Nucleo-δ-peptides Derived from Conformationally Constrained Nucleo-δ-amino Acids: Preparation of Monomers

Article abstract of DOI:10.1002/1522-2675(20000607)83:6<1049::AID-HLCA1049>3.0.CO;2-1

Cyclic nucleo-δ-amino-acids that constitute monomers of a conformationally constrained nucleo-δ-peptide base-pairing system have been prepared. Their synthesis starts with an enantioselectively analyzed chirogenic Diels-Alder reaction, proceeds via a regioselective ε-iodolactamisation process, and ends with a regio- as well as stereoselective introduction of nucleobases through S_N2-type opening of a transiently formed N-acylaziridine ring. Extensive use of X-ray crystal-structure analysis has been made to support structure assignments.

Full text of DOI:10.1002/1522-2675(20000607)83:6<1049::AID-HLCA1049>3.0.CO;2-1

Helvetica Chimica Acta ± Vol. 83 (2000)
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d-Peptide Analogues of Pyranosyl-RNA
Part 11)
Nucleo-d-peptides Derived from Conformationally Constrained Nucleo-d-amino
2
Acids: Preparation of Monomers )3)
by Gunter Kariga), Andreas Fuchsa), Arne Büsinga), Tilmann Brandstetterb), Stefan Schererb), Jan W. Batsa),
Albert Eschenmoserc)*, and Gerhard Quinkerta)*
a) Institut für Organische Chemie der Universität, Marie-Curie-Strasse 11, D-60439 Frankfurt am Main
b) Aventis Research & Technologies, D-65926 Frankfurt am Main
c) Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, Universitätstrasse 16,
CH-8092 Zürich, and the SKAGGS Institute for Chemical Biology at The SCRIPPS Research Institute,
10550 North Torrey Pines Road, La Jolla, CA-92037
Cyclic nucleo-d-amino acids that constitute monomers of a conformationally constrained nucleo-d-peptide
base-pairing system have been prepared. Their synthesis starts with an enantioselectively catalyzed chirogenic
Diels-Alder reaction, proceeds via a regioselective e-iodolactamization process, and ends with a regio- as well as
diastereoselective introduction of nucleobases through SN2-type opening of a transiently formed N-acylaziridine
ring. Extensive use of X-ray crystal-structure analysis has been made to support structure assignments.
1. Introduction. ± 1.1. General Introduction to a Series of Publications. Pyranosyl-
RNAs (p-RNAs; B) [9][10] are structurally close relatives of RNAs (A), with a
ribopyranosyl moiety and with sugar centers C(2') and C(4') rather than C(3') and C(5')
linked by phosphodiester groups. The nucleo-d-peptides that we will describe in this
series of papers (NDPs; see C) are conformational analogues of p-RNAs; they contain
cyclohexane rings in place of pyranose rings, and carbamoylmethyl groups instead of
phosphodiester bridges. In three parts, we will report on the synthesis of NDPs, their
structure, and their base-pairing properties.
NDPs are new members of the growing class of nucleic-acid analogues that contain
peptide-like backbones in place of the natural phosphodiesters and still have the
capability of base-pairing [11].
The term peptides [12] covers polymers formed by condensation of the respective
amino and carboxy groups of amino acids. Emil Fischer [13] has coined the term
polypeptides which is now used in addition to oligopeptides and proteins to subclassify
peptides. As amino acids, taking account of the growing separation of the two
1
)
)
)
Part 2: [1]; Part 3: [2].
2
3
From diploma theses or postdoctoral reports of G.K. [3], A.F. [4], A.B. [5], T.B. [6], and S.S. [7].
Abbreviations used in this paper: ap: anti-periplanar; Boc: tert-butoxycarbonyl; BOM: (benzyloxy)methyl;
DMAP: 4-(dimethylamino)pyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide: NOE:
nuclear Overhauser enhancement; PMBz: 4-methoxybenzoyl; TADDOL: a,a,a',a'-tetraaryl-1,3-dioxo-
lane-4,5-dimethanols; THF: tetrahydrofuran; TMS: tetramethylsilane. For acronyms of NMR techniques,
see [8].

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Helvetica Chimica Acta ± Vol. 83 (2000)
functional groups, are subdivided into a-, b-, g-, d-, . . . amino acids, it is only consequent
to follow Seebach [14] and Gellman [15] who subdivide peptides similarly into a-, b-, g-,
d-. . .peptides. The b and d centers of the d-amino acids (and related d-peptides) are
connected by a trimethylene bridge to form a cyclohexane ring (see D) and to give rise
to a conformationally constrained d-amino acid (and the corresponding d-peptide).
The C-atoms of the cyclohexane ring are numbered in such a way that the (C(4'), C(3'),
C(2')) segment corresponds to the (b, g, d) segment of the d-peptide backbone.
Substitution of the cyclohexane ring at C(1') by a nucleobase (Ade or Thy in this paper)
leads to nucleo-d-amino acids (NDAas for short), which serve as the building blocks
for conformationally constrained NDPs.
1.2. Introduction to Part 1. Oligomers B and C are configurationally and conforma-
tionally as close as possible. b-d-Ribopyranosyl-(2' ± 4')-oligonucleotides of type B are
nearest to (1'R,2'R,4'R)-nucleo-d-peptides of type C. Because of practical reasons, the
oligomer types C and ent-C have been chosen as targets to be synthesized. In this paper,
we describe the preparation of the NDAa-building blocks 1 and 2. For preparation and
pairing of oligomers of type ent-C4), see Part 3 [2]. For NMR-spectroscopic analysis of
the duplex formed by self-pairing of the chosen (1'S,2'S,4'S)-(phba)-NDP(AATAT)
pentamer (3)5), see Part 2 [1].
4
)
Because of closer relationship between B and C, the latter has been chosen for figuration here in spite of the
fact that examples of ent-C will be reported in Part 2 of this series.
Ade and Thy, as usual, specify the residues of the nucleobases adenine and thymine. A and Trefer to NDAa
residues containing Ade and Thy; phba defines the [(HO)2P(ˆO)ÀOÀ(CH2)3ÀCˆO] radical fixed to the
N-terminal radical of a NDP.
5
)

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2. Stereoselective Synthesis of Nucleo-d-amino Acids. ± 2.1. A Chirogenic Opening
Move. 1r,2t,4t-Trisubstituted cyclohexyl building blocks of type D (or ent-D) may be
obtained straightforwardly from cyclohex-3-ene derivatives F (or ent-F), via type E (or
ent-E) bicyclic lactams.
The two pathways6) to enantiomeric lactams 12a and ent-12a (see Scheme 1) both
begin with a chirogenic Diels-Alder reaction between buta-1,3-diene (4) and 3-(propenoyl)-
1,3-oxazolidin-2-one (5) (Exper. 1.1.1) [16], catalyzed by a Seebachꢀs TADDOL catalyst
[17]. The absolute configuration of the Diels-Alder adduct obtained (in over 85%
chemical yield) reflects the sense of chirality of the catalyst, which is, in this case,
(4R,5R)-or (4 S,5S)-2-methyl-a,a,a',a'-2-pentaphenyl-1,3-dioxolane-4,5-dimethanol
(6) [18][19] or (ent-6) [18][20], in situ complexed with (i-PrO)2TiCl2. The resulting
complex Lewis acid [17] is essential for the reaction to take place under the mild
conditions required for the preferential formation of 7 or ent-77). The enantioselection
follows the pattern laid down by Seebach et al. [17][24]. By conventional techniques,
6
)
)
Optimization was performed in the racemic series (see details in Scheme 1).
7
Combination of a,b-unsaturated N-acryloyloxazolidinones and Lewis acid promotors was introduced by
Evans et al. [21] into the Diels-Alder field. Use of chiral, non-racemic dienophiles leads to diastereose-
lection. According to observations of Narasaka et al. [22] on use of chiral, non-racemic promotors
enantioselection takes place. Ti Complexes, especially, were most effective, if Seebachꢀs-TADDOLs
[17][23] were used.

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Scheme 1
cyclohex-3-enecarboxylic-acid derivative 7 (ent-7) was converted, via intermediates 8b
(ent-8b) through 10 (ent-10), into the amide 11 (ent-11) in over 75% overall yield.
2.2. Central Role of Iodolactams of Type 12a. The enantiomerically enriched
amides8) of type 11 (ˆ F) are converted in over 60% chemical yield into enantiomeri-
cally enriched 12a/ent-12a>>1 by means of iodolactamization [25][26] proceeding via
an N,O-bis(trimethylsilyl) derivative. After recrystallization, ent-12a can no longer be
detected9). Single-crystal X-ray structure analysis (see Fig. 1)10) proves incontrovert-
8
)
)
)
The 11/ent-11 ratio (and vice versa) has been determined by optical rotation using ent-11 as reference
(Exper. 2.1).
Contrary to 12a/ent-12a 96 :4, further enantioselection could not be achieved by fractional crystallization of
11/ent-11 97:3.
9
10
For numbering of the atoms, see Fig. 1,a.

Helvetica Chimica Acta ± Vol. 83 (2000)
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Fig. 1. Representation of the crystal structure of 12a (Exper. 1.1.6). a) Molecular structure; b) H-bonded chains
viewed down b; c) crystal packing viewed down a.

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ibly that the constitution is that of a d-lactam (and not a d-lactone), as well as the
relative (1c,5r,8t) and absolute (in this case (1S,5S,8S)) configurations of 12a11).
The six-membered heterocyclic ring containing the ap-oriented amide group has a
conformation somewhere between a chair and a half-chair. The amide group is slightly
non-planar with a torsion angle C(3)ÀNÀC(1)ÀC(2) of 13(1)8. The six-membered
carbocyclic ring has a chair conformation, with the I-atom in an axial position. This
latter has an ap-orientation with respect to the amide group (Fig. 1,a). The amide
group is involved in an intermolecular H-bonding with the amide groups of neighboring
molecules (Fig. 1,b). The dimensions of the H-bonds are: NÀH ´´´ O (symmetry code:
x À 0.5, 0.5 À y, 1 À z) with NÀH: 0.98 Š, H ´´´ O: 1.96 Š, N ´´´ O: 2.808(9) Š and angle
NÀHÀO: 1438. The H-bonded molecules form a zigzag chain in the crystallographic a-
direction, corresponding to the needle axis of the crystal (Fig. 1,c). The crystal packing
shows no other intermolecular contacts shorter than the van der Waals distances.
2.3. From Iodolactams of Type 12a to Various NDAas. With compounds of type 12a,
replacement of the I-atom by a nucleobase anion proceeded in two steps via a
transitory N-acylaziridine [25] and with overall retention of configuration. Exploratory
treatment of rac-12a with purine-2,6-diamine (see Scheme 2) led to rac-13 in 80% yield.
Scheme 2
On recrystallization, spontaneous resolution takes place: the crystal used here
contained the (1R,5R,8R)-enantiomer ent-13 exclusively12). This ± and the fact that all
substituents present are axially oriented ± is revealed by X-ray crystal-structure analysis
(Fig. 2)13).
11
)
(S)-Configuration, determined by anomalous scattering of (À)-12a, can be traced back to (À)-7 (see
Scheme 1). For the latter compound, erroneously, (R)-configuration has been reported [16].
(1R,5R,8R)-Configuration was determined by anomalous scattering.
12
13
)
)
For numbering of the atoms, see Fig. 2,a.

Helvetica Chimica Acta ± Vol. 83 (2000)
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The six-membered heterocyclic ring shows a small deviation from a half-chair
conformation. The amide group is slightly non-planar, with a torsion angle
C(11)ÀN(12)ÀC(13)ÀC(14) of À 8.9(2)8. The six-membered carbocyclic ring has a
slightly distorted chair conformation. The diaminopurine moiety is in an axial position
with respect to this ring (Fig. 2,a). The purine system is approximately planar. The NH2
group at C(2) shows a significant deviation from planarity, with the N-atom by 0.14 Š
outside the plane through C(2), HaÀN(2), and HbÀN(2). The non-planarity of this
NH2 group may result from H-bonding forces. The NH2 group at C(6), involved in only
one H-bond, shows a much smaller deviation from planarity (the N-atom lies by 0.05 Š
away from the plane through C(6), HaÀN(6), and HbÀN(6)). The shortest intra-
molecular contact distance is 2.51(1) Š between N(3) and HÀC(11), and approaches
the van der Waals contact distance.
The crystal packing shows a three-dimensional network of the H-bonds. Two
parallel H-bonds interconnect the amide group and the diaminopurine group of
neighboring molecules (Fig. 2,b). In addition, each H2O molecule is connected by four
H-bonds to the diaminopurine groups of three different molecules. The H-atom
HaÀN(6) is not involved in H-bonding. The crystal packing (Fig. 2,c) shows one
additional short intermolecular contact between O(13) and HÀC(8) of a neighboring
molecule (symmetry: 1.5 À x, 2 À y, 0.5 ‡ z). The observed distance of 2.29(1) Š
between O(13) and HÀC(8) is slightly shorter than the van der Waals distance of 2.4 Š
between O- and H-atoms.
Reaction of rac-12a with thymine afforded the substitution product rac-14 in 41%
yield (Scheme 2). X-Ray crystal-structure analysis was also performed on this
compound (Fig. 3)14).
The conformation of the lactam ring is close to a C(12)-envelope conformation
(Fig. 3,a). The amide group is slightly non-planar with a ring torsion angle
C(13)ÀN(14)ÀC(15)ÀC(16) of 5.7(3)8. The cyclohexane ring has a distorted chair
conformation, with both the thymine and the amide groups in axial positions. The
thymine group is approximately planar, and the largest torsion angle in the thymine
ring is 1.8(3)8. The shortest intramolecular contact distance is 1.98(3) Š between
HÀC(6) and HaÀC(10), and is equal to the van der Waals distance between H-atoms.
The crystal structure of rac-14 shows zigzag chains of the H-bonded molecules running
in the crystallographic [101] direction (Fig. 3,b). Each thymine moiety is connected by
two H-bonds to the amide group of a neighboring molecule. H2O Molecules form weak
H-bonds between the amide O-atoms of different chains, giving rise to a three-
dimensional network of H-bonds (Fig. 3,c).
Nucleobase-bearing lactams of types 13 and 14 (Scheme 2) can be prepared,
without the need for protecting groups, from iodolactams of type 12a and deprotonated
purine-2,6-diamine or thymine. To convert these hydrolytically into the target NDAa, it
is necessary to substitute the H-atom of the lactam group with, for example, a Boc
group.
The advantages of the Boc group are not only that it prevents lactam proton
abstraction, nor just that it facilitates the desired attack of a suitable nucleophile on the
14
)
For numbering of the atoms, see Fig. 3,a.

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(Fig. 2)

Helvetica Chimica Acta ± Vol. 83 (2000)
1057
Fig. 2. Representation of the crystal structure of ent-13 (Exper. 2.2). a) Molecular structure; b) H-bonding
network in a layer parallel to the bc plane; c) crystal packing viewed down b.
lactam CˆO group. As well as these, it also withstands the conditions required in the
later oligomerizationof the NDAas.
Since we were unsuccessful in selectively protecting the amide N-atom of rac-16a
(ˆ14) with the Boc group, we next concentrated on the reaction of 3-(benzyloxy-
methyl)thymine [27] with lactams of type 12a, obtaining substitution products of type
16b inyields of > 50%. These were then converted into the completely protected
derivatives of type 16c (see Scheme 3).
In a similar fashion, reaction of 6-(benzoylamino)purine [28] with 12a (rac-12a)
initially afforded 18a (rac-18a) in73% (70%) yield (see Scheme 4).
The structure of the deprotected adenyl derivative rac-18b (ˆ rac-15) was
determined by X-ray crystal-structure analysis (Fig. 4)15).
The adenine group is approximately planar. The Atom C(10) deviates by 0.20 Š
from the plane of the adenine group. The amide group shows a significant deviation
from planarity with a ring torsion angle C(15)ÀN(16)ÀC(17)ÀC(18) of 9.2(2)8. The
cyclohexane ring has a chair conformation and is slightly flattened at the C(10)ÀC(11)
and C(11)ÀC(12) bonds. Both the adenine and the amide groups are in axial positions
with respect to the carbocyclic ring (Fig. 4,a). The shortest intramolecular distance is
2.13(2) Š betweenH ÀC(8) and HbÀC(12) and is just outside the van der Waals
distance between H-atoms. There is only one direct H-bond between molecules
(Fig. 4,b). This connects the amide N-atom with N(7) of the adenine group of a
neighboring molecule, resulting in H-bonded chains of molecules in the b-direction. All
other H-bonds involve the H2O molecule. This donates the H-bonds to atoms N(1) and
15
)
For numbering of the atoms, see Fig. 4,a.

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O(17) of two different molecules and accepts a H-bond from the amino group (N(6)) of
a third molecule, leading to a three-dimensional network of H-bonds (Fig. 4,c). The
amino H-atom H(6b) has an intermolecular contact distance of 2.63(2) Š with N(3) of
a neighboring molecule. This distance is too long to be classified as a H-bond. The
crystal structure shows parallel arrangements of neighboring adenine planes, which are
related by a crystallographic inversion center (Fig. 4,c). The interplanar distance is
3.32 Š. The shortest interatomic distances within these adenine dimers are C(5) ´´´
C(5): 3.366(2) Š, C(6) ´´´ C(8): 3.390(2) Š, and N(9) ´´´ C(6): 3.402(2) Š.
The doubly protected lactams of the type 16c may be converted into cyclohexane
derivatives of the type 17a by LiOOH-catalyzed16) hydrolysis inyields > 60%
(Scheme 3). X-Ray crystal-structure analysis was performed on the completely
deprotected racemic mixture rac-17c (Fig. 5)17).
The cyclohexane ring has a chair conformation, with all three side-chains in
equatorial positions (Fig. 5,a). The thymine group shows a small deviation from
Fig. 3. Representation of the crystal structure of rac-14 (Exper. 2.3). a) Molecular structure; b) H-bonded chains
inthe [101] direction; c) crystal packing viewed down b.
16
)
)
LiOOH has been introduced as an exceptionally selective reagent for oxazolidone deacylation by Evans
et al. [29] and was assumed to preferentially attack the ring CˆO group inBoc-protected amides.
For numbering of the atoms, see Fig. 5,a.
17

Helvetica Chimica Acta ± Vol. 83 (2000)
1059
Fig. 3 (cont.)
planarity with C(2) by 0.09 Š out of the plane of the other five ring atoms. This deviation
from planarity may result from crystal-packing forces. The shortest intramolecular
distance is 2.28(2) Š between O(1) and HÀC(6), and approaches the van der Waals
contact distance of 2.4 Š between O and H. The crystal packing shows a three-
dimensional network of intermolecular H-bonds (Fig. 5,b and c). All H-bonds except
the N(3)ÀHc ´´´ O(3) bond involve the H2O molecules. Two additional intermolecular
O ´´´ H distances approach the van der Waals contact distance: O(2) ´´´ HbÀC(7):
2.40(2) (À x, 2 À y, À z) and O(6) ´´´ HÀC(4): 2.44(2) Š (x, 1.5 À y, 0.5 ‡ z).
Inthe case of 18f (Scheme 4), hydrolysis of the lactam to cyclohexane derivative 19
was carried out with the aid of LiOH18). Cyclohexane derivatives 17b (ˆ2) an d19
(ˆ1), activated inthe form of in situ produced azabenzotriazyl esters, are promising
candidates for NDAa solid-phase oligomerization, to be described in [1].
18
)
Regioselective hydrolysis of N-Boc lactams with LiOH to the corresponding w-amino acids was introduced
by Grieco and co-workers [30], and applied by Weller and co-workers [31].

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Scheme 3
This work was supported by the German Bundesministerium für Bildung, Wissenschaft, Forschung und
Technologie (Project No. 0311030). We thank Prof. Utz-Hellmuth Felcht,then of Hoechst AG,Frankfurt am
Main,for his enthusiastic interest in establishing and running the joint postdoctoral research program. We thank
Drs. Wolfgang Döring and Dieter Reuschling for their cooperation (vide infra).
Experimental Part
General. Solvents: THF and Et2O were freshly distilled from sodium benzophenone ketyl,hexane, p-
xylene,and pyridine from CaH under Ar. TLC: glass plates 20  20 cm; silica gel P/UV 254 ‡ 366, Riedel de
2
Haen; preprepared Kieselgel 60F/UV 254, Merck or Woelm; layer thickness 0.25 mm. Glass plates 100 Â 20 cm;
silica gel P/UV 254 ‡ 366; Riedel de Haen; layer thickness 1 mm; activated for 4 h at 1408. Chromatograms were
made visible using Fluotest (Quarzlampengesellschaft,Hanau) or I 2. Column chromatography (CC): silica gel
(63 ± 200 m), Macherey & Nagel, Merck or Woelm. Flash chromatography (FC): silica gel (40 ± 63 m), Merck.
High-pressure liquid chromatography: anal. HPLC by Waters 204 with BBC Metrawatt Servogor 220 two-
channel potentiometer recorder; prep. HPLC by Waters Prep LC System 500; bracketed information gives,in
order,mobile phase,stationary phase,pump throughput,detector wavelength,and/or volume injected if
appropriate. M.p (uncorrected): Kofler hot-plate microscope. UV: Cary 15/Zeiss PMQ II/Perkin Elmer 552. IR:
Beckmann 4230/Perkin Elmer 257: in cmÀ1; band positions standardized with a calibration film on polystyrene.
NMR: Varian T60 (1H-NMR)/Bruker HX90 with Nicolet 1080 computer; Bruker WH 270 with BNC 28 and
Aspect 2000 computer; Nicolet NT 300 WB with NIC 1280 data processor; Bruker AM 300 with Aspect 3000
computer (1H- and 13C-NMR); d values in ppm relative to TMS as internal standard (ˆ0.00 ppm); J in Hz; usual
abbreviations apply for signal fine structure; a y prefix denotes pseudomultiplicity; f.s. ˆ fine structure. Probes
for NOE measurements were degassed in high vacuum and sealed; positions of 13C-NMR signals were taken
from the broad-band-decoupled spectra,fine structure ( s, d, t, q) from the ꢀoff-resonanceꢁ spectra. If not
mentioned otherwise,CDCl 3 was used as solvent in NMR measurements. MS: Varian CH 7/Varian MAT SM 1 B.
MS: Electrospray ionization (ES) mass spectra were measured on a VG single quadrupole mass spectrometer

Helvetica Chimica Acta ± Vol. 83 (2000)
1061
Scheme 4
(Fisons,Manchester,UK). Elemental analyses were performed by the own laboratory ( M. Christof).
Crystallographic data (excluding structure factors) for 12a, rac-12b, ent-13, rac-14, rac-15,and rac-17c have been
deposited with the Cambridge Crystallographic Data Centre (CCDC) as deposition No. CCDC-111523 for 12a,
CCDC-111524 for rac-12b,CCDC-111525 for ent-13,CCDC-111526 for rac-14,CCDC-111527 for rac-15,and
CCDC-111528 for rac-17c. Copies of the data can be obtained free of charge on application to the CCDC,12
Union Road,Cambridge CB21E2,UK (fax: ‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
1. Preparation of Monomer Building Blocks. 1.1. Common Route to Iodo Lactams of Type 12a (Scheme 1).
1.1.1. (1S)-3-[(Cyclohex-3-en-1-yl)carbonyl]-1,3-oxazolidin-2-one (7)19). To an oven-dried,2-l,three-necked,
round-bottomed flask,equipped with an efficient mechanical stirrer,a thermometer,and,a pressure-equalizing
addition funnel with an Ar inlet were added (i-PrO)2TiCl2 (9.79 g; 41.5 mmol) in anh. xylene (800 ml; distilled
from CaH2 and stored over 4-Š molecular sieves) and 6 [16] (24.1 g,45.6 mmol). The mixture was stirred at r.t.
for 1 h. Then, 5 [16]20) (35.3 g,0.25 mmol),powdered 4-Š molecular sieves (1.90 g),and heptane (800 ml;
distilled from CaH2 and stored over 4-Š molecular sieves) were added. The ivory suspension was stirred at r.t.
for 15 min and then cooled down to 10 ± 158 with an ice-bath. Buta-1,3-diene (4; 130 g; 2.4 mmol) from a
commercial cylinder controlled by a needle valve with gentle flow was introduced into the suspension.
Afterwards,the mixture,which gradually became viscous,was stirred at r.t. for 5 d. H 2O (300 ml) was added,the
mixture effectively stirred for 15 min,and filtered through Celite. The remaining solid material was washed,first
with H2O (250 ml) and then with Et2O (250 ml). The aq. soln. was extracted twice with Et2O (400 ml each),and
the combined Et2O extracts were dried (MgSO4) and evaporated. FC (petroleum ether/AcOEt 2 :1) yielded
19
)
)
The mixture (7/ent-7 ꢀ 1) was prepared by a modified version of the Ti-TADDOLate mediated Diels-Alder
reaction of 4 with 5 [16].
The acryloylation of oxazolidin-2-one was performed according to [32].
20

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crude TADDOL 3 (26.6 g) which, by FC (hexane/AcOEt 20 :1 ‡ 30% CH2Cl2) could be purified for further use,
and 4/ent-4 (ratio ꢀ 1; 42.5 g; 87%), which, without decrease in ee, could be purified by a bulb-to-bulb
23
23
23
distillation (1808/0.25 Torr). TLC (hexane/AcOEt 1 :1): Rf ˆ 0.42. [a] ˆ À20.8; [a] ˆ À21.5; [a] ˆ À23.6;
589
578
546
23
23
23
[a] ˆ À32.4; [a] ˆ À31.9 (c ˆ 1.76, CH2Cl2; [14]):[ a] ˆ À20.2 (c ˆ 1.75, CH2Cl2; 89% ee; with reference
436
365
589
to [14] the optical purity amounted to 92%). Determination of ee by HPLC (Daicel OD-H Chiralcel, hexane/
EtOH 50 :1, 1.0 ml/min, 210 nm): > 92%. IR (KBr):3025 m (ˆCÀH); 2917s, 2839m (ÀCÀH); 1789s, 1778s,
1770s, 1694s (CˆO); 1651m (CˆC). 1H-NMR:1.59 ± 1.75 ( m, HÀC(6')); 1.93 ± 2.01 (m, H'ÀC(6')); 2.04 ± 2.36
(m, 2 HÀC(2'), 2 HÀC(5')); 3.74 (m, HÀC(1')); 4.00 ± 4.14 (m, 2 HÀC(4)); 4.38 ± 4.45 (m, 2 HÀC(5)); 5.69 ±
5.71 (m, HÀC(3'), HÀC(4')). The signals were assigned by a 1H,1H-COSY spectrum. Cross signals between
1.59 ± 1.75/1.93 ± 2.36; 1.59 ± 1.75/3.74; 1.93 ± 2.01/2.04 ± 2.36; 1.93 ± 2.01/3.74; 2.04 ± 2.36/3.74; 2.04 ± 2.36/5.69 ±
5.71; 4.00 ± 4.14/4.38 ± 4.45. 13C-NMR:24.6, 27.1 (C(2 '), C(5')); 25.5 (C(6')); 38.1 (C(1')); 42.8 (C(4)); 61.9
(Fig. 4)

Helvetica Chimica Acta ± Vol. 83 (2000)
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Fig. 4. Representation of the crystal structure of rac-15 (Exper. 1.2.2.2). a) Molecular structure; b) H-bonded
chains in the b direction; c) crystal packing viewed down b.
(C(5)); 125.0, 126.6 (C(3'), C(4')); 153.2, 176.4 (C(2), C(7')). The signals were assigned by a 1H,13C-COSY
spectrum. Cross signals between 1.59 ± 2.04/25.5; 1.93 ± 2.36/24.6; 1.93 ± 2.36/27.1; 3.74/38.1; 4.00 ± 4.14/42.8;
4.38 ± 4.45/61.9; 5.69 ± 5.71/125.0; 5.69 ± 5.71/126.6. Anal. calc. for C10H13NO3 (195.22):C 61.53, H 6.71, N 7.17;
found:C 61.24, H 6.73, N 7.10.
23
(1R)-3-[(Cyclohex-3-enyl)carbonyl]-1,3-oxazolidin-2-one (ent-7; 7/ent-7 ꢀ 1; 90%):[ a]2D3 ˆ ‡21.1; [a]
ˆ
578
23
23
23
‡21.8; [a] ˆ ‡23.9; [a] ˆ ‡32.9; [a] ˆ ‡32.8 (c ˆ 1.5, CH2Cl2; with reference to [16] the optical purity
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amounted to 93%). Determination of ee by HPLC (vide supra): > 92%.
1.1.2. Methyl (1S)-Cyclohex-3-ene-1-carboxylate (8b)21). A 1-l, three-necked, round-bottomed flask
equipped with a mechanical stirrer, a condenser fitted with an anh. CaSO4 filled drying tube, and a pressure-
equalizing dropping funnel was charged with Mg turnings (814 mg, 33.5 mmol) and anh. MeOH (375 ml) and
stirred overnight. A soln. of 7/ent-7 ꢀ 1 (64.1 g, 328 mmol; see Exper. 1.1.1) in anh. Et2O (150 ml) was added
over 15 min under stirring. The pale yellow soln., after stirring for another 30 min, was distributed between sat.
aq. NH4Cl soln. (200 ml) and CH2Cl2 (200 ml). The aqueous phase was extracted twice with CH2Cl2 (150 ml
each), and the combined organic soln. was washed with sat. aq. NaCl soln., dried (Na2SO4) and evaporated (508/
350 Torr). Bulb-to-bulb distillation (1008/15 Torr) yielded 8b/ent-8b as a clear oil (42.9 g, 93%):TLC (hexane/
23
23
23
23
23
AcOEt 1:1): Rf 0.71. [a] ˆ À82.2; [a] ˆ À85.9; [a] ˆ À97.7; [a] ˆ À167.2; [a] ˆ À260.6 (c ˆ 0.94, in
589
578
546
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365
23
CH2Cl2) [33]:[ a] ˆ À86.3 (c ˆ 1.00, CHCl3). With reference to [33]:optical purity 91%. IR (film):3027
s
589
21
)
The Mg(OMe)2 mediated conversion of 7/ent-7 ꢀ 1 into 8b/ent-8b ꢀ 1 has been described for a similar case
[16].

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Helvetica Chimica Acta ± Vol. 83 (2000)
(ˆCÀH); 2951s, 2929s, 2842s (ÀCÀH); 1736s (ester); 1654s (CˆC). 1H-NMR:1.60 ± 1.77 ( m, HÀC(6)); 1.95 ±
2.13 (m, H'ÀC(6), 2 HÀC(5)); 2.23 ± 2.28 (m, 2 HÀC(2)); 2.51 ± 2.63 (m, HÀC(1)); 3.69 (s, MeO); 5.63 ± 5.70
(m, HÀC(3), HÀC(4)).
25
Methyl (1R)-Cyclohex-3-ene-1-carboxylate (ent-8b; 8b/ent-8b ꢁ 1; 93%):[ a] ˆ ‡80.4 (c ˆ 1.06 in
589
CHCl3); [33]: ‡86.5 (c ˆ 1.05, in CH2Cl2); with reference to [28], the optical purity amounted to 86%.
1.1.3. (1S)-Cyclohex-3-enemethanol (9a). An oven-dried, 1-l, three-necked, round-bottomed flask equipped
with a mechanical stirrer, a thermometer, and a pressure-equalizing dropping funnel was purged with dry Ar and
charged with anh. THF (300 ml) and LiAlH4 (17.4 g; 458 mmol) in limited portions at 08 (ice-bath) under
stirring. To the cooled mixture, a soln. of 8b/ent-8b (42.5 g; 303 mmol; see Exper. 1.1.2) in anh. THF (120 ml)
was added under vigorous stirring at such a rate that the temp. did not rise above 208. After 90 min stirring at 08,
THF/H2O 5 :1 was carefully added until gas production has ceased. The mixture was transferred to a 2-l
separatory funnel, and H2SO4 (15% aqueous soln.) was added until the precipitate was dissolved. Ice was added
to bring the temp. down to r.t., and the aq. soln. was extracted with Et2O (3 Â 250 ml). The Et2O extracts were
combined, washed with sat. aq. NaHCO3 soln., dried (MgSO4), and evaporated (508/100 Torr) to yield a faintly
yellow oil (42.5 g), which, after bulb-to-bulb distillation (1208/36 Torr), afforded 9a/ent-9a ꢀ 1 (33.9 g, 99%).
23
23
23
23
23
23
[a] ˆ À90.1; [a] ˆ À94.1; [a] ˆ À107.1; [a] ˆ À183.7; [a] ˆ À287 (c ˆ 1.7, MeOH). [34]:[ a]
ˆ
589
578
546
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365
589
À100.4 (c ˆ 1.71, MeOH; with reference to [29], the optical purity amounted to 90%). IR (film):3332 s (OH);
(Fig. 5)

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Helvetica Chimica Acta ± Vol. 83 (2000)
3022s (ˆCÀH); 291s, 2838s (ÀCÀH); 1652s (CˆC). 1H-NMR: 1.24 ± 1.40 (m, HÀC(1')); 1.41 (br. s, partially
superimposed, exchangable on treatment with D2O, OH); 1.69 ± 1.86, 2.05 ± 2.16 (2m, 2 HÀC(2'), 2 HÀC(5'),
2 HÀC(6')); 3.53 (yd, J(HÀC(1),H'ÀC(1)) ˆ 5.9, HÀC(1)); 3.55 (yd, J(H'ÀC(1),HÀC(1)) ˆ 5.9, H'ÀC(1));
5.67 ± 5.69 (m, HÀC(3'), HÀC(4')). Anal. calc for C7H12O (112.17): C 74.95, H 10.78; found: C 74.74, H 10.89.
(1R)-Cyclohex-3-enemethanol (ent-9a). The mixture 9a/ent-9a ꢀ 1 (99%): [a]2D2 ˆ ‡91.2; [a] ˆ ‡95.1;
22
578
[a] ˆ ‡108.3; [a] ˆ ‡185.9; [a] ˆ ‡290.4 (c ˆ 1.6; MeOH). [35]: [a]2D2 ˆ ‡96.0 (c ˆ 3, MeOH). [31]:
22
22
22
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22
22
22
22
[a]2D2 ˆ ‡87.9; [a] ˆ ‡91.3; [a] ˆ ‡103.5; [a] ˆ ‡168.7; [a] ˆ ‡202.4 (c ˆ 0.9, MeOH); [a]2D2 ˆ ‡95.9;
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[a] ˆ ‡106.1; [a] ˆ ‡120.5; [a] ˆ ‡205.4; [a] ˆ ‡324.6 (c ˆ 6.0, CHCl3). [34]: ent-9a [a]2D2 ˆ ‡100.4
22
22
22
22
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(c ˆ 1.71, MeOH). With reference to [34], the optical purity amounts to 91%.
1.1.4. (1S)-Cyclohex-3-eneacetonitril (10). An oven-dried, 500-ml, three-necked, round-bottomed flask
equipped with a pressure-equalizing dropping funnel capped with a gas outlet, a thermometer, and gas inlet was
purged with dry Ar, and charged at 08 (bath temp.) with anh. pyridin (210 ml) and freshly distilled MsCl
(33.9 ml, 428 mmol). A soln. of 9a/ent-9a ꢁ 1 (32.7 g, 292 mmol; see Exper. 1.1.3) in anh. pyridin (110 ml) was
added under stirring at such a rate that the temp. did not exceed 108. The resulting orange suspension, after
stirring for 2 h at 08, was transferred to a 2-l separatory funnel halfly filled with ice-water (600 g). By careful
addition of conc. aq. HCl, the soln. was acidified (pH ꢂ 1 ± 2) and extracted with Et2O (3 Â 300 ml). The
combined extracts were washed first with sat. aq. NaHCO3 soln., and then with H2O, dried (MgSO4), and
evaporated to yield a clear oil (55 g), which was used without purification for the preparation of 10/ent-10 ꢁ 1
(vide infra). From a similarly obtained batch the crude product was purified by a bulb-to-bulb distillation (1308/
0.1 Torr) to afford (S)-cyclohex-3-en-1-yl methanesulfonate (9b/ent-9b ꢁ 1), which showed the following
20
20
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20
properties: TLC (hexane/AcOEt 1:1): Rf 0.49. [a] ˆ À63.0; [a] ˆ À65.7; [a] ˆ À74.8; [a] ˆ À128.7;
589
578
546
436
20
[a] ˆ À201.88 (c ˆ 1.1, CH2Cl2). IR (film): 3026s (ˆCÀH); 2920s, 2841s (ÀCÀH); 1652m (CˆC); 1355s,
365
1175s (SˆO). 1H-NMR: 1.33 ± 1.42 (m, HÀC(1)); 1.78 ± 1.89 (m, 2 HÀC(6)); 2.02 ± 2.22 (m, 2 HÀC(2),
2 HÀC(5)); 3.01 (s, Me); 4.12 (yd, J(HÀC(7),HÀC(1) ˆ 6.5, 2 HÀC(7)); 5.62 ± 5.74 (m, HÀC(3), HÀC(4)).
Anal. calc. for C8H14O3S (190.26): C 50.50, H 7.42; found: C 50.60, H 7.52.
NaCN (21.5 g; 438 mmol) was slowly dissolved, at ca. 808, in anh. DMSO (320 ml) placed in a 1-l, three-
necked, round-bottomed flask equipped with a magnetic stirring bar, a condenser fitted with a MgSO4-filled
drying tube, and a pressure-equalizing dropping funnel. A soln. of the crude material containing 9b/ent-9b ꢁ 1)
(vide supra) in DMSO (160 ml) was slowly added. After the mixture had been heated at 110 ± 1208 for 90 min, it
was poured into ice-water. The soln. was extracted with Et2O (3 Â 250 ml), and the combined extracts were
washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated to yield a pale yellow oil (35.6 g), which was
purified by bulb-to-bulb distillation (1208/10 Torr) to give 10/ent-10 ꢁ 1 (33.1 g, 94%) with an unpleasant smell.
23
23
23
23
TLC (hexane/AcOEt 1:1): Rf 0.58. [14]: [a] ˆ À92.9; [a] ˆ À97.0; [a] ˆ À110.8; [a] ˆ À191.3;
589
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546
23
[a] ˆ À301.1 (c ˆ 1.0, CH2Cl2). IR (film): 3026s (ˆCÀH); 2920s, 2840s (ÀCÀH); 2246s, (CꢃN); 1652m
365
(CˆC). 1H-NMR: 1.37 ± 1.52 (m, HÀC(1')); 1.56 ± 2.30 (m, 2 HÀC(2'), 2 HÀC(5'), 2 HÀC(6')); 2.34 (yd,
J(HÀC(2),HÀC(1')) ˆ 6.9, 2 HÀC(2)); 5.60 ± 5.73 (m, HÀC(3'), HÀC(4)).
(1R)-Cyclohex-3-eneacetonitril (ent-10). The mixture 10/ent-10 ꢀ 1 (95%): [a]2D0 ˆ ‡92.3; [a] ˆ ‡96.5;
20
578
20
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20
[a] ˆ ‡110.2; [a] ˆ ‡190.3; [a] ˆ ‡300.0 (c ˆ 1.1, CH2Cl2).
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1.1.5. (1S)-Cyclohex-3-eneacetamide (11)22). A 1-l, four-necked, round-bottomed flask equipped with a gas
inlet, a condenser capped with a gas outlet, a mechanical stirrer, and a thermometer was purged with dry Ar and
charged with an aq. suspension of Cu (60 g; Raney-Cu, 50% aq. suspension; Fluka), degassed H2O (325 ml),
and a soln. of 7/ent-7 ꢁ 1 (32.7 g, 270 mmol; Exper. 1.1.4) in anh. DMSO (130 ml). The stirred mixture was
heated under Ar for 17 h at 95 ± 1058. The catalyst was filtered off and washed with hot H2O (2 Â 80 ml). From
the filtrate, first at r.t. and then at 48, the product crystallized. The crystals were filtered off and washed with
cyclohexane (160 ml). Mother liquor and cyclohexane phase were combined, sat. with NaCl, and extracted with
CH2Cl2 (5 Â 160 ml). The combined org. phases were dried (MgSO4) and evaporated to give an oily residue,
which was purified by bulb-to-bulb distillation (1008/15 Torr). The resulting solid material was crystallized from
H2O (50 ml), and the filtered crystals were washed with cyclohexane (30 ml). The combined crystal fractions
(37.6 g) were freed from traces of solvent to give a solid, which was recrystallized from hot CCl4 to furnish (11/
ent-11 ꢁ 1) (33.2 g, 88%). M.p. 143 ± 1458 (H2O). TLC (hexane/AcOEt 1:1): Rf 0.05; (CH2Cl2/acetone 1:1): Rf
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0.45. [a] ˆ À74.9; [a] ˆ À78.4; [a] ˆ À89.3; [a] ˆ À153.0; [a] ˆ À239.18 (c ˆ 1.0, CH2Cl2; with
589
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reference to Exper. 2.1, the optical purity amounted to 94%). IR (KBr): 3353s, 3178s (NÀH); 3025m (ˆCÀH);
2917m (ÀCÀH); 1664s, 1628s (amide). 1H-NMR: 1.22 ± 1.40 (m, HÀC(1')); 1.71 ± 1.84 (m, 2 HÀC(6')); 2.03 ±
The Cu0 -catalyzed hydration of 10 to 11 was performed, by and large, according to a general method [37].
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Helvetica Chimica Acta ± Vol. 83 (2000)
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2.23 (m, 2 HÀC(2'), 2 HÀC(5'), 2 HÀC(2)); 5.30 (br. s, exchangeable on treatment with D2O, NH2); 5.63 ± 5.68
(m, HÀC(3'), HÀC(4')). Anal. calc. for C8H13NO (139.20): C 69.03, H 9.41, N 10.06; found: C 68.88, H 9.34,
N 10.02.
20
(1R)-Cyclohex-3-eneacetamide (ent-11; 11/ent-11 ꢀ 1; 86%): M.p. 1438 (H2O). [a]2D0 ˆ ‡76.1; [a]
ˆ
578
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20
‡79.6; [a] ˆ ‡90.6; [a] ˆ ‡155.3; [a] ˆ ‡242.8 (c ˆ 1.0, CH2Cl2). An authentic sample of ent-11, which
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had been obtained by a sequence of transformations (Exper. 2.1.2), preceded by a resolution of rac-8a (Exper.
2.1.1) [32], showed the following data for optical rotation: [a]2D0 ˆ ‡80.0; [a] ˆ ‡83.2; [a] ˆ ‡94.6;
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546
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[a] ˆ ‡162.6; [a] ˆ ‡254.0 (c ˆ 1.026 inCH2Cl2; with reference to the latter the optical purity amounted to
436
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95%.
(1RS)-Cyclohex-3-eneacetamide (rac-11)23): M.p. 142 ± 1438 (acetone). TLC (CH2Cl2/acetone 2 :5): Rf ˆ
0.43. IR: (KBr) 3347s (NH), 3177m (NH), 3016w (ˆCH), 2905w, 2825w (ÀCH), 1664s, 1624s (CˆO, amide).
1H-NMR (CDCl3): 1.28 ± 140 (m, HÀC(1')); 1.68 ± 1.84 (m, 2 HÀC(6')); 2.06 ± 2.23 (m, 2 HÀC(2'), 2 HÀC(5'));
5.30 ± 5.40 (br. s, 2 H, amide NH, D2O); 5.60 ± 5.70 (ydt, HÀC(3'), HÀC(4')). Anal. calc. for C8H13NO (139.2):
C 69.03, H 9.41, N 10.06; found: C 68.83, H 9.13, N 10.36.
1.1.6. (1S,5S,8S)-8-Iodo-2-azabicyclo[3.3.1]nonan-3-one (12a)24). An oven-dried, 500-ml, three-necked,
round-bottomed flask equipped with magnetic stirrer bar, septum, and a glass stopper was purged with dry Ar,
and charged with 11/ent-11 ꢁ 1 (18.4 g, 132 mmol; see Exper. 1.1.5) in dry pentane (140 ml) and anh. Et3N
(46.0 ml, 330 mmol; added via syringe). To the stirred soln. trimethylsilyl trifluoromethanesulfonate (59,6 ml,
330 mmol) was added via syringe. The rapidly stirred mixture was cooled (ice-bath), as soon as 1/5 of the reagent
was added. After the addition, the mixture was stirred for 1 h at r.t. When the stirring was stopped, the glass
stopper was substituted by a septum, and two layers formed were allowed to separate.
A second, dry, 500-ml, three-necked, round-bottomed flask was equipped with magnetic stirring bar,
septum, glas stopper, and vacuum-pump connection. The top-pentane layer from the first flask, which contained
the bis(trimethylsilyl) imidate, was carefully transferred to the second flask by cannula, maintaining the Ar
atmosphere and leaving the oily trimethylammonium trifluoromethanesulfonate layer behind. This remaining
salt was triturated with pentane/Et2O 2 :1 (50 ml) by stirring for 15 min, allowing the layers to separate, then
transferring the extract to the second flask as before. The trituration was repeated with anh. Et2O (50 ml), and
the combined extracts in the second flask were concentrated with stirring. Excessive solvents and reagents were
removed by thorough evaporation.
A third, dry, 1-l, three-necked, round-bottomed flask equipped with an addition funnel, magnetic stirring
bar, and septum was purged with dry Ar and charged with I2 (100.6 g; 396 mmol) in anh. Et2O (250 ml). The
mixture was stirred for 1 h. The concentrated org. extract in the second flask was now added to the I2 soln. under
effective stirring and cooling (ice-bath). Anh. Et2O (130 ml) was used to transfer the rest in flask two to flask
three. After the addition, funnel was substituted by a glas stopper, the mixture was stirred for another 3 h under
Ar. Near the end of the procedure, part of the mixture solidified, and the solid residue was gently broken up
using a spatula. The reaction is quenched by removing the addition funnel and stopper, and by slowly (vigorous
gas evolution!) adding, alternatively, sat. aq. NaHCO3 and Na2SO3 solns. The mixture separated into a faintly
yellow org. layer, an intensive yellow aq. layer, and a white precipitate. It is extracted with CH2Cl2 (1 Â 500 and
2 Â 250 ml portions). The combined extracts were washed with sat. aq. Na2SO3 and NaHCO3 solns. (100 ml
each), dried (MgSO4), and evaporated to yield 12a/ent-12a ꢁ 1 as a yellow solid (32 g). A sample, after semi-
20
20
prep. HPLC (dioxane/AcOMe 10 :4) gave a solid with [a] ˆ À14.8 (c ˆ 1.0 in CH2Cl2); [a] ˆ À15.8;
589
578
20
20
20
[a] ˆ À19.6; [a] ˆ À50.8; [a] ˆ À118.88. According to specific rotation of a recrystallized sample (from
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THF/cyclohexane), the optical purity amounted to 93%. According to HPLC (Daicel OD-H 250 Â 4.6; hexane/
i-PrOH 7 :3; 1.5 ml/min; 228 nm) the ee amounted to 92%.
Recrystallization from THF (330 ml) and cyclohexane (165 ml) furnished colorless needles (Fraction 1:
17.8 g; 51%). Concentration of the mother liquor afforded another 3.19 g (Fraction 2: 9%) and 3.84 g (Fraction
3: 11%). Fractions 2 and 3 were combined and recrystallized (80 ml of THF, 40 ml of cyclohexane) to furnish
4.38 g (Fraction 4: 13%). The ee of Fractions 1 and 4 were determined by HPLC (vide supra) to be > 99%. M.p.
23
23
23
23
198 ± 1998. TLC (CH2Cl2/acetone 1:1): Rf 0.47. [a] ˆ À15.7; [a] ˆ À16.7; [a] ˆ À20.9; [a] ˆ À54.5;
589
578
546
436
23
[a] ˆ À129.8 (c ˆ 1.0, CH2Cl2). IR (KBr): 3474m, 3185s (NÀH); 2940s, 2929s, 2861s (ÀCÀH); 1667s
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23
)
)
Prepared by following the route described in [38] via rac-9a, rac-9b, and rac-10. An authentic sample of rac-
11 was prepared according to [39].
24
The iodolactamization of (11/ent-11 ꢁ 1) followed as close as possible the detailed procedure for the
conversion of another g,d-unsaturated amide into the corresponding iodolactame [26].

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Helvetica Chimica Acta ± Vol. 83 (2000)
(amide). 1H-NMR: 1.54 ± 1.57 (m, HÀC(7)); 1.77 ± 1.90 (m, HÀC(4), HÀC(6)); 1.93 ± 2.13 (m, H'ÀC(7),
HÀC(9)); 2.19 ± 2.26 (m, HÀC(5), H'ÀC(6)); 2.54 ± 2.59 (m, H'ÀC(9)); 2.68 (dd, J(H'ÀC(4),HÀC(4)) ˆ 18.6,
J(H'ÀC(4),HÀC(5)) ˆ 7.2, H'ÀC(4)); 3.73 (s, HÀC(1)); 4.37 (s, HÀC(8)); 7.03 (br. s, exchangeable on
treatment with D2O, HÀN(2)). The signals were assigned by a 1H,1H-COSY spectrum. Cross signals between
1.54 ± 1.57/1.77 ± 1.90, 1.93 ± 2.13, 2.19 ± 2.26, 4.37; 1.77 ± 1.90/1.93 ± 2.13, 2.19 ± 2.26, 2.54 ± 2.59, 3.74, 4.37; 1.93 ±
2.13/2.19 ± 2.26, 2.68, 4.37; 2.19 ± 2.26/2.54 ± 2.59, 2.68; 2.54 ± 2.59/3.74; 3.74/4.37, 7.03. 13C-NMR: 25.90 (C(6));
25.93 (C(9)); 26.4 (C(4)); 27.5 (C(7)); 31.6 (C(8)); 37.5 (C(5)); 53.0 (C(1)); 173.7 (C(3)). The signals were
assigned by a 1H,13C-COSY spectrum. Cross signals between: 1.54 ± 1.57/27.5; 1.77 ± 2.26/ 25.90, 26.4; 1.93 ± 2.13/
25.93, 27.5; 2.68/26.4; 3.73/53.0; 4.37/31.6. Anal. calc. for C8H12INO (265.09): C 36.25, H 4.56, N 5.28; found:
C 36.31, H 4.59, N 5.24.
Crystal Structure Analysis of 12a (see Fig. 2). Suitable crystals (orthorhombic) were obtained from THF/
cyclohexane at ‡48. Space group P212121 (No. 19); cell: a ˆ 7.958(2) Š; b ˆ 9.998(2) Š; c ˆ 11.535(2) Š; Vˆ
917.8(5) Š3; Z ˆ 4; Dc ˆ 1.918 g ´ cmÀ3. Octant up to 2Vmax ˆ 1408. 2598 reflections, 1655 independent reflections,
1648 reflections with I > 1 of a colorless, transparent crystal (size 0.05 Â 0.52 mm). Number of variables: 101.
À3
The final difference density was less than 0.5 e ´ ŠÀ3, in the vicinity of the I-atom 1.3 e ´ Š
.
(1R,5R,8R)-8-Iodo-2-azabicyclo[3.3.1]nonan-3-one (ent-12a)25). A 2-l, four-necked, round-bottomed flask
equipped with a mechanical stirrer, a 500-ml pressure-equalizing dropping funnel, a thermometer, and a glass
stopper was purged with dry Ar and charged with 11/ent-11 ꢀ 1 (104.4 g, 0.75 mol; see Exper. 1.1.5) and a soln. of
anh. Et3N (265 ml, 1.9 mol) in pentane (800 ml). To the stirred soln., trimethylsilyl trifluoromethanesulfonate
(500 ml, 1.83 mol) was added at such a rate (within 5 min), that the temp. ± with the help of an ice-bath ± was
kept at 32 ± 358. After cooling to r.t., stirring was continued for 1 h and then stopped. The glass stopper was
substituted by a septum. The mixture separated into two layers, and the top layer was transferred via a Teflon
tube into a 2-l, three-necked, round-bottomed flask equipped with a magnetic stirrring bar, reflux condenser,
vacuum pump connection, and a septum. The bottom layer of the first flask was mixed with pentane (250 ml)
under stirring, and the separated pentane layer was sucked into the second flask. The last procedure was
repeated twice. The combined pentane solns. were evaporated at 40 ± 608 under reduced pressure (300 À
15 mbar), and the oily residue was stirred for 1 h under heating (bath temp. 608) and reduced pressure
(0.5 mbar). The concentrate was dissolved in dry Et2O (750 ml), and the soln. was passed into a pressure-
equalizing 1-l dropping funnel, which was put to a 6-l three-necked, round-bottomed flask, additionally
equipped with a mechanical stirrer and a glass stopper, and charged with a soln. of I2 (571.3 g; 2.25 mol) in Et2O
(1.4 l). The content of the dropping funnel, at 108 (cooling with an ice-bath), was passed into the stirred soln. in
the flask as rapidly as possible (within 5 ± 10 min), and the mixture was stirred for 1 h at r.t. The mixture was
carefully (gas evolution!) treated successively with sat. aq. solns. of NaHCO3 and Na2SO3 (5 Â 300 ml each).
Decolorization occured, and a precipitation was formed, which was collected by suction filtration. The Et2O
soln. was concentrated, the resulting solid was combined with that obtained before and dissolved in CH2Cl2. The
soln. was washed successively with sat. aq. solns. of NaHCO3, Na2SO3, and NaCl, and dried (MgSO4). After
evaporation, a solid material (180 g) remained, which was crystallized from MeCN to furnish 150.5 g (75.5%) of
20
12a/ent-12a ꢀ 1. M.p. 197 ± 1988 (THF/cyclohexane). [a] ˆ ‡14.9 (c ˆ 1.145 in CH2Cl2). According to specific
589
rotation of a recrystallized sample (vide infra), the optical purity amounted to 94%. According to HPLC (Daicel
OD-H 250 Â 4.6; hexane/i-PrOH 7:3; 1.5 ml/min; 228 nm), ee amounted to 95%. After recrystallisation: ent-
20
20
20
20
20
12a. [a] ˆ ‡15.8; [a] ˆ ‡17.1; [a] ˆ ‡21.3; [a] ˆ ‡56.1; [a] ˆ ‡133.10 (c ˆ 1.0 in CH2Cl2). No 12a
589
578
546
436
365
was detectable by HPLC on chiral column.
(1RS,5RS,8RS)-8-Iodo-2-azabicyclo[3.3.1]nonan-3-one (rac-12): M.p. 1858 ± 1868 (THF/hexane). TLC
(CH2Cl2/acetone 1:1): Rf 0.26. IR: (KBr) 3174m, 3056m (NH lactam), 2944m, 2913s, 2853m (CH), 1671s, 1651s
(CˆO), 1407s, 1182s, 1091s, 830m, 769m, 555m. 1H-NMR (CDCl3): 1.50 ± 1.59 (m, HÀC(6)); 1.78 ± 1.92 (m,
H'ÀC(9), H'ÀC(7)); 1.99 ± 2.11 (m, HÀC(7), HÀC(6)); 2.20 ± 2.24 (m, H'ÀC(4), HÀC(5)); 2.55 ± 2.58 (yd,
HÀC(9)); 2.64 ± 2.70 (dd, J(HÀC(4),HÀC(5) ˆ 7); 3.74 (m, HÀC(1)); 4.37 (m HÀC(8)); 7.10 ± 7.27 (br., NH,
exchangeable with D2O). 13C-NMR (CDCl3): 25.99 (C(5)); 26.03 (C(7)); 26.48 (C(9)); 27.63 (C(6)); 31.69
(C(8)); 37.59 (C(4)); 53.07 (C(1)); 173.75 (CˆO). Anal. calc. for C8H12INO (265.09): C 36.25, H 4.56, N 5.28;
found: C 36.16, H 4.53, N 5.43.
25
)
Prepared by Dr. Dieter Reuschling of Aventis Research and Technology as part of a scale-up performance:
solvents used here were used without further purification.

Helvetica Chimica Acta ± Vol. 83 (2000)
1069
In the presence of triethylammonium trifluoromethanesulfonate the intermediately formed N,O-bis(tri-
methylsilyl) derivative preceding iodolactamization was iodinated forming finally diiodo lactams of type 12b.
(1S,4R,5S,8S)-4,8-Diiodo-2-azabicyclo[3.3.1]nonan-3-one (12b26); see Scheme 1): M.p. 215 ± 2178 (THF/
20
20
20
20
cyclohexane; dec.). TLC (CH2Cl2/acetone 1 :1): Rf 0.74. [a] ˆ ‡7.7 ; [a] ˆ ‡7.8 ; [a] ˆ ‡8.1; [a] ˆ ‡3.8
589
570
546
436
(c ˆ 1.0, CH2Cl2). IR (KBr): 3450w, 3180m, 3084m (NH); 2933m, 2848w (ÀCÀH); 1674s, 1624s (CˆO).
1H-NMR: 1.76 ± 2.12 (m, 4 aliphat. H); 2.46 ± 2.50 (m, 3 aliph. H); 3.84 (ys, HÀC(1)); 4.28 ± 4.29 (m, HÀC(8));
4.61 ± 4.62 (m, HÀC(4)); 5.97 (br. ys, exchangeable on treatment with D2O, NH). Anal calc. for C18H11I2NO
1
(390.98): C 24.58, H 2.84, N 3.58; found: C 24.70, H 2.82, N 3.54. IR and H-NMR spectra of 12b/ent-12b ꢁ 1
identical with those of rac-12b.
(1RS,4SR,5RS,8RS)-4,8-Diiodo-2-azabicyclo[3.3.1]nonan-3-one (rac-12b): M.p. 204 ± 2068 (CHCl3/hex-
ane). TLC (hexane/AcOEt 1:2): Rf 0.5. IR (KBr): 3170m, 3061m (NH lactam), 2933m, 2911m, 2883w
(ÀCÀH), 1646s (CˆO), 1475m, 1411m, 1331m, 1198m, 1173m, 1091s, 970s, 829s, 774s. 1H-NMR: 1.76 ± 1.84 (m,
HÀC(7), HÀC(6)); 1.92 ± 2.17 (yqt, HÀC(7'), HÀC(6')); 2.44 ± 2.53 (m, HÀC(9), HÀC(5)); 3.80 ± 3.85 (m,
HÀC(1)), 4.25 ± 4.3 (m, HÀC(8)); 4.60 (yd, HÀC(4)); 6.60 ± 6.65 (br., HN, exchangeable on treatment with
D2O). 13C-NMR: 22.65 (C(9)); 25.23 (C(4)); 25.28 (C(7)); 27.34 (C(6)); 30.53 (C(8)); 38.98 (C(5)); 53.43
(C(1)); 172.10 (CˆO). Anal. calc. for: C8H11I2NO: C 24.58, H 2.84, N 3.58; found: C 24.75, H 2.98, N 3.49.
Crystal-Structure Analysis of rac-12b (see Fig. 6)27). Suitable crystals (triclinic) were obtained from CHCl3/
hexane at r.t.; space group P1 (No. 2); cell: a ˆ 6.548(2) Š; b ˆ 8.702(3) Š; c ˆ 9.653(1) Š; a ˆ 92.55(2)8; b ˆ
102.18(1)8; g ˆ 96.61(3)8; Vˆ 532.7(5) Š3; Z ˆ 2; Dc ˆ 2.437 g ´ cmÀ3. Sphere up to Vmax ˆ 1208. 2847 reflections,
1577 independent reflections, 1571 reflections with I > 0 of a colorless, transparent crystal (size 0.17 Â 0.20 Â
0.30 mm). Number of variables 109. R(F) ˆ 0.086; wR(F) ˆ 0.115.
The hetereocyclic ring has a conformation between a chair and a half chair. The lactam group is slightly
non-planar with a torsion angle C(3)ÀNÀC(1)ÀC(2) of 13(2)8. The carbocyclic ring has an almost regular chair
conformation. Both I-atoms are in an axial or pseudo-axial orientation (Fig. 6,a). The crystal structure contains
centrosymmetric pairs of molecules connected by H-bonds between the two lactam groups (Fig. 6,b and c). The
dimensions of the H-bonds are: NÀH ´´´ O (symmetry code: 1 À x; À y; 1 À z), NÀH: 1.00 Š, H ´´´ O: 1.91 Š, N
´´´ O: 2.91(1) Š and angle NÀHÀO: 1778. A number of intermolecular distances approach the van der Waals
contact distances: I(1) ´´´ I(2): 4.170(1) Š (x, y, z À 1), I(1) ´´´ O: 3.40(1) Š (x, y, z À 1), I(2) ´´´ O: 3.38(1) Š (x À
1, y, z), I(1) ´´´ HbÀC(7): 3.23 Š (1 À x, 1 À y, À z) and I(2) ´´´ HaÀC(7): 3.23 Š (x À 1, y, z).
1.2. Separate Routes to Individual Monomers. 1.2.1. Thymine Monomer Building Blocks of Type 17
(Scheme 3). 1.2.1.1. 3-[(Benzyloxy)methyl]-5-methyl-1-[(1S,5S,8S)-3-oxo-2-azabicyclo[3.3.1]nonan-8-yl]pyri-
midine-2,4(1H,3H)-dione (16b). NaH (148 mg of a 65% dispersion in mineral oil; 4.0 mmol) was placed in a dry,
50-ml Löwenthal flask and washed free of mineral oil with three portions of pentane. Remaining pentane was
evaporated, and the flask was purged with dry N2 prior to adding anh. DMF (20 ml) and 3-(benzyloxyme-
thyl)thymine [26] (493 mg, 2.0 mmol; in several portions). After the evolution of H2, ceased, 12a (Exper. 1.1.6;
530 mg; 2.0 mmol; in several portions) was added. The mixture was stirred for 20 min and left overnight at r.t.
NH4Cl (1 ml of a sat. aq. soln.) was added. The resulting soln. was concentrated under reduced pressure first
with a rotary evaporator and then by bulb-to-bulb distillation (708/0.5 Torr) to yield an orange oil (1.71 g). FC
(150 g of silica gel; CH2Cl2/MeOH 30 :1 ! 15 :1) furnished a solid residue, which was digested with Et2O,
filtered, and ground. Traces of solvent were removed under reduced pressure to leave a colorless powder
(405 mg, 53%). A sample was crystallized to show the following properties: m.p. 160 ± 1628 (THF/cyclo-
23
hexane)28). TLC (CH2Cl2/MeOH 15 :1): Rf 0.41. [a] ˆ À43.3 (c ˆ 1.10, CH2Cl2). UV (MeCN): lmax 274.2
589
(9623). IR (KBr): 3447w, 3189w, 3090w, 2949m, 2906m, 1703s, 1652s, 1464s, 1405s, 1357s, 1270s, 1076s. 1H-NMR:
1.59 (mc, HÀC(4'), 2 HÀC(9')); 1.85 (mc, HÀC(3')); 1.88 (s, Me); 2.00 ± 2.14 (m, H'ÀC(3'), H'ÀC(4'),
HÀC(6')); 2.20 (br. s, HÀC(5')); 2.47 (dd, J(H'ÀC(6'),HÀC(6')) ˆ 18.5, J(H'ÀC(6'),HÀC(5')) ˆ 7.5,
H'ÀC(6')); 3.58 (br. m, HÀC(1')); 4.22 (br. m, HÀC(2')); 4.60 (s, PhCH2O); 5.35 (mc, 2 H, OCH2N); 7.22 ±
7.35 (m, 5 arom. H); 7.54 (s with f.s., HÀC(6)); 7.99 (d, J(HÀN(8'),HÀC(1')) ˆ 4.6, HÀN(8')). The signals were
assigned by a 1H,1H-COSY spectrum. 13C-NMR: 12.75 (Me); 17.90 (C(3')); 23.82 (C(9'); 24.66 (C(5')); 27.47
(C(4')); 37.15 (C(6')); 47.27 (C(1')); 55.55 (C(2')); 70.45 (OCH2N); 71.06 (PhCH2O); 107.82 (C(5)); 127.06,
26
)
The X-ray crystal-structure determination of rac-12b (vide infra) revealed pseudo-axial orientation of the I-
atom at C(4). Identity of IR and 1H-NMR spectra of 12b with those of rac-12b then indicated (4R)
configuration of 12b.
For the numbering of atoms, see Fig. 6,a.
M.p. of rac-16b: 186 ± 1888 (THF/cyclohexane).
27
28
)
)

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Helvetica Chimica Acta ± Vol. 83 (2000)
127.29, 128.03 (5 arom. C); 137.40 (C(6)); 138.18 (Cipso); 151.04 (C(2)); 162.67 (C(4)); 170.83 (C(7')). The signals
‡
‡
were assigned bya 1H,13C-COSY spectrum. ESI-MS: 767.8 ([2M ‡ H] ), 384.5 ([M ‡ H] ). Anal. calc. for
C21H25N3O4 (383.45): C 65.78, H 6.57, N 10.96; found: C 65.68, H 6.64, N 10.84.
1.2.1.2. 3-[(Benzyloxy)methyl]-2-{[(tert-butoxy)carbonyl]amino}-5-methyl-1-[(1S,5S,8S)-3-oxo-2-azabicy-
clo[3.3.1]nonan-8-yl]pyrimidine-2,4(1H,3H)-dione (16c). A dry, 500-ml, three-necked, round-bottomed flask
equipped with a magnetic stirring bar, glass stopper, and pressure-equalizing dropping funnel was charged with a
soln. of 16b (Exper. 1.2.1.2; 8.75 g, 22.8 mmol) in anh. THF (100 ml). Successively, anh. Et3N (6.3 ml,
45.6 mmol) and (Boc)2O (15.0 g, 68.4 mmol) were added to the stirred soln. Subsequently, DMAP (5.6 g;
45.6 mmol) was added in several portions, and the yellow soln. was stirred for 3 h at r.t. Solvents and excessive
reagents were removed byevaporation under reduced pressure to give a stickyresidue, which was dissolved in
CH2Cl2 (100 ml) and successivelywashed with 1 n aq. HCl and sat. aq. NaHCO3 soln. The org. phase was dried
(MgSO4) and evaporated under reduced pressure to give a brown oil (15.6 g)29), which was chromatographed
(275 g of silica gel; AcOEt/heptane 2 :1) to afford a pale yellow solid (10.4 g), which, after crystallization from
THF (50 ml)/cyclohexane (100 ml) furnished colorless crystals (9.52 g, 86%) of 16c. M.p. 124 ± 1268 (THF/
23
cyclohexane)30). TLC (AcOEt/heptane 2 :1): Rf: 0.13. [a] ˆ À10.3 (c ˆ 1.37, CH2Cl2). UV (MeCN): lmax 273.6
589
(10200). IR (KBr): 3447w, 2934w, 1744s, 1701m, 1663s, 1448m, 1363m, 1260s, 1153m, 1078m. 1H-NMR: 1.49 (s, t-
Bu); 1.52 ± 1.63, 1.74 ± 2.13 (2m, 2 HÀC(3'), 2 HÀC(4'), 2 HÀC(9')); 1.88 (s, MeÀC(5)); 2.33 (br. s, HÀC(5'));
2.38 (d, J(HÀC(6'),H'ÀC(6')) ˆ 18.2, HÀC(6')); 2.70 (dd, J(H'ÀC(6'),HÀC(6')) ˆ 18.2, J(H'ÀC(6'),
HÀC(5')) ˆ 6.7, H'ÀC(6')); 4.27 (mc, HÀC(1')); 4.40 (mc, HÀC(2')); 4.65 (s, PhCH2O); 5.45 (mc, OCH2N);
7.14 ± 7.32 (m, HÀC(6), 5 arom. H). The signals were assigned bya 1H,1H-COSY spectrum. 13C-NMR: 13.39
(MeÀC(5)); 19.63 (C(3')); 24.90 (C(9'); 25.37 (C(5')); 27.39 (C(4')); 27.84 (Me3C); 41.03 (C(6')); 53.36 (C(1'));
57.71 (C(2')); 70.80 (OCH2N); 72.25 (PhCH2O); 89.97 (Me3C); 109.73 (C(5)); 127.55, 128.20 (5 arom. C); 137.17
(C(6)); 138.16 (Cipso); 151.19, 152.15 (COON, C(2)); 163.30 (C(4)); 170.45 (C(7')). The signals were assigned by
‡
‡
a
1H,13C-COSY spectrum. ESI-MS: 501.7 ([M ‡ H] ), 384.5 ([M ‡ H À Boc] ). Anal. calc. for C26H33N3O6
(483.56): C 64.58, H 6.88, N 8.69; found: X 64.45, H 6.91, N 8.59.
1.2.1.3. (1S,3S,4S)-4-{3-[(Benzyloxy)methyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxopyrimidin-1-yl}-3-{[(tert-
butoxy)carbonyl]amino}cyclohexane)acetic Acid (17a). A 500-ml, round-bottomed flask was charged with a
soln. of 16c (Exper. 1.2.1.3; 7.81 g, 16.2 mmol) in THF (225 ml) and H2O (50 ml). To the cooled (ice-bath) soln.,
Fig. 6. Representation of the crystal structure of rac-12b (Exper. 1.1.6). a) Molecular structure; b) H-bonded
pairs; c) crystal packing viewed down a.
29
)
)
The oil without purification maybe directlysubmitted to ring opening (see Exper. 1.2.1.3).
M.p. of rac-16c: 125 ± 1278 (THF/cyclohexane).
30

Helvetica Chimica Acta ± Vol. 83 (2000)
1071
Fig. 6 (cont.)
H2O2 (7.33 g of a 30% aq. soln.; 64.8 mmol) and LiOH (1.36 g of LiOH ´ H2O in 25 ml of H2O; 32.3 mmol) were
added successively. The opaque soln. was allowed to warm to r.t. and stirred for 45 min. Na2SO3 (25 ml of a 1.5m
aq. soln.) and NaHCO3 (75 ml of a sat. aq. soln.) were added, and the soln. was concentrated under reduced

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Helvetica Chimica Acta ± Vol. 83 (2000)
pressure (up to 508/75 Torr). The concentrate was diluted with H2O (350 ml) and made alkaline (pH > 12) with
aq. 2n NaOH. The milky suspension was extracted with CH2Cl2 (3 Â 350 ml), the extracts were combined, dried
(MgSO4), and evaporated under reduced pressure to yield crude 16b, which was purified by crystallization
(THF/cyclohexane 1 :2) to give 1.55 g of 16b. The aq.-alkaline phase was acidified (pH 1 ± 2) using half-conc.
HCl, extracted with AcOEt (3 Â 350 ml), dried (Na2SO4), and evaporated under reduced pressure to give 17a
(5.09 g, 63%) as a fine-crystalline solid. M.p. 89 ± 918 (after washing with Et2O)31). TLC (CH2Cl2/MeOH 15 :1):
23
Rf 0.37. [a] ˆ À24.0 (c ˆ 0.99, MeOH). UV (MeCN): lmax 273.2 (10890). IR (KBr): 3373m, 2974m, 2932m,
589
1706s, 1691s, 1664s, 1647s, 1534m, 1469m, 1452m, 1365m, 1290m, 1255m, 1175m. 1H-NMR: 0.88 ± 1.30 (m,
HÀC(4), HÀC(6)); 1.19 (s, t-Bu); 1.66 ± 2.00 (m, 2 HÀC(3), H'ÀC(4), HÀC(5), H'ÀC(6)); 1.80 (s,
MeÀC(5')); 2.16 (mc, CH2CO2H); 3.79 (mc, HÀC(1)); 4.27 (mc, HÀC(2)); 4.58 (s, PhCH2O); 5.34 (s,
OCH2N); 6.86 (d, J(NH, HÀC(1)) ˆ 9.6, NH); 7.23 ± 7.37 (m, 5 arom. H); 7.68 (br. s, HÀC(6')); 12.09 (br. s,
CH2CO2H). The signals were assigned by a 1H,1H-COSY spectrum. 13C-NMR: 13.09 (MeÀC(5')); 28.11
(Me3C); 30.13 (C(3)); 31.07 (C(4); 33.38 (C(5)); 39.23 (C(6)); 40.18 (CH2CO2H); 51.38 (C(1)); 58.19 (C(2));
70.83 (OCH2N); 72.17 (PhCH2O); 80.05 (Me3C); 110.06 (C(5')); 127.62, 127.69, 128.27 (5 arom. C); 135.46
(C(6')); 138.00 (Cipso); 152.72, 155.43 (COON, C(2')); 163.20 (C(4')); 176.30 (CH2CO2H). The signals were
‡
assigned by a 1H,13C-COSY spectrum. ESI-MS: 519.7 ([M ‡ H ‡ H2O] ). Anal. calc. for C26H35N3O7 (501.58):
C 62.26, H 7.03, N 8.38; found: C 62.00, H 6.96, N 8.17.
1.2.1.4. (1S,2S,4S)-4-[(tert-Butoxy)carbonyl]amino}-4-[1,2,3,4-tetrahydro-5-methyl-2,4-dioxopyrimidin-1-
yl]cyclohexaneacetic Acid (17b). A soln. of 17a (Exper. 1.2.1.4; 2.01 g, 4.0 mmol) in THF (90 ml) was
hydrogenated using Pd/C (300 mg; 10%). The catalyst was removed by filtration of the mixture through Celite,
and the solvent was evaporated to yield a colorless foam(1.96 g), which was dissolved in a soln. of MeONa
(454 mg, 8.40 mmol) in anh. MeOH (90 ml). The mixture was kept overnight excluding air moisture. NH4Cl
(6 ml of a sat. aq. soln.) was added, and the soln. was concentrated under reduced pressure. The concentrate was
poured into H2O (50 ml), and the resulting soln. was acidified (pH 1 ± 2) with 2n aq. HCl and extracted with
AcOEt (4 Â 50 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure. The
residual foamwas digested with Et O (20 ml), filtered, and dried (in) to give 17b (1.43 g, 94%) as a colorless
2
solid. An anal. sample, after recrystallization, showed the following properties: m.p. 235 ± 2378 (MeOH/H2O;
23
dec.)32). TLC (CH2Cl2/MeOH 5 :1): Rf 0.38. [a] ˆ À21.9 (c ˆ 0.57, MeOH). UV (H2O): lmax 272.4 (11450).
589
IR (KBr): 3374s, 3187w, 2978w, 2935w, 1702s, 1648s, 1522s, 1394w, 1366w, 1282s, 1254m, 1170m. 1H-NMR: 0.85 ±
1.38 (m, HÀC(4), HÀC(6)); 1.27 (s, t-Bu); 1.62 ± 2.00 (m, 2 HÀC(3), H'ÀC(4), HÀC(5), H'ÀC(6)); 1.73 (s,
MeÀC(5')); 2.15 (mc, CH2CO2H); 3.75 (mc, HÀC(1)); 4.19 (mc, HÀC(2)); 6.77 (d, J(NH,HÀC(1)) ˆ 9.6, NH);
7.56 (s, HÀC(6')); 11.09 (s, HÀN(3')); 12.08 (br. s, CH2CO2H). Low-intensity signals in the region of 6.00 ± 10.0
1
disappear on heating up to 808. The signals were assigned by a H,1H-COSY spectrum. 13C-NMR (75.5 MHz,
(D6)DMSO): 12.03 (MeÀC(5')); 27.90 (Me3C); 29.16 (C(3)); 30.72 (C(4)); 32.72 (C(5)); 38.06 (C(6)); 40.30
(CH2CO2H); 49.71 (C(1)); 57.05 (C(2)); 77.51 (Me3C); 107.65 (C(5')); 138.32 (C(6')); 151.28, 154.79 (COON,
C(2')); 163.60 (C(4')); 173.35 (CH2CO2H). The signals were assigned by a 1H,13C-COSY spectrum. ESI-MS:
‡
382.3 ([M ‡ H] ). Anal. calc. for C18H27N3O6 (381.43): C 56.68, H 7.13, N 11.02; found: C 56.45, H 7.16, N 10.80.
1.2.1.5. (1S,3S,4S)-3-Amino-4-(1,2,3,4-tetrahydro-5-methylpyrimidin-1-yl)cyclohexaneacetic Acid (17c). A
50-ml, round-bottomed flask was charged with 17b (Exper. 1.2.1.5; 1.42 g, 3.72 mmol) and 2n aq. HCl (25 ml).
The suspension was slowly heated to 958, when a clear soln. arose. This temp. was kept for 45 min. Then, TLC
control (CH2Cl2/MeOH 5 :1) showed no educt left behind. Solvent was removed under reduced pressure, the
residue was suspended in AcOEt (20 ml), filtered, and dried (h.v.) to give the hydrochloride of 17c (1.08 g). A
soln. of the hydrochloride in 1n aq. NaOH (6.9 ml) was passed through a column of ion exchange resin (35 g of
Amberlite IR-120; developed with 2n aq. HCl and then washed free fromchlorides with H 2O; a test portion of
the effluent should be neutral). The amino acid was eluted with 1n aq. ammonia soln. The collected soln. was
concentrated under reduced pressure to yield 17c (737 mg, 70%) as a colorless solid. Instead of showing a sharp
melting interval, it sintered above 2008 and decomposed above 2508. An anal. sample was crystallized from
23
H2O33). TLC (i-PrOH/H2O/NH3 14 :2 :1): Rf 0.29. [a] ˆ À143 (c ˆ 0.61, H2O). UV (H2O): lmax 269.0 (8750).
589
IR (KBr): 3369s, 2973m, 2934m, 1691s, 1665s, 1648s, 1539s, 1470m, 1452s, 1176m. 1H-NMR: 1.26 (mc, HÀC(4));
1.41 (mc, HÀC(6)); 1.80 ± 2.07 (m, 2 HÀC(3), H'ÀC(4), HÀC(5)); 1.91 (s, Me); 2.09 ± 2.31 (m, CH2CO2;
H'ÀC(6)); 3.65 (br. s, HÀC(1)); 4.62 (br. s, HÀC(2)); 7.62 (s, HÀC(6')). The signals were assigned by a 1H,1H-
31
)
)
)
M.p. of rac-17a: 168 ± 1708 (THF/cyclohexane).
M.p. of rac-17b: 231 ± 2338 (MeOH/H2O; dec.).
M.p. of rac-17c: 172 ± 1748 (H2O; dec.).
32
33

Helvetica Chimica Acta ± Vol. 83 (2000)
1073
COSY spectrum. 13C-NMR: 14.35 (Me); 31.93 (C(3)); 33.17 (C(4)); 35.99 (C(5)); 38.47 (C(6)); 46.77
(CH2CO2); 54.45 (C(1)); 58.43 (C(2)); 115.04 (C(5')); 140.67 (C(6')); 155.53 (C(2')); 169.12 (C(4')); 184.25
‡
(CH2CO2). The signals were assigned by a 1H,13C-COSY spectrum. ESI-MS: 282.2 ([M ‡ H] ). Anal. calc. for
C13H19N3O4 ´ 2H2O (317.34): C 49.20, H 7.30, N 13.24; found: C 48.96, H 7.32, N 13.15.
Crystal-Structure Analysis of rac-17c (see Fig. 5). Suitable crystals (monoclinic) are obtained from H2O.
Space group P21/c (No. 14). Cell: a ˆ 7.845(1) Š; b ˆ 12.809(3) Š; c ˆ 14.987(2) Š; b ˆ 97.97(1)8; Vˆ
1491.5(4) Š3. Z ˆ 4; Dc ˆ 1.413 g ´ cmÀ3
Sphere up to 2qmax ˆ 578; 22063 reflections, 3526 independent
.
reflections, 3409 reflections with I > 0 of a colorless, transparent crystal (size: 0.14 Â 0.18 Â 0.20 mm3). Number
of variables: 292. RF ˆ 0.106; wR(F) ˆ 0.059; S ˆ 1.00.
1.2.2. Adenine Monomer Building Blocks of Type 19 (Scheme 4). 1.2.2.1. (1S,5S,8S)-8-(6-Benzamido-9H-
purin-9-yl)-2-azabicyclo[3.3.1]nonan-3-one (18a). A 500-ml, two-necked, round-bottomed flask, equipped with
a magnetic stirring bar, an Ar inlet adapter, and an oil bubbler was purged with Ar and charged with dry DMF
(180 ml) and NaH (2.25 g of a 64% suspension in mineral oil; 60 mmol). 6-N-benzoyladenine [27] (7.18 g,
30 mmol) was added portionwise, and the mixture was stirred, until gas evolution ceased. After 15 min, 12a
(7.95 g, 30 mmol) was added, and the soln. was stirred in the dark for 22 h. The soln., cooled down 08 and
neutralized by addition of aq. HCl (24 ml of a 1m soln.), was evaporated under reduced pressure (608/0.3 Torr).
The resulting residue was dissolved in MeOH (100 ml) and preabsorbed onto silica gel (15 g). FC on silica gel
(7 Â 15 cmfilling; CH 2Cl2/MeOH 12 :1) yielded a yellow oil (17 g), which was crystallized fromMeOH (15 ml)
to give 18a (8.2 g, 73%) as a colorless solid, pure enough for further reaction. For anal. purposes, a small sample
was recrystallized fromMeOH/Et 2O. M.p. 269 ± 2718 (dec.)34). TLC (CH2Cl2/MeOH 10 :1): Rf 0.28. [a]2D0
ˆ
‡35.9 (c 1.03, MeOH). UV (MeOH): lmax 280 (20330). IR: 3500 ± 3000s, 2938m, 1685m, 1654s, 1610s, 1542w,
1508w, 1490m, 1458s, 1400m, 1341m, 1286s, 1254s, 1168w, 1098m, 799w, 713m, 643w. 1H-NMR (d6-DMSO):
1.53 ± 1.72 (m, 3 H); 2.08 ± 2.32 (m, 5 H); 2.48 ± 2.58 (m, 1 H); 4.27 (br. m, HÀC(1')); 4.63 (br. m, HÀC(2'));
7.52 ± 7.58 (m, 2 arom. H); 7.62 ± 7.68 (m, 1 arom. H); 8.04 ± 8.08 (m, 2 arom. H); 8.14 (d, J(HÀN(8'),H(C(1')) ˆ
4.3, HÀN(8')); 8.70, 8.75 (2s, HÀC(2); HÀC(8)); 11.18 (s, HÀNC(6)). 13C-NMR ((D6)DMSO): 18.89, 24.21,
27.27 (C(3'), C(4'), C(9')); 25.15 (C(5')); 36.95 (C(6')); 47.44 (C(1')); 54.21 (C(2')); 125.32 (C(5)); 128.34, 132.28,
133.34 (Ph); 143.05 (C(8)); 150.17 (C(4)); 151.12 (C(2)); 152.59 (C(6)); 165.49 (Bz CˆO); 171.39 (lactam
‡
CˆO). ESI-MS: 377 (100, [M ‡ H] ). Anal. calc. for C20H20N6O2: C 63.83, H 5.32, N 22.34; found: C 63.90,
H 5.45, N 22.14.
1.2.2.2. (1S,5S,8S)-8-(6-Amino-9H-purin-9-yl)-2-azabicyclo[3.3.1]nonan-3-one (18b ˆ 15; Schemes 4 and
2). A 500-ml, round-bottomed flask, equipped with a magnetic stirring bar and a reflux condenser fitted with a
CaCl2-filled drying tube was charged with 18a (8.2 g; 22 mmol) and dry MeOH (250 ml). The suspension was
heated until 18a was completely dissolved, and a soln. of NaOMe (1.62 g) in MeOH (5.5 ml) was added, and the
mixture was stirred for 19 h at r.t. The resulting suspension was filtered, and the precipitate was washed with
‡
Et2O. The filtrate was neutralized by adding ion-exchange resin (Amberlite IR-120, H form; activated with 1m
HCl, washed with H2O until the filtrate became neutral). The resin was filtered off, and the solvent was removed
under reduced pressure. The residue was dissolved in MeOH (4 ml), precipitated by adding Et2O (30 ml), and
the precipitate was filtered off. The combined precipitates were dried in vacuo to give 18b (5.8 g, 97%), which
was pure enough for further reactions. An anal. sample is recrystallized from MeOH/H2O. M.p. 300 ± 3028
(dec.). TLC (MeOH): Rf 0.35. [a]2D0 ˆ ‡42.8 (c ˆ 0.40, MeOH). UV (MeOH): lmax 260 (16375). IR: 3367s,
3179s, 3101m, 2926m, 2864w, 1651s, 1600s, 1563m, 1470m, 1337m, 1296m, 1258m, 1229m, 1166w, 1107w, 1005w,
1
802w, 724w, 668w. H-NMR ((D6)DMSO): 1.48 ± 1.67 (m, 3 H); 2.04 ± 2.24 (m, 5 H); 2.46 ± 2.54 (m, 1 H); 4.20
(br. m, HÀC(1')); 4.46 (br. m, HÀC(2')); 7.26 (s, NH2); 8.06 (d, J(HÀN(8'),HÀC(1')) ˆ 4.3, HÀN(8')); 8.14,
8.35 (2s, HÀC(2), HÀC(8)). 13C-NMR ((D6)DMSO): 18.94, 24.15, 27.36 (C(3'), C(4'), C(9')); 25.20 (C(5'));
37.03 (C(6')); 47.47 (C(1')); 53.85 (C(2')); 118.75 (C(5)); 139.18 (C(8)); 149.70 (C(4)); 152.15 (C(2)); 156.03
‡
(C(6)); 178.91 (lactamC ˆO). ESI-MS: 273 (100, [M ‡ H] ). Anal. calc. for C13H16N6O ´ H2O: C 53.78, H 6.25,
N 28.95; found: C 53.65, H 6.24, N 29.12.
Crystal Structure Analysis of rac-15 (see Fig. 4). Suitable crystals (monoclinic) were obtained from MeOH/
H2O. Space group P21,/n (No. 14); cell: a ˆ 9.5482(8) Š; b ˆ 7.2199(6) Š; c ˆ 19.763(1) Š; b ˆ 93.30(1)8; Vˆ
1360.1(3) Š3; Z ˆ 4; Dc ˆ 1.418 g ´ cmÀ3. Hemisphere up to 2qmax ˆ 1308. 4521 reflections, 2316 independent
reflections, 2286 reflections with I > 0. Number of variables: 263. R(F) ˆ 0.036, wR(F) ˆ 0.052.
1.2.2.3. (1S,5S,8S)-8-(6-{[Dimethylamino)methylidene]amino}-9H-purin-9-yl)-2-azabicyclo[3.3.1]nonan-3-
one (18c). A 500-ml, round-bottomed flask, equipped with a magnetic stirring bar and a reflux condenser fitted
34
)
M.p. of rac-18a: 280 ± 2838 (dec.).

1074
with
Helvetica Chimica Acta ± Vol. 83 (2000)
a
CaCl2-filled drying tube was charged with 18b (5.58 g, 20 mmol), dry DMF (200 ml), and
dimethylformamid diethylacetale (17.1 ml, 100 mmol; Fluka). The mixture was kept for 3 h at 808. The
resulting clear soln. was concentrated under reduced pressure (608/0.4 Torr) to give crude 18c (6.9 g)35), which
was used without further purification. TLC (Al2O3; CH2Cl2/MeOH 20 :1): Rf 0.75. 1H-NMR: 1.58 ± 1.79 (m,
2 H); 1.89 ± 1.93 (m, 1 H); 2.16 ± 2.28 (m, 2 H); 2.38 ± 2.51 (m, 3 H); 2.69 ± 2.78 (m, 1 H); 3.23, 3.28 (2s, 2 Me);
4.38 (br. m, HÀC(1')); 4.68 (br. m, HÀC(2')); 6.62 (d, J(HÀN(8'),H(C(1')) ˆ 4.3, HÀN(8')); 8.13, 8.54 (2s,
‡
HÀC(2); HÀC(8)); 8.97 (s, 1 H, formamidine H). ESI-MS: 328 (100, [M ‡ H] ).
1.2.2.4. (1S,5S,8S)-2-[(tert-Butoxy)carbonyl]-8-(6-{[(dimethylamino)methyliden]amino}-9H-purin-9-yl)-2-
azabicyclo[3.3.1]nonan-3-one (18d). A 250-ml, round-bottomed flask, equipped with a magnetic stirring bar
and a CaCl2-filled drying tube was charged with crude 18c ((6.9 g; 20 mmol) and dry CH2Cl2 (100 ml). Under
stirring, Et3N (2.8 ml, 20 mmol) was added, followed by (Boc)2O (8.7 g; 40 mmol) and DMAP (2.44 g,
20 mmol)). The soln. was stirred for 16 h at r.t., when TLC (silica gel; CH2Cl2/MeOH 1 :1) showed no starting
material and only one product. The solvent was removed under reduced pressure, and the resulting residue was
purified by FC (7 Â 16 cmsilica gel filling; CH 2Cl2/MeOH 2 :1) to give 8.2 g of a yellow solid, which was
transferred to a 100-ml, round-bottomed flask. Et2O (50 ml) was added, and the mixture was sonicated for 2 h
under reflux. After cooling to r.t., the mixture was filtered, and the precipitate was treated with Et2O and
ultrasound once again. Filtration gave 18d (6.66 g, 78%) as a pale yellow solid, which was pure enough for
further reaction. TLC (CH2Cl2/MeOH 1:1): Rf 0.66. 1H-NMR: 1.54 (s, t-Bu); 1.84 ± 2.36 (m, 7 H); 2.44 (d, J ˆ
18.5, 1 H); 2.77 (dd, J ˆ 7.0, 18.5, 1 H); 3.14, 3.20 (2s, 2 formamidine Me); 4.80 (br. m, HÀC(1')); 5.23 (br. m,
‡
HÀC(2')); 8.04, 8.48 (2s, HÀC(2); HÀC(8)); 8.87 (s, 1 formamidine H). ESI-MS: 428 (100, [M ‡ H] ).
1.2.2.5. (1S,5S,8S)-2-[(tert-Butoxy)carbonyl]-8-(6-amino-9H-purin-9-yl)-2-azabicyclo[3.3.1]nonan-3-one
(18e). A 250-ml, round-bottomed flask, equipped with a magnetic stirring bar and a CaCl2-filled drying tube
was charged with 18d (6.64 g; 15.5 mmol) and dry CH2Cl2 (150 ml). Then, p-toluenesulfonohydrazide (11.55 g;
62.0 mmol) was added, followed by TsOH (1.47 g, 7.75 mmol), and the soln. was stirred at r.t. for 44 h. After
addition of CH2Cl2 (150 ml), the soln. was washed with H2O three times (pH > 12, adjusted by addition of 2m
NaOH). The combined aq. washings were re-extracted with 100 ml of CH2Cl2, and the combined org. layers
were dried (MgSO4). After filtration, the solvent was removed under reduced pressure, and the resulting
residue was purified by FC (5.2 Â 20 cmsilica-gel filling: CHCl 3/MeOH 30 :1) to give 18e (4.96 g; 86%), which
was pure enough for further reaction. An anal. sample was recrystallized from THF/cyclohexane. M.p. 2118 (gas
evol.), 300 ± 3028 (dec.)36). TLC: (CHCl3/MeOH 30 :1): Rf 0.23. [a]2D0 ˆ ‡80.6 (c ˆ 1.32, CH2Cl2). UV (MeCN/
H2O 1 :9): lmax 260 (14136). IR: 3406m, 3328m, 3206m, 2941w, 1756s, 1724s, 1701m, 1668s, 1645s, 1597s, 1570m,
1479m, 1414w, 1304m, 1273s, 1251s, 1228m, 1145s, 1034w, 996w, 853w, 760w. 1H-NMR (300 MHz, CDCl3): 1.62 (s,
t-Bu); 1.81 ± 1.89 (m, 3 H); 2.19 ± 2.37 (m, 4 H); 2.54 (d, J ˆ 18.5, 1 H); 2.86 (dd, J ˆ 7.0, 18.5, 1 H); 4.86 (br. m,
HÀC(1')); 5.28 (br. m, HÀC(2')); 5.64 (s, NH2); 8.06, 8.38 (2s, HÀC(2); HÀC(8)). 13C-NMR (75 MHz,
(D6)DMSO): 19.93, 25.45, 27.23 (C(3'), C(4'), C(9')); 25.97 (C(5')); 28.01 (Me3C); 40.24 (C(6')); 52.65 (C(1'));
53.68 (C(2')); 84.12 (Me3C); 119.82 (C(5)); 139.20 (C(8)); 150.59 (C(4)); 152.58 (C(2)); 155.55 (C(6)); 158.46
‡
(Boc CˆO); 171.14 (lactamC ˆO). ESI-MS: 373 (100, [M ‡ H] ). Anal. calc. for: C18H24N6O3: C 58.05, H 6.50,
N 22.57; found: C 58.13, H 6.51, N 22.85.
1.2.2.6. (1S,5S,8S)-2[(tert-Butoxy)carbonyl]-8-[6-(4-methoxybenzamido)-9H-purin-9-yl]-2-azabicyclo[3.3.1]-
nonan-3-one (18f). A 100-ml, two-necked, round-bottomed flask, equipped with a magnetic stirring bar, a
pressure-equalizing dropping funnel, and a CaCl2-filled drying tube was charged with 18e (4.96 g, 13.3 mmol)
and dry CH2Cl2 (60 ml). Then, dry pyridine (5.35 ml, 66.5 mmol) was added, followed by DMAP (1.59 g,
1.3 mmol). After cooling to 08, 4-methoxybenzoyl chloride (5.4 ml, 39.9 mmol) was added dropwise, and the
mixture was stirred at 08 for 15 min. The ice bath was removed and the mixture was stirred at r.t. for 22 h. The
mixture was then again cooled to 08, and 35 ml of MeOH were added dropwise. After 30 min at 08, 80 ml of a sat.
soln. of NH3 in MeOH was added dropwise. A white precipitate was formed, which dissolved after the addition
was complete. After 30 min, the ice-bath was removed, and the mixture was stirred at r.t. for further 2 h. The
solvent was removed under, reduced pressure, and the resulting residue was dissolved in 200 ml of CH2Cl2. The
soln. was successively washed with 150 ml sat. NaHCO3 soln. and aq. citric acid (20%, 2 Â 100 ml,), dried
(MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by FC (5.2 Â 18 cmsilica gel;
AcOEt/MeOH 40 :3) to give 5.93 g 18f (88%). M.p. 110 ± 1128 (dec.)37). TLC: (CH2Cl2/MeOH 40 :1): Rf 0.44.
35
)
)
)
Verbindung rac-18c (93%), recrystallized fromCH Cl2/AcOEt, was used without further purification.
M.p. of rac-18e (THF/cyclohexane): 164 ± 1678 (dec.).
M.p. of rac-18f: 172 ± 1758 (dec.).
2
36
37

Helvetica Chimica Acta ± Vol. 83 (2000)
1075
[a]2D0 ˆ ‡58.3 (c ˆ 1.32, CH2Cl2). UV (MeOH): lmax 288 (30459). IR: 3600 ± 3050m, 2940m, 1757s, 1707m,
1671m, 1604s, 1577m, 1506s, 1458m, 1402m, 1342m, 1251s, 1168m, 1145s, 1100m, 1024m, 893w, 848m, 794w,
761m, 644w. 1H-NMR (300 MHz, CDCl3): 1.63 (s, t-Bu); 1.84 ± 1.91 (m, 3 H); 2.24 ± 2.40 (m, 4 H); 2.55 (d, J ˆ
18.5, 1 H); 2.88 (dd, J ˆ 7.0, 18.5, 1 H); 3.92 (s, MeO); 4.95 (br. m, HÀC(1')); 5.28 (br. m, HÀC(2')); 7.01 ± 7.04
(m, 2 arom. H); 8.01 ± 8.04 (m, 2 arom. H); 8.26, 8.81 (2s, HÀC(2), HÀC(8)); 8.91 (s, HÀNC(6)). 13C-NMR
(75 MHz, CDCl3): 19.95, 25.55, 27.24 (C(3'), C(4'), C(9')); 25.95 (C(5')); 28.06 (Me3C); 40.28 (C(6')); 52.61
(C(1')); 53.99 (C(2')); 55.54 (MeO); 84.27 (Me3C); 114.08 (arom. C); 123.12 (C(5)); 126.24 (arom. C); 130.03
(arom. C); 141.58 (C(8)); 149.87 (C(4)); 152.00 (C(2)); 152.31 (C(6)); 152.54, 163.31, 164.02 (arom. C, benzoyl
‡
CˆO, BocÀCˆO); 171.14 (lactamÀCˆO). ESI-MS: 507 (100, [M ‡ H] ). Anal. calc. for: C26H30N6O5:
C 61.66, H 5.93, N 16.60; found: C 61.75, H 6.01, N 16.69.
1.2.2.7. (1S,2S,4S)-3-{[(tert-Butoxy)carbonyl]amino}-4-[6-(4-methoxybenzamido)-9H-purin-9-yl]cyclohex-
aneacetic Acid (19). A 500-ml, two-necked, round-bottomed flask, equipped with a magnetic stirring bar and a
pressure-equalizing dropping funnel was charged with 5.25 g of 18f (10.36 mmol) and 200 ml of THF. After
cooling to 08, a soln. of 2.17 g of LiOH ´ H2O (51.8 mol) in 50 ml of H2O was added dropwise over a period of
20 min. Then, 30 ml of MeOH were added, the ice bath was removed, and the mixture was stirred at r. t. for 1 h.
‡
Ion-exchange resin (Amberlite IR-120, H form) was added until pH reached 7. The resin was removed by
filtration, and the soln. was concentrated under reduced pressure to a volume of 100 ml. 200 ml of H2O were
added, and pH 2 was adjusted by addition of 1m aq. HCl. The soln. was extracted with AcOEt (3 Â 200 ml), and
the combined org. extracts were dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was
dissolved in 25 ml of hot MeOH. The product was precipitated by addition of 10 ml of H2O. The precipitate was
filtered, washed with H2O, and dried (P4O10) to give 1.95 g of 19. Another 0.57 g could be obtained fromthe
mother liquor and washings to give a total yield of 46% . M.p. 238 ± 239838). TLC. (CH2Cl2/MeOH 10 :1): Rf
0.39. [a]2D0 ˆ ‡19.9 (c ˆ 0.55, MeOH). UV (MeCN/H2O): lmax 290 (22722). IR: 3368m, 2939w, 1710m, 1683s,
1608s, 1577m, 1528m, 1507m, 1458m, 1306m, 1250s, 1175s, 1030w, 842w, 761w. 1H-NMR (300 MHz, (D6)-
DMSO): 1.08 (s, t-Bu); 1.09 ± 1.40 (m, 2 H); 1.80 ± 2.35 (m, 7 H); 3.86 (s, MeO); 4.07, 4.36 (2 br. m, HÀC(1'),
HÀC(1'), HÀC(2')); 6.87 (br. s, NHBoc); 7.06 ± 7.09 (m, 2 arom. H); 8.00 ± 8.05 (m, 2 arom. H); 8.42, 8.86 (2s,
HÀC(2), HÀC(8)); 10.88 (s, C(6)ÀNH). 13C-NMR (75 MHz, CDCl3): 27.73 (Me3C); 30.35, 30.46, 37.95 (C(3'),
C(5'), C(6')); 32.89 (C(4')); 40.32 (CH2CO2H); 51.30 (C(2')); 55.38 (MeO); 77.45 (Me3C); 113.55 (arom. C);
125.24 (C(5)); 125.63 (arom. C); 131.41 (arom. C); 143.48 (C(8)); 150.03 (C(4)); 150.69 (C(2)); 152.38 (C(6));
‡
154.53, 162.38, 164.77 (arom. C, benzoyl CˆO, Boc CˆO); 173.36 (CO2H). MS: 525 (100, [M ‡ H] ). Anal.
calc. for: C26H32N6O6: C 59.53, H 6.15, N 16.02; found: C 59.35, H 6.32, N 15.89.
2. Reference and Model Compounds39). ± 2.1. Preparation of Reference Compound ent-11 (Scheme 1). 2.1.1.
Preparation of ent-8a by Resolution of rac-8a. A mixture of rac-8a (25.0 g; 198 mmol) and acetone (150 ml) was
placed in a 250-ml Erlenmeyer flask and heated to boiling. To the hot soln., a soln. of (S)-phenylethylamine
(24.0 g; 198 mmol) in acetone (150 ml) was added dropwise under stirring. The resulting soln. was allowed to
cool. The formed salt separated as white needles, which were collected on a filter and dried under reduced
pressure to give a mixture of diastereoisomeric salts (25.4 g, 52%). Recrystallization (350 ml acetone) yielded
25
25
25
25
25
12.0 g (24%). [a] ˆ ‡21.8 (c ˆ 1, MeOH); [a] ˆ ‡22.8; [a] ˆ ‡25.8; [a] ˆ ‡42.8; [a] ˆ ‡63.7.
589
578
546
436
365
25
Recrystallization fromacetone (150 ml) afforded white needles (6.2 g, 13%): [ a] ˆ ‡30.7 (c ˆ 1, MeOH);
589
25
25
25
25
[a] ˆ ‡32.2, [a] ˆ ‡36.4; [a] ˆ ‡60.5; [a] ˆ ‡90.4. Recrystallization fromacetone (60 ml) gave white
578
546
436
365
25
25
25
25
25
needles (4.0 g, 8.2%): [a] ˆ ‡34.8 (c ˆ 1, MeOH); [a] ˆ ‡36.2; [a] ˆ ‡40.9; [a] ˆ ‡68.1; [a]
ˆ
589
578
546
436
365
25
‡101.9. Recrystallization fromacetone (50 ml) provided white needles (2.3 g, 4.7%): [ a] ˆ ‡38.5 (c ˆ 1,
589
25
25
25
25
MeOH); [a] ˆ ‡40.0; [a] ˆ ‡45.4; [a] ˆ ‡75.6; [a] ˆ ‡113.4. Recrystallization fromacetone (25 ml)
578
546
436
365
25
25
25
25
led to white needles (2.6 g, 3.3%): [a] ˆ ‡39.6 (c ˆ 1, MeOH); [a] ˆ ‡41.2; [a] ˆ ‡46.8; [a] ˆ ‡77.7;
589
578
546
436
25
25
[a] ˆ ‡115.9. Recrystallization fromacetone (15 ml) furnished white needles (1.15 g; 2.3%): [ a] ˆ ‡40.1
365
589
25
25
25
25
25
(c ˆ 1, MeOH); [a] ˆ ‡41.7; [a] ˆ ‡47.3; [a] ˆ ‡79.2; [a] ˆ ‡119.2; [2]: [a] ˆ ‡40.5 (c ˆ 1,
578
546
436
365
589
MeOH). A mixture of the purified salt (11.5 g) and H2O (50 ml) was slightly acidified with 1n aq. HCl soln.
The resulting mixture was shaken with CH2Cl2 (5 Â 25 ml). After the combined org. extracts had been washed
with sat. aq. NaCl soln. (30 ml) and dried (MgSO4), the solvent was distilled, and the residual liquid was used
directly for further reaction.
2.1.2. From ent-8a to ent-11. An oven-dried, 100-ml, two-necked Loewenthal flask equipped with a
magnetic stirring bar, rubber septum, and reflux condenser was charged under Ar with a suspension of LiAlH4
38
)
)
M.p. of rac-19: 236 ± 2398.
Prepared by Dr. Wolfgang Döring.
39

1076
Helvetica Chimica Acta ± Vol. 83 (2000)
(212 mg, 5.6 mmol) in dry THF (20 ml). A soln. of ent-8a (587 mg; 4.6 mmol) in dry THF (10 ml) was added at
08 via syringe. The mixture was stirred at r.t. for 3 h, quenched by ice-water and shaken with Et2O (4 Â 20 ml
each). The combined Et2O extracts were dried (MgSO4) and concentrated on a rotary evaporator. The IR
spectrumof the residual oil (522 mg) proved to be identical with that one of rac-9a (Exper. 1.1.3).
A 25-ml, two-necked, round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing
condenser, and a septum, was charged with a soln. of ent-9 (522 mg, 4.6 mmol) in dry pyridine (5 ml) and cooled
to 08. After MsCl (430 ml, 5.6 mmol) had been added dropwise by syringe while stirring, the mixture was left for
3 h at r.t., and afterwards distributed between 1n aq. HCl and CH2Cl2. The aq. layer is shaken thrice with
CH2Cl2. The combined org. phases were washed successively with 1n aq. HCl and aq. NaHCO3 soln., dried
(MgSO4), and distilled (bulb-to-bulb; oven temp. ca. 1408/0.15 Torr), after evaporation of solvent, to give ent-6b
(806 mg, 91%). The IR spectrum of the colorless oil was identical with that of rac-9b.
A 25-ml, two-necked, round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing
condenser, and a septum was charged with a soln. of NaCN (250 mg, 5.0 mmol) in dry DMSO (10 ml) and
heated to 908 while stirring. After ent-9b (800 mg, 4.2 mmol) had been added dropwise by syringe, the red
mixture was stirred for 3 h at 1208 and 15 h at r.t. The mixture was poured into a slurry of H2O and ice, and
extracted four times with Et2O. The combined org. phases are dried (MgSO4) and concentrated under reduced
pressure to furnish ent-10 (433 mg; 85%) as a colorless oil, the IR spectrum of which is identical with that of rac-
10.
Into a 25-ml, two-necked Loewenthal flask, equipped with a magnetic stirring bar and a septum was placed
CuSO4 ´ 5H2O (807 mg, 3.3 mmol) in H2O (8 ml) under Ar. A soln. of NaBH4 (136 mg, 3.3 mmol) and NaOH
(129 mg, 3.3 mmol) in H2O (5 ml), while stirring, was added through the septum within 30 min under external
cooling with an ice-bath. The mixture was stirred for another h at this temp. The formed precipitate was filtered
through a Schlenck fritte, washed with H2O until the washings were neutral, and transferred into a 50-ml
Schlenck flask, equipped with a pressure-equalizing condenser. A soln. of ent-10 (400 mg, 3.3 mmol) in DMSO
(5 ml) was added. The mixture was heated under Ar for 24 h at 908, and the catalyst was filtered off (using a
Schlenck fritte) and washed with hot H2O. The filtrate was allowed to cool to r.t. and skaken with Et2O (4 times).
The combined Et2O extracts were evaporated under reduced pressure to give ent-11 (367 mg, 80%). M.p. 138 ±
20
20
20
1408 (H2O). TLC(CH2Cl2/acetone 2 :5): Rf 0.4. [a] ˆ ‡80.0 (c ˆ 1.026, CH2Cl2); [a] ˆ ‡83.20; [a]
ˆ
589
578
546
20
20
‡94.6; [a] ˆ ‡162.6; [a] ˆ ‡254.0. IR(KBr): 3348s, 3175m (NH); 3014w (ˆCÀH); 2907w, 2828w
436
365
(ÀCÀH); 1665s, 1622s (CˆO, amide I,II). 1H-NMR (CDCl3): 1.24 ± 1.39 (m, HÀC(1')); 1.69 ± 1.85 (m, 2
HÀC(6')); 2.03 ± 2.22 (m, 2 HÀC(2), 2 HÀC(2'), 2 HÀC(5')); 5.49 (br. s, with D2O exchangeable, NH); 5.59 ±
5.71 (m, HÀC(3'), HÀC(4'), 1H with D2O exchangeable, NH). Anal. calc. for: C8H13NO (139.20): C 69.03,
H 9.41, N 10.06; found: C 69.05, H 9.12, N 10.01. IR und 1H-NMR spectra were identical with those of rac-11 [7].
2.2. Preparation of (1RS,5RS,8RS)-8-(2,6-diamino-9H-purin-9-yl)-2-azabicyclo[3.3.1]nonan-3-one (rac-
13) . To a soln. of 2,6-diaminopurine (75 mg, 0.5 mmol) in anh. DMF (10 ml), NaH (30 mg of a 80% suspension;
1.0 mmol) was added. The resulting suspension was stirred for 1 h at r.t. The white suspension was treated with
rac-12a (133 mg; 0.5 mmol) and the mixture was stirred for 15 h. The solvent was removed under reduced
pressure (bulb-to-bulb distillation, 508/0.1 Torr). The residue was dissolved in boiling H2O (10 ml). The soln.
was filtered through cotton-wool to give white crystals (115 mg, 80%) of rac-13. M.p. > 2508. TLC: (reversed
phase SiO2; MeOH/H2O 1 :1 ‡ 1% TFA): Rf 0.5. UV (MeOH): lmax 258.0 (9600); 281.5 (11600). IR (KBr):
3414s, 3319s (NH, amine); 3195s (NH, lactam); 2932m, 2866m (ÀCÀH); 1662s, 1654s, 1640s, 1626s, 1616s,
1603s, 1594s, 1588s, 1508m (CˆO, CˆN, CˆC). 1H-NMR ((D6)DMSO): 1.61 (ys, HÀC(16), 2 HÀC(18));
1.97 ± 2.14 (m, HÀC(14), HÀC(15), H'ÀC(16), 2 HÀC(17)); 2.44 ± 2.54 (m, H'ÀC(14)); 3.32 (s, H2O); 4.19 (ys,
HÀC(11)); 4.27 (ys, HÀC(10)); 5.63 (s, NH2); 6.69 (s, NH2); 7.88 (d, J(HÀN(12),HÀC(11)) ˆ 4.3, HÀN(12));
7.92 (s, HÀC(8)). The signals were assigned by 1H,1H-COSY spectrum. Cross signals between: 1.61/1.97 ± 2.14;
1.61/4.19; 2.05 ± 2.14/2.44 ± 2.54; 1.97 ± 2.14/4.27; 4.19/4.27; 4.19/7.88 ppm. Relative configuration at
C(10)ÀC(11) follows froma ROESY spectrum. Cross signals between: 1.61/1.97 ± 2.14; 2.05 ± 2.14/2.44 ± 2.54;
1.97 ± 2.14/4.27; 1.97 ± 2.14/7.92; 4.19/4.27; 4.19/7.88; 4.27/7.88. Anal. calc. for C13H17N7O ´ H2O (305.34): C 51.14,
H 6.27, N 32.11; found: C 51.32, H 6.25, N 32.04.
Crystall-Structure Analysis of ent-13 (see Fig. 2). Suitable crystals of ent-1340) (needles; orthorhombic)
were obtained fromEtOH/H 2O. Space group: P212121 (No. 19); cell: a ˆ 9.267(2) Š; b ˆ 10.960(1) Š; c ˆ
14.058(2) Š; Vˆ 1427.9(7) Š3; Z ˆ 4; Dc ˆ 1.420 g cmÀ3. Hemisphere up to 2qmax ˆ 1308. 3938 reflections, 2314
independent reflections, 2305 reflections with I > 0. Number of variables: 276. R(F) ˆ 0.028; wR(F) ˆ 0.038.
40
)
Spontaneous resolution has taken place on crystallization.

Helvetica Chimica Acta ± Vol. 83 (2000)
1077
2.3. 5-Methyl-1-[(1RS,5RS,8RS)-3-oxo-2-azabicyclo[3.3.1]nonan-8-yl]pyrimidine-2,4(1H,3H)-dione (rac-
14a ˆ rac-14; Scheme 2). NaH (3.69 g of a 65% dispersion in mineral oil; 100 mmol) was placed in a dry, 500-ml,
three-necked, round-bottomed flask equipped with a magnetic stirring bar, Ar inlet, outlet, and pressure-
equalizing dropping funnel, and washed with pentane (2 Â 30 ml each). The flask was purged with dry Ar prior
to adding anh. DMSO (250 ml) and thymine (6.31 g, 50.0 mmol). After stirring for 5 min at r.t., rac-12a (13.3 g;
50.0 mmol) was added. The mixture was stirred for 48 h at r.t., NH4Cl (20 ml of a sat. aq. soln.) was added, and
the solvent was evaporated (708/1 Torr). The oily residue was adsorbed on silica gel (20 g) and filtered through
silica gel (200 g; 3 l of AcOEt; 1 l of Et2O; 1.6 l of CH2Cl2/MeOH 15 :1; 1.1 l of CH2Cl2/MeOH 10 :1; 1.2 l of
CH2Cl2/MeOH 5 :1). The residue of the concentrated eluate (18 g) was dissolved in a small amount of MeOH,
and to the resulting soln., CH2Cl2 was added under stirring. The colorless precipitate formed was filtered and
dried (P2O5 in a vacuumdesiccator) to give rac-13a (4.49 g, 34%). The mother liquor was concentrated, traces of
solvent were removed by a bulb-to-bulb distillation (1208/0.3 Torr), and the residue was purified by FC (150 g;
CH2Cl2/MeOH 15 :1) to afford additional product (1.20 gm, 9%), hereby increasing the overall yield to 41%.
M.p. 304 ± 3068 (MeOH/H2O). TLC (CH2Cl2/MeOH 10 :1): Rf 0.22. UV (H2O): lmax 273.0 (11470). IR (KBr):
1
3611m, 3432s, 3257s, 3190s, 2944s, 2812s, 1704s, 1663s, 1621s, 1486s, 1430s, 1398s, 1365s, 1268s, 1116s. H-NMR
((D6)-DMSO): 1.42, 1.65 (m, HÀC(4'), 2 HÀC(9')); 1.69 ± 1.88 (m, HÀC(3'), Me); 1.89 ± 2.05 (m, H'ÀC(3'),
H'ÀC(4'), HÀC(6')); 2.10 (br. s, HÀC(5')); 2.42 (dd, J(H'ÀC(6'),HÀC(6')) ˆ 18.0, J(H'ÀC(6'),HÀC(5')) ˆ 7.5,
H'ÀC(6')); 3.58 (br. m, HÀC(1')); 4.15 (br. m, HÀC(2')); 7.52 (s, HÀC(6)); 7.97 (d, exchangeable on treatment
with D2O, J(HÀN(8),HÀC(1)) ˆ 4.5, HÀN(8)); 11.29 (s, exchangeable on treatment with D2O, HÀN(3)).
13C-NMR (50 MHz, (D6)-DMSO): 12.18 (Me); 17.99 (C(3')); 23.76 (C(9')); 24.64 (C(5')); 27.48 (C(4')); 37.13
(C(6')); 47.40 (C(1')); 54.63 (C(2')); 108.64 (C(5)); 138.12 (C(6)); 151.00 (C(2)); 163.70 (C(4)); 171.19 (C(7')).
‡
The signals were assigned by DEPT and 1H,13C-COSY spectra. ESI-MS: 264.3 ([M ‡ H] ). Anal. calc. for
C13H17N3O3 ´ H2O (281.31): C 55.51, H 6.81, N 14.94; found: C 55.64, H 6.83, N 15.08.
Crystal-Structure Analysis of rac-16a (see Fig. 3). Suitable crystals (monoclinic) were obtained from
MeOH ´ H2O. Space group C2/c (No. 15); cell: a ˆ 21.472(3) Š; b ˆ 11.304(1) Š; c ˆ 14.028(3) Š; b ˆ 127.81(1);
Vˆ 2689(1) Š3; Z ˆ 8; Dc ˆ 1.389 g ´ cmÀ3. Hemisphere up to 2qmax ˆ 1308. 4779 reflections, 2289 independent
reflections, 2254 reflections with I > 0. Number of variables: 250. R(F) ˆ 0.054, wR(F) ˆ 0.074.
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Received November 23, 1999