Synthesis of substituted conformationally constrained 6,5- and 7,5-fused bicyclic lactams as dipeptide mimics

Article abstract of DOI:10.1016/S0040-4020(03)01018-4

Using a convenient and practical route we report the preparation of a series of rigid surrogates of amino acids and dipeptides for application within constrained peptide analogues, and for employment as input for combinatorial science. These substituted 2-oxo-1-azabicycloalkane amino acids have the potential of replicating the backbone geometry and side-chain function of dipeptide residues like serine, lysine, glutamate, and related amino acids.

Full text of DOI:10.1016/S0040-4020(03)01018-4

Tetrahedron 59 (2003) 6241–6250
Synthesis of substituted conformationally constrained 6,5- and
7,5-fused bicyclic lactams as dipeptide mimics
Erica Artale,a Gaia Banfi,a Laura Belvisi,a Lino Colombo,b Matteo Colombo,a
a
Leonardo Manzonic and Carlo Scolastico
,
,
*
*
aDipartimento di Chimica Organica e Industriale and Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali (CISI),
University of Milano, Via Venezian 21, I-20133 Milano, Italy
bDipartimento di Chimica Farmaceutica, University of Pavia, Via Taramelli 12, I-27100 Pavia, Italy
cCIR-Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Venezian 21, I-20133 Milano, Italy
Received 28 April 2003; revised 27 May 2003; accepted 26 June 2003
Abstract—Using a convenient and practical route we report the preparation of a series of rigid surrogates of amino acids and dipeptides for
application within constrained peptide analogues, and for employment as input for combinatorial science. These substituted 2-oxo-1-
azabicycloalkane amino acids have the potential of replicating the backbone geometry and side-chain function of dipeptide residues like
serine, lysine, glutamate, and related amino acids.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
and thus can serve to control selective delivery of drugs
which may be appended to the lactam substituent.12
Design and synthesis of novel bicyclic lactams as
peptidomimetics is currently an area of intensive research
in the field of peptide and medicinal chemistry.1 Because of
the intrinsic interest of these substrates as ligands for a wide
variety of biological receptors, incorporation of these
scaffolds into peptide chains can be used to generate novel
structures of significant relevance to biological application.
In the course of our studies on peptide secondary structure
mimics, we have synthesised several 6,5- and 7,5-fused
azabicycloalkane amino acids.2–7 These structures can be
regarded as conformationally restricted substitutes for Ala-
Pro and Phe-Pro dipeptide units.8–10 Functionalizing these
molecules with different appendages is a very attractive
target, because the side-chains could improve peptide–
receptor affinity by interacting with hydrophobic or
hydrophilic pockets of the receptor. On the other hand,
diversification of bicyclic lactams by tethering of different
pharmacophoric groups may generate library members
exhibiting different biological activity. Finally, similarly
to the unsubstituted constrained dipeptide mimics,11 these
lactams can be incorporated into cyclic pseudopeptides
containing the RGD epitope. As such, these molecules can
be homed selectively to tissues that over-express these
receptors (e.g. epithelial cells involved in vascular growth),
The generation of different conformationally constrained
dipeptide mimetic units broadens the scope of our library of
structures. In the light of the importance of amino acid side-
chains as sites for interaction in various recognition events,
we report here an extension of the versatile approach to the
synthesis of azabicyclo[X.Y.0]alkanes5 that possess hetero-
atom-substituted side-chains at the 7 (or 8)-position
(Scheme 1).
The synthetic plan relies on the (Z)-selective Horner–
Emmons/double bond reduction that we have described for
the unsubstituted compounds,5 but uses as starting material
the aldehydes 1 and 2, which carry an appendage on the C4
position of Pro ring. The resulting lactams 5a,b and 6a,b
feature a protected hydroxy terminal side-chain. Elaboration
of the side-chain through a conversion of the primary
hydroxy group into an azide function is also demonstrated
starting from 5b.
2. Results and discussion
2.1. Chemistry
The synthesis of lactams 5a,b and 6a,b was accomplished
following the general synthetic plan outlined in Scheme 1.
The starting aldehydes 1 and 2 were stereoselectively
synthesized from the 3-allyl-pyroglutamic ester 7
Keywords: peptide mimetics; amino acids; Wittig reactions.
*
Corresponding authors. Tel.: þ39-02-50314088; fax: þ39-02-50314072;
e-mail: leonardo.manzoni@unimi.it; Tel.: þ39-02-50314090; fax: þ39-
0250314072; e-mail: carlo.scolastico@unimi.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01018-4

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E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
Scheme 1. General scheme for the synthesis of functionalized bicyclic lactams.
(Scheme 2), readily obtainable from glutamic acid via a
known procedure.13 After the conversion of the methyl ester
into the corresponding tert-butyl derivative,14 ozonolysis of
8 followed by treatment with NaBH4 gave the correspond-
ing alcohol which was protected as a thexyldimethylsilyl
ether giving 9 in 78% yield over two steps. The lactam 9 was
N-protected as a N-Cbz derivative using LiHMDS and
CbzCl in a THF solution15 affording 10 in 80% yield.
aldehyde 1 which was converted into 3 by standard Horner–
Emmons protocol with the commercially available (Z)-a-
phosphonoglycine trimethyl ester18 in 65% yield over two
steps [9:1 (Z)/(E) ratio]. The N-Cbz group adjacent to the
methyl ester was further protected as a Boc derivative and
the resulting fully protected compound was submitted to
catalytic hydrogenation which effected, in one operation,
the removal of both N-Cbz protective groups and reduction
of the double bond. Final lactam formation was accom-
plished by refluxing the crude hydrogenation product in
methanolic iPr2EtN. The bicyclic lactams 5a and b were
thus obtain in 66% yield (over the three steps) as a 2:8
mixture of diastereoisomers. The stereochemistry of the
newly formed stereocentre was determined by NOESY
experiments. In compound 5a a strong NOE crosspeaks
between H3 and H6 was observed while in compound 5b
this effect was not detected.
Selective reduction of the imide 10 to the hemiaminal 11
was performed using lithium triethylborohydride at
2788C.16 The hemiaminal was then treated with allyl-
tributyltin17 in the presence of tert-butyldimethylsilyl-
triflate7 in anhydrous CH2Cl2 to afford 12 in 62% yield
after the two steps as the only isomer. The stereochemistry
of the newly formed stereocentre was determined by
NOESY experiments. The trans arrangement was evidenced
by the presence of NOE cross peaks between the proton H5
of the proline moiety and the protons adjacent to the
heteroatom on the side-chain in position C4. The nucleo-
philic addition of the allyl unit selectively occurs trans to
the adjacent side-chain, as we have already observed in
previous work on related systems.7
The aldehyde 2 was prepared starting from the 5-allyl
proline 12 by hydroboration and Swern oxidation (67% over
2 steps). The homologous aldehyde was treated with the
(Z)-a-phosphonoglycine trimethyl ester to give 4, mainly as
a Z-isomer, in 92% yield. N-Boc protection followed by
methyl ester hydrolysis with NaOH in THF gave the
corresponding acid, which was reduced (H2/Pd–C) and
subsequently cyclized with condensing agents HATU,
HOAt, 2,4,6-collidine, DMF) to give the easily separated
lactams 6a and b in 5.4:1.0 ratio and 46% overall yield.
The stereochemistry of the final products was
The 5-allyl proline 12 was exploited as the common
intermediate for the synthesis of both series of 2-oxoaza-
bicycloalkane 5a,b and 6a,b according to Scheme 3.
Reductive ozonolysis of the double bond in 12 gave the
Scheme 2. Reagents and conditions: (i) NaOH, THF, 99%; (ii) O-tert-butyl-N,N-diisopropyl-isourea, CH2Cl2, reflux, 99%; (iii) O3, MeOH, NaBH4, 80%;
(iv) TBDMSCl, imidazole, DMF, 98%; (v) CbzCl, LiHMDS, THF, 80%; (vi) LiEt3BH, THF, 2788C; (vii) allyltributyltin, TBDSOTf, CH2Cl2, 2788C, 62%
over two steps.

E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
6243
Scheme 3. Reagents and conditions: (i) O3, MeOH, Me2S, 80%; (ii) (^)-(Z)-a-phosphonoglycine trimethyl ester, tBuOK, CH2Cl2, 2788C, 81%; (iii) Boc2O,
4-DMAP, THF, 91%; (iv) H2, Pd/C, MeOH; (v) MeOH, DIPEA, reflux, 73% over two steps; (vi) 9-BBN, THF, 83%; (vii) (COCl)2, DMSO, TEA, CH2Cl2,
2608C, 81%; (viii) (^)-(Z)-a-phosphonoglycine trimethyl ester, tBuOK, CH2Cl2, 2788C, 92%; (ix) Boc2O, 4-DMAP, THF, 87%; (x) NaOH, THF; (xi) H2,
Pd/C, MeOH; (xii) HATU, HOAt, 2,4,6-collidine, DMF, 53% over three steps.
unequivocally determined by NOESY experiments. In the
compound 6a a strong NOE crosspeak between H3 and H12
was observed while in compound 6b this effect was not
detected.
starting material for the preparation of Ala-Arg dipeptide
unit when a guanidine is inserted instead of the azido group.
2.2. Molecular modeling
Finally, modification of the lactam side-chain was demon-
strated in the case of 5b, as shown in Scheme 4. Thus, silyl
ether deprotection of 5b (TBAF, THF 98%) and activation
of 13 with MsCl followed by nucleophilic displacement
with sodium azide in DMF at 808C gave azide 14. The azide
was isolated in 94% overall yield from 5b. This structure
can be regarded as conformational restricted substitute for
Ala-Lys dipeptide unit and can be considered a suitable
Computational studies designed to investigate the ability of
the new bicyclic scaffolds to adopt reverse-turn confor-
mations were performed on the N-acetyl-N0-methylamide
dipeptide analogues 15a,b and 16a,b19 (Fig. 1).
Each structure was subjected to an extensive, unconstrained
Monte Carlo/Energy Minimization (MC/EM) confor-
mational search20 by molecular mechanics methods in
Scheme 4. Reagents and conditions: (i) TBAF, THF, 98%; (ii) MsCl, TEA, CH2Cl2, 08C; (iii) NaN3, DMF, 808C, 96% over two steps.

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E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
of hydrogen bonding (distance between the carbonyl oxygen
and the amide hydrogen atom, and directional require-
ments).
A summary of the reverse-turn mimetic properties of the
calculated structures of compounds 15a,b and 16a,b is
reported in Table 1. The turn propensity was quantitatively
assessed by computing the percentage of conformations
within 6 kcal/mol from the global minimum for which the
aforementioned parameters assume typical turn values.24
The percentage of all conformers with a virtual torsion angle
b (absolute value) of less than 308 or 608 shows that 15b and
16b, having the carboxy and amino groups on the same face
of the bicyclic system (3S-Pro Ca S configuration) are of
potential use as reverse-turn mimetics, although there is a
dependence on the lactam ring size. On the contrary, among
the (3R-Pro Ca S) diastereoisomers only the 7,5-fused
lactam 16a is able to enforce a turn which actually induces
the peptide backbone to reverse direction.
Figure 1. Bicyclic dipeptide mimics used in modelling studies.
The percentages of conformers forming intramolecular
hydrogen bonds show that the reverse-turn mimetic units
15b and 16a,b can promote either a g-turn (7-membered
ring H-bond) or a b-turn (10-membered ring H-bond). In the
6,5-fused bicyclic lactam 15a, the formation of a g-turn is
not sufficient to reverse the peptide direction, as indicated
by the values of the torsion angle b and the distance da. The
relative stabilities of the principal backbone geometries
calculated for compounds 15a,b and 16a,b are given in the
last column of Table 1.
water as implicitly represented by the GB/SA solvation
model21 (see Section 4.2). According to the previously
reported conformational analysis of unsubstituted
azabicycloalkane amino acids,8 reverse-turn inducing
properties of the minimum energy conformations of
15a,b, 16a,b were assessed by computing and analyzing
different geometrical parameters (Table 1): the Cai2Caiþ3
distance (da) between capping groups on the N- and C
termini, the f and c backbone torsion angles in
residues iþ1 and iþ2,22 the virtual torsion angle b
(Ci2Caiþ12Caiþ22Niþ3),23 and parameters indicative
The quantitative characterization of the turn propensity of
the functionalized azabicycloalkane amino acid scaffolds
Table 1. Quantitative characterization of the reverse-turn forming ability of the conformers (MC/EM, AMBER p , H2O GB/SA) calculated for dipeptide
mimics 15a,b, 16a,b
a
% da ,7 A
b
b
%H-bondc
7-membered ring,
g-turn
%H-bondc
10-membd. ring,
b-turn
DE
(kcal/mol)
g-turn/b-turn
˚
Compound
%lbl ,308
%lbl ,608
15a
15b
16a
16b
0
1
18
95
97
66
29
27
21
21
0þ0d
0.5e/-
32
30
60
64
76
26
22þ9d
0þ20d
24þ11d
0.6e/0.3f
0.2e/2.9g
1.8e/0.0h
a
˚
% da is the percentage of all conformers for which the distance between Cai and Caiþ3 is ,7 A.
b
c
d
e
f
% lbl is the percentage of all conformers in which the virtual torsion angle b (absolute value) is ,308 (or 608).
% H-bond is the percentage of all conformers in which H· · ·O distance ,2.5 A, N–H· · ·O bond angle .1208, and H· · ·OvC angle .908.
˚
˚
Percentage of conformers in which 2.5 A ,H· · ·O distance ,4 A.
Inverse g-turn.
Type II0 b-turn.
˚
g
h
Distorted type II0 b-turn.
Type I b-turn.

E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
6245
suggests that these systems are more effective as reverse-
turn than as beta-turn mimics, in agreement with the results
obtained for the corresponding unsubstituted bicyclic
lactams.8 Nevertheless, the functionalized bicyclic lactams
15b and 16b show b-turn mimetic properties higher than the
corresponding unsubstituted scaffolds.8,25
the stereocenter in 6 and 9 and 7 and 10, respectively, in the
bicyclic lactams, was achieved by a stereoselective allyl-
ation of the hemiaminal 11. After hydrogenation, the
lactams were obtained as easily separable mixtures of
stereoisomers epimeric at the carbon adjacent to the lactam
carbonyl group.
The lowest energy conformers mimicking a b-turn of the
dipeptide mimics 15b and 16b are shown in Figure 2.
Applications of these compounds as reverse-turn inducers
and as scaffolds for the synthesis of biologically active
compounds are being studied in our laboratory.
4. Experimental
4.1. Chemistry
General remarks. 1H and 13C NMR spectra were recorded in
CDCl3 solution as indicated, at 200 (or 300, 400) and
50.3 MHz, respectively. The chemical shift values are given
in ppm and the coupling constants in Hz. Optical rotation
data were obtained with a Perkin–Elmer model 241
polarimeter. Thin-layer chromatography (TLC) was carried
out using Merck precoated silica gel F-254 plates. Flash
chromatography was carried out using Macherey–Nagel
silica gel 60, 230–400 mesh. Solvents were dried according
to standard procedures, and reactions requiring anhydrous
conditions were performed under nitrogen. Solutions
containing the final products were dried with Na2SO4,
filtered, and concentrated under reduced pressure using a
rotary evaporator. Elemental analyses were performed by
the staff of the microanalytical laboratory in our department.
Abbreviations: HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate, HOAt: 1-hydroxy-7-
azabenzotriazole, DMAP: 4-(dimethylamino)pyridine,
TBAF: tetrabutylammonium fluoride, DMF: N,N-dimethyl-
formamide, THF: tetrahydrofuran, Boc2O: di-tert-butyl
dicarbonate, DMSO: methyl sulfoxide.
General procedure A, preparation of acrylic ester 3 and 4 by
Horner–Emmons reaction (Scheme 1). To a stirred solution
of tBuOK (0.115 mmol) in dry CH2Cl2 (1 mL) under
nitrogen, a solution of (Z)-a-phosphonoglycine trimethyl
ester (0.115 mmol) in dry CH2Cl2 (0.5 mL) was added at
2788C. The resulting mixture was stirred for 30 min at this
temperature and then a solution of the appropriate aldehyde
(0.076 mmol) in dry CH2Cl2 (1 mL) was added. After 5 h,
the solution was allowed to warm to room temperature and
neutralised with phosphate buffer. The aqueous phase was
extracted with CH2Cl2, the combined extracts were dried
over Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography
(hexane/ethyl acetate) to afford the acrylic ester as a (Z)/(E)
diastereoisomeric mixture.
Figure 2. (a) Minimum energy conformer of 15b featuring the type II0
b-turn. (b) Minimum energy conformer of 16b featuring the type I b-turn.
3. Conclusion
In conclusion, using a convenient and practical route we
have reported the preparation of novel conformationally
constrained scaffolds with the potential of replicating the
backbone geometry and side-chain function of dipeptide
residues like serine, lysine, glutamate, and related amino
acids. These amino acid motifs may be used as confor-
mationally constrained entities that mimic segments of
natural peptide substrates. Alternatively, the functionalised
side-chain could be used as a site to append pharmacologi-
cally relevant groups to enhance protein–protein or
receptor–substrate interaction. The trans relation between
General procedure B, preparation of the N-Boc-protected
acrylic ester. A solution of the acrylic ester (0.058 mmol),
(Boc)2O (0.117 mmol), and a catalytic amount of DMAP in
dry THF (1 mL) was stirred for 30 min under nitrogen. The
solution was then quenched with water (1 mL) and extracted
with ethyl acetate. The combined organic extracts were
dried over Na2SO4 and the solvent was evaporated under
reduced pressure. The residue was purified by flash

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E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
chromatography (hexane/ethyl acetate) to yield the Boc-
protected acrylic ester.
evaporated and the crude was purified by flash chromato-
graphy (hexane/ethyl acetate 1:1) to yield 1.12 g of 9 (98%)
1
as a colorless oil. [a]2D0¼þ10.0 (c¼1.0, CHCl3). H NMR
4.1.1. Synthesis of the intermediate 12 (Scheme 2). Ester
8. To a solution of 713 (1.7 g, 9.34 mmol) in THF (94 mL)
was added 2N NaOH (9.34 mL, 18.68 mmol). After stirring
for 30 min at room temperature Amberlite IR 120Hþ was
added and then the reaction mixture was filtered and the
solvent was evaporated under reduced pressure to yield
1.56 g of acid (99%) as a white solid; mp 123–1248C.
[a]2D0¼þ57.1 (c¼0.9, CHCl3). 1H NMR (200 MHz, CDCl3):
d¼1.95 (m, 1H, –HCH–), 2.21 (m, 1H, –HCH–), 2.61 (m,
2H, –CH2–), 3.71 (m, 1H, –CHCvO), 4.32 (m, 1H, –
CHCO2H), 5.09 (m, 2H, –CHvCH2), 5.72 (m, 1H,
–CHvCH2), 7.52 (bs, 1H, NH), 8.35 (bs, 1H, –COOH).
13C NMR (50.3 MHz, CDCl3): d¼180.6, 174.9, 134.6,
117.5, 54.5, 41.2, 34.7, 30.2. FABþMS: calcd. For
C8H11NO3 169.07; found 170. C8H11NO3 (169.07): calcd.
C 56.80, H 6.55, N 8.28; found C 56.71, H 6.52, N 8.29. To a
solution of acid (1.58 g, 9.34 mmol) in dry CH2Cl2
(93.4 mL) was added O-tert-butyl-N,N-diisopropyl-isourea
(6.7 mL, 28.01 mmol) and the mixture was refluxed for
48 h. The solvent was then evaporated and the residue was
treated with Et2O to remove the urea formed as the major
by-product. The collected organic solvents were evaporated
and the crude was purified by flash chromatography
(hexane/ethyl acetate, 3:7) affording 2.08 g of 8 (99%) as
a colorless oil. [a]D20¼þ31.9 (c¼1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d¼1.48 (s, 9H, C(CH3)3), 1.81 (m, 1H,
–HCH–), 2.17 (m, 1H, –HCH–), 2.55 (m, 3H), 4.12 (m,
1H, –CHCO2tBu), 5.13 (m, 2H, –CHvCH2), 5.71 (m, 1H,
–CHvCH2), 5.81 (bs, 1H, NH). 13C NMR (50.3 MHz,
CDCl3): d¼178.5, 170.9, 135.2, 117.0, 82.2, 54.3, 40.6,
35.0, 30.4, 27.9. FABþMS: calcd. For C12H19NO3 225.14;
found 226. C12H19NO3 (225.14): calcd. C 63.98, H 8.50, N
6.22; found C 64.04, H 8.55, N 6.28.
(400 MHz, CDCl3): d¼0.12 (s, 6H, –Si(CH3)2), 0.83–0.90
(m, 12H, –CH3), 1.50 (s, 9H, –C(CH3)3), 1.55 (m, 1H,
–HCHCH2OSi), 1.63 (m, 1H, –CH(CH3)2), 1.90 (m, 1H,
–HCHCH2OSi), 2.15 (m, 1H, –HCHCHCOOtBu), 2.60 (m
1H, –CHCvO), 2.71 (m, 1H, –HCHCHCOOtBu), 3.75 (m,
2H, –CH2OSi), 4.12 (m, 1H, –CHCOOtBu), 6.22 (bs, 1H,
NH). 13C NMR (50.3 MHz, CDCl3): d¼179.1, 170.8, 60.8,
54.4, 38.7, 34.0, 33.8, 32.1, 27.8, 20.2, 18.4, 23.5, 23.6.
FABþMS: calcd. For C19H37NO4Si 371.25; found 372.
C19H37NO4Si (371.25): calcd. C 61.41, H 10.04, N 3.77;
found C 61.51, H 10.10, N 3.87.
N-Cbz-protected silyl derivative 10. To a solution of 9
(0.552 g, 1.48 mmol) in THF (5 mL) was added LiHMDS
1 M in THF (1.63 mL, 1.63 mmol) at 2508C. After 20 min
benzyl chloroformate (0.230 mL, 1.63 mmol) was added
and the solution was stirred for 20 min after which a
saturated solution of NH4Cl was added, the aqueous phase
was extracted with EtOAc and the organic phase dried over
Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude material was purified by flash
chromatography (hexane/ethyl acetate 8:2) yielding 0.603 g
(80%) of 10 as a colorless oil. [a]2D0¼210.6 (c¼1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): d¼0.12 (s, 6H,
–Si(CH3)2), 0.61 (m, 12H, –CH3), 1.48 [s, 9H, –C(CH3)3],
1.55 (m, 2H, –HCHCH2OSi, –CH(CH3)2), 1.75 (m, 1H,
–HCHCHCOOtBu), 2.11 (m, 1H, –HCHCH2OSi), 2.55 (m,
1H, –HCHCHCOOtBu), 2.71 (m, 1H, –CHCvO), 3.70 (m,
2H, –CH2OSi), 4.48 (m, 1H, –CHCOOtBu), 5.25 (s, 2H,
–CH2Ph), 7.30 (m, 5H, aromatics). 13C NMR (50.3 MHz,
CDCl3): d¼175.2, 170.2, 128.4, 128.3, 128.1, 82.2, 68.2,
60.3, 58.0, 39.9, 34.0, 28.1, 27.7, 20.2, 18.4, 23.6.
FABþMS: calcd. For C27H43NO6Si 505.29; found 506.
C27H43NO6Si (505.29): calcd. C 64.12, H 8.57, N 2.77;
found C 64.21, H 8.66, N 2.84.
Silyl derivative 9. A stirred solution of 8 (1.16 g,
5.16 mmol) in MeOH (52 mL) was cooled to 2608C,
whereupon O3 was bubbled through it (flow rate¼30 L/h).
After 1.5 h N2 was bubbled through the reaction mixture in
order to eliminate the excess of O3. NaBH4 was then added
in portions until the ozonide had completely disappeared.
The solvent was evaporated under reduced pressure and the
residue was redissolved in EtOAc and washed with brine.
The organic phases were dried over Na2SO4 and the solvent
was evaporated under reduced pressure. The residue was
purified by flash chromatography (ethyl acetate) to yield
0.946 g of alcohol (80%) as a white solid. Mp 82–838C.
[a]2D0¼214.2 (c¼1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): d¼1.48 (s, 9H, –C(CH3)3), 1.75 (m, 1H,
–HCHCH2OH), 1.81 (m, 1H, –HCHCHCOOtBu), 2.04
(m, 1H, –HCHCH2OH), 2.69 (m, 1H, –CHCvO), 2.72 (m,
1H, –HCHCHCOOtBu), 3.65 (m, 1H, –HCHOH), 3.79 (m,
2H, –HCHOH, –OH), 4.15 (m, 1H, –CHCOOtBu), 5.92
(bs, 1H, NH). 13C NMR (50.3 MHz, CDCl3): d¼179.4,
170.0, 81.8, 60.7, 54.4, 40.0, 33.4, 31.7, 27.3. FABþMS:
calcd. For C11H19NO4 229.13; found 230. C11H19NO4
(229.13): calcd. C 57.62, H 8.35, N 6.11; found C 57.51, H
8.21, N 6.05. — To a stirred solution of the alcohol (0.708 g,
3.09 mmol), in DMF (4 mL), texyldimethylsilyl chloride
(1.82 mL, 9.27 mmol) and imidazole (1.26 g, 18.55 mmol)
were added sequentially. After 16 h the solvent was
Hemiaminal 11. To a solution of 10 (0.754 g, 1.49 mmol) in
dry THF (14.8 mL), LiEt3BH 1 M (1.79 mL, 1.79 mmol)
was added at 2788C and the solution was stirred for 3 h,
then a saturated NH4Cl solution (10 mL) was added. The
aqueous phase was extracted with EtOAc, the combined
organic layers were dried over Na2SO4, filtered and the
solvent was removed under reduced pressure. The crude, as
a yellowish oil, was submitted to the next reaction without
1
further purification. H NMR (200 MHz, CDCl3): d¼0.12
[s, 6H, –Si(CH3)2], 0.81 (m, 12H, –CH3), 1.42 [s, 9H,
–C(CH3)3], 1.55–2.20 (m, 6H), 3.60 (m, 2H, –CH2OTDS),
4.20 (m, 1H, –CHCOOtBu), 5.05 (s, 2H, –CH2Ph), 5.41,
5.43 (2 m, 2H, –CHOH), 7.3 (m, 5H, aromatics).
Allyl pyrrolidine 12. To a solution of 11 (0.678 g,
1.34 mmol) and allyltributyltin (0.48 mL, 1.61 mmol) in
dry CH2Cl2 (13 mL), under argon atmosphere and at
2788C,
tert-butyldimethylsilyltriflate
(0.37 mL,
1.61 mmol) was added dropwise. The reaction mixture
was stirred for 1 h, then a NaHCO3 satured solution (10 mL)
was added and the aqueous phase was extracted with
CH2Cl2. The collected organic phases were dried over
Na2SO4, filtered and evaporated. The crude was purified by
flash chromatography (hexane/ethyl acetate 9:1) affording

E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
6247
0.44 g (62% over two steps) of 12 (only trans-isomer) as a
colorless oil. [a]D20¼243.1 (c¼1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): d¼0.02 (s, 6H, –Si(CH3)2), 0.85 (m,
12H, –CH3), 1.47 (s, 9H, –C(CH3)3), 1.53 (m, 1H,
–HCHCH2OSi), 1.60 (m, 1H, –CH(CH3)2), 1.73 (m, 1H,
–HCHCH2OSi), 1.78 (m, 1H, –HCHCHCOOtBu), 2.30 (m,
2H, –CH2CHvCH2), 2.40 (m, 1H, –HCCH2CH2OSi), 2.52
(m, 1H, –HCHCHCOOtBu), 3.55 (m, 2H, –CH2OSi), 3.85
(m, 1H, –CHCH2CHvCH2), 4.21 (m, 1H, –CHCOOtBu),
5.1 (m, 4H, –CH2Ph, CH2v), 5.71 (m, 1H, –CHvCH2),
7.35 (m, 5H, aromatics). 13C NMR (HETCOR, 100.6 MHz,
CDCl3): d¼129.2, 118.3, 67.2, 64.5, 61.2, 60.1, 38.2, 38.0,
37.5, 34.0, 28.2, 20.1. FABþMS: calcd. For C30H49NO5Si
531.34; found 532. C30H49NO5Si (531.34): calcd. C 67.76,
H 9.29, N 2.63; found C 67.65, H 9.12, N 2.56.
(400 MHz, CDCl3) (signals are split due to amidic
isomerism): d¼0.10 [s, 6H, –Si(CH3)2], 0.80 (m, 12H,
–CH3), 1.39 [s, 9H, –C(CH3)3], 1.55 [m, 1H, –CH(CH3)2],
1.71–2.65 (5 m, 7H), 3.52 (m, 2H, –CH2OSi), 3.70 (s, 3H,
–CO2CH3), 3.82 (m, 1H, –CHCH2CHv), 4.20 (m, 1H,
–CHCOOtBu), 5.15 (m, 4H, –CH2Ph), 6.53 (m, 1H,
–CHv), 6.80 (bs, 1H, –NH), 7.40 (m, 10H, aromatics).
13C NMR (50.3 MHz, CDCl3) (signals are split due to
amidic isomerism): d¼171.7, 154.5, 154.0, 130.7, 128.4,
128.3, 128.2, 128.1, 128.0, 127.9, 81.2, 67.4, 67.1, 66.9,
63.5, 62.6, 60.7, 59.8, 52.2, 39.7, 39.6, 36.6, 33.3, 33.1,
31.5, 27.9, 27.6, 24.9, 20.2, 18.4, 23.61, 23.69. FABþMS:
calcd. For C40H58N2O9Si 738.39; found 739. C40H58N2O9Si
(738.39): calcd. C 65.01, H 7.91, N 3.79; found C 65.18, H
7.82, N 3.89.
4.1.2. Synthesis of functionalized 6,5-fused bicyclic
lactams (Scheme 3). Aldehyde 1. A stirred solution of 12
(0.335 g, 0.63 mmol) in MeOH (6.3 mL) was cooled to
2788C, whereupon O3 was bubbled through the reaction
(flow rate¼30 L/h). After 1.5 h N2 was bubbled through it in
order to eliminate the excess of O3. The solution was then
warmed to 08C by means of an ice bath and Me2S
(39.7 mmol, 0.29 mL) was added. After stirring for 24 h at
room temperature, the solvent was evaporated under
reduced pressure and the crude product was purified by
flash chromatography (hexane/ethyl acetate 9:1) to yield
0.268 g of aldehyde 1 (80%) as a colorless oil. [a]2D0¼226.1
trans-6,5-Fused bicyclic lactams 5a and b. According to the
general procedure B, 3 was N-Boc-protected. The crude
product was purified by flash chromatography (hexane/ethyl
acetate, 6:4) to yield the acrylic ester (91%). Mixture of two
1
diastereoisomers: H NMR (400 MHz, CDCl3) (signals are
split due to amidic isomerism): d¼0.10 [s, 6H, –Si(CH3)2],
0.85 (m, 12H, –CH3), 1.31 [s, 9H, –C(CH3)3], 1.40 [m, 1H,
–CH(CH3)2], 1.45 [s, 9H, –C(CH3)3], 1.74–2.60 (m, 7H),
3.48 (m, 2H, –CH2OSi), 3.74, 3.92 (2 s, 3H, –CO2CH3),
3.93 (m, 1H, –CHCH2CHv), 4.20 (m, 1H, –CHCOOtBu),
5.10 (m, 4H, –CH2Ph), 6.85 (m, 1H, –CHv), 7.30 (m,
10H, aromatics). 13C NMR (50.3 MHz, CDCl3) (signals are
split due to amidic isomerism): d¼171.7, 163.7, 151.7,
138.7, 137.7, 136.4, 136.2, 135.2, 130.0, 128.3, 128.2,
128.0, 127.9, 127.8, 83.4, 81.3, 81.2, 68.3, 67.1, 66.9, 62.8,
62.2, 61.2, 61.1, 60.2, 59.6, 52.2, 40.3, 38.8, 36.8, 34.0,
33.9, 32.8, 31.4, 27.8, 27.7, 24.9, 20.2, 18.4, 23.6.
FABþMS: calcd. For C45H66N2O11Si 838.44; found 839.
C45H66N2O11Si (838.44): calcd. C 64.41, H 7.93, N 3.34;
found C 64.50, H 8.00, N 3.43. A solution of the N-Boc-
protected compound (0.0647 g, 0.077 mmol) in MeOH
(2 mL) containing a catalytic amount of 10% Pd/C was
stirred for 16 h under H2. The catalyst was then removed by
filtration through a Celite pad and the filtrate was
concentrated to dryness under reduced pressure. The residue
was redissolved in MeOH (20 mL) and DIPEA (0.066 mL,
0.38 mmol) was added. The mixture was refluxed for 48 h.
The solvent was removed and the two diastereoisomers
obtained were separated by flash chromatography (hexane/
ethyl acetate, 8:2) to yield 5.7 mg of 5a and 24.8 mg of 5b
(73% over two steps) in a 1.0:4.3 diastereoisomeric ratio as
a colorless oil. 5a: [a]2D0¼262.5 (c¼0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): d¼0.10 [s, 6H, –Si(CH3)2], 0.80 (m,
12H, –CH3), 1.48 (m, 1H, H10), 1.50 (m, 1H, H5), 1.51 (m,
1H, H8), 1.51 [s, 9H, –C(CH3)3], 1.53 [s, 9H, –C(CH3)3],
1.60 [m, 1H, –CH(CH3)2], 1.65 (m, 1H, H4), 1.78 (m, 1H,
H100), 1.90 (m, 1H, H7), 2.11 (m, 1H, H50), 2.40 (m, 1H,
H40), 2.52 (m, 1H, H80), 3.38 (m, 1H, H6), 3.67 (m, 2H,
H11), 4.30 (m, 1H, H3), 4.37 (m, 1H, H9), 5.55 (s, 1H, NH).
13C NMR (50.3 MHz, CDCl3): d¼171.1, 81.7, 79.6, 61.8,
60.9, 59.0, 50.8, 43.8, 34.8, 34.3, 29.8, 28.1, 27.1, 25.2,
25.0, 20.5, 20.2, 18.6, 23.2. FABþMS: calcd. For
C28H52N2O6Si 540.36; found 541. C28H52N2O6Si
(540.36): calcd. C 62.18, H 9.69, N 5.18; found C 62.24,
H 9.75, N 5.21. 5b: [a]2D0¼221.8 (c¼0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): d¼0.00 [s, 6H, –Si(CH3)2], 0.87 (m,
12H, –CH3), 1.40 (m, 1H, H10), 1.45 (m, 1H, H5), 1.45 (m,
1
(c¼1.0, CHCl3). H NMR (400 MHz, CDCl3) (signals are
split due to amidic isomerism): d¼0.12 [s, 6H, –Si(CH3)2],
0.81 (m, 12H, –CH3), 1.40 [s, 9H, –C(CH3)3], 1.55 (m,
1H, –HCHCH2OSi), 1.65 [m, 1H, –CH(CH3)2], 1.75 (m,
1H, –HCHCHCOOtBu), 1.81 (m, 1H, –HCHCH2OSi),
2.12 (m, 1H, –CHCH2CH2OSi –), 2.48 (m, 1H,
–HCHCHCOOtBu), 2.65 (m, 1H, –HCHCHO), 2.85 (m,
1H, –HCHCHO), 3.61 (m, 2H, –CH2OSi), 4.22 (m, 1H,
–CHCH2CHO), 4.25 (m, 1H, –CHCOOtBu), 5.12 (m, 2H,
–CH2Ph), 7.28 (m, 5H, aromatics), 9.85, (s, 1H, –CHO).
13C NMR (DEPT, 50.3 MHz, CDCl3) (signals are split due
to amidic isomerism): d¼128.4, 128.2, 128.1, 127.8, 81.4,
67.0, 60.6, 59.8, 59.7, 48.7, 47.5, 40.0, 36.3, 36.2, 34.0,
33.9, 32.7, 27.8, 27.7, 24.9, 20.2, 18.4, 23.7, 23.6.
FABþMS: calcd. For C29H47NO6Si 533.32; found 534.
C29H47NO6Si (533.32): calcd. C 65.25, H 8.88, N 2.62;
found C 65.38, H 8.96, N 2.72.
Acrylic ester 3. According to the General Procedure A, 1
was subjected to the Horner–Emmons reaction. The crude
product was purified by flash chromatography (hexane/ethyl
acetate, 7:3) to afford the acrylic ester 3 in 81% yield
[diastereomeric ratio (Z)/(E)¼9:1]. For the sake of charac-
terization, a sample of the diastereomeric mixture was
1
separated by flash chromatography. (E)-isomer: H NMR
(400 MHz, CDCl3) (signals are split due to amidic
isomerism): d¼20.10 [s, 6H, –Si(CH3)2], 0.85 (m, 12H,
–CH3), 1.35 [s, 9H, –C(CH3)3], 1.55 [m, 1H, –CH(CH3)2],
1.72–3.03 (m, 7H), 3.55 (m, 2H, –CH2OSi), 3.71 (s, 3H,
–CO2CH3), 3.92 (m, 1H, –CHCH2CHv), 4.30 (m, 1H,
–CHCOOtBu), 5.10 (m, 4H, –CH2Ph), 6.93 (m, 2H,
–CHv, –NH), 7.40 (m, 10H, aromatics). FABþMS:
calcd. For C40H58N2O9Si 738.39; found 739.
C40H58N2O9Si (738.39): calcd. C 65.01, H 7.92, N 3.79;
found C 65.10, H 7.97, N 3.93. (Z)-isomer: 1H NMR

6248
E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
1H, H8), 1.45 [s, 9H, –C(CH3)3], 1.50 [s, 9H, –C(CH3)3],
1.60 [m, 1H, –CH(CH3)2], 1.70 (m, 1H, H4), 1.75 (m, 1H,
H100), 1.85 (m, 1H, H7), 2.15 (m, 1H, H50), 2.58 (m, 1H,
H40), 2.60 (m, 1H, H80), 3.30 (m, 1H, H6), 3.65 (m, 2H,
H11), 4.10 (m, 1H, H3), 4.30 (m, 1H, H9), 5.55 (s, 1H, NH).
13C NMR (50.3 MHz, CDCl3): d¼171.4, 167.5, 156.2, 81.4,
79.5, 64.6, 60.7, 58.1, 52.3, 43.1, 34.7, 34.1, 28.6, 28.3,
28.0, 26.3, 20.3, 18.4, 23.5. FABþMS: calcd. For
C28H52N2O6Si 540.36; found 541. C28H52N2O6Si
(540.36): calcd. C 62.18, H 9.69, N 5.18; found C 62.28,
H 9.76, N 5.24.
33.9, 32.8, 29.7, 27.9, 27.8, 26.6, 26.0, 25.9, 25.1, 20.3,
18.5, 23.5, 25.4. FABþMS: calcd. For C30H49NO6Si
547.33; found 548. C30H49NO6Si (547.33): calcd. C 65.78,
H 9.02, N 2.56; found C 65.67, H 8.98, N 2.59.
Acrylic ester 4. According to the general procedure A, 2 was
subjected to the Horner–Emmons reaction. The crude
product was purified by flash chromatography (hexane/ethyl
acetate, 8:2) to afford the acrylic ester 4 in 92% yield
[diastereomeric ratio (Z)/(E)¼9:1] as a yellow oil. Mixture
1
of two geometrical isomers: H NMR (200 MHz, CDCl3)
(signals are split due to amidic isomerism): d¼0.01 [s, 6H,
–Si(CH3)2], 0.82 (m, 12H, –CH3), 1.33 [s, 9H, –C(CH3)3],
1.55 [m, 1H, –CH(CH3)2], 1.70–2.52, (m, 9H), 3.57 (m,
2H, –CH2OSi), 3.72 (s, 3H, –CO2CH3), 3.78 (m, 1H,
–CHN–), 4.30 (m, 1H, –CHCOOtBu), 5.05 (m, 4H,
–CH2Ph), 6.54 (m, 2H, –CHv, –NH), 7.40 (m, 10H,
aromatics). 13C NMR (50.3 MHz, CDCl3) (signals are split
due to amidic isomerism): d¼171.9, 154.6, 136.6, 136.3,
128.4, 128.0, 127.8, 126.0, 81.2, 67.2, 66.9, 64.2, 63.5, 60.8,
60.2, 59.8, 52.2, 39.3, 38.2, 37.9, 37.1, 36.9, 34.1, 33.9,
33.3, 32.8, 31.7, 29.6, 27.8, 25.9, 25.0, 24.8, 24.4, 20.3,
18.5, 23.4. FABþMS: calcd. For C41H60N2O9Si 752.41;
found 753. C41H60N2O9Si (752.41): calcd. C 65.40, H 8.03,
N 3.72; found C 65.33, H 8.08, N 3.78.
4.1.3. Synthesis of functionalized 7,5-fused bicyclic
lactams (Scheme 3). Aldehyde 2. To a stirred solution of
12 (0.181 g, 0.341 mmol) in dry THF (3.4 mL) was added a
0.5 M solution of 9-BBN in THF (2.1 mL, 1.05 mmol). The
reaction mixture was stirred for 3 h, then cooled to 08C,
whereupon water (3 mL), aqueous 3 M NaOH solution
(1.03 mL) and 30% H2O2 (0.317 mL) were added. The
resulting mixture was stirred for 1 h at room temperature
and then refluxed for a further 16 h. After cooling, the
aqueous phase was extracted with EtOAc and the combined
organic phases were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/ethyl acetate 7:3)
to yield 0.156 g of the corresponding alcohol (83%) as a
yellow oil. [a]D20¼232.9 (c¼1.0, CHCl3). 1H NMR
(200 MHz, CDCl3) (signals are split due to amidic
isomerism): d¼0.10 [s, 6H, –Si(CH3)2], 0.81 (m, 12H,
–CH3), 1.30 [s, 9H, –C(CH3)3], 1.40–2.6 (m, 10H), 3.40–
3.90 (m, 6H, –CH2OSi, –CH2OH, –OH, –CHN–), 4.20
(m, 1H, –CHCOOtBu), 5.12 (s, 2H, –CH2Ph), 7.35 (m, 5H,
aromatics). 13C NMR (50.3 MHz, CDCl3) (signals are split
due to amidic isomerism): d¼171.9, 171.5, 154.6, 136.3,
134.8, 128.4, 128.2, 128.1, 127.9, 127.8, 127.6, 117.2, 81.2,
67.0, 66.9, 66.8, 63.8, 63.5, 63.0, 62.4, 62.2, 61.3, 60.6,
60.3, 60.0, 59.7, 40.8, 39.1, 39.0, 38.1, 37.0, 34.7, 34.3,
34.1, 33.7, 32.7, 32.1, 30.5, 30.4, 29.7, 28.8, 28.5, 27.8,
27.7, 26.7, 24.9, 20.2, 18.4, 23.6. FABþMS: calcd. For
C30H51NO6Si 549.35; found 550. C30H51NO6Si (549.35):
calcd. C 65.54, H 9.35, N 2.55; found C 65.63, H 9.38, N
2.53. To a stirred solution of oxalyl chloride (0.093 mL,
1.071 mmol) in CH2Cl2 (2 mL), DMSO (0.104 mL,
1.46 mmol), a solution of the alcohol produced in the
previous reaction (0.196 g, 0.357 mmol) in CH2Cl2 (3 mL),
and TEA (0.41 mL, 2.93 mmol) was added at 2608C. The
reaction mixture was allowed to warm to room temperature
for 1 h at which time water (2 mL) was added and the
aqueous phase was extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the crude was
purified by flash chromatography (hexane/ethyl acetate 8:2)
to yield 0.158 g of 2 (81%) as a colorless oil. [a]2D0¼241.2
trans-7,5-Fused bicyclic lactams 6a and b. According to the
general procedure B, 4 was N-Boc-protected. The crude
product was purified by flash chromatography (hexane/ethyl
acetate, 8:2) to yield the N-Boc derivative (87%). Mixture
of two diastereoisomers: 1H NMR (200 MHz, CDCl3)
(signals are split due to amidic isomerism): d¼0.10 [s,
6H, –Si(CH3)2], 0.85 (m, 12H, –CH3), 1.31 [s, 9H,
–C(CH3)3], 1.40 [m, 1H, –CH(CH3)2], 1.45 [s, 9H,
–C(CH3)3], 1.32–2.52 (m, 9H), 3.54 (m, 2H, –CH2OSi),
3.68 (s, 3H, –CO2CH3), 3.75 (m, 1H, –CHN–), 4.15 (m,
1H, –CHCOOtBu), 5.10 (m, 4H, –CH2Ph), 6.78 (m, 1H,
–CHv), 7.25 (m, 10H, aromatics). 13C NMR (50.3 MHz,
CDCl3) (signals are split due to amidic isomerism):
d¼171.9, 171.4, 170.8, 164.1, 154.6, 154.3, 153.7, 146.1,
145.8, 141.8, 141.3, 136.5, 135.4, 128.7, 128.4, 128.2,
127.8, 127.6, 83.5, 81.2, 68.7, 68.2, 66.8, 64.6, 64.1, 63.9,
63.5, 61.2, 60.8, 60.1, 52.1, 39.5, 39.1, 38.9, 38.1, 37.8,
34.1, 33.7, 32.9, 32.1, 31.9, 31.0, 30.1, 29.9, 29.3, 27.8,
25.8, 25.0, 24.7, 24.0, 22.6, 20.3, 18.4, 23.4. FABþMS:
calcd. For C46H68N2O11Si 852.46; found 853.
C46H68N2O11Si (852.46): calcd. C 64.76, H 8.03, N 3.28;
found C 64.87, H 7.99, N 3.22. To a solution of the N-Boc
protected compound (0.15 g, 0.17 mmol) in THF (2 mL)
was added 2N aqueous NaOH (1.36 mmol, 0.68 mL) and
heated to 508C. After 16 h the solution was acidified to pH 2
with Amberlite IR 120Hþ and then filtered. The solvent was
evaporated and the crude residue was used in the next
reaction without further purification. Mixture of two
1
(c¼1.0, CHCl3). H NMR (200 MHz, CDCl3) (signals are
1
split due to amidic isomerism): d¼0.11 [s, 6H, –Si(CH3)2],
0.92 (m, 12H, –CH3), 1.38 [s, 9H, –C(CH3)3], 1.40–2.61
(m, 10H), 3.45 (m, 2H, –CH2OSi), 3.63 (m, 1H, –CHN–),
4.20 (m, 1H, –CHCOOtBu), 5.05 (m, 2H, –CH2Ph), 7.22
(m, 5H, aromatics), 9.45, 9.63 (2 s, 1H. –CHO). 13C NMR
(50.3 MHz, CDCl3) (signals are split due to amidic
isomerism): d¼201.6, 201.1, 171.9, 154.6, 128.5, 128.3,
128.1, 128.0, 81.3, 67.2, 67.0, 66.9, 63.6, 62.8, 61.5, 60.8,
60.6, 60.5, 60.2, 59.8, 40.5, 40.2, 39.2, 38.1, 36.9, 34.2,
diastereoisomers: H NMR (200 MHz, CDCl3) (signals are
split due to amidic isomerism): d¼0.07 [s, 6H, –Si(CH3)2],
0.84 (m, 12H, –CH3), 1.31 [s, 9H, –C(CH3)3], 1.46 [s, 9H,
–C(CH3)3], 1.45–2.00 (m, 6H), 2.00–2.65 (m, 3H), 3.58
(m, 2H, –CH2OSi), 3.82 (m, 1H, –CHN–), 4.23 (m, 1H,
–CHCOOtBu), 5.10 (m, 2H, –CH2Ph), 6.05, 6.44 (2 bs,
1H, –NH), 6.63 (m, 1H, –CHv), 7.30 (m, 5H, aromatics).
13C NMR (50.3 MHz, CDCl3) (signals are split due to
amidic isomerism): d¼172.2, 171.8, 168.9, 155.0, 154.8,

E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
6249
141.0, 137.6, 137.5, 136.7, 136.6, 128.6, 128.5, 128.3,
128.2, 128.1, 127.6, 127.1, 81.5, 67.3, 67.2, 65.2, 64.5, 63.8,
61.1, 60.9, 60.3, 59.9, 39.3, 38.1, 37.2, 34.3, 34.0, 32.9,
31.7, 30.5, 29.8, 28.2, 28.3, 27.9, 25.2, 25.0, 20.5, 18.7,
23.2.
1.71 (m, 1H, –HCHCHNHBoc), 1.85 (m, 2H), 2.15 (m,
1H), 2.60 (m, 2H, –HCHCHCOOtBu, –HCHCHNHBoc),
3.38 (ddd, 1H, J¼3.9, 10.8, 10.8 Hz, –CHN), 3.71 (m, 3H,
–CH2OH, –OH), 4.08 (m, 1H, –CHNHBoc), 4.32 (dd, 1H,
J¼8.6, 8.6 Hz, –CHCOOtBu), 5.32 (bs, 1H, –NH). 13C
NMR (100.6 MHz, CDCl3): d¼65.4, 61.5, 58.8, 52.8, 43.6,
35.0, 34.3, 30.1, 29.0, 28.7, 26.5. FABþMS: calcd. For
C20H34N2O6 398.24; found 399. C20H34N2O6 (398.24):
calcd. C 60.28, H 8.60, N 7.03; found C 60.32, H 8.66, N
7.09.
A solution of the crude compound in MeOH (1 mL)
containing a catalytic amount of 10% Pd/C was stirred
for 16 h under H2. The catalyst was then removed by
filtration through Celite and the collected solid was
washed with MeOH. The combined filtrate and washings
were then concentrated under reduced pressure and the
crude was used for the next reaction without further
purification.
Synthesis of azide 14. Alcohol 13 (17.5 mg, 0.04 mmol) in
3 mL of CH2Cl2 was treated with methanesulfonyl chloride
(6.2 mL, 0.08 mmol) and Et3N (13.9 mL, 0.1 mmol) and
stirred at 08C for 1 h. The ice bath was removed, and the
reaction mixture was stirred an additional 1 h at room
temperature. The solution was diluted with CH2Cl2 (1 mL)
and washed with a phosphate buffer solution (3 mL), dried,
To a mixture of the aforementioned crude product, HOAt
(0.0456 g, 0.335 mmol), and HATU (0.127 g, 0.335 mmol)
was added DMF (8 mL) and then 2,4,6-collidine
(0.335 mmol, 47 mL). The solution was stirred for 48 h.
Thereafter, the solvent was evaporated under reduced
pressure, EtOAc was added and washed with a satured
solution of NaHCO3 and 1 M HCl. The organic phase was
dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude was purified by flash chromatography
(hexane/ethyl acetate 8:2) to afford 42.1 mg of 6a and
7.8 mg of 6b in a 5.4:1.0 diastereoisomeric ratio (53% over
3 steps). 6a: [a]D20¼219.4 (c¼2.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d¼0.10 [s, 6H, –Si(CH3)2], 0.90 (m,
12H, –CH3), 1.34 (m, 1H, H6), 1.45 [s, 18H, –C(CH3)3],
1.51 (m, 1H, H4), 1.52 (m, 1H, H11), 1.60 [m, 1H,
–CH(CH3)2], 1.72 (m, 1H, H9), 1.80 (m, 1H, H110), 1.81
(m, 1H, H5), 1.89 (m, 1H, H60), 1.95 (m, 1H, H50), 2.10 (m,
1H, H40), 2.10 (m, 1H, H8), 2.40 (m, 1H, H90), 3.59 (m, 1H,
H7), 3.62 (m, 2H, H12), 4.24 (m, 1H, H3), 4.32 (m, 1H,
H10), 5.55 (s, 1H, NH). 13C NMR (100.6 MHz, HETCOR,
CDCl3): d¼65.0, 61.7, 61.0, 55.0, 44.0, 37.5, 35.5, 34.9,
33.0, 32.5, 28.0, 20.0. FABþMS: calcd. For C29H54N2O6Si
554.38; found 555. C29H54N2O6Si (554.38): calcd. C 62.78,
H 9.81, N 5.05; found C 62.87, H 9.88, N 5.02. 6b:
–[a]2D0¼214.9 (c¼0.4, CHCl3). 1H NMR (400 MHz,
CDCl3): d¼0.10 [s, 6H, –Si(CH3)2], 0.85 (m, 12H,
–CH3), 1.36 (m, 1H, H11), 1.41 (m, 1H, H9), 1.46 [s,
18H, –C(CH3)3], 1.47 (m, 1H, H5), 1.60 [m, 1H,
–CH(CH3)2], 1.62 (m, 1H, H50), 1.66 (m, 1H, H6), 1.80
(m, 1H, H110), 1.86 (m, 1H, H8), 2.02 (m, 1H, H60), 2.04 (m,
2H, H4), 2.48 (m, 1H, H90), 3.31 (m, 1H, H7), 3.65 (m, 2H,
H12), 4.22 (m, 1H, H3), 4.39 (m, 1H, H10), 5.74 (s, 1H,
NH). 13C NMR (100.6 MHz, CDCl3): d¼65.0, 61.5, 61.1,
53.2, 43.5, 35.3, 35.1, 34.8, 33.6, 29.1, 28.5, 23.8, 20.9,
19.1, 3.3. FABþMS: calcd. For C29H54N2O6Si 554.38;
found 555. C29H54N2O6Si (554.38): calcd. C 62.78, H 9.81,
N 5.05; found C 62.70, H 9.78, N 5.00.
1
evaporated and used without further purification. H NMR
(200 MHz, CDCl3): d¼1.45, 1.48 [2 s, 18H, –C(CH3)3],
1.55–2.21 (m, 7H), 2.55 (m, 2H), 3.01 (s, 3H, –CH3), 3.37
(m, 1H, –CHN–), 4.01 (m, 1H, –CHNHBoc), 4.20–4.40
(m, 3H, –CHCOOtBu, –CH2OMs), 5.22 (bs, 1H, –NH).
The crude residue was dissolved in DMF (3 mL), treated
with NaN3 (7.8 mg, 0.12 mmol) stirred at 808C for 3 h, and
evaporated. The crude was dissolved in EtOAc (2 mL),
washed with a phosphate buffer solution (2 mL), dried and
evaporated to give 14 (16.2 mg, 96%) as a pale yellow oil.
[a]2D0¼219.3 (c¼1.6, CHCl3). 1H NMR (200 MHz,
CDCl3): d¼1.43, 1.48 [2 s, 18H, –C(CH3)3], 1.55–2.03
(m, 6H), 2.12 (m, 1H), 2.51 (m, 2H), 3.38 (m, 3H, –CH2N3,
–CHN–), 4.01 (m, 1H, –CHNHBoc), 4.32 (dd, 1H, J¼9.2,
9.2 Hz, –CHCOOtBu), 5.25 (bs, 1H, –NH). 13C NMR
(50.3 MHz, CDCl3): d¼171.1, 167.3, 156.1, 81.6, 79.5,
64.3, 57.9, 52.2, 49.5, 43.3, 34.3, 30.2, 29.6, 28.2, 27.9,
26.3. FABþMS: calcd. For C20H33N5O5 423.25; found 424.
C20H33N5O5 (423.25): calcd. C 56.72, H 7.85, N 16.54;
found C 56.67, H 7.88, N 16.65.
4.2. Computational methods
Molecular mechanics calculations were performed within
the framework of MacroModel26 version 5.5 using the
MacroModel implementation of the Amber all-atom force
field27 (denoted AMBER p ) and the implicit water GB/SA
solvation model of Still et al.21 The torsional space of each
molecule was randomly varied with the usage-directed
Monte Carlo conformational search of Chang, Guida, and
Still.20 Ring-closure bonds were defined in the six- and
seven-membered rings of the 6,5- and 7,5-fused bicyclic
lactams, respectively. Amide bonds were included among
the rotatable bonds.
Synthesis of alcohol 13. Compound 5b (27.9 mg,
0.051 mmol) in 1 mL of THF was treated with 1 M solution
in THF of TBAF (62 mL, 0.062 mmol) and stirred for 2 h at
room temperature. The reaction mixture was washed with
brine (1 mL), dried and evaporated. The residue was
chromatographed using EtOAc to give the alcohol 13
(21.6 mg, 98%) as a white solid. Mp 144–1458C.
[a]2D0¼236.7 (c¼0.9, CHCl3). 1H NMR (400 MHz,
CDCl3): d¼1.32 [s, 9H, –C(CH3)3], 1.49 (m, 1H,
–HCHCHCOOtBu), 1.50 [m, 2H and 9H, –C(CH3)3],
For each search, at least 2000 starting structures for each
variable torsion angle were generated and minimized until
the gradient was less than 0.05 kJ/Amol using the truncated
Newton–Raphson method28 implemented in MacroModel.
Duplicate conformations and those with an energy greater
than 6 kcal/mol above the global minimum were discarded.
The nature of the stationary points individuated was tested
by computing the eigenvalues of the second-derivative
matrix.
˚

6250
E. Artale et al. / Tetrahedron 59 (2003) 6241–6250
14. (a) Hayen, A.; Kock, R.; Saak, W.; Haase, D.; Metzger, J. O.
Acknowledgements
J. Am. Chem. Soc. 2000, 122, 12458. (b) Mathias, L. J.
Synthesis 1979, 561.
The authors thank Sigma-Tau (Pomezia, Italy), CNR and
MURST (COFIN research programs) for financial support.
15. Li, H.; Sakamoto, T.; Kato, M.; Kikugawa, Y. Synth. Commun.
1995, 4045.
16. (a) Marais, W.; Holzapfel, C. W. Synth. Commun. 1998, 3681.
(b) Collado, I.; Ezquerra, J.; Jose-Vaquero, J.; Pedregal, C.
Tetrahedron Lett. 1994, 35, 8037.
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˚
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˚
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