycloaddition to N-methylmaleimide (NMM) to
give enantiopure spiro-cycloadducts 8a–c in 84–93% yield
with concomitant increase in the number of chiral centres
from 2 to 5 (Scheme 2). The reaction proceeds via a formal
1,2-prototropy generating intermediate NH azomethine
ylide 7 in which the original C(9) chirality is destroyed.
Hence, the enantioselectivity of these cycloaddition is
controlled solely by the C(1) centre and the locked
conformation of the bicyclic system.
2. Metal ion catalysed cycloaddition
The imines 6a–c undergo LiBr-DBU catalysed (MeCN,
room temperature) regio- and stereo-specific cycloaddition
to a range of achiral and chiral dipolarophiles giving
enantiopure spiro-cycloadducts in excellent yield via litho
azomethine ylides. Thus imines 6a and 6c react regio- and
Scheme 2.

H. A. Dondas et al. / Tetrahedron 59 (2003) 8481–8487
8483
Figure 1. X-Ray crystal structure of 8a.
Scheme 3.
stereo-specifically with methyl acrylate under the influence
of lithium bromide and DBU in acetonitrile over 3.5 h to
give single cycloadducts 10a and 10b in 82 and 86% yield,
respectively (Scheme 3).
In these reactions a green colour develops immediately the
imine is contacted with LiBr-DBU and this colour
discharges as the reaction proceeds. This colour is believed
to arise from the lithio dipole 9. The stereochemistry of 10a
and 10b was assigned on the basis of 2-D Cosy studies and
an X-ray crystal structure of an analogue (vide infra). In these
cases an analogous facial shielding effect to that discussed
previously is operating and since the stereochemistry of the
metallo azomethine ylide 9 is analogous to that of 7, the
stereochemical outcome of Scheme 3 is identical to that of
Scheme 2. The new stereocentres are thus 2R, 4S, 5R.
A second series of cycloadducts was prepared from imines
6a–c and the chiral dipolarophile (R)-5(1R)-menthyloxy-2-
(5H)-furanone 11 (Scheme 3). Reaction of 6a–c with 11
occurred over 3–6 h at room temperature in acetonitrile
using lithium bromide-DBU as the catalyst. Enantiopure
cycloadducts 12a–c were obtained as single stereoisomers
in 81–93% yield. The stereochemistry of 12a–c is based on
a single crystal X-ray structure of 12c (Fig. 2) and 2-D Cosy
studies. In these reactions the stereochemistry of the
cycloaddition is as observed in the previous two series
discussed above. Once again the process proceeds via an
Figure 2. X-Ray crystal structure of 12c.
endo transition state and as expected the lithio azomethine
ylide adds to the face of the dipolarophile 11 trans to the
O-menthyl group.18 Hence, the newly created stereocentres
are 1S, 2R, 4S, and 5R (Scheme 4).
3. Conclusions
Imines derived from amine 4b undergo stereo- and

8484
H. A. Dondas et al. / Tetrahedron 59 (2003) 8481–8487
Scheme 4.
regio-specific thermal and metallo-azomethine ylide
cascade cycloaddition reactions giving enantiopure
products which are (R)-pro-(S)-pro peptidomimetics
bearing two or three additional chiral centres in the newly
created proline moiety. A flexible approach to a wide range
of potentially bioactive peptidomimetics has been
developed.
C, 67.55; H, 6.75; N, 9.45%; d (300 MHz): 8.41 (s, 1H,
CHvN), 8.1–7.42 (m, 7H, ArH), 5.39 (m, 1H, 1a), 4.65 (m,
1H, 9a), 4.35 (m, 1H, 4b), 3.61 (m, 1H, 7b), 2.81 (m, 1H, 4a),
2.65–2.15(m, 4H, 2b, 7a, 8a, 2b), 1.95–1.53 (m, 3H, 2a, 3a,
3b), 1.40 (s, 9H, OtBu); m/z (%): 435 (Mþ, 12), 379 (23), 223
(100), 194 (64), 114 (26), 85 (72), 57 (88) and 41 (78).
4.1.2. (1S,9S)-6,10-Dioxo-9-[(pyridin-2-ylmethylene)-
amino]-octahydro pyridazino [1,2-a][1,2]diazepine-1-
carboxylic acid tert-butyl ester 6b. The product (89%)
precipitated from ether–petroleum ether as a pale yellow
amorphous solid, mp 87–898C; [a]2D0¼2109.2 (1 g/100 mL,
EtOH). HRMS (EI), found: 386.1949, C20H26N4O4 requires:
386.1954; d (300 MHz): 8.61 and 8.15 (2£d, 2£1H, pyridine-
H), 8.32 (s, 1H, CHvN), 7.72 and 7.31 (2£m, 2H, pyridine-
H), 5.41 (m, 1H, 1a), 4.70 (m, 1H, 9a), 4.40 (m, 1H, 4b), 3.65
(m, 1H, 7b), 2.81 (m, 1H, 4a), 2.67–2.20 (m, 4H, 2b, 7a, 8a,
2b), 2.02–1.60 (m, 3H, 2a, 3a, 3b), 1.42 (s, 9H, OtBu); m/z
(%) (FAB): 387 (Mþ1, 100), 331 (35), 202 (32) and 131 (21).
4. Experimental
Melting points were determined on a Kofler hot stage
apparatus and are uncorrected. Mass spectra were recorded
at 70 eV on a VG Autospec mass spectrometer. Nuclear
magnetic resonance spectra and decoupling experiments
were determined at 300 and 400 MHz on a Bruker
spectrometers as specified. Chemical shifts are given in
parts per million (d) downfield from tetramethylsilane as
internal standard. Spectra were determined in deuterio-
chloroform except where otherwise stated. The following
abbreviations are used; s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad and brs¼broad singlet.
Flash column chromatography was performed using silica
gel 60 (230–400 mesh). Kieselgel columns were packed
with silica gel GF254 (Merck 7730). Petroleum ether refers
the fraction with bp 40–608C unless otherwise specified.
Microanalyses were obtained using a Carlo–Erba Model
1106 instrument. Optical rotations were determined on an
Optical Activity Ltd., AA1000 polarimeter. (R)-5(1R)-
Menthyloxy-2-(5H)-furanone was purchased from Aldrich
and used as received.
4.1.3. (1S,9S)-9-(Benzylidine-amino)-6,10-dioxo-octa-
hydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid
tert-butyl ester 6c. The product (91%) was obtained as pale
yellow thick oil, [a]2D0¼2178.6 (0.3 g/100 mL, EtOH).
HRMS (EI), found: 385.2000, C21H27N3O4 requires:
385.2000; d (300 MHz): 8.28 (s, 1H, CHvN), 7.93–7.32
(m, 5H, ArH), 5.38 (m, 1H, 1a), 4.62 (m, 1H, 9a), 4.31 (m,
1H, 4b), 3.60 (m, 1H, 7b), 2.79 (m, 1H, 4a), 2.61–2.13 (m,
4H, 2b, 7a, 8a, 2b), 1.90–1.50 (m, 3H, 2a, 3a, 3b), 1.39 (s,
9H, OtBu); m/z (%) (FAB): 386 (Mþ1, 100), 330 (51), 197
(17), 130 (51), 91 (12) and 55 (9).
4.2. General procedure for thermal cycloaddition
4.1. General procedure for imine formation
A solution of imine (1 mmol), and N-methylmaleimide
(1 mmol) in dry degassed toluene (30 mL) was boiled under
reflux under a nitrogen atmosphere for 9–16 h. The solvent
was then evaporated under reduced pressure and the residue
crystallised from an appropriate solvent.
A mixture of aldehyde (1 equiv.), amine (1.05 equiv.) and
˚
activated 4 A molecular sieves in dry DCM was stirred
either at room temperature or 408C for an appropriate time
(6–7 h). After removal of the molecular sieves the solvent
was evaporated under reduced pressure (bath temperature
not higher than 308C) and the residue crystallised from an
appropriate solvent.
4.2.1. Cycloadduct 8a (1S,2R,4S,5R,10S). After a reaction
time of 14 h and work up the product (89%) crystallised
from dichloromethane–hexane as colourless prisms, mp
135–1378C. [a]2D0¼2198.4 (0.5 g/100 mL, EtOH). Found:
C, 64.45; H, 6.15; N, 9.75, C30H34N4O6·0.5H2O requires: C,
64.85; H, 6.30; N, 10.1%; d (400 MHz): 7.75–7.40 (m, 5H,
Ar-H), 5.5 (m, 1H, H10), 4.71 (dd, 1H, J¼3.9, 9.4 Hz, HA),
4.49 (m, 1H, H40), 3.81 (m, 1H, H70), 3.50.(dd, 1H, J¼7.1,
4.1.1. (1S,9S)-9-[(Naphthalen-2-ylmethylene)-amino]-
6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-
carboxylic acid tert-butyl ester 6a. The product (93%)
crystallised from ether–petroleum ether as colourless
prisms, mp 151–1538C. [a]2D0¼271 (0.5 g/100 mL, EtOH).
Found: C, 67.4; H, 6.9; N, 9.15, C25H29N3O4·0.5H2O requires:

H. A. Dondas et al. / Tetrahedron 59 (2003) 8481–8487
8485
9.4 Hz, HB), 3.24 (d, 1H, J¼7.1 Hz, HC), 3.15 (m, 1H, H400),
2.66 (s, 3H, NMe), 2.4 (br, 1H,0N0 H), 2.35 (m, 1H, H800), 2.2–
1.95 (m, 4H, H20, H200, H80, H7 ), 1.71 (m, 1H, H30), 1.65 (m,
1H, H300) and 1.46 (s, 9H, OtBu); m/z (%) (FAB): 547 (Mþ1,
93), 491 (76), 333 (58), 242 (41), 85 (48) and 57 (100).
from ether–petroleum ether as a colourless prisms, mp
105–1078C. [a]2D0¼2103.2 (0.5 g/100 mL, EtOH). HRMS
(EI), found: 496.2318, C26H32N4O6 requires: 496.2322; d
(300 MHz): 7.30 (m, 5H, Ar-H), 5.52 (t, 1H, J¼5.3 Hz,
H10), 4.65 (dd, 1H, J¼9.3, 3.0 Hz, HA), 4.45 (m, 1H, H400),
3.91 (m, 1H, H70), 3.58 (dd, 1H, J¼7.0, 9.3 Hz, HB), 3.33 (d,
1H, J¼7.0 Hz, HC), 3.22 (m, 1H, H40), 2.95 (br, 1H, NH),
2.708 (s,003H, NMe), 2.68 (m, 1H, H800), 2.41–2.16 (m, 4H,
H2 , H2 , H80, H700), 1.82 (m, 1H, H30), 1.6 (m, 1H, H300) and
1.49 (s, 9H, OtBu); m/z(%) (FAB): 497 (Mþ1, 15), 441 (18),
367 (5), 283 (19), 81 (59), 69 (75) and 55 (100).
4.3. General procedure for the lithium bromide
catalysed cycloaddition reactions
A mixture of the imine (1 mmol), DBU (1.1 mmol),
dipolarophile (1 mmol) and LiBr (1.5 mmol) in freshly
distilled acetonitrile (30 mL) was stirred at room tempera-
ture under an atmosphere of nitrogen until reaction was
complete. The reaction mixture was then quenched by
addition of saturated aqueous ammonium chloride solution,
and extracted with methylene chloride (2£). The combined
organic layers were washed with brine, dried (MgSO4),
filtered and the solvent evaporated. The residue was
crystallised from an appropriate solvent.
4.2.2. Cycloadduct 8b (1S,2R,4S,5R,10S). Work up after a
reaction time of 14 h afforded the product (84%) which
crystallised from ether–ethanol as colourless prisms, mp
215–2178C. [a]2D0¼2188.8 (0.5 g/100 mL, EtOH). Found:
C, 60.5; H, 6.4; N, 13.9, C25H31N5O6 requires: C, 60.35; H,
6.30; N, 14.05%. d (400 MHz): 8.45 (d, 1H, pyridine-Ha),
7.7 (t, 1H, pyridine-Hc), 7.35 (d, 1H, pyridine-Hd), 7.5 (m,
1H, pyridine-Hb), 5.5 (t, 1H, J¼5.400Hz, H10), 4.72 (d, 1H,
J¼9.4 Hz, HA), 4.50 (m, 1H, H4 ), 3.9 (m, 1H, H70),
3.69.(dd, 1H, J¼6.9, 9.4 Hz, HB), 3.44 (d, 1H, J¼7.1 Hz,
HC), 3.25 (m, 1H, H40), 3.0 (br, 1H, NH), 2.76 (s, 3H, NMe),
2.5 (m, 1H, H800), 2.4–2.15 (m, 4H, H20, H200, H80, H700), 1.8
(m, 1H, H30), 1.6 (m, 1H, H300) and 1.47 (s, 9H, OtBu)
m/z(%) (FAB): 498 (Mþ1, 54), 442 (27), 368 (16), 284 (31),
68 (67) and 55 (100).
4.3.1. Cycloadduct 10a (2R,4S,5R,10S). After a reaction
time of 3.5 h and work up the product (82%) precipitated
from petroleum ether (60–80) as a colourless low mp solid,
mp 27–308C). [a]2D0¼276 (0.3 g/100 mL, EtOH). Found:
C, 66.5; H, 6.9; N, 8.3, C29H35N3O6 requires: C, 66.75; H,
6.8; N, 8.050; d (300 MHz): 7.84–7.20 (m, 7H, ArH), 5.51
(m, 1H, H1 ), 4.80 (d, 1H, J¼7.7 Hz, HA), 4.52 (m, 1H,
H400), 3.85–3.45 (m, 4H), 3.22 (m, 1H, H40), 3.16 (s, 3H,
CO2Me), 2.9 (m, 1H), 2.6–1.5 (m, 7H) and 1.49 (s, 9H,
OtBu); m/z (%): 522 (Mþ1, 27), 466 (8), 153 (100) and 69
(47).
4.3.2. Cycloadduct 10b (2R,4S,5R,10S). After a reaction
time of 4 h and work up the product (86%) crystallised from
petroleum ether (60–80) as a low mp solid, mp 37–408C;
[a]2D0¼292.8 (0.5 g/100 mL, EtOH). Found: C, 59.45; H,
7.30; N, 8.9; C25H33N3O6.2H2O requires: C, 59.25; H, 7.30;
N, 8.7%. HRMS (EI), found: 471.2380; C25H33N3O6
requires: 471.2370; d (300 MHz): 7.15 (m, 5H, ArH), 5.50
(m, 1H, H10), 4.80 (d, 1H, J¼8.0 Hz, HA), 4.50 (m, 1H,
H400), 3.75 (m, 3H), 3.45 (m, 3H, H40), 3.34 (s, 3H, CO2Me),
2.9 (m, 1H), 2.82 (m, 1H), 2.5–1.6 (m, 5H) and 1.48 (s, 9H,
OtBu); m/z (%) (FAB): 471 (Mþ, 62), 416 (22), 342 (29),
258 (44), 239 (100), and 55 (86).
4.3.3. Cycloadduct 12a (1S,2R,4S,5R,10S). After a reaction
time of 4 h and work up the product (81%) crystallised from
petroleum ether (60–80) ether as colourless needles, mp
103–1058C. [a]2D0¼2192 (0.5 g/100 mL, EtOH). Found: C,
68.4; H, 7.9; N, 6.35, C39H50N3O7·0.5H2O requires: C, 68.6;
H, 7.5; N, 6.15%; d (300 MHz): 7.93–7.410(m, 7H, Ar-H),
5.6 (d, 1H, J¼3.9 Hz, HD), 5.28 (m, 1H, H1 ), 4.70 (dd, 1H,
J¼4.4, 9.7 Hz, HA), 4.52 (m, 1H, H400), 3.87 (m, 1H, H70),
3.55 (m, 2H, HBþmenthyl–CHO), 3.40 (m, 1H, H40), 3.02
(dd, 1H, J¼4.0, 8.0 Hz, HC), 3.6 (m, 1H, H700), 2.43–1.6 (m,
15H), 1.49 (s, 9H, OtBu), 0.62 (d, 3H, J¼6.6 Hz, CHMe),
0.83 and 0.95 (2£d, 6H, J¼6.9 Hz, CHMe2); m/z (%)
4.2.3. Cycloadduct 8c (1S,2R,4S,5R,10S). After a reaction
time of 16 h and work up the product (93%) precipitated

8486
H. A. Dondas et al. / Tetrahedron 59 (2003) 8481–8487
(FAB): 674 (Mþ1, 40), 462 (19), 240 (38), 206 (50), 153
Crystal
data
for
13c.
C35H49N3O7·CH2Cl2,
(100), 83 (52) and 55 (72).
0.48£0.11£0.10 mm, M¼708.7, orthorhombic, space
group P212121, a¼9.6778(1), b¼15.4738(2), c¼
4.3.4. Cycloadduct 12b (1S,2R,4S,5R,10S). Reaction time
5 h. After work up the product (89%) crystallised from
ether–hexane–ethanol as colourless prisms, mp 83–878C.
[a]2D0¼2188.8 (0.5 g/100 mL, EtOH). Found: C, 65.3; H,
8.0; N, 8.9, C34H47N4O7 requires: C, 65.35; H, 7.75; N,
8.95%; d (300 MHz): 8.6 (d, 1H, pyridine-H), 7.7 (m, 1H,
pyridine-H) 7.4 (d, 1H, pyridine-H), 7.13 (m, 1H, pyridine-
H), 5.58 (d, 1H, J¼4.1 Hz, HD), 5.3 (m, 1H, H0), 4.66 (m,
2H, HA and H400), 3.90 (d, 1H, J¼9.7 Hz, HB), 3.81 (m, 1H,
H70), 3.061 (m, 2H, menthyl–CHOþmenthyl–H)), 3.45 (m,
1H, H4 ), 3.12 (dd, 1H, J¼4.2, 8.1 Hz, HC), 2.43–1.6 (m,
15H), 1.49 (s, 9H, OtBu), 0.60 (d, 3H, J¼6.7 Hz, CHMe),
0.88 and 0.95 (2£d, 6H, J¼6.9 Hz, CHMe2); m/z (%)
(FAB): 625 (Mþ1, 100), 495 (16), 469 (24), 413 (17), 97
(37), 83 (74) and 55 (94).
24.5585(3) A, U¼3677.69(8) A , Z¼4, Dc¼1.28 Mg m
m¼0.23 mm21, F(000)¼1512, T¼150 K.
,
3
23
˚
˚
Data collection. 1.0,2u,52.08; 7045 unique data were
collected [Rint¼0.058]; 6602 reflections with Fo.4.0s(Fo).
Structure refinement. Number of parameters¼440,
goodness of fit, s¼1.047; wR2¼0.1129, R1¼0.0467.
Full supplementary crystallographic data, which include
hydrogen co-ordinates, thermal parameters and complete
bond lengths and angles, have been deposited at the
Cambridge Crystallographic Data Centre (8a, CCDC
167657; 12c, CCDC 167658) and are available on request.
4.3.5. Cycloadduct 12c (1S,2R,4S,5R,10S). Reaction time
5 h. After work up the product (93%) crystallised from
hexane–ethanol as colourless prisms, mp 205–2078C.
[a]2D0¼2195.2 (0.5 g/100 mL, EtOH). Found: C, 66.95; H,
8.0; N, 6.50C35H49N3O7 requires: C, 67.35; H, 7.90; N,
6.75%. HRMS (EI), found: 623.3565, C35H49N3O7 requires:
623.3570; d (300 MHz): 7.51–7.15 (m, 5H, Ar-H), 5.54 (d,
1H, J¼4.0 Hz, HD), 5.25 (m, 1H, H10), 4.64 (dd, 1H, J¼4.2,
9.4 Hz, HA), 4.51 (m, 1H, H400), 3.81 (m, 1H, H70), 3.51 (m,
1H, menthyl–CHO), 3.48 (m, 2H, HB and H40), 3.02 (dd, 1H,
J¼3.8, 7.8 Hz, HC), 2.53 (m, 1H, H700), 2.48–1.52 (m, 16H),
1.48 (s, 9H, OtBu), 0.68 (d, 3H, J¼6.9 Hz, CHMe), 0.83
and 0.92 (2£d, 6H, J¼6.8 Hz, CHMe2); m/z (%) (FAB):
624 (Mþ1, 45), 412 (16), 153 (30), 97 (38), 83 (69) and 55
(100).
Acknowledgements
We thank Leeds University, Mersin University for support
and Technical Research Council of Turkey–The Royal
Society—UK (TUBITAK-ESEP-Royal Society) for a
scholarship to Dr H. Ali DONDAS and Roche for a
generous gift of starting material 5.
References
1. Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699–1720.
Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bos, M.; Cook,
C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn,
M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.;
Vincent, G. P.; Voss, M. E. J. Med. Chem. 1993, 36,
3039–3049.
4.4. Single-crystal X-ray analyses
Crystallographic data for both 8a and 12c were measured on
a Nonius Kappa CCD area-detector diffractometer using a
mixture of area detector v- and f-scans and graphite
2. Olson, G. L.; Voss, M.; Hill, D. E.; Kahn, M.; Madison, V. S.;
Cook, C. M. J. Am. Chem. Soc. 1990, 112, 323–333.
3. Gavra, S. H.; Brunner, H. R.; Turini, G. A. N. Engl. J. Med.
1978, 298, 991–995. Natoff, I. L.; Attwood, M. R.; Eichler,
D. A.; Kogler, P.; Kleinbloesem, C. H.; Brummelen, P. V.
Cardiovasc. Drug Rev. 1985, 569, 580.
˚
monochromated Mo Ka radiation (l¼0.71073 A). Both
structures were solved by direct methods using SHELXS-
8619 and were refined by full-matrix least-squares (based on
F 2) using SHELXL-97.20,21 The weighting scheme used
was w¼[s 2(F2o)þ(xP)2þyP]21 where P¼(Fo2þ2F2c)/3. All
non-hydrogen atoms of both structures were refined with
anisotropic displacement parameters whilst hydrogen
atoms were constrained to predicted positions using a
riding model. The residuals wR2 and R1, given below, are
4. Natesh, R.; Schwager, S. L.; Sturrock, E. D.; Acharya, K. R.
Nature 2003, 421, 551–554.
5. Tipnis, S. R.; Hooper, N. M.; Hyde, R.; Karran, E.; Christie,
G.; Turner, A. J. J. Biol. Chem. 2000, 275, 33238–33243.
6. Crackower, M. A.; Serao, R.; Oudit, E. Y.; Yagil, C.;
Kozieradzki, I.; Scanga, S. E.; Oliveira-dos-Santos, A. J.; da
Costa, J.; Zhang, L.; Pei, Y.; Scholey, J.; Ferrario, C. M.;
Manoukian, A. S.; Chappell, M. C.; Baxx, P. H.; Yogil, Y.;
Penninger, J. M. Nature 2002, 417, 822–828.
P
P
defined as wR ¼( [w(F2o2Fc2)2]/ [wFo2]2)1/2 and R1¼
P
P2
llFol2lFcll/ lFol.
Crystal data for 8a. C30H34N4O6, 0.70£0.23£0.13 mm,
M¼546.61, orthorhombic, space group P212121,
7. Guy, J. L.; Jackson, R. M.; Acharya, K. R.; Sturrock, E. D.;
Hooper, N. M.; Turner, A. J. Submitted for publication.
¨
8. Attwood, R. M.; Hassall, C. H.; Krohn, A.; Lawton, G.;
˚
a¼12.4953(1), b¼15.9514(2), c¼16.1880(2) A, U¼
3
3226.55(6) A , Z¼4, Dc¼1.13 Mg m23, m¼0.08 mm21
,
˚
Redshaw, S. J. Chem. Soc., Perkin Trans. 1 1986, 1011–1019.
9. Thomas, W. A.; Gilbert, P. J. J. Chem. Soc., Perkin Trans. 2
1985, 1077–1082.
F(000)¼1160, T¼150 K.
Data collection. 1.0,2u,52.08; 6302 unique data were
collected [Rint¼0.058]; 6081 reflections with Fo.4.0s(Fo).
10. Thomas, W. A.; Whitcombe, I. W. A. J. Chem. Soc., Perkin
Trans. 2 1986, 747–755.
11. Grigg, R.; Sridharan, V. Advances in Cylcoaddition, JAI
Press Inc: New York, 1993; Vol. 3, pp 161–204.
12. Barr, D. A.; Dorrity, M. J.; Grigg, R.; Hargreaves, S.; Malone,
Structure refinement. Number of parameters¼370,
goodness of fit, s¼1.071; wR2¼0.1014, R1¼0.0368.

H. A. Dondas et al. / Tetrahedron 59 (2003) 8481–8487
8487
J. F.; Montgomery, J.; Redpath, J.; Stevenson, P.; Thornton-
Pett, M. Tetrahedron 1995, 51, 273–294.
17. Grigg, R.; McMeekin, P.; Sridharan, V. Tetrahedron 1995, 51,
13347–13356.
13. Dondas, H. A.; Grigg, R.; Thornton-Pett, M. Tetrahedron
1996, 52, 13455–13466.
18. Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P.;
Redpath, J. Tetrahedron 1995, 51, 7791–7808.
14. Grigg, R.; McMeekin, P.; Sridharan, V. Tetrahedron 1995, 51,
13347–13356.
19. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
20. Sheldrick, G. M. SHELX-93. Program for Refinement of
Cyristal Structures; Universty of Gottingen: Germany, 1993.
21. Flack, H. Acta Crystallogr., Sect. A 1983, 39, 876–881.
15. We thank Roche-UK for a generous gift of 5.
16. Barr, D. A.; Dorrity, M. J.; Grigg, R.; Hargreaves, S.; Malone,
J. F.; Montgomery, J.; Redpath, J.; Stevenson, P.; Thornton-
Pett, M. Tetrahedron 1995, 51, 273–294.