Synthesis of spiropyrimidodiazepines and spirodiazepinopurines by tandem nitroso-ene/Diels - Alder reactions

Article abstract of DOI:10.1002/hlca.200790238

New spirocyclic heterocycles 8, 16, 19/20, 25, 27, and 30 derived from pyrimido[4,5-b][1,4]diazepin]-8′(9′H)-one were synthesised by a tandem nitroso-ene/Diels - Alder reaction of 4-(alkenoylamino)-5- nitrosopyrimides. The crystal structure of 16 was esta

Full text of DOI:10.1002/hlca.200790238

Helvetica Chimica Acta – Vol. 90 (2007)
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Synthesis of Spiropyrimidodiazepines and Spirodiazepinopurines by Tandem
Nitroso-ene/Diels – Alder Reactions
by Fang-Li Zhang and Andrea Vasella*
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH Zürich, HCI, CH-8093 Zürich
New spirocyclic heterocycles 8, 16, 19/20, 25, 27, and 30 derived from pyrimido[4,5-b][1,4]diazepin]-
8’(9’H)-one were synthesised by a tandem nitroso-ene/Diels – Alder reaction of 4-(alkenoylamino)-5-
nitrosopyrimides. The crystal structure of 16 was established by X-ray analysis. It is characterised by four
pairs of intermolecular H-bonds linking every two molecules in the unit cell. Sequential imine reduction
and intramolecular condensation of the C(4’)-(acylamino)-pyrimido[4,5-b][1,4]diazepines 27 and 30 led
to the [1,4]diazepino[1,2,3-gh]purines 28/29 and 31, respectively.
Introduction. – The nitroso-ene reaction of 4-(alkenoylamino)-5-nitrosopyrimi-
dines 1 generates allylic hydroxylamines, and is followed by in situ elimination of H2O,
leading in high yield to C(6)-substituted pteridinones 2 [1]. We wondered about the ene
reaction of the 4-(acylamino)-5-nitrosopyrimidines I (Scheme 1), possessing an N-
alkenoyl group substituted at C(2) rather than at C(3). The ene reaction of I may lead
either to 6,6-disubstituted pteridinones II, via the reacting conformer Ia, or to
pyrimido[4,5-b][1,4]diazepines IV, via conformer Ib. Dehydration of the initial ene
products should generate the quinonoid III and/or lead to pyrimido[4,5-b][1,4]diaze-
pines V. The expected high reactivity of the intermediates and products suggested
intercepting them. We planned to do so by combining the nitroso-ene reaction with a
cycloaddition. The cycloaddition of V to 2,3-dimethylbuta-1,3-diene is expected to lead
to spiropyrimidodiazepines VI. This imine, or the presumably more stable amine VII,
should facilitate the analysis of the regioselectivity of the ene reaction, and lead to a
new ring system. No issue of regioselectivity is expected for the ene raction of 4-
(alkenoylamino)-5-nitrosopyrimidines I that lack the CH2R4 substituent. Their tandem
ene/Diels – Alder reaction was thought to lead exclusively to pyrimido[4,5-b][1,4]diaze-
pines, and appeared particularly attractive.
Two pyrimido[4,5-b][1,4]diazepines, 6-acetyl-2-amino-7,8-dihydro-9H-pyrimi-
do[4,5-b][1,4]diazepin-4(3H)-one (PDA, 3) and drosopterin (4), occur in nature.
PDA is the biogenetic precursor of drosopterin, aurodrosopterin, and neodrosopterin,
red eye pigments of Drosophila melanogaster [2]. There is considerable interest in
these heterocycles on account of the biological activity of analogous compounds, such
as benzodiazepines [3][4], pyridino-1,4-diazepines [5], and pyrimido-azepine-based
folates [6].
Most pyrimido[4,5-b][1,4]diazepines were prepared by condensing 4,5-diaminopyr-
imidines with 1,3-dicarbonyl compounds, or with a,b-unsaturated ketones [7][8]. As a
rule, the products possessing different substituents at C(6) and C(8) are obtained as
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 1
mixtures of regioisomers, a disadvantage that is avoided by condensing 4-chloro-5-
nitropyrimidines with b-amino ketones (Polonovski – Boon-type reactions) [9][10].
Only a few examples of spirobenzodiazepines are known [4][11][12] and, to the best of
our knowledge, no synthesis of spiropyrimido[4,5-b][1,4]diazepines has been reported.
We planned to study the nitroso-ene/Diels – Alder reaction of the tigloylamide 7 (see
Scheme 2 below), the simplest amide with a substituent corresponding to CH2R4, of the
methacryloyl derivative 15 (see Scheme 3 below), lacking this substituent, and of the
amides 24 and 26, possessing a 6-amino, or a 6-(acylamino) instead of a benzyloxy
group (see Scheme 4 below).
Results and Discussion. – Acylating 2,4-diamino-6-(benzyloxy)-5-nitrosopyrimi-
dine (5) [13] with tigloyl chloride (6; Scheme 2) yielded 54% of the tigloyl amide 7.

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Scheme 2
a) K2CO3, ꢀ 188, THF; 54%. b) 1208 (sealed V-vial), toluene; 50% of 8. c) NaBH4, MeOH; 82%.
d) Me3SiCl (TMSCl), LiBr, MeCN; 81%. e) NaBH4, MeOH; < 5%.
Similarly as reported for related compounds, the moderate yield of 7 is due to its
insufficient stability under acylating conditions (cf. [1]). Heating 7 in toluene in the
presence, or absence, of a Lewis acid such as Sc(OTf)3 provided a multitude of
products. Considering the high reactivity of the initially formed hydroxylamine [1][14]
and of the expected dehydration product 9, we heated 7 in the absence of a Lewis acid,
but in the presence of excess 2,3-dimethylbuta-1,3-diene. HPLC-MS of the product
evidenced the formation of the imines 8 (Mr 391) and 9 (Mr 309), and of the
dihydropteridinone 10 (Mr 311). Flash chromatography of the crude provided 50% of
8, besides small amounts of a mixture 9/10. The formation of 9 is supported by the
isolation, after reduction of 9/10 with NaBH4, of less than 5% of the cis-configured 11.
1
The H-NOE difference spectra evidence a different distance between the two Me

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groups to either HꢀC(6) or HꢀC(7) and thus, for a chair-like conformer, the cis-configu-
ration as in cis-11-02 (Scheme 2). The dihydropteridinone 10 was not isolated; it is thought
to arise (by disproportionation?) from precursor II (Scheme 1). Addition of butadiene
subsequent to the disappearance of the blue colour of 7 resulted in a lower yield of 8.
The 1H-NMR spectrum of 8 in CDCl3 shows conspicuous signals of the allylic CH2
group linked to the spiro centre (2d at 2.78 and 2.52 ppm, J ¼ 17.1), and of the Me group
at C(6’) (s at 2.21 ppm). The spiro center is revealed by a 13C s at 55.70 ppm.
Reduction of the imine 8 by NaBH4 led to a mixture 12a/12b of diastereoisomers
(major/minor 3 :1; Scheme 2). The 1H-NOE difference spectrum in deuteriated
benzene of the two separated quintuplets of HꢀC(6’) evidences the (1RS,6’SR)
configuration of the major component 12a and the (1RS,6’RS)-configuration of the
minor 12b. Debenzylation of the mixture 12a/12b with in situ generated Me3SiBr
(TMSBr) yielded 81% of a 3 :1 mixture of the spiropyrimido[4,5-b][1,4]diazepines 13a
and 13b.
The methacryloyl amide 15 was obtained in a yield of 45% by acylating 5 with
methacryloyl chloride (14; Scheme 3). Heating 15 in the presence of 2,3-dimethylbuta-
1,3-diene provided the spirodiazepine 16 in a yield of 68%. It was reduced with
NaBH(OAc)3 to the amine 17 (97%) that was debenzylated with TMSBr to 18 that
precipitated from solution, and was isolated in a yield of 92%. Heating 15 in the
Scheme 3
a) K2CO3, ꢀ 188, THF; 45%. b) 1108 (sealed V-vial), 0.5 h, toluene; 68%. c) NaBH(OAc)3, AcOH,
CH2Cl2; 97%. d) TMSCl, LiBr, MeCN; 92%. e) 1108 (sealed V-vial), 0.5 h, toluene; 85%, then
NaBH(OAc)3, AcOH, CH2Cl2; 94%. f) CF3COOH (TFA), Et3SiH; 90%.

Helvetica Chimica Acta – Vol. 90 (2007)
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presence of cyclopentadiene [15] resulted in a 7:3 mixture of imines (85%) that were
directly reduced to a mixture of the endo-amine 19 and its exo-isomer 201).
The amines 19/20 were separated by preparative HPLC (NH2-phase silica gel), and
their configuration was deduced on the basis of the Ha,bꢀC(3) signals appearing at 1.70
(d, J ¼ 11.4, 1 H) and 1.40 ppm (dd, J ¼ 11.4, 3.0, 1 H) for the endo-isomer 19 (Dda,b
¼
0.30 ppm), and at 2.35 (dd, J ¼ 11.6, 3.0, 1 H) and 0.87 ppm (d, J ¼ 11.6, 1 H) for the
exo-isomer 20 (Dda,b ¼ 1.48 ppm), revealing the combined effect of the deshielding
C(8’)¼O group and the shielding C(5)¼C(6) bond on H2C(3) [16]. Debenzylation of
19 and 20 with TMSBr gave rise to a considerable amount of by-products, while
debenzylation with TFA and Et3SiH led in high yields to the pyrimidinones 21 and 22.
The structure of the imine 16 was established by X-ray analysis of crystals that were
t
obtained by slow evaporation of a solution in BuOH/CH2Cl2 (2 :1; Fig.). In the unit
Figure. Crystal structure of 16 showing the conformation and the intermolecular H-bonds
1
)
The endo/exo configuration refers to the orientation of C(8’)¼O. Heating 15 in the presence of
cyclohexa-1,3-diene afforded mainly an unstable product of an intermolecular nitroso-Diels – Alder
cycloaddition.

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cell, there are four symmetrically independent molecules of 16 and at least two solvent
(CH2Cl2) molecules, of which only one could be localised completely. Four pairs of
intermolecular H-bonds (compare [17]) link the H2NꢀC¼N and O¼CꢀNH groups of
two molecules, with H ··· N/O distances in the range of 2.09 – 2.20 Š. The seven-
membered diazepine ring in 16 adopts a B4a,7,9a boat conformation [7].
The transformation of 16 to 17 is evidenced by the disappearance of the N¼CH s at
6.94 ppm and the N¼CH d at 154.84 ppm, and by the appearance of new signals for
NHCH2 at 4.72 – 4.69 ppm (m, D2O exchangeable, 1 H); for NHCH2 at 3.06 ppm (dd,
J ¼ 13.7, 5.6, 1 H) and 2.88 ppm (dd, J ¼ 13.7, 3.2, 1 H), and by a NHCH2 t at 46.17 ppm.
The UV spectrum of 17 is characterised by a maximum at 337 nm (log e ¼ 3.71) with a
shoulder at 273 nm (log e ꢁ 3.62), while 16 shows a maximum at 305 nm (log e ¼ 4.02).
This may be rationalized by an impaired conjugation of 16 in a B4a,7,9a conformation, as
it is found in the solid state (45 – 508 deviation between the p-planes of the pyrimidine
and both the amido moieties), whereas full conjugation is found for the half-chair
7
conformation (6H7 and/or H6) of 17. The UV spectrum of the debenzylated 18 is
characterised by a maximum at 344 nm (log e ¼ 3.81), and its IR spectrum shows C¼O
bands at 1631 and 1611 cmꢀ1. The UV spectra of 19 and 20 are similar to the one of 17,
and those of 21 and 22 are similar to the one of 18.
To test the effect on the ene reaction of substituting the benzyloxy by an amino or
an acylamino group, we acylated the poorly soluble 2,4,6-triamino-5-nitrosopyrimidine
(23) [18] with methacryloyl chloride (14), and obtained a mixture 24/26 of mono- and
diacylated products that were difficult to separate (Scheme 4). Acylation of 23 with 1.3
equiv. of 14 at ꢀ 188 in DMF yielded 40% of the mono-amide 24 as the major product,
while acylation with 2.2 equiv. of 14 at ꢀ 5 to ꢀ 108 in THF provided mainly the
diamide 26 (38%). The modest yield of the amides is again due to the insufficient
stability of the nitroso compounds under acylating conditions.
Heating the mono-amide 24 to 1558 and the diamide 26 to 1108, both in the presence
of 2,3-dimethylbuta-1,3-diene, provided the imines 25 (94%) and 27 (97%),
respectively (Scheme 4). The higher temperature required for the transformation of
24 may reflect its lower electrophilicity. Reduction of the imine 27 with NaBH(OAc)3
and AcOH was accompanied by a condensation, as in the Traube synthesis of purines
[19][20], leading to the spiro[1,4]diazepino[1,2,3-gh]purine 28 (41%) and its N-ethyl
analogue 29 (37%; Scheme 4). The 2-ethylamino derivative 29 is presumably formed by
reductive alkylation of 28, with NaBH(OAc)3 as the source of the Et group. As ca. 10%
starting material remained when 27 was treated with 5 equiv. NaBH(OAc)3 and 50
equiv. AcOH, we increased the amount of reducing agent, but only observed the
formation of a higher percentage of the 2-ethylamino derivative 29.
The structure of the condensed purine 28 is confirmed by a high-resolution (HR)
MS, and by HSQC and HMBC spectra, and by elemental analysis. The difference
between the NMR spectra of the starting material 27 and product 28 shows that an
imino group was transformed into an NꢀCH2 rather than into the expected NHCH2
group, and that one amide NH signal disappeared. The HMBC spectrum shows cross-
peaks between the singlet of CH2(7) and C(2’), C(6’), C(5), C(8), C(9), and C(10b),
evidencing the structure of 28.
Heating 26 in the presence of cyclopentadiene (Scheme 4) yielded 84% of a
presumably endo/exo-mixture 30 of the expected imines (7:3). Treatment of 30 with

Helvetica Chimica Acta – Vol. 90 (2007)
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Scheme 4
a) K2CO3, ꢀ 188, DMF; 40%. b) 1558 (sealed V-vial), toluene; 94%. c) K2CO3, ꢀ 5 to ꢀ 108, THF; 38%.
d) 1108 (sealed V-vial), toluene; 97%. e) NaBH(OAc)3, AcOH; 41% of 28 and 37% of 29. f) 1108
(sealed V-vial), toluene; 84%. g) NaBH(OAc)3, AcOH, CH2Cl2; 47%.
excess NaBH(OAc)3 and AcOH provided an endo/exo-mixture of the purines 31 (47%)
resulting from reduction, condensation, and N-ethylation.
The spiro[1,4]diazepino[1,2,3-gh]purines 28, 29, and 31 are representatives of a new
ring system. The only naturally occurring [1,4]diazepino[1,2,3-gh]purines are the
asmarines A – F, cytotoxic marine alkaloids isolated by Kashman and co-workers from
the Red Sea sponge Raspailia sp. [21]. A few syntheses of [1,4]diazepino[1,2,3-
gh]purines are known; they proceed by annulating the diazepine ring onto a purine.
Thus, Suzuki et al. reported the synthesis of a [1,4]diazepino[1,2,3-gh]purin-2-one by
cyclization via silylation and amination of 7-(aminoalkyl)-3-propylpurine-2,4-diones
[22]. The Kashman group reported the synthesis of 9-substituted tetrahydro[1,4]dia-
zepino[1,2,3-gh]purines by intramolecular alkylation at NꢀC(6) of an C(6)-(benzyl-
oxy)aminoadenine in view of a synthesis of asmarines A – F [23][24], and Ohba and
Tashiro proceeded towards the same goal by cyclization of the 6-chloro-7-[3-
(hydroxyamino)propyl]purine [25].
In summary, the tandem nitroso-ene/Diels – Alder reaction and the ensuing
reduction/condensation offers a rapid and convenient approach to spiropyrimido[4,5-b]-
[1,4]diazepines and spiro[1,4]diazepino[1,2,3-gh]purines.

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We thank the ETH Zürich and F. Hoffmann-La Roche AG, Basel, for generous support, Dr. Bruno
Bernet for checking the analytical data, Dr. W. Bernd Schweizer for the X-ray analysis, Prof. Dr. Bernhard
Jaun for a critical discussion of the NOE assignments, Prof. Dr. W. Pfleiderer for stimulating discussions
about the UV spectra, and Brigitte Brandenberg and Chao Zou for the NMR spectra.
Experimental Part
General. See [26]. Flash chromatography (FC): Merck silica gel 60 (0.063 – 0.200 mm). FT-IR
Spectra: neat (ATR), absorption in cmꢀ1. UV Spectra: in MeOH, lmax (log e). HR-MALDI-MS: in 3-
hydroxypicolinic acid (3-HPA) matrix.
(E)-N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-2-methylbut-2-enamide (7). A suspension
of 5 (368 mg, 1.5 mmol) in THF (60 ml) was treated with K2CO3 (1.7 g, 12 mmol), cooled to ꢀ 188, and
treated with 6 (0.26 ml, 2.2 mmol) within 2 h (addition via a syringe pump). The mixture was stirred for
0.5 h, diluted with CH2Cl2 (100 ml), washed with cold H2O (2 Â 50 ml) and brine (50 ml), dried
(MgSO4), and evaporated. The green residue was washed with CH2Cl2/AcOEt 2 :1 (20 ml). Filtration
gave 7 (265 mg, 54%). Blue powder. M.p. > 1398 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.50. UV: 204 (4.39),
259 (4.14), 350 (4.33). IR (ATR): 3375w, 3319m, 3236m, 1712m, 1649s, 1634s, 1591s, 1579m, 1519s, 1497m,
1456s, 1435s, 1402s, 1352s, 1329m, 1310m, 1255s, 1188s, 1145s, 1129s, 1076s, 1042s, 1017m, 979m, 939w,
879m, 851w, 827m. 1H-NMR (300 MHz, (D6)DMSO): 13.10 (br. s, NH); 8.78, 8.72 (2 br. s, NH2); 7.57 –
7.37 (m, 5 arom. H); 6.67 (br. q, J ¼ 5.4, HꢀC(3)); 5.63 (s, PhCH2); 1.88 (br. s, 2 Me). 13C-NMR (75 MHz,
(D6)DMSO): 166.24 (s, C¼O); 164.17 (s, C(6’)); 139.08 (s, C(4’)); 135.53 (s); 135.29 (d, C(3)); 132.41 (s,
C(2)); 128.45 (2d); 128.33 (2d); 128.17 (d); 68.31 (t, PhCH2); 14.29, 11.81 (2q, 2 Me); signals of C(2’) and
C(5’) not visible due to coalescence. HR-MALDI-MS: 328.1409 (40, [M þ H]þ, C16H18N5O3þ ; calc.
328.1410), 350.1219 (100, [M þ Na]þ, C16H17N5NaO3þ ; calc. 350.1224).
(1RS)-2’-Amino-4’-(benzyloxy)-3,4,6’-trimethylspiro[cyclohex-3-ene-1,7’-pyrimido[4,5-b][1,4]diaze-
pin]-8’(9’H)-one ((Æ)-8). A mixture of 7 (32.7 mg, 0.1 mmol) and 2,3-dimethylbuta-1,3-diene (0.09 ml,
0.8 mmol) in toluene (5 ml) in a sealed V-vial was rapidly heated to 1208, and stirred for 4 h. The resulting
brown suspension was concentrated. FC (cyclohexane/AcOEt 4 :1) gave 8 (19 mg, 50%) and a fraction
containing 8 and 9. White powder. M.p. 121 – 1238 (dec.). Rf (cyclohexane/AcOEt 1:2) 0.53. UV: 206
(4.50), 217 (4.497), 307 (4.11). IR (ATR): 3480w, 3321w, 3202m, 2925w, 2855w, 1655m, 1625s, 1594s,
1549s, 1482m, 1424s, 1381m, 1345s, 1312m, 1271m, 1236m, 1202w, 1179m, 1153m, 1092m, 1060w, 1041w,
986w, 951w, 909w, 847w, 824w. 1H-NMR (300 MHz, CDCl3): 11.85 (br. s, NH); 7.43 – 7.28 (m, 5 arom. H);
6.20 (br. s, NH2); 5.63, 5.46 (2d, J ¼ 12.9, PhCH2); 2.78, 2.52 (2d, J ¼ 17.1, 2 HꢀC(2)); 2.21 (s,
1
MeꢀC(6’)); 1.98 – 1.66, 1.50 – 1.40 (2m, 2 CH2); 1.74, 1.59 (2s, 2 Me). H-NMR (300 MHz, (D6)DMSO,
353 K): 10.19 (br. s, NH); 7.46 – 7.30 (m, 5 arom. H); 6.22 (br. s, NH2); 5.46 (s, PhCH2); 2.56, 2.32 (2d, J ¼
18.9, 2 HꢀC(2)); 2.08 (s, MeꢀC(6’)); 1.90 – 1.70, 1.60 – 1.50 (2m, 2 CH2); 1.65, 1.55 (2s, 2 Me). 13C-NMR
(75 MHz, CDCl3): 169.00 (s, C¼O); 164.78 (s, C(4’)); 161.65 (s, C(6’)); 159.30 (s, C(2’)); 146.60 (s,
C(9’a)); 136.75 (s); 128.25 (2d); 127.67 (d); 127.51 (2d); 125.74, 124.15 (2s, C(3), C(4)); 111.79 (s, C(4’a));
68.15 (t, PhCH2); 55.70 (s, C(1)); 37.77 (t, C(2)); 29.40, 23.12 (2t, C(5), C(6)); 25.58 (q, MeꢀC(6’)); 19.00,
18.33 (2q, 2 Me). 13C-NMR (75 MHz, (D6)DMSO): 166.78 (s, C¼O); 163.91 (s, C(4’)); 160.11 (s, C(6’));
158.96 (s, C(2’)); 147.41 (s, C(9’a)); 136.95 (s); 128.32 (2d); 127.91 (2d); 127.78 (d); 125.74, 124.15 (2s,
C(3), C(4)); 110.37 (s, C(4’a)); 66.97 (t, PhCH2); 55.03 (s, C(1)); 37.43 (t, C(2)); 29.06, 22.43 (2t, C(5),
C(6)); 25.13 (q, MeꢀC(6’)); 18.98, 18.16 (2q, 2 Me). HR-MALDI-MS: 392.2086 (100, [M þ H]þ,
C22H26N5Oþ2 ; calc. 392.2087), 414.1913 (5, [M þ Na]þ, C22H25N5NaOþ2 ; calc. 414.1906).
(1RS,6’SR)- and (1RS,6’RS)-2’-Amino-4’-(benzyloxy)-3,4,6’-trimethyl-5’,6’-dihydrospiro[cyclohex-
3-ene-1,7’-pyrimido[4,5-b][1,4]diazepin]-8’(9’H)-one ((Æ)-12a and (Æ)-12b). A soln. of 8 (43 mg,
0.11 mmol) in MeOH/THF 3 :1 (20 ml) was treated with NaBH4 (42 mg, 1.1 mmol), heated to reflux for
1 h, treated with additional NaBH4 (2 Â 42 mg, 1.1 mmol) after 1 and 2 h, and diluted with CH2Cl2
(60 ml). The org. phase was washed with 1n NaOH, H2O (2 Â 30 ml), and brine (30 ml), dried (MgSO4),
and evaporated. FC (CH2Cl2/AcOEt 6 :1) gave 12a/12b (35 mg, 82%). White powder. M.p. 98 – 1008
(dec.). Rf (CH2Cl2/AcOEt 2 :1) 0.44. UV: 205 (4.45), 269 (3.77), 343 (3.85). IR (ATR): 3311w, 3200w,
2969w, 2912w, 2855w, 1635m, 1572s, 1494m, 1436s, 1407s, 1376m, 1352s, 1284m, 1237m, 1210m, 1173m,

Helvetica Chimica Acta – Vol. 90 (2007)
2323
1090s, 1028w, 947w, 909w, 843w. 1H-NMR (500 MHz, CD2Cl2; 3 :1 mixture of diastereoisomers): 9.44 (s,
0.25 H), 9.33 (s, 0.75 H) (HꢀN(9’), exchange with D2O); 7.43 – 7.33 (m, 5 arom. H); 5.36 (s, PhCH2); 5.18
(s, 0.5 H), 5.12 (s, 1.5 H) (H2NꢀC(2’), exchange with D2O); 4.06 (br. s, 0.75 H), 4.00 (br. s, 0.25 H)
(HꢀN(5’), exchange with D2O); 3.33 (m, HꢀC(6’), addn. of D2O ! q, J ¼ 6.0); 2.72 (d, 0.75 H), 2.19 (d,
0.25 H) (J ꢁ 15.0, HꢀC(2)); 2.13 – 1.67 (m, H’ꢀC(2), CH2CH2); 1.63, 1.59 (2s, 4.5 H), 1.59, 1.54 (2s,
1.5 H) (MeꢀC(3), MeꢀC(4)); 1.09 (d, J ¼ 6.0, MeꢀC(6’)). 13C-NMR (125 MHz, CD2Cl2; 3 :1 mixture of
diastereoisomers): major: 177.24 (s, C¼O); 161.47 (s, C(4’)); 154.87 (s, C(2’)); 140.99 (s, C(9’a)); 137.32
(s); 129.07 (2d); 128.84 (2d); 128.73 (d); 124.66, 123.61 (2s, C(3), C(4)); 108.64 (s, C(4’a)); 69.17 (t,
PhCH2); 51.98 (s, C(1)); 50.00 (d, C(6’)); 38.46 (t, C(2)); 29.59, 28.72 (2t, C(5), C(6)); 19.46 (q,
MeꢀC(6’)); 18.85, 18.82 (2q, 2 Me); minor: 178.20 (s, C¼O); 161.63 (s, C(4’)); 155.24 (s, C(2’)); 142.05 (s,
C(9’a)); 137.36 (s); 128.77 (2d); 128.75 (d); 128.71 (2d); 125.27, 122.98 (2s, C(3), C(4)); 108.60 (s, C(4’a));
69.08 (t, PhCH2); 51.40 (s, C(1)); 49.48 (d, C(6’)); 38.22 (t, C(2)); 29.36, 28.83 (2t, C(5), C(6)); 19.59 (q,
MeꢀC(6’)); 18.90, 18.35 (2q, 2 MeꢀC(3,4)). HR-MALDI-MS: 394.2239 (100, [M þ H]þ, C22H28N5O2þ ;
calc. 394.2238), 416.2073 (3, [M þ Na]þ, C22H27N5NaO2þ ; calc. 416.2062).
2-Amino-4-(benzyloxy)-6,7-dihydro-6,7-dimethyl-5H-pyrimido[4,5-b][1,4]diazepin-8(9H)-one (11).
The pooled by-products obtained by FC of 8 (22 mg) was treated with excess NaBH4 in MeOH/THF
3 :1. Workup as for 12a/12b and chromatography gave 11 (8 mg). White powder. Rf (cyclohexane/AcOEt
2 :1) 0.30. UV: 214 (4.39), 255 (3.88), 323 (3.75). IR (ATR): 3444m, 3380w, 3330w, 3227w, 3083w, 2963w,
2928w, 1664s, 1619s, 1570s, 1497m, 1479s, 1450m, 1438m, 1417s, 1380m, 1368m, 1354s, 1290m, 1270s,
1
1206w, 1173m, 1145m, 1084m, 1072m, 1053m, 1029w, 1003w, 986w, 954w, 904w, 862w, 801m. H-NMR
(300 MHz, (D6)DMSO): 9.56 (br. s, HꢀN(9)); 7.49 – 7.30 (m, 5 arom. H); 5.96 (br. s, NH2); 5.36 (s,
PhCH2); 4.06 (d, J ¼ 4.5, HꢀN(5)); 3.67 – 3.62 (dq, J ¼ 3.0, 5.5, HꢀC(6), after D2O exchange); 2.72 – 2.67
(dq, J ¼ 3.0, 6.0, HꢀC(7), after D2O exchange); 1.02 (d, J ¼ 6.0, MeꢀC(6)); 0.92 (d, J ¼ 6.0, MeꢀC(7)).
13C-NMR (75 MHz, (D6)DMSO): 174.59 (s, C¼O); 161.62 (s, C(4)); 155.84 (s, C(2)); 149.11 (s, C(9a));
137.05 (s); 128.52 (2d); 128.06 (2d); 127.98 (d); 108.83 (s, C(4a)); 67.17 (t, PhCH2); 58.12 (d, C(6)); 41.92
(d, C(7)); 18.27, 12.46 (2q, 2 Me). HR-MALDI-MS: 314.1612 (100, [M þ H]þ, C16H20N5O2þ ; calc.
314.1612).
(1RS,6’SR)- and (1RS,6’RS)-2’-Amino-5’,6’-dihydro-3,4,6’-trimethylspiro[cyclohex-3-ene-1,7’-pyri-
mido[4,5-b][1,4]diazepine]-4’,8’(3’H,9’H)-dione ((Æ)-13a and (Æ)-13b). A soln. of anh. LiBr (14.4 mg,
0.16 mmol) in MeCN (1.5 ml) was treated with Me3SiCl (22 ml, 0.2 mmol), stirred at 238 under Ar for
5 min, treated with dry 12a/12b (16 mg, 0.04 mmol), stirred at 238, and treated with Me3SiCl (2 Â 22 ml,
0.2 mmol) after 8 and 24 h. After stirring for a total of 40 h, an off-white fine precipitate was formed. The
suspension was cooled to 08, treated with MeOH (0.1 ml), filtered (washing with Et2O), and dried i.v. to
afford 13a/13b (10 mg, 81%). Off-white powder. M.p. > 2458 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.28. UV:
204 (4.15), 223 (4.19), 252 (3.83), 346 (3.76). IR (ATR): 3336w, 3244w, 3135w, 3042w, 2974w, 1697s,
1651s, 1577w, 1530w, 1491w, 1442w, 1384m, 1351w, 1312m, 1281m, 1249w, 1196w, 1131w, 1085w, 1064w,
910w. 1H-NMR (300 MHz, (D6)DMSO), 3 :1 mixture of diastereoisomers): 11.72 (0.25 H), 11.23
(0.75 H) (2 br. s, HꢀN(3’)); 9.48 (0.25 H), 9.27 (0.75 H) (2s, HꢀN(9’)); 7.40 (0.5 H), 7.31 (1.5 H) (2 br. s,
NH2); 5.48 (br. s, HꢀN(5’)); 3.37 (m, HꢀC(6’)); 2.76 – 2.40, 2.20 – 1.62 (2m, 6 HꢀC(2,5,6)); 1.59, 1.56 (2s,
4.5 H), 1.56, 1.54 (2s, 1.5 H) (MeꢀC(3), MeꢀC(4)); 1.06 (0.75 H), 0.97 (2.25 H) (2d, J ꢁ 6.0,
MeꢀC(6’)). 13C-NMR (125 MHz, (D6)DMSO); only signals of the major isomer are assigned): 174.00
(s, C(8’)); 157.82 (s, C(4’)); 149.20 (s, C(2’)); 123.53, 122.54 (2s, C(3), C(4)); 104.72 (s, C(4’a)); 50.87 (s,
C(1)); 49.27 (d, C(6’)); 37.32 (t, C(2)); 28.67, 27.70 (2t, C(5), C(6)); 18.92 (q, MeꢀC(6’)); 18.43 (q,
MeꢀC(3), MeꢀC(4)); the signal of C(9’a) was not observed. HR-MALDI-MS: 304.1763 (100, [M þ
H]þ, C15H22N5Oþ2 ; calc. 304.1768), 326.1590 (4, [M þ Na]þ, C15H21N5NaOþ2 ; calc. 326.1587).
N-[2-Amino-6-(benzyloxy)-5-nitrosopyrimidin-4-yl]-2-methylprop-2-enamide (15). A suspension of
5 (1 g, 4.1 mmol) in THF (150 ml) was treated with K2CO3 (4.6 g, 32.7 mmol), cooled to ꢀ 188, treated
dropwise with 14 (0.6 ml, 6.1 mmol) within 2 h (addition via a syringe pump), stirred for 0.5 h, diluted
with CH2Cl2 (200 ml), washed with cold H2O (2 Â 100 ml) and brine (100 ml), dried (MgSO4), and
evaporated. FC (CH2Cl2/AcOEt 3 :1) of the green residue gave 15 (568 mg, 45%). Blue powder. M.p.
> 1508 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.50. UV: 205 (4.35), 261 (4.11), 353 (4.34). IR (ATR): 3481m,
3299w, 3200m, 1712m, 1630s, 1597s, 1543s, 1496m, 1483w, 1450s, 1401m, 1377w, 1346s, 1307s, 1289s,
1268m, 1194s, 1148s, 1100s, 1078m, 1060m, 1029m, 1002m, 946s, 910m, 889w, 845m, 810m. 1H-NMR

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Helvetica Chimica Acta – Vol. 90 (2007)
(300 MHz, (D6)DMSO): 13.15 (br. s, NH); 8.83, 8.76 (2 br. s, NH2); 7.57 – 7.35 (m, 5 arom. H); 5.97 (br. s,
HꢀC(3)); 5.82 (d, J ¼ 1.2, H’ꢀC(3)); 5.63 (s, PhCH2); 1.99 (s, Me). 1H-NMR (300 MHz, CDCl3): 13.22
(br. s, NH); 7.54 – 7.34 (m, 5 arom. H); 7.02, 6.05 (2 br. s, NH2); 6.16 (br. s, HꢀC(3)); 5.79 (d, J ¼ 1.2,
H’ꢀC(3)); 5.72 (s, PhCH2); 2.10 (s, Me). 13C-NMR (75 MHz, CDCl3): 167.00 (s, C¼O); 164.45 (s, C(6’));
139.80 (s, C(4’)); 139.43 (s, C(2)); 135.16 (s); 128.55 (2d); 128.40 (d); 128.20 (2d); 124.30 (t, C(3)); 69.53
(t, PhCH2); 18.15 (q, Me); signals of C(2’) and C(5’) not visible due to coalescence. HR-MALDI-MS (low
intensity due to ene reaction during measurement): 314.1249 (33, [M þ H]þ, C15H16N5O3þ ; calc.
314.1248), 336.1084 (1, [M þ Na]þ, C15H15N5NaOþ3 ; calc. 336.1067).
(1RS)-2’-Amino-4’-(benzyloxy)-3,4-dimethylspiro[cyclohex-3-ene-1,7’-pyrimido[4,5-b][1,4]diaze-
pin]-8’(9’H)-one ((Æ)-16). A mixture of 15 (35 mg, 0.11 mmol) and 2,3-dimethylbuta-1,3-diene (0.1 ml,
0.88 mmol) in toluene (6 ml) in a sealed V-vial was put into an oil-bath of 1108, and stirred for 0.5 h. The
resulting light-brown suspension was evaporated, and FC (cyclohexane/AcOEt 3 :1) gave 16 (29 mg,
68%). White powder. M.p. 203.8 – 205.08 (dec.). Rf (cyclohexane/AcOEt 1:1) 0.38. UV: 210 (4.47), 305
(4.02). IR (ATR): 3400m, 3322m, 3216m, 3038w, 2924m, 2885m, 2855m, 2836m, 1666s, 1638s, 1593s,
1545s, 1508m, 1488s, 1455m, 1425s, 1383m, 1340s, 1307s, 1276m, 1238m, 1224m, 1202w, 1153s, 1132m,
1
1083s, 1059m, 1031w, 946m, 909m, 883m, 849m, 819m. H-NMR (300 MHz, (D6)DMSO): 10.60 (br. s,
NH); 7.46 – 7.31 (m, 5 arom. H); 6.94 (s, N¼CH); 6.68 (br. s, NH2); 5.44, 5.38 (2d, J ¼ 12.3, PhCH2); 2.42
(d, J ¼ 16.8), 2.13 (d, J ¼ 17.4) (2 HꢀC(2)); 1.88 – 1.44 (m, CH2CH2); 1.60, 1.55 (2s, 2 Me). 13C-NMR
(75 MHz, (D6)DMSO): 168.08 (s, C¼O); 164.62 (s, C(4’)); 159.53 (s, C(2’)); 154.84 (d, C(6’)); 147.75 (s,
C(9’a)); 136.54 (s); 128.21 (2d); 127.92 (2d); 127.75 (d); 124.52, 122.85 (2s, C(3), C(4)); 109.83 (s, C(4’a));
67.32 (t, PhCH2); 51.52 (s, C(1)); 35.98 (t, C(2)); 28.40 (t, C(5)); 23.81 (t, C(6)); 19.21, 18.51 (2q, 2 Me).
HR-MALDI-MS: 378.1919 (100, [M þ H]þ, C21H24N5Oþ2 ; calc. 378.1925), 400.1745 (4, [M þ Na]þ,
C21H23N5NaOþ2 ; calc. 400.1744). Anal. calc. for C21H23N5O2 (377.45): C 66.83, H 6.14, N 18.55; found: C
66.83, H 6.21, N 18.26.
X-Ray Analysis of 162). Slow evaporation of a soln. of 16 in tBuOH/CH2Cl2 (2 :1) gave single crystals
suitable for X-ray-analysis (dimensions: 0.02 Â 0.25 Â 0.35 mm; colourless). 4(C21H23N5O2) · CH2Cl2, Mr
¯
1679.62, triclinic, P1, a ¼ 13.9256(10), b ¼ 17.2683(14), c ¼ 8.013(2) Š, a ¼ 92.962(3), b ¼ 106.058(3), g ¼
90.082(4)8, V¼ 4156.5(6) Š3; Z ¼ 4, Dcalc. ¼ 1.268 Mg/m3. Intensities were measured on a Nonius Kappa
CCD diffractometer, with MoKa radiation l ¼ 0.71073 Š, q ¼ 3.7 – 22.88, m ¼ 0.150 mmꢀ1, T¼ 223 K.
There are four symmetrically independent molecules in the unit cell, which contains also at least two
solvent (CH2Cl2) molecules, of which only one could be localised completely. In addition, diffraction of
small crystal fragments stuck to the target crystal was interfering with intensities, resulting in an impaired
agreement factor.
(1RS)-2’-Amino-4’-(benzyloxy)-5’,6’-dihydro-3,4-dimethylspiro[cyclohex-3-ene-1,7’-pyrimido[4,5-
b][1,4]diazepin]-8’(9’H)-one ((Æ)-17). A soln. of NaBH(OAc)3 (22.4 mg, 0.11 mmol) and AcOH (26 ml,
0.45 mmol) in CH2Cl2 (5 ml) at 08 was treated with a soln. of 16 (25 mg, 0.07 mmol) in CH2Cl2 (5 ml),
stirred at r.t. for 2 h, diluted with CH2Cl2 (20 ml), and poured into H2O (20 ml). After basification by
addition of sat. NaHCO3, the org. phase was washed with H2O (2 Â 20 ml) and brine (20 ml), dried
(MgSO4), and evaporated. FC (cyclohexane/AcOEt 3 :1) gave 17 (24.5 mg, 97%). Very hygroscopic
white powder. M.p. 87 – 898 (dec.). Rf (CH2Cl2/AcOEt 2 :1) 0.38. UV: 204 (4.36), 273 (3.62), 337 (3.71).
IR (ATR): 3315w, 3204w, 2921w, 2847w, 1652m, 1628m, 1579s, 1468s, 1429s, 1365s, 1341s, 1316m, 1289m,
1
1236m, 1159s, 1128m, 1095m, 1029w, 958w, 912w, 847w. H-NMR (300 MHz, (D6)DMSO): 8.88 (br. s,
NH); 7.51 – 7.32 (m, 5 arom. H); 5.74 (br. s, NH2); 5.37, 5.32 (2d, J ¼ 12.9, PhCH2); 4.72 – 4.69 (m,
NHCH2); 3.06 (dd, J ¼ 13.7, 5.6), 2.88 (dd, J ¼ 13.7, 3.2) (NHCH2); 2.45 (HꢀC(2), overlapping with
signal of (D6)DMSO); 2.18 – 2.02 (m, H’ꢀC(2)); 1.82 – 1.66 (m, CH2CH2); 1.57 (s, 2 Me). 13C-NMR
(75 MHz, (D6)DMSO): 177.63 (s, C¼O); 159.26 (s, C(4’)); 154.12 (s, C(2’)); 143.21 (s, C(9’a)); 136.61 (s);
128.14 (2d); 127.77 (2d); 127.63 (d); 123.37, 122.23 (2s, C(3), C(4)); 109.45 (s, C(4’a)); 67.15 (t, PhCH2);
46.77 (s, C(1)); 46.17 (t, NHCH2); 37.00 (t, C(2)); 28.07 (t, C(5)); 27.18 (t, C(6)); 19.08, 18.67 (2q, 2 Me).
2
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
deposition No. CCDC-636601. Copies of the data can be obtained, free of charge, on application to
the CCDC, 12 Union Road, Cambridge CB2 1EZ (fax: þ 44(1223)336033; e-mail: deposit@ccdc.
cam.ac.uk).

Helvetica Chimica Acta – Vol. 90 (2007)
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HR-MALDI-MS: 380.2074 (100, [M þ H]þ, C21H26N5Oþ2 ; calc. 380.2081), 402.1900 (4, [M þ Na]þ,
C21H25N5NaOþ2 ; calc. 402.1900).
(1RS)-2’-Amino-5’,6’-dihydro-3,4-dimethylspiro[cyclohex-3-ene-1,7’-pyrimido[4,5-b][1,4]diaze-
pine]-4’,8’(3’H,9’H)-dione ((Æ)-18). A soln. of anh. LiBr (28 mg, 0.32 mmol) in MeCN (2.5 ml) was
treated with Me3SiCl (40 ml, 0.32 mmol), stirred at 238 under Ar for 5 min, and treated with dry 17
(30 mg, 0.08 mmol). The mixture was treated twice with Me3SiCl (50 ml, 0.4 mmol), after stirring at 238
for 8 h and 24 h, resp. An off-white precipitate was formed. The resulting suspension was stirred for 8 h,
cooled to 08, treated with MeOH (0.3 ml), and filtered. The filter content was washed with Et2O and
dried i.v. to afford 18 (16.3 mg). Evaporation of the combined filtrate and washing, and FC (AcOEt/
MeOH 20 :0 ! 20 :1) gave additional 18 (4.8 mg; total yield: 92%). Off-white powder. M.p. > 2508
(dec.). Rf (CH2Cl2/MeOH 20 :1) 0.25. UV: 203 (4.34), 226 (4.30), 344 (3.81). IR (ATR): 3334w, 3242w,
3148w, 3019w, 2912w, 1704m, 1631s, 1611s, 1542w, 1503w, 1463m, 1389m, 1315m, 1289m, 1213w, 1175w,
1088w, 1043w, 891w, 848w. 1H-NMR (300 MHz, (D6)DMSO): 11.57 (br. s, HꢀN(3’)); 9.11 (s, HꢀN(9’));
6.65 (br. s, NH2); 5.95 (br. s, HꢀN(5’)); 3.13, 2.96 (2d, J ¼ 13.8, 2 HꢀC(6’)); 2.45 (overlapping with signal
of (D6)DMSO, HꢀC(2)); 2.14 – 1.98 (m, H’ꢀC(2)); 1.83 – 1.61 (m, CH2CH2); 1.57 (s, 2 Me). 13C-NMR
(75 MHz, (D6)DMSO): 176.02 (s, C(8’)); 158.29 (s, C(4’)); 148.21 (s, C(2’)); 123.57, 122.02 (2s, C(3),
C(4)); 108.02 (s, C(4’a)); 47.53 (s, C(1)); 46.39 (t, C(6’)); 37.04 (t, C(2)); 28.06 (t, C(5)); 27.28 (t, C(6));
19.97, 18.56 (2q, 2 Me); the signal of C(9’a) not observed. HR-MALDI-MS: 290.1613 (100, [M þ H]þ,
C14H20N5Oþ2 ; calc. 290.1612). Anal. calc. for C14H19N5O2 · 0.5 H2O (298.34): C 56.36, H 6.76, N 23.47;
found: C 56.36, H 6.27, N 23.05.
(1RS,2RS,4RS) (i.e. endo)- and (1RS,2SR,4RS) (i.e. exo)-2’-Amino-4’-(benzyloxy)-5’,6’-dihydro-
spiro[bicyclo[2.2.1]hept-5-ene-2,7’-pyrimido[4,5-b][1,4]diazepin]-8’(9’H)-one (19 and 20). A mixture of
15 (54 mg, 0.17 mmol) and cyclopenta-1,3-diene (0.12 ml, 1.36 mmol) in toluene (6 ml) in a sealed V-vial
was put into an oil-bath of 1108, and stirred for 20 min. The resulting light-brown suspension was
evaporated and FC (cyclohexane/AcOEt 4 :1) gave the endo/exo-imines (53 mg, 85%) as white powder.
A soln. of the crude endo/exo-imines (30 mg, 0.08 mmol) in CH2Cl2 (8 ml) was added to a soln. of
NaBH(OAc)3 (27 mg, 0.12 mmol) and AcOH (30 ml, 0.52 mmol) in CH2Cl2 (8 ml) at 08, stirred at r.t. for
2 h, diluted with CH2Cl2 (30 ml), and poured into H2O (20 ml). After neutralisation with sat. NaHCO3
soln., the org. layer was separated, washed with H2O (2 Â 20 ml) and brine (20 ml), dried (MgSO4), and
evaporated. FC (cyclohexane/AcOEt 4 :1) gave a 7:3 mixture 19/20 (28.5 mg, 94%). White powder. Rf
(CH2Cl2/AcOEt 2 :1) 0.30 (20), 0.25 (19). UV: 205 (4.44), 261 (3.75), 335 (3.77). IR (ATR): 3494w,
3448w, 3407w, 3337w, 3191w, 3080w, 2969w, 2938w, 2847w, 1616s, 1571s, 1485s, 1454m, 1426s, 1368s, 1343s,
1286m, 1239m, 1216m, 1193m, 1171m, 1141m, 1087m, 1047w, 1030w, 1003w, 957m, 909w, 847m. 1H-NMR
(300 MHz, CDCl3; endo/exo 7:3): 9.89 (br. s, 0.7 H), 9.49 (br. s, 0.3 H) (HꢀN(9’)); 7.42 – 7.29 (m, 5 arom.
H); 6.28 – 6.21, 6.12 – 6.09 (2m, HꢀC(5), HꢀC(6)); 5.38 (s, 0.6 H), 5.37 (s, 1.4 H) (PhCH2); 5.37 (br. s,
NHCH2); 3.55, 3.43 (2d, J ¼ 13.2, 1.4 H), 3.18, 2.98 (2d, J ¼ 13.2, 0.6 H) (NHCH2); 2.98, 2.89 (2 br. s,
1.4 H), 3.04, 2.78 (2 br. s, 0.6 H) (HꢀC(1), HꢀC(4)); 2.60 (dd, J ¼ 12.0, 3.6, 0.3 H), 1.99 (dd, J ¼ 12.0, 2.1,
0.7 H) (HꢀC(3)); 1.67 – 1.30 (m, 0.7 H’ꢀC(3), 2 HꢀC(7)); 0.96 (dd, J ¼ 12.0, 2.7, 0.3 H’ꢀC(3)); the
signal of H2NꢀC(2’) was not observed. 13C-NMR (75 MHz, CDCl3; endo/exo 7:3): major: 176.81 (s, C¼O);
160.88 (s, C(4’)); 154.17 (s, C(2’)); 141.34 (s, C(9’a)); 138.39, 134.19 (2d, C(5), C(6)); 136.02 (s); 128.53
(2d); 128.36 (d); 128.33 (2d); 109.82 (s, C(4’a)); 68.86 (t, PhCH2); 56.24 (s, C(2)); 52.76 (t, C(6’)); 47.08 (t,
C(7)); 47.08, 42.35 (2d, C(1), C(4)); 36.70 (t, C(3)); minor: 177.66 (s, C¼O); 160.67 (s, C(4’)); 153.50 (s,
C(2’)); 141.34 (s, C(9’a)); 139.48, 133.45 (2d, C(5), C(6)); 136.01 (s); 128.53 (2d); 128.36 (d); 128.33 (2d);
110.53 (s, C(4’a)); 68.87 (t, PhCH2); 56.86 (s, C(2)); 49.87 (t, C(6’)); 47.57 (t, C(7)); 48.51, 42.04 (2d, C(1),
C(4)); 36.22 (t, C(3)). HR-MALDI-MS: 364.1774 (100, [M þ H]þ, C20H22N5O2þ ; calc. 364.1768).
The soln. of the 7:3 mixture 19/20 (35 mg) in 15 ml of CH2Cl2/AcOEt 75 :25 was separated in three
batches by prep. HPLC (Lichrospher 100 (250 Â 25 mm), NH2 phase, 5 mm, UV detection at 254 nm,
10 ml/min) to yield 20 (11 mg; tR 55 min) and 19 (21 mg; tR 74 min).
Data of 19: M.p. 213 – 2158 (dec.). 1H-NMR (300 MHz, (D6)DMSO): 9.10 (NH, exchange with
D2O); 7.50 – 7.30 (m, 5 arom. H); 6.14 – 6.11, 5.94 – 5.91 (2m, HꢀC(5), HꢀC(6)); 5.79 (s, NH2, exchange
with D2O); 5.38 (s, PhCH2); 4.67 (br. t, J ¼ 4.5, NHCH2, exchange with D2O); 3.37 (d, J ¼ 4.5, 2 H of
NHCH2); 2.78, 2.75 (2 br. s, HꢀC(1), HꢀC(4)); 1.70 (d, J ¼ 11.4, HꢀC(3)); 1.55 (d, J ¼ 9.0, HꢀC(7));
1.40 (dd, J ¼ 11.4, 3.0, H’ꢀC(3)); 1.27 (d, J ¼ 9.0, H’ꢀC(7)). 13C-NMR (125 MHz, (D6)DMSO): 175.22 (s,

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Helvetica Chimica Acta – Vol. 90 (2007)
C¼O); 160.25 (s, C(4’)); 154.42 (s, C(2’)); 144.03 (s, C(9’a)); 137.75, 134.48 (2d, C(5), C(6)); 136.89 (s);
128.33 (2d); 127.86 (2d); 127.79 (d); 109.32 (s, C(4’a)); 67.17 (t, PhCH2); 55.73 (s, C(2)); 53.34 (t, C(6’));
46.85, 41.68 (2d, C(1), C(4)); 46.73 (t, C(7)); 36.18 (t, C(3)). HR-MALDI-MS: 364.1762 (100, [M þ H]þ,
C20H22N5Oþ2 ; calc. 364.1768).
1
Data of 20: M.p. 197 – 2008 (dec.). H-NMR (300 MHz, (D6)DMSO): 9.14 (s, NH, exchange with
D2O); 7.49 – 7.29 (m, 5 arom. H); 6.28 – 6.22, 6.16 – 6.10 (2m, HꢀC(5), HꢀC(6)); 5.754, 5.74 (2s, NH2,
exchange with D2O); 5.37 (s, PhCH2); 4.55 (br. s, NHCH2, exchange with D2O); 3.02 (d, J ¼ 12.6, 1 H),
2.94 (dd, J ¼ 12.6, 4.8, 1 H) (NHCH2); 2.88, 2.80 (2 br. s, HꢀC(1), HꢀC(4)); 2.35 (dd, J ¼ 11.6, 3.0,
HꢀC(3)); 1.46, 1.29 (2d, J ¼ 7.7, 2 H ꢀC(7)); 0.87 (d, J ¼ 11.6, H’ꢀC(3)). 13C-NMR (125 MHz,
(D6)DMSO): 176.58 (s, C¼O); 159.82 (s, C(4’)); 154.09 (s, C(2’)); 143.07 (s, C(9’a)); 136.85 (s); 136.59,
133.81 (2d, C(5), C(6)); 128.25 (2d); 127.74 (2d); 127.70 (d); 109.75 (s, C(4’a)); 67.07 (t, PhCH2); 55.89 (s,
C(2)); 50.54 (t, C(6’)); 48.16, 41.42 (2d, C(1), C(4)); 46.95 (t, C(7)); 36.12 (t, C(3)). HR-MALDI-MS:
364.1762 (100, [M þ H]þ, C20H22N5O2þ ; calc. 364.1768).
(1RS,2RS,4RS) (i.e., endo)- and (1RS,2SR,4RS) (i.e., exo)-2’-Amino-5’,6’-dihydrospiro[bicy-
clo[2.2.1]hept-5-ene-2,7’-pyrimido[4,5-b][1,4]diazepine]-4’,8’(3’H,9’H)-dione (21 and 22, resp.). A 7:3
mixture 19/20 (36.3 mg, 0.1 mmol) and Et3SiH (25 ml, 0.15 mmol) was treated with TFA (0.6 ml) and
stirred at 238 for 1.5 h. The mixture was concentrated to ca. 0.1 ml, Et2O was added, and the resulting off-
white precipitate was collected by filtration and recrystallized in MeOH to afford 21/22 7:3 (24 mg, 90%)
as an off-white powder. M.p. > 2108 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.28. UV: 203 (4.28), 225 (4.30),
340 (3.80). IR (ATR): 3347w, 3179w, 3054w, 2981w, 1714s, 1663m, 1625s, 1569w, 1551w, 1465m, 1431m,
1
1412m, 1377m, 1328m, 1281m, 1197s, 1178s, 1142s, 1097w, 1066w, 1037w, 1004w, 950w, 834w. H-NMR
(300 MHz, (D6)DMSO; endo/exo 7:3): 10.90 (br. s, HꢀN(3’)); 8.73 (br. s, HꢀN(9’)); 6.27 – 6.25, 6.14 –
6.12 (2m, 0.6 H), 6.14 – 6.12, 5.93 – 5.91 (2m, 1.4 H) (CH¼CH); 5.81 (br. s, NH2); 4.72 (0.7 H), 4.09
(0.3 H) (2 br. s, HꢀN(5’)); 3.26 (s, 1.4 H), 3.16 (s, 0.6 H) (2 HꢀC(6’)); 3.00 – 2.85 (m, 0.6 H), 2.78 (br. s,
1.4 H) (HꢀC(1), HꢀC(4)); 2.37 (d, 0.3 H), 1.66 (d, 0.7 H) (J ¼ 11.4, HꢀC(3)); 1.55 (d, J ¼ 8.1, 0.7
HꢀC(7)); 1.44 – 1.20 (m, 0.7 H’ꢀC(3), 0.3 HꢀC(7), 1 H’ꢀC(7)); 0.85 (d, J ¼ 11.4, 0.3 H’ꢀC(3)).
13C-NMR (125 MHz, (D6)DMSO; endo/exo 7:3): major: 174.72 (s, C(8’)); 159.21 (s, C(4’)); 146.28 (s,
C(2’)); 137.44, 134.62 (2d, (C(5), C(6)); 135.51 (s, C(9’a)); 112.15 (s, C(4’a)); 56.26 (s, C(2)); 53.48 (t,
C(6’)); 46.48, 41.74 (2d, C(1), C(4)); 46.65, 35.83 (2t, C(3), C(7)); minor: 175.91 (s, C(8’)); 159.08 (s,
C(4’)); 146.12 (s, C(2’)); 138.49, 133.56 (2d, C(5), C(6)); 135.01 (s, C(9’a)); 112.35 (s, C(4’a)); 56.26 (s,
C(2)); 50.43 (t, C(6’)); 47.83, 41.44 (2d, C(1), C(4)); 47.00, 35.90 (2t, C(3), C(7)). HR-MALDI-MS:
273.1218 (100, Mþ, C13H15N5O2þ ; calc. 274.1226), 274.1301 (78, [M þ H]þ, C13H16N5Oþ2 ; calc. 274.1299).
Anal. calc. for C13H15N5O2 (273.29): C 57.13, H 5.53, N 25.63; found: C 56.81, H 5.71, N 24.27.
Debenzylation of pure 19 and 20 as described above for the mixture led to 21 and 22, resp.
1
Data of 21: H-NMR (300 MHz, (D6)DMSO): 11.20 (br. s, NH); 9.20 (s, NH); 6.47 (br. s, NH2);
6.14 – 6.12, 5.95 – 5.93 (2m, HꢀC(5), HꢀC(6)); 4.22 (br. s, NHCH2, overlapping with signal of H2O); 3.43
(br. s, NHCH2); 2.82, 2.78 (2 br. s, HꢀC(1), HꢀC(4)); 1.72 (d, J ¼ 11.4, HꢀC(3)); 1.53 (d, J ¼ 8.1,
HꢀC(7)); 1.44 (dd, J ¼ 11.4, 3.0, H’ꢀC(3)); 1.28 (d, J ¼ 8.1, H’ꢀC(7)).
1
Data of 22: H-NMR (300 MHz, (D6)DMSO): 11.18 (br. s, NH); 9.05 (s, NH); 6.26, 6.11 (2 br. s,
HꢀC(5), HꢀC(6)); 6.18 (br. s, NH2); 4.59 (br. s, NHCH2, overlapping with signal of H2O); 3.01 (br. s,
NHCH2); 2.94, 2.80 (2 br. s, HꢀC(1), HꢀC(4)); 2.32 (dd, J ¼ 11.4, 3.0, HꢀC(3)); 1.38, 1.30 (2d, J ¼ 7.8, 2
HꢀC(7)); 0.91 (d, J ¼ 11.4, H’ꢀC(3)).
N-(2,6-Diamino-5-nitrosopyrimidin-4-yl)-2-methylprop-2-enamide (24). A soln. of 2,4,6-triamino-5-
nitrosopyrimidine (23, 308 mg, 2.0 mmol) in DMF (50 ml) was treated with K2CO3 (1.4 g, 10 mmol),
cooled to ꢀ 188, treated dropwise with 14 (0.26 ml, 2.6 mmol) within 2 h (addition via a syringe pump),
stirred for 0.5 h, and poured into cold H2O (200 ml). After extraction with AcOEt (3 Â 100 ml), the org.
layer was washed with brine (50 ml), dried (MgSO4), and evaporated. The green residue was washed
with (CH2Cl2/THF 4 :1) to give pure solid 24 (145 mg). FC (CH2Cl2/THF 4 :1) of the filtrate gave
additional 24 (30 mg, total yield: 40%). Green powder. M.p. > 1778 (dec.). Rf (AcOEt) 0.16. UV: 203
(4.20), 217 (4.19), 262 (3.97), 341 (4.27). IR (ATR): 3467w, 3437w, 3321w, 3107m, 1650s, 1627s, 1521s,
1478s, 1461s, 1399m, 1349m, 1312s, 1292m, 1226m, 1145s, 1106m, 1036w, 1004w, 945m, 894w, 820w.
1H-NMR (300 MHz, (D6)DMSO; 3 :2 mixture of H-bonded isomers [1]): 13.72 (s, 0.6 H), 10.55 (s, 0.4 H)
(HNꢀC(4’)); 9.83, 8.17 (2 br. d, J ¼ 3.2, 0.8 H), 8.57, 7.98 (2 br. s, 1.2 H) (H2NꢀC(6’)); 8.07, 7.80 (2 br. s,

Helvetica Chimica Acta – Vol. 90 (2007)
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1.2 H), 7.98, 7.88 (2 br. s, 0.8 H) (H2NꢀC(2’)); 5.95, 5.78 (2s, 1.2 H), 5.89, 5.63 (2 br. s, 0.8 H) (CH2¼C);
1.98 (s, 1.8 H), 1.95 (s, 1.2 H) (Me). 13C-NMR (75 MHz, (D6)DMSO); 3 :2 mixture of H-bonded
isomers): 165.95, 165.25 (2s, C¼O); 165.80, 164.05 (2s, C(5’)); 165.04, 162.63 (2s, C(4’)); 150.20, 146.23
(2s, C(2’)); 140.24, 138.52 (2s, C(2)); 140.12, 136.95 (2s, C(6’)); 122.98, 122.10 (2t, C(3)); 18.18, 17.94 (2q,
Me). HR-MALDI-MS: 223.0928 (100, [M þ H]þ, C8H11N6O2þ ; calc. 223.0938), 245.0756 (14, [M þ Na]þ,
C8H10N6NaOþ2 ; calc. 245.0757).
N,N’-(2-Amino-5-nitrosopyrimidine-4,6-diyl)bis(2-methylprop-2-enamide) (26). A soln. of 2,4,6-
triamino-5-nitrosopyrimidine (23, 308 mg, 2.0 mmol) in THF (60 ml) was treated with K2CO3 (2.2 g,
16 mmol), cooled to ꢀ 5 to ꢀ 108, treated dropwise with 14 (0.44 ml, 4.4 mmol) within 2 h (addition via a
syringe pump), stirred for 2 h, and poured into cold H2O (100 ml). After extraction with CH2Cl2 (3 Â
100 ml), the combined org. layer was washed with brine (50 ml), dried (MgSO4), and evaporated. FC
(CH2Cl2/AcOEt 1:1) of the green residue gave 26 (222 mg, 38%). Green powder. M.p. > 1498 (dec.). Rf
(AcOEt) 0.30. UV: 231 (4.29), 279 (4.18), 356 (4.29). IR (ATR): 3313w, 3181m, 2993w, 2957w, 2920w,
1668s, 1637m, 1614m, 1527s, 1473s, 1448s, 1377m, 1340s, 1306s, 1163s, 1127m, 1080s, 1016w, 1002w, 953w,
1
930m, 907w, 798s. H-NMR (300 MHz, CDCl3): 13.06 (br. s, NH); 10.74 (br. s, NH); 7.03 (br. s, NH2);
6.14, 5.96, 5.82, 5.70 (4s, 2 CH2¼C); 2.10 (s, 2 Me). 13C-NMR (125 MHz, (D6)DMSO): 165.67 (s, 2 C¼O);
164.72 (s, C(4’)); 139.96 (s, 2 C(2)); 137.95 (s, C(6’)); 123.13 (br. t, 2 C(3)); 17.99 (q, 2 Me); signals of C(2’)
and C(5’) not visible due to coalescence. HR-MALDI-MS (low intensity due to ene reaction during
measurement): 291.1196 (18, [M þ H]þ, C12H15N6Oþ3 ; calc. 291.1200), 313.1013 (43, [M þ Na]þ,
C12H14N6NaOþ3 ; calc. 313.1020).
(1RS)-2’,4’-Diamino-3,4-dimethylspiro[cyclohex-3-ene-1,7’-pyrimido[4,5-b][1,4]diazepin]-8’(9’H)-
one ((Æ)-25). A mixture of 24 (32 mg, 0.14 mmol) and 2,3-dimethylbuta-1,3-diene (0.16 ml, 1.1 mmol) in
toluene (6 ml) in a sealed V-vial was heated for 0.5 h at 1558. The resulting suspension was evaporated,
and the residue was washed with CH2Cl2 to afford (Æ)-25 (38.8 mg, 94%). Light-brown powder.
M.p. 237 – 2398 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.38. UV: 220 (4.39), 305 (3.93). IR (ATR): 3473w,
3314w, 3201w, 3100w, 2912w, 2875w, 2827w, 1676m, 1628s, 1603m, 1587m, 1552s, 1520m, 1453m, 1393m,
1374w, 1309m, 1235m, 1218w, 1168w, 1138w, 1082w, 983w, 869m, 822m. 1H-NMR (300 MHz,
(D6)DMSO): 10.32 (br. s, NH); 6.85 (s, HC ¼ N); 6.53, 6.06 (2 br. s, 2 NH2); 2.46, 2.14 (2d, J ¼ 16.5, 2
HꢀC(2)); 1.86 – 1.42 (m, CH2CH2); 1.63, 1.56 (2s, 2 Me). 13C-NMR (75 MHz, (D6)DMSO): 167.93 (s,
C(8’)); 161.41 (s, C(4’)); 160.64 (s, C(2’)); 152.68 (d, C(6’)); 145.62 (s, C(9’a)); 124.49, 122.91 (2s, C(3),
C(4)); 107.58 (s, C(4’a)); 50.92 (s, C(1)); 35.98 (t, C(2)); 28.23 (t, C(5)); 23.13 (t, C(6)); 19.06, 18.32 (2q, 2
Me). HR-MALDI-MS: 287.1611 (100, [M þ H]þ, C14H19N6Oþ; calc. 287.1615).
(1RS)-N-{2’-Amino-8’,9’-dihydro-3,4-dimethyl-8’-oxospiro[cyclohex-3-ene-1,7’-pyrimido[4,5-b][1,4]-
diazepin]-4’-yl}-2-methylprop-2-enamide ((Æ)-27). A mixture of 26 (43 mg, 0.15 mmol) and 2,3-
dimethylbuta-1,3-diene (0.16 ml, 1.2 mmol) in toluene (6 ml) in a sealed V-vial was put into an oil-
bath of 1108 and stirred for 0.5 h. The resulting off-white suspension was evaporated. FC (AcOEt) gave
27 (50.8 mg, 97%). White powder. M.p. > 1438 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.50. UV: 230 (4.45),
326 (4.08). IR (ATR): 3328w, 3218w, 2919w, 2852w, 1715m, 1674m, 1617s, 1549s, 1466s, 1376m, 1299m,
1239m, 1171m, 1114m, 1053w, 1033w, 1003w, 929w, 862w, 818w. 1H-NMR (300 MHz, CDCl3): 11.77 (br. s,
2 NH, distinguishable as 10.71 (N(9’)ꢀH) and 9.72 (HNꢀC(4’)) in (D6)DMSO); 9.52 (s, NH2); 7.01 (s,
HC¼N); 5.86 (br. s), 5.56 (d, J ¼ 1.5) (H2C ¼ C); 2.69, 2.23 (2d, J ¼ 17.1, 2 HꢀC(2)); 2.05 (s, Me); 1.98 –
1.76 (m, CH2CH2); 1.68, 1.62 (2s, MeꢀC(3), MeꢀC(4)). 13C-NMR (75 MHz, CDCl3): 169.96 (s, C(8’));
164.83 (s, C¼O); 161.05 (s, C(4’)); 156.22 (s, C(2’)); 156.16 (d, C(6’)); 147.34 (s, C(9’a)); 140.62 (s,
C¼CH2); 125.69, 122.80 (2s, C(3), C(4)); 121.54 (t, CH2¼C); 110.13 (s, C(4’a)); 52.16 (s, C(1)); 36.83 (t,
C(2)); 28.88 (t, C(5)); 24.51 (t, C(6)); 19.54, 18.84 (2q, MeꢀC(3), MeꢀC(4)); 18.62 (q, Me); assignment
based on a DEPTand a HMBC spectrum. HR-MALDI-MS: 355.1873 (100, [M þ H]þ, C18H23N6O2þ ; calc.
355.1877); 377.1710 (9, [M þ Na]þ, C18H22N6NaOþ2 ; calc. 377.1696).
(1RS)-2-Amino-7,8,9,10-tetrahydro-3’,4’-dimethyl-5-(1-methylethenyl)spiro[cyclohex-3-ene-1’,8-
[1,4]diazepino[1,2,3-gh]purine]-9-one (28) and (1RS)-2-(Ethylamino)-7,8,9,10-tetrahydro-3’,4’-dimethyl-
5-(1-methylethenyl)spiro[cyclohex-3-ene-1’,8-[1,4]diazepino[1,2,3-gh]purine]-9-one (29). A soln. of
NaBH(OAc)3 (0.21 g, 1.0 mmol) and AcOH (0.57 ml, 10 mmol) in CH2Cl2 (15 ml) was cooled to 08,
treated with a soln. of (Æ)-27 (71 mg, 0.2 mmol) in CH2Cl2 (10 ml), stirred at r.t. for 34 h, diluted with
CH2Cl2 (50 ml), and poured into H2O (30 ml). After neutralisation with sat. NaHCO3 soln., the org.

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Helvetica Chimica Acta – Vol. 90 (2007)
layer was separated, washed with H2O (30 ml) and brine (30 ml), dried (MgSO4), and evaporated. FC
(cyclohexane/AcOEt 3 :1 ! 0 :1) gave a mixture of 29 and 27. Elution with CH2Cl2/MeOH (20 :1) gave
28 (28 mg, 41%). Chromatography of the mixture 29/27 on neutral Al2O3 (activity IV, AcOEt/MeOH
100 :3) afforded 29 (27 mg, 37%), each as a white powder.
Data of (Æ)-28: M.p. 181 – 1838 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.35. UV: 199 (4.21), 230 (4.54), 332
(3.91). IR (ATR): 3338w, 3204w, 3125w, 2975w, 2916w, 2861w, 1679m, 1636s, 1585s, 1487m, 1403m, 1364s,
1303m, 1272m, 1231m, 1169w, 1138w, 1101w, 1021w, 923w, 792m, 728w. 1H-NMR (300 MHz, (D6)DMSO,
353 K): 10.28 (s, HꢀN(10)); 5.79 (s, H2NꢀC(2)); 5.68 (br. s), 5.35 (d, J ¼ 0.9) (CH2¼C); 4.22 (s, 2
HꢀC(7)); 2.45, 1.97 (2d, J ¼ 15, 2 HꢀC(2’)); 2.15 (s, Me); 1.79 – 1.70 (m, CH2CH2); 1.56, 1.53 (2s,
MeꢀC(3’), MeꢀC(4’)). 13C-NMR (75 MHz, (D6)DMSO): 175.02 (s, C(9)); 161.51 (s, C(2)); 160.33 (s,
C(3a)); 154.72 (s, C(5)); 144.30 (s, C(10a)); 133.28 (s, C¼CH2); 123.61, 122.20 (2s, C(3’), C(4’)); 121.57 (t,
CH2¼C); 110.13 (s, C(10b)); 46.97 (t, C(7)); 46.14 (s, C(8)); 36.10 (t, C(2’)); 27.71, 26.41 (2t, C(5’), C(6’));
21.69 (q, Me); 18.83, 18.06 (2q, MeꢀC(3’), MeꢀC(4’)); assignment based on a HSQC and a HMBC
spectrum. HR-MALDI-MS: 339.1926 (100, [M þ H]þ, C18H23N6Oþ; calc. 339.1928), 361.1749 (4, [M þ
Na]þ, C18H22N6NaOþ; calc. 361.1747). Anal. calc. for C18H22N6O (338.41): C 63.89, H 6.55, N 24.83;
found: C 63.73, H 6.75, N 24.09.
Data of (Æ)-29. M.p. 213 – 2158 (dec.). Rf (CH2Cl2/MeOH 20 :1) 0.45. UV: 202 (4.36), 233 (4.52), 337
(3.87). IR (ATR): 3323w, 3204w, 3119w, 2961m, 2925m, 2860m, 1726w, 1674m, 1635s, 1584s, 1507m,
1468m, 1445m, 1403s, 1366s, 1350s, 1324m, 1305m, 1274s, 1221s, 1135m, 1071w, 1043w, 1011w, 919w, 848w.
1H-NMR (300 MHz, (D6)DMSO): 10.64 (br. s, HꢀN(10)); 6.50 (br. t, J ꢁ 5.7, HNꢀC(2)); 5.70, 5.33 (2 br.
s, CH2¼C); 4.22 (s, 2 HꢀC(7)); 3.28 (quint., J ꢁ 7.0, CH2Me); 2.13 (s, MeC¼CH2); 2.00 – 1.40 (m, 6
HꢀC(2’,5’,6’)); 1.54 (br. s, MeꢀC(3’), MeꢀC(4’)); 1.12 (t, J ¼ 7.2, MeCH2). 13C-NMR (75 MHz,
(D6)DMSO): 175.09 (s, C(9)); 161.46 (s, C(2)); 159.53 (s, C(3a)); 154.63 (s, C(5)); 144.27 (s, C(10a));
133.36 (s, C¼CH2); 123.59, 122.25 (2s, C(3’), C(4’)); 121.64 (t, CH2¼C); 108.61 (s, C(10b)); 47.00 (t,
C(7)); 46.22 (s, C(8)); 35.54 (t, C(2’)); 28.18 (t, MeCH2); 27.79, 26.53 (2t, C(5’), C(6’)); 21.78 (q,
MeC¼CH2); 18.95, 18.17 (2q, MeꢀC(3’), MeꢀC(4’)); 14.81 (q, MeCH2). HR-MALDI-MS: 367.2247
(100, [M þ H]þ, C20H27N6Oþ; calc. 367.2246), 389.2085 (4, [M þ Na]þ, C20H26N6NaOþ; calc. 389.2066).
(1RS,2RS,4RS) (i.e., endo)- and (1RS,2SR,4RS) (i.e., exo)-N-{2’-Amino-8’,9’-dihydro-8’-oxospiro-
[bicyclo[2.2.1]hept-5-ene-2,7’-pyrimido[4,5-b][1,4]diazepin]-4’-yl}-2-methylprop-2-enamide (endo-30
and exo-30, resp.). A mixture of 26 (50 mg, 0.17 mmol) and cyclopenta-1,3-diene (0.12 ml, 1.36 mmol)
in toluene (6 ml) in a sealed V-vial was put into an oil-bath of 1108 and stirred for 0.5 h. The resulting
suspension was evaporated, and FC (CH2Cl2/AcOEt 2 :1) gave endo-30/exo-30 7:3 (48 mg, 84%). White
powder. M.p. > 1228 (dec.). Rf (CH2Cl2/AcOEt 1:1) 0.15. UV: 229 (4.41), 328 (4.02). IR (ATR): 3555w,
3369w, 3306w, 3198w, 3083w, 2973w, 2847w, 1737m, 1704m, 1665m, 1627s, 1616s, 1549s, 1465s, 1450s, 1382s,
1334m, 1310s, 1229m, 1173s, 1118m, 1076w, 1044m, 1026m, 951w, 937w, 870m, 818m. 1H-NMR (300 MHz,
CD2Cl2; endo/exo 7:3): 11.87 (s, 0.3 H), 11.84 (br. s, 0.7 H) (HNꢀC(8’)); 9.38 (br. s, 0.7 H), 9.28 (s, 0.3 H)
(HNꢀC(4’)); 7.35 (s, 0.7 H), 7.13 (s, 0.3 H) (HꢀC(6’)); 6.34 – 6.31 (m, 0.6 H), 6.25 (br. s, 1.4 H)
(HꢀC(5), HꢀC(6)); 6.25 (br. s, NH2); 5.83 (br. s, 0.7 H), 5.79 (br. s, 0.3 H) (CHH’¼); 5.54 (q, J ¼ 1.2,
0.7 H), 5.52 (q, J ¼ 1.2, 0.3 H) (CHH’¼); 3.51 (s, 0.3 H), 3.28 (br. s, 0.7 H) (HꢀC(1)); 2.90 (s, 0.3 H), 2.84
(br. s, 0.7 H) (HꢀC(4)); 2.01 (s, 2.1 H), 1.99 (s, 0.9 H) (Me); 1.69 – 1.42 (m, 2.8 H), 1.28 – 1.12 (m, 1.2 H)
(2 HꢀC(3), 2 HꢀC(7)). 1H-NMR (300 MHz, (D6)DMSO; endo/exo 7:3): 10.71 (s, 0.3 H), 10.62 (s,
0.7 H) (HNꢀC(8’)); 9.88 (s, 0.7 H), 9.74 (s, 0.3 H) (HNꢀC(4’)); 7.33 (br. s, 0.7 H), 7.12 (s, 0.3 H)
(HꢀC(6’)); 6.61 (br. s, NH2); 6.38 – 6.12 (m, HꢀC(5), HꢀC(6)); 5.85 (s, 0.7 H), 5.77 (s, 0.3 H)
(CHH’¼); 5.56 (s, 0.7 H), 5.51 (s, 0.3 H) (CHH’¼); 3.37 – 3.27 (m, HꢀC(1)); 2.82 – 2.73 (m, HꢀC(4));
1.89 (s, 2.1 H), 1.86 (s, 0.9 H) (Me); 1.64 – 1.30 (m, 2 HꢀC(3), 2 HꢀC(7)). 13C-NMR (75 MHz, CD2Cl2;
endo/exo 7:3): 170.95, 169.00 (2s, C(8’)); 165.50, 165.42 (2s, C¼O); 161.53, 161.48 (2s, C(4’)); 159.51,
159.07 (2d, C(6’)); 155.99, 155.96 (2s, C(2’)); 148.24, 147.73 (2s, C(9’a)); 141.78, 137.63 (2d, C(6)); 136.29,
133.37 (2d, C(5)); 140.74 (s, C¼CH2); 121.91 (t, CH2¼); 111.88, 111.34 (2s, C(4’a)); 61.38, 60.87 (2s,
C(2)); 48.76, 48.10 (2t, C(7)); 47.62, 46.50 (2d, C(1)); 42.74, 41.34 (2d, C(4)); 40.54, 38.86 (2t, C(3)); 18.28
(q, Me). HR-MALDI-MS: 339.1558 (34, [M þ H]þ, C17H19N6O2þ ; calc. 339.1564), 361.1383 (4, [M þ
Na]þ, C11H18N6NaO2þ ; calc. 361.1383). Signals of the ene product (retro-Diels – Alder product):
273.1084 (100, [M þ H]þ, C12H13N6O2þ ; calc. 273.1095), 295.0914 (5, [M þ Na]þ, C12H12N6NaOþ2 ; calc.
295.0914).

Helvetica Chimica Acta – Vol. 90 (2007)
2329
(1’RS,2’RS,4’RS) (i.e., endo)- and (1’RS,2’SR,4’RS) (i.e., exo)-2-(Ethylamino)-7,8,9,10-tetrahydro-5-
(1-methylethenyl)spiro[bicyclo[2.2.1]hept-5-ene-2’,8-[1,4]diazepino[1,2,3-gh]purine]-9-one (endo-31 and
exo-31, resp.). A soln. of NaBH(OAc)3 (0.29 g, 1.3 mmol) and AcOH (0.38 ml, 6.5 mmol) in CH2Cl2
(8 ml) was cooled to 08, treated with a soln. of endo-30/exo-30 7:3 (43 mg, 0.13 mmol) in CH2Cl2 (8 ml),
stirred at r.t. for 2 d, diluted with CH2Cl2 (40 ml), and poured into H2O (20 ml). After neutralisation with
sat. NaHCO3 soln., the org. layer was separated, washed with H2O (2 Â 20 ml) and brine (20 ml), dried
(MgSO4), and evaporated. FC (CH2Cl2/AcOEt 2 :1 to 0 :1) gave endo-31/exo-31 7:3 (21 mg, 47%).
White powder. M.p. > 1738 (dec.). Rf (AcOEt) 0.25. UV: 198 (4.16), 237 (4.61), 346 (3.87). IR (ATR):
3320m, 3107w, 3058w, 2972w, 2941w, 2912w, 2872w, 1679s, 1634s, 1587s, 1513m, 1472m, 1401m, 1360s,
1336m, 1317m, 1292w, 1276m, 1252m, 1228s, 1161w, 1139w, 1121w, 1103w, 1071w, 1007w, 948w, 880w,
826w, 805m. 1H-NMR (300 MHz, CD2Cl2; endo/exo 7:3): 11.06 (br. s, HꢀN(10)); 7.05 (br. s, HNꢀC(2));
6.34 – 6.29 (m, 0.6 H), 6.23, 6.01 (2 br. s, 1.4 H) (CH(5’)¼CH(6’)); 5.74 (0.7 H), 5.68 (0.3 H) (2s,
CHH’¼); 5.34 (0.7 H), 5.26 (0.3 H) (2s, CHH’¼); 4.41 (s, 1.4 H), 4.09 (s, 0.6 H) (2 HꢀC(7)); 3.48 – 3.40
(m, MeCH2); 3.18 – 2.48 (m, HꢀC(1’), HꢀC(4’)); 2.27 (s, 2.1 H), 2.25 (s, 0.9 H) (MeC¼CH2); 2.00 – 1.40
(m, 2 HꢀC(3’), 2 HꢀC(7’)); 1.27 (t, 2.1 H), 1.14 (t, 0.9 H) (J ¼ 7.2, MeCH2). 13C-NMR (75 MHz, CD2Cl2;
only peaks of major isomer are assigned): 176.41 (br. s, C(9)); 162.82 (s, C(2)); 160.42 (s, C(3a)); 156.71
(s, C(5)); 144.76 (s, C(10a)); 140.82, 131.52 (2 br. d, C(5’), C(6’)); 134.47 (s, C¼CH2); 122.14 (t, CH2¼);
109.90 (br. s, C(10b)); 57.12 (s, C(8)); 51.72 (br. t, C(3’)); 48.35 (d, C(1’)); 46.98 (t, C(7)); 45.85 (br. t,
C(7’)); 42.60 (d, C(4’)); 36.66 (t, MeCH2); 22.22 (q, MeC¼CH2); 14.62 (q, MeCH2). HR-MALDI-MS:
351.1931 (100, [M þ H]þ, C19H23N6Oþ; calc. 351.1933); 373.1752 (4, [M þ Na]þ, C19H22N6NaOþ; calc.
373.1753).
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Received November 6, 2007