Synthesis of spiroazabicycloalkane amino acid scaffolds as reverse-turn inducer dipeptide mimics

Article abstract of DOI:10.1016/S0040-4020(00)01008-5

A practical approach to the synthesis of a conformationally constrained spiroazabicycloalkane aminoacid scaffold as a reverse-turn inducer dipeptide mimic is described.

Full text of DOI:10.1016/S0040-4020(00)01008-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 249±255
Synthesis of spiroazabicycloalkane amino acid scaffolds as
reverse-turn inducer dipeptide mimics
Leonardo Manzoni,a Matteo Colombo,a Emanuela Mayb and Carlo Scolasticoa,c,
*
a
Á
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, Italy
bDipartimento di Chimica Fisica ed Elettrochimica, Via Golgi 19, I-20133 Milano, Italy
cCentro CNR per lo studio delle Sostanze Organiche Naturali, via G. Venezian 21, I-20133 Milano, Italy
Received 24 July 2000; revised 2 October 2000; accepted 19 October 2000
AbstractÐA practical approach to the synthesis of a conformationally constrained spiroazabicycloalkane aminoacid scaffold as a reverse-
turn inducer dipeptide mimic is described. q 2000 Elsevier Science Ltd. All rights reserved.
Peptidomimetics have gained enormous popularity and
relevance in recent years because they can mimic a natural
peptide without changing its biological effect, but at the
same time improve its metabolic stability.1
reduced (LiEt3BH), the hydroxy group acetylated and the
acetoxy derivatives were treated with allyltributyl tin and
BF3´Et2O to afford the 5-allyl-pyrrolidine 4 via a N-acyl
immonium ion in 70% yield over three steps4 (Scheme 1).
Our efforts in this area are directed towards the development
of general methods for the synthesis of conformationally
restricted molecules that mimic Ala-Pro dipeptide units, or
more generally, molecules able to replace the central (i11
and i12) residues of b-turns.
Dihydroxylation of 4 with OsCl3, Me3NO in 8:1 acetone/
water, followed by NaIO4 cleavage and reductive work-up
(NaBH4) gave the alcohols 5a and 5b (1.5:1), which were
easily separated by ¯ash chromatography. The con®guration
of the two diastereoisomeric alcohols was secured by single
crystal diffraction analysis5,6 performed on 5b (Fig. 2).
In the course of our studies we have shown that the azaoxo-
bicyclo[X.3.0]alkane skeleton can induce a reverse-turn
when inserted in a peptide chain.2 The possibility of func-
tionalizing these molecules with hydrophobic appendages is
very attractive because they could improve peptide-receptor
af®nity by interacting with hydrophobic pockets. With this
aim we have designed the synthesis of the spiro-bicyclic
lactams 14±17 (Fig. 1).
The alcohol 5b (Scheme 2) was oxidised using the Swern
procedure affording 8 (80% yield) which was submitted to
Horner±Emmons ole®nation with the potassium enolate of
(^)-Z-a-phosphonoglycine7 trimethyl ester, thus setting up
the necessary carbon chain in 82% yield. Reaction of the
The synthesis was so designed that all four possible stereo-
isomers would be accessible in a facile manner from the
same starting material.
Starting from the known compound 1,3 hydrogenolysis (Pd±
C, MeOH) followed by LiOH hydrolysis afforded an acid
which was treated with t-BuOAc in the presence of HClO4
to yield the tert-butyl ester 2 (65% over the 3 steps). The
ester 2 was then protected at the nitrogen atom as a carbo-
benzyloxy derivative 3 (CbzCl, NaH, THF, 94%); the car-
bonyl group in position 5 of the pyrrolidine moiety was
Keywords: spiroazabicycloalkane; dipeptide; reverse-turn inducer.
* Corresponding author. Dipartimento di Chimica Organica ed Industriale,
Via Venezian 21, I-20133 Milano, Italy. Tel.: 139-2-2367593; fax: 139-
2-2363079; e-mail: carlo.scolastico@unimi.it
Figure 1. Spiroazabicyclo[4.3.0]nonane aminoacids 14±17.
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01008-5

250
L. Manzoni et al. / Tetrahedron 57 (2001) 249±255
Scheme 1. Synthesis of the intermediate alcohols 5a±b and 7. (a) H2, Pd±C, MeOH, 95%; (b) LiOH, MeOH, 86%; (c) t-BuOAc, HClO4, 80%; (d) CbzCl,
NaH, THF, 94%; (e) LiEt3BH, THF, 2788C; (f) Ac2O, pyridine, 08C; (g) Allyltributyl tin, BF3´Et2O, CH2Cl2, 278 8C, 70% over 3 steps; (h) OsCl3,
Me3NO´2H2O, acetone/H2O; (i) NaIO4; (j) NaBH4, MeOH, 87% over 3 steps; (k) H2, Pd±C, MeOH; (l) (CF3CO)2O, Et3N, CH2Cl2, 88% over two steps.
dehydroaminoester 10 (pure Z isomer) with (Boc)2O gave
12, which was hydrogenated (Pd±C) and re¯uxed in xylene
to give a mixture of easily separated 14 and 15 (1:2.5) in
69% yield over the two steps.
zation afforded a separable mixture of 16 and 17 (1:2.5) in
37% yield over three steps.
In conclusion, we have shown that our methodology for the
synthesis of fused bicyclic2c lactams can be extended to the
preparation of more complex molecules that could ®nd
applications as conformationally constrained peptidomi-
metics, and we have prepared a small library of four 6,5-
fused spiro-substituted bicyclic lactams.
To further explore the potential of this strategy we have also
performed the synthesis of compounds 16 and 17 using a
tri¯uoroacetamide as the nitrogen protecting group. For this
purpose, the alcohol 5a was hydrogenated (Pd±C, MeOH)
and the crude material was treated with (CF3CO)2O and
Et3N affording the suitably protected compound 7.
Compound 7 was submitted to the same synthetic sequence
described above (Scheme 3) to afford in comparable yields
the N-Boc-acrylester 13. Hydrogenation of 13 (Pd±C,
MeOH), treatment with NaBH4 in MeOH and thermal cycli-
1. Experimental
1.1. General
1H and 13C NMR spectra were recorded in CDCl3 as indi-
cated, at 200 and 50.3 MHz, respectively (the usual abbre-
viations are used: sˆsinglet, dˆdoublet, tˆtriplet, qˆ
quartet, mˆmultiplet). The positive chemical shift values
are given in ppm and the coupling constants in Hz. Ele-
mental analyses were performed with a Perkin±Elmer 240
instrument. Mass spectra were obtained with a VG 7070 EQ
spectrometer. Optical rotations were measured in 1 dm
pathlength cells of 1 mL capacity by using a Perkin±
Elmer 241 polarimeter. Thin-layer chromatography (TLC)
was carried out using Merck precoated silica gel F-254
plates. Flash chromatography was carried out with
Macherey±Nagel Silica Gel 60, 230±400 mesh. Solvents
were dried using standard procedures and reactions requir-
ing anhydrous conditions were performed under a positive
nitrogen atmosphere. Final product solutions were dried
over Na2SO4, ®ltered and evaporated under reduced pres-
sure on a rotary evaporator.
Figure 2. X-Ray structure of alcohol 5b.

L. Manzoni et al. / Tetrahedron 57 (2001) 249±255
251
Scheme 2. Synthesis of 14 and 15 from 5b. (a) (COCl)2, DMSO, Et3N, CH2Cl2, 2608C, 80%; (b) (^)-Z-a-phosphonoglycine trimethyl ester, t-BuOK, CH2Cl2,
2788C, 82%; (c) (Boc)2O, 4-DMAP, THF, 98%; (d) H2, Pd±C, MeOH; xylene, re¯ux, 70% over two steps.
Scheme 3. Synthesis of 16 and 17 from 7. (a) (COCl)2, DMSO, Et3N, CH2Cl2, 2608C, 78%; (b) (^)-Z-a-phosphonoglycine trimethyl ester, t-BuOK, CH2Cl2,
2788C, 78%; (c) (Boc)2O, 4-DMAP, THF, 89%; (d) H2, Pd±C, MeOH; (e) NaBH4, MeOH; (f) MeOH, re¯ux, 37% over three steps.
1.1.1. tert-Butyl ester (2). A solution of 1 (4.2 g,
12.7 mmol) and a catalytic quantity of Pd±C 10% in
MeOH (130 mL) was stirred under hydrogen for 12 h, the
catalyst was then ®ltered through celite and the ®ltration pad
was washed with MeOH. The solvent was evaporated under
reduced pressure yielding 4.1 g (95%) of menthyl ester as a
white solid.
20.7, 21.8, 22.0, 22.1, 23.0, 25.2, 26.1, 31.2, 32.6, 32.9,
34.0, 35.6, 40.5, 44.0, 46.8, 52.7, 75.5, 171.9, 181.9;
Elemental analysis for C20H33NO3: Calculated: C, 55.77;
H, 15.44; N, 6.50; Found: C, 55.44; H, 15.41; N, 6.46;
MS (FAB1): M1 335.
To a crude solution of the menthyl ester (3.95 g, 11.8 mmol)
in MeOH (100 mL) a 2N solution of LiOH (5 equiv.) was
added and the solution was stirred for 2 h. The solvent
was evaporated and the residue was diluted with water
(25 mL) and extracted with Et2O. The aqueous solution
was acidi®ed with 2N HCl to pH 4 and extracted with
EtOAc. The collected organic phases were dried over
Na2SO4, ®ltered and evaporated yielding 2 g (86%) of
acid as white solid.
1
1.1.2. Menthyl ester. Mp 162±1638C; H NMR (CDCl3):
0.78 (d, 3H, Jˆ6.5 Hz, CH3CH), 0.93 (m, 6H, CH3CHCH3),
1.0±2.05 (m, 19H, CH2), 2.10±2.22 (dd, 1H, Jˆ14, 6 Hz,
HCH±CHCOO±Menthyl), 2.35±2.50 (dd, 1H, Jˆ14, 9 Hz,
HCH±CHCOO±Menthyl), 4.16 (dd, 1H, Jˆ9, 6 Hz,
CHCOO±Menthyl), 4.76 (ddd, 1H, J1ˆJ2ˆ11, 6.6 Hz,
CHOCO), 5.90 (bs, 1H, NH); 13C NMR (CDCl3): 15.8,

252
L. Manzoni et al. / Tetrahedron 57 (2001) 249±255
1
1.1.3. Acid. H NMR (D2O): 1.0±1.60 (m, 10H, CH2),
1.90±2.04 (dd, 1H, Jˆ14, 6 Hz, HCH±CHCOOH), 2.35±
2.48 (dd, 1H, Jˆ14, 9 Hz, HCH±CHCOOH), 4.18 (dd, 1H,
Jˆ9, 6 Hz, CHCOOH).
08C. The solution was stirred at room temperature for 20 h
then the solvent was evaporated and AcOEt was added to
the residue. The organic phases were washed with phos-
phate buffer (25 mL) then dried with Na2SO4, ®ltered and
evaporated. The crude material, as a yellowish oil, was
submitted to the next reaction without further puri®cation.
To a solution of crude acid (2 g) in tert-butyl acetate
(50 mL) was added HClO4 70% (0.3 mL) and stirred for
24 h then was neutralised with a saturated solution of
NaHCO3 and extracted with EtOAc. The organic layers
were dried over Na2SO4, ®ltered and evaporated yielding
2 g (80%) of 2 as white solid.
1.1.9. 5-Acetoxy-pyrrolidine (cis/trans mixture). 1H NMR
(CDCl3): 1.20±2.45 (m, 24H, CH2), 1.40 (s, 9H, COOt-Bu),
1.45 (s, 9H, COOt-Bu), 2.0 (s, 3H, CH3COO), 2,1 (s, 3H,
CH3COO), 4.05 (dd, 1H, Jˆ9, 5 Hz, CHCOOt-Bu), 4.22
(dd, 1H, Jˆ9, 5 Hz, CHCOOt-Bu), 5.05±5.38 (m, 4H,
PhCH2OCO), 6.40 (bs, 1H, CHOAc), 7.30±7.50 (m, 10H,
PhCH2OCO).
1
1.1.4. Ester 2. Mp 148±1508C; H NMR (CDCl3): 1.20±
1.84 (m, 10H, CH2), 1.48 (s, 9H, COOt-Bu), 2.03±2.15 (dd,
1H, Jˆ 14, 6.5 Hz, HCH±COOt-Bu), 2.33±2.48 (dd, 1H,
Jˆ14, 9 Hz, HCH±COOt-Bu), 4.08 (dd, 1H, Jˆ9, 6.5 Hz,
CHCOOt-Bu), 6.40 (sb, 1H, NH); 13C NMR (CDCl3): 22.0,
22.2, 25.2, 27.9, 32.3, 33.0, 35.7, 53.0, 82.2, 171.3, 181.7;
Elemental analysis for C14H23NO3: Calculated: C, 66.37; H,
9.15; N, 5.53; Found: C, 66.2; H, 9.05; N, 5.38; MS (FAB1):
M1 253.
To a solution of BF3´Et2O (1.4 mL, 10.5 mmol) in dry
CH2Cl2 (25 mL) at 2788C and under nitrogen, a solution
of the crude 5-acetoxy-pyrrolidine (2.6 g, 6 mmol) and
allyltributyltin (2.8 mL, 9 mmol) in dry CH2Cl2 (35 mL)
was added. The solution was stirred at this temperature for
3 h, then warmed to room temperature. After 3 h, a buffer
solution (20 mL) was added and the aqueous phase was
extracted with CH2Cl2 The collected organic phases were
dried over Na2SO4, ®ltered and evaporated The crude
material was puri®ed by ¯ash chromatography (hexane/
EtOAc 9:1) affording 1.7 g (70%) of 4 as a colourless oil
in a 1.5:1 cis:trans diastereoisomeric mixture.
1.1.5. N-Cbz-tert-Butyl ester (3). To a suspension of NaH
(0.360 g, 9 mmol, 60% dispersion in oil) in THF (20 mL)
was added a solution of 2 (2 g, 7,9 mmol) in THF (80 mL),
and after 15 min benzyl chloroformate (1.24 mL,
8.69 mmol) was added and the solution was stirred over-
night. Then a NH4Cl saturated solution was added, the
aqueous phase extracted with EtOAc and the organic
phase dried over Na2SO4, ®ltered and evaporated. The
crude material was puri®ed by ¯ash chromatography
(Hexane/EtOAc 6:4) yielding 2.8 g (94%) of 3 as white
solid.
1.1.10. 5-Allyl-pyrrolidine (cis/trans mixture) 4. 1H NMR
(CDCl3): 1.35, 1.45 (2 s, 18H, COOt-Bu), 1.35±2.77 (m,
28H, CH2), 3.70±3.95 (m, 2H, CH2CHN), 4.10±4.30 (m,
2H, CHCOOt-Bu), 4.85±5.20 (m, 8H, CH2vCH,
PhCH2OCO), 5.65±6.18 (m, 2H, CH2vCH), 7.30±7.50
(m, 10H, PhCH2OCO); 13C NMR (CDCl3): 14.1, 22.0,
22.4, 23.3, 23.4, 25.9, 27.7, 27.8, 29.6, 32.4, 33.0, 33.2,
33.5, 34.7, 35.1, 35.7, 36.1, 37.6, 38.8, 43.8, 44.5, 44.8,
45.2, 58.4, 58.5, 58.7, 60.2, 65.3, 65.6, 66.2, 66.7, 66.8,
80.9, 115.9, 117.3, 117.4, 127.5, 127.7, 129.2, 129.7,
134.9, 135.2, 136.4, 136.6, 154.4, 154.8, 155.1, 155.5,
171.0, 171.6, 171.9, 172.1; Elemental analysis for
C25H34NO4: Calculated: C, 72.79; H, 8.31; N, 3.40;
Found: C, 72.59; H, 8.23; N, 3.30; MS (FAB1): M1 412.
1.1.6. Ester 3. Mp 798C; 1H NMR (CDCl3): 1.25±1.87 (m,
10H, CH2), 1.40 (s, 9H, COOt-Bu), 1.97±2.10 (dd, 1H,
Jˆ14, 5 Hz, HCH±COOt-Bu), 2.15±2.30 (dd, 1H, Jˆ14,
9 Hz, HCH±COOt-Bu), 4.48 (dd, 1H, Jˆ9, 5 Hz,
CHCOOt-Bu), 5.30 (s, 2H, PhCH2OCO), 7.30±7.50 (m,
5H, PhCH2OCO); 13C NMR (CDCl3): 21.6, 21.7, 25.0,
27.6, 32.6, 32.7, 33.8, 45.9, 56.5, 68.1, 82.2, 128.0, 128.2,
128.4, 128.5, 135.0, 151.2, 170.4, 177.7; Elemental analysis
for C22H29NO5: Calculated: C, 66.37; H, 9.15; N, 5.53;
Found: C, 66.56; H, 9.16; N, 5.54; MS (FAB1): M1 387.
1.1.11. Alcohols (5a), (5b). To a solution of 4 (1.6 g,
3.87 mmol) in 8:1 acetone/water (35 mL) were added
OsCl3 (0.114 g, 0,387 mmol) and Me3NO´2H2O (0.860 g,
7.74 mmol), and the solution was stirred for 2 h. Then
NaIO4 (1.8 g) was added and after 30 min the solution
was evaporated. The crude material was dissolved in
MeOH, and NaBH4 (0.250 g, 6.7 mmol) was added. When
the reaction was completed, it was diluted with water
(5 mL) and the aqueous layers were extracted with
EtOAc, the collected organic phases were dried over
Na2SO4, ®ltered and evaporated. The crude was puri®ed
by ¯ash chromatography (hexane/EtOAc 8:2) affording
1.21 g (87%) of 5a and 5b in 1.5:1 diastereoisomeric ratio.
1.1.7. Allyl pyrrolidine (4). To a solution of 3 (2.8 g,
7.23 mmol) in dry THF (50 mL), LiEt3BH 1 M (9 mL,
9 mmol) was added at 2788C and the solution was stirred
for 3 h then warmed to room temperature. A saturated
NaHCO3 solution (20 mL) and H2O2 (5 mL) were added
and the mixture was stirred for 30 min then extracted with
EtOAc. The organic layers were dried over Na2SO4, ®ltered
and evaporated. The crude, as a yellowish oil, was submitted
to the next reaction without further puri®cation.
1.1.8. 5-Hydroxy-pyrrolidine (cis/trans mixture). 1H
NMR (CDCl3): 0.75±2.45 (m, 24H, CH2), 1.37 (s, 9H,
COOt-Bu), 1.45 (s, 9H, COOt-Bu), 3.0 (db, 2H, OH),
4.0±4.31 (m, 2H, CHCOOt-Bu), 5.10±5.33 (m, 6H,
CHOH, PhCH2OCO), 7.30±7.50 (m, 10H, PhCH2OCO).
1
1.1.12. Alcohol 5a (cis). White solid mp 109±1108C; H
NMR (CDCl3): 1.30 (s, 9H, COOt-Bu), 1.32±1.55 (m,
10H, CH2), 1.55±1.67 (dd, 1H, Jˆ14, 11 Hz, HCH±
COOt-Bu), 1.72±1.90 (m, 2H, CH2CH2OH), 2.10±2.26
(dd, 1H, Jˆ14, 8 Hz, HCH±COOt-Bu), 3.60±3.90 (m, 2H,
CH2CH2OH), 4.0±4.10 (dd, 1H, Jˆ13.3, 4.4 Hz, CH2CHN),
To a solution of the crude mixture (2.65 g, 6.81 mmol) in
pyridine (50 mL) was added acetic anhydride (3.5 mL) at

L. Manzoni et al. / Tetrahedron 57 (2001) 249±255
253
4.15±4.29 (dd, 1H, Jˆ11, 8 Hz, CHCOOt-Bu), 4.28 (bs,
1H, OH), 4.98±5.28 (AB system, 2H, Jˆ13.3 Hz,
PhCH2OCO), 7.25±7.40 (m, 5H, PhCH2OCO); 13C NMR
(CDCl3): 22.5, 23.1, 25.9, 27.7, 32.3, 32.6, 35.0, 38.9, 44.4,
58.4, 61.6, 67.5, 81.3, 127.6, 127.9, 128.3, 136.0, 156.6,
171.9; Elemental analysis for C24H35NO5: Calculated: C,
69.04; H, 8.45; N, 3.35; Found: C, 68.9; H, 8.40; N, 3.28;
MS (FAB1): M1 417.
water and the aqueous phase was extracted with CH2Cl2.
The collected organic layers were dried over Na2SO4. The
solvent was evaporated under reduced pressure and the
crude material puri®ed by ¯ash chromatography (hexane/
EtOAc 8:2), yielding 0.106 g (80%) of aldehyde 8 as a
colourless oil.
1.1.19. Aldehyde 8. 1H NMR (CDCl3): 1.36 (s, 9H, COOt-
Bu), 1.8±2.8 (m, 14H, CH2), 4.1 (m, 2H, CH2CHN,
CHCOOt-Bu), 5.1 (s, 2H, PhCH2OCO), 7.3 (s, 5H,
PhCH2OCO), 9.85 (s, 1H, CHO); Elemental analysis for
C24H32NO5: Calculated: C, 69.54; H, 7.78; N, 3.38;
Found: C, 69.34; H, 7.52; N, 3.10; MS (FAB1): M1 414.
1.1.13. Alcohol 5b (trans). White solid mp 111±1138C; 1H
NMR (CDCl3): 1.35 (s, 9H, COOt-Bu), 1.33±1.70 (m, 10H,
CH2), 1.75±2.15 (m, 4H, CH2CH2OH, CH2CH±COOt-Bu),
3.40±3.70 (m, 2H, CH2CH2OH), 4.0±4.19 (m, 2H,
CH2CHN, CHCOOt-Bu), 4.95±5.28 (AB system, 2H,
Jˆ13.3 Hz, PhCH2OCO), 7.25±7.40 (m, 5H, PhCH2OCO);
13C NMR (CDCl3): 22.4, 23.3, 25.8, 27.7, 33.2, 33.4, 35.3,
38.7, 43.5, 57.6, 58.4, 61.8, 67.4, 81.2, 127.9, 128.3, 136.0,
156.4, 171.0; Elemental analysis for C24H35NO5: Calcu-
lated: C, 69.04; H, 8.45; N, 3.35; Found: C, 69.2; H, 8.35;
N, 3.40; MS (FAB1): M1 417.
1.1.20. Aldehyde 9. Prepared according to the method
described for 8, starting from 7, in 78% yield as a colourless
oil. [a]2D2ˆ244.5 (cˆ1.05, CHCl3); 1H NMR (CDCl3): 1.45
(s, 9H, COOt-Bu), 2.3±3.0 (m, 14H, CH2), 4.3±4.6 (m, 2H,
CH2CHN, CHCOOt-Bu), 9.80 (s, 1H, CHO); 13C NMR
(CDCl3): 22.8, 23.0, 27.6, 31.9, 34.0, 34.2, 34.7, 43.9,
46.4, 58.3, 58.4, 59.3; Elemental analysis for
C18H26NO4F3: Calculated: C, 57.29; H, 6.94; N, 3.71;
Found: C, 57.03; H, 6.90; N, 3.78; MS (FAB1): M1 377.
1.1.14. Alcohol (6). A solution of 5a (cis) (0.420 g,
1.007 mmol) and a catalytic quantity of Pd±C 10% in
MeOH (10 mL) was stirred under hydrogen for 12 h. The
catalyst was then ®ltered through celite and the ®ltration pad
was washed with MeOH. The solvent was evaporated under
reduced pressure yielding alcohol 6 (0.275 g) as a yellowish
oil which was used without further puri®cation.
1.1.21. Acrylester (10). To a stirred solution of t-BuOK
(0.0285 g, 0.254 mmol) in 2 mL of dry CH2Cl2 under nitro-
gen atmosphere, at 2788C, was added a solution of Z-(a)-
phosphonoglycine trimethyl ester (0.0842 g, 0.254 mmol)
in 1 mL of dry CH2Cl2. The solution was stirred for
30 min at this temperature and then a solution of aldehyde
8 (0.088 g, 0.212 mmol) in dry CH2Cl2 (1 mL) was added.
After 5 h the solution was neutralised with a phosphate
buffer. The aqueous phase was extracted with CH2Cl2,
dried over Na2SO4 and the solvent evaporated under
reduced pressure. The crude material was puri®ed by ¯ash
chromatography (hexane/EtOAc 7:3), affording 0.101 g
(82%) of acrylester 10 (only Z-isomer) as a sticky solid.
1
1.1.15. Alcohol 6. H NMR (CDCl3): 1.50 (s, 9H, COOt-
Bu), 1.20±1.80 (m, 12H, CH2), 1.89±2.10 (m, 2H,
CH2CHCOOt-Bu), 2.92±3.05 (dd, 1H, Jˆ11.1, 4.4 Hz,
CH2CHN), 3.18 (sb, 2H, OH, NH), 3.80±3.96 (m, 3H,
CH2CH2OH, CHCOOt-Bu).
1.1.16. Alcohol (7). To a solution of 6 (0.270 g,
0.954 mmol) in dry CH2Cl2 (10 mL) (CF3CO)2O
(0.15 mL, 1.05 mmol) and Et3N (0.15 mL, 1.05 mmol)
was added at room temperature. After 5 h the reaction was
quenched with a saturated NaHCO3 solution (15 mL) and
extracted with CH2Cl2. The organic phase was dried over
Na2SO4 and the solvent evaporated under reduced pressure.
The crude material was puri®ed by ¯ash chromatography
(hexane/EtOAc 8:2) affording 0.318 g (88%) of 7 as a
colourless oil.
1
1.1.22. Acrylester 10 (Z). H NMR (CDCl3): 1.36, (s, 9H,
COOt-Bu), 1.8±2.8 (m, 14H, CH2), 3.7 (s, 3H, COOCH3),
3.8 (m, 1H, CH2CHN), 4.2 (m, 1H, CHCOOt-Bu), 5.15 (m,
4H, PhCH2OCO), 6.5 (dd, 1H, J1ˆJ2ˆ13 Hz, CH2CHv),
7.0 (bs, 1H, NH), 7.2±7.5 (m, 10H, PhCH2OCO); Elemental
analysis for C35H44N2O8: Calculated: C, 67.72; H, 7.14; N,
4.51; Found: C, 67.50; H, 6.89; N, 4.30; MS (FAB1): M1
620.
1.1.17. Alcohol 7. 1H NMR (CDCl3): 1.3 (s, 9H, COOt-Bu),
1.3±2.0 (m, 13H, CH2), 2.35±2.5 (m, 1H, HCH±COOt-Bu),
3.60±3.80 (m, 3H, OH, CH2CH2OH), 4.3±4.4 (dd, 1H,
Jˆ13.0, 4.0 Hz, CH2CHN), 4.45±4.6 (m, 1H, CHCOOt-
Bu); 13C NMR (CDCl3): 22.3, 22.9, 25.6, 27.6, 27.7, 29.5,
31.6, 32.1, 34.8, 39.4, 43.2, 58.2, 58.3, 64.0, 82.6, 113.5,
119.0, 170.5; Elemental analysis for C18H28NO4F3 Calcu-
lated: C, 56.98; H, 7.44; N, 3.68; Found: C, 56.84; H, 7.48;
N, 3.70; MS (FAB1): M1 379.
1.1.23. Acrylester 11 (Z/E mixture, mainly Z isomer).
Prepared according to the method used for 10, starting
from 9, in 78% yield, as a colourless oil. 1H NMR
(CDCl3): 1.40, (s, 18H, COOt-Bu), 1.6±1.8 (m, 12H,
CH2), 2.2±2.6 (m, 16H, CH2), 3.75 (s, 6H, COOCH3),
4.3±4.5 (m, 4H, CH2CHN, CHCOOt-Bu), 5.15 (m, 4H,
PhCH2OCO), 6.5±6.7 (m, 2H, CH2CHv), 7.1 (bs, 2H,
NH), 7.2±7.4 (m, 10H, PhCH2OCO); 13C NMR (CDCl3):
22.1, 22.3, 23.7, 25.6, 27.6, 27.7, 29.2, 29.5, 30.0, 31.6,
32.1, 32.2, 34.4, 34.7, 35.5, 39.3, 43.4, 46.2, 52.2, 52.3,
58.2, 59.8, 65.6, 66.3, 66.9, 67.1, 82.6, 83.6, 113.0, 127.5,
127.8, 127.9, 128.0, 128.2, 128.3, 131.5, 132.1, 135.9,
135.2, 154.2, 154.5, 164.7, 164.8, 170.4, 171.6; Elemental
analysis for C29H37N2O7F3: Calculated: C, 59.79; H, 6.40;
N, 4.81; Found: C, 59.89; H, 6.29; N, 4.66; MS (FAB1): M1
582.
1.1.18. Aldehyde (8). To a stirred solution of oxalyl chlo-
ride (0.0838 mL, 0.961 mmol) in 3 mL of CH2Cl2, cooled at
2608C, were added in sequence DMSO (0.0932 mL,
1.312 mmol), the alcohol 5b (0.134 g, 0.320 mmol)
dissolved in 2 mL of CH2Cl2 and Et3N (0.365 mL,
2.624 mmol). The reaction was warmed to room tempera-
ture. After one hour the reaction was washed with 5 mL of

254
L. Manzoni et al. / Tetrahedron 57 (2001) 249±255
1.1.24. N-Boc-acrylester (12). A solution of acrylester 10
(0.098 g, 0.168 mmol), (Boc)2O (0.0733 g, 0.336 mmol)
and a catalytic quantity of DMAP in 1 mL of dry THF,
was stirred for 30 min under nitrogen. The solution was
then quenched with water (1 mL) and extracted with ethyl
acetate. The organic phase was dried over Na2SO4 and the
solvent evaporated under reduced pressure. The crude mate-
rial was puri®ed by ¯ash chromatography (hexane/EtOAc
7:3), yielding 0.111 g (98%) of 12 as a colourless oil.
1.1.30. 6,5-Fused bicyclic lactam (16), (17). A solution of
13 (0.150 g, 0.220 mmol) and a catalytic quantity of Pd±C
10% in 2.5 mL of MeOH was stirred under hydrogen for one
night. The catalyst was ®ltered through celite and the ®ltra-
tion pad was washed with MeOH. The solvent was evapo-
rated under reduced pressure, the crude was dissolved in
MeOH (2.5 mL) and NaBH4 (0.033 g, 0.880 mmol) was
added. After 2 h the reaction was washed with 4 mL of
water and extracted with EtOAc. The organic layer was
dried over Na2SO4, the solvent was evaporated under
reduced pressure and the crude material was dissolved in
MeOH and re¯uxed for 2 days. The solvent was removed
and the two diastereoisomers formed were separated by
¯ash chromatography (hexane/EtOAc 7:3) yielding 0.01 g
of 16 and 0.024 g of 17 (37%) (1:2.5 diastereoisomeric
ratio) as white foams.
1.1.25. N-Boc-acrylester 12. 1H NMR (CDCl3): 1.36, 1.41
(2 s, 18H, COOt-Bu), 1.8±2.8 (m, 14H, CH2), 3.7 (s, 3H,
COOCH3), 3.9 (m, 1H, CH2CHN), 4.2 (m, 1H, CHCOOt-
Bu), 5.0±5.3 (m, 4H, PhCH2OCO), 6.8 (m, 1H, CH2CHv),
7.1±7.5 (m, 10H, PhCH2OCO); 13C NMR (CDCl3): 20.9,
22.2, 25.7, 27.3, 32.7, 35.6, 51.7, 52.2, 58.3, 66.9, 68.3,
127.8, 127.9, 128.1, 128.2, 128.4; Elemental analysis for
C40H52N2O10: Calculated: C, 66.65; H, 7.27; N, 3.89;
Found: C, 66.43; H, 7.38; N, 3.88; MS (FAB1): M1 720.
1.1.31. 6,5-Fused bicyclic lactam 16. Mp 74±778C;
1
[a]2D2ˆ222.6 (cˆ0.31, CHCl3); H NMR (CDCl3): 1.41,
1.43 (2 s, 18H, COOt-Bu), 1.0±2.0 (m, 14H, CH2), 2.3
(m, 1H, HCH), 2.6 (m, 1H, HCH), 3.22 (m, 1H,
CH2CHN), 3.94 (m, 1H, CHNHBoc), 4.3 (m, 1H,
CHCOOt-Bu), 5.4 (bs, 1H, NH); 13C NMR (CDCl3): 19.9,
20.9, 22.9, 25.9, 26.9, 28.5, 28.6, 35.2, 36.8, 52.6, 58.3,
70.6; Elemental analysis for C23H38N2O5: Calculated: C,
65.38; H, 9.06; N, 6.63; Found: C, 65.20; H, 8.93; N,
6.60; MS (FAB1): M1 422.
1.1.26. N-Boc-acrylester 13 (Z/E mixture, mainly Z
isomer). Prepared according to the method used for 12,
starting from 11, in 89% yield, as a colourless oil. H
1
NMR (CDCl3): 1.4 (s, 36H, COOt-Bu), 2.0±2.6 (m, 28H,
CH2), 3.7 (s, 6H, COOCH3), 3.9±4.5 (m, 4H, CH2CHN,
CHCOOt-Bu), 5.1±5.2 (m, 4H, PhCH2OCO), 6.8±7.1 (m,
2H, CH2CHv), 7.3±7.4 (m, 10H, PhCH2OCO); Elemental
analysis for C34H45N2O9F3: Calculated: C, 59.82; H, 6.64;
N, 4.10; Found: C, 59.59; H, 6.58; N, 4.03; MS (FAB1): M1
682.
1.1.32. 6,5-Fused bicyclic lactam 17. Mp 76±798C;
[a]2D2ˆ211.3 (cˆ0.78, CHCl3); H NMR (CDCl3): 1.41,
1
1.43 (2 s, 18H, COOt-Bu), 1.0±2.0 (m, 14H, CH2), 2.15
(m, 1H, HCH), 2.4 (m, 1H, HCH), 3.35 (dd, 1H,
Jˆ6.12 Hz, CH2CHN), 4.15 (m, 1H, CHNHBoc), 4.3 (dd,
1H, Jˆ4.5, 9.0 Hz, CHCOOt-Bu), 5.5 (bs, 1H, NH); 13C
NMR (CDCl3): 21.2, 21.9, 23.3, 26.9, 27.9, 28.2, 28.4,
36.6, 38.0, 56.2, 58.2, 71.6; Elemental analysis for
C23H38N2O5: Calculated: C, 65.38; H, 9.06; N, 6.63;
Found: C, 65.30; H, 8.98; N, 6.60; MS (FAB1): M1 422.
1.1.27. 6,5-Fused bicyclic lactam (14), (15). A solution of
12 (0.380 g, 0.56 mmol) and a catalytic quantity of Pd±C
10% in 5 mL of MeOH was stirred under H2 for one night.
The catalyst was then ®ltered through celite and the ®ltra-
tion bed was washed with MeOH. The solvent was evapo-
rated under reduced pressure, the residue was dissolved in
xylene and re¯uxed for 48 h. The solvent was removed and
the two diastereoisomers formed were separated by ¯ash
cromatography (hexane/EtOAc 7:3), yielding 0.032 g of
14 and 0.08 g of 15 (70%) (1:2.5 diastereoisomeric ratio)
as white foams.
Acknowledgements
This work was supported by the MURST COFIN 1998±99
`Nuove Metodologie e Strategie di Sintesi di Composti di
Interesse Biologico' and Consiglio Nazionale delle
Ricerche (CNR).
1.1.28. 6,5-Fused bicyclic lactam 14. Mp 75±788C;
1
[a]2D2ˆ254.8 (cˆ0.29, CHCl3); H NMR (CDCl3): 1.45,
1.49 (2 s, 18H, COOt-Bu), 1.0±2.0 (m, 14H, CH2), 2.3
(m, 1H, HCH), 2.5 (m, 1H, HCH), 3.4 (dd, 1H, Jˆ6.3 Hz,
CH2CHN), 4.1 (m, 1H, CHNHBoc), 4.3 (dd, 1H, Jˆ8.1 Hz,
CHCOOt-Bu), 5.5 (bs, 1H, NH); 13C NMR (CDCl3): 20.1,
22.0, 23.9, 27.2, 27.9, 28.1, 28.3, 35.4, 36.9, 52.6, 58.6,
69.6; Elemental analysis for C23H38N2O5: Calculated: C,
65.38; H, 9.06; N, 6.63; Found: C, 65.01; H, 8.98; N,
6.58; MS (FAB1): M1 422.
References
1. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789±12854.
2. (a) Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C.;
Piarulli, U.; Manzoni, L. Eur. J. Org. Chem. 1999, 379±
388. (b) Belvisi, L.; Bernardi, A.; Manzoni, L.; Potenza, D.;
Scolastico, C. Eur. J. Org. Chem. 2000, 2563±2569. (c)
Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti, E.; Checchia,
A.; Crippa, L.; Manzoni, L.; Scolastico. C. Eur. J. Org. Chem.
2000, 2571±2581.
1.1.29. 6,5-Fused bicyclic lactam 15. Mp 74±758C;
1
[a]2D2ˆ233.8 (cˆ1.43, CHCl3); H NMR (CDCl3): 1.41,
1.43 (2 s, 18H, COOt-Bu), 1.1±1.9 (m, 14H, CH2), 2.4±2.7
(m, 2H, CH2), 3.4 (m, 1H, CH2CHN), 4.0 (m, 1H,
CHNHBoc), 4.2 (dd, 1H, Jˆ7.8 Hz, CHCOOt-Bu), 5.3 (bs,
1H, NH); 13C NMR (CDCl3): 21.1, 21.9, 23.1, 26.0, 27.9,
28.1, 28.2, 34.6, 37.0, 52.2, 57.0, 68.6; Elemental analysis
for C23H38N2O5: Calculated: C, 65.38; H, 9.06; N, 6.63;
Found: C, 65.20; H, 8.95; N, 6.50; MS (FAB1): M1 422.
3. Crossley, M. J.; Reid, R. C. J. Chem. Soc., Chem. Commun.
1994, 2237±2338.
4. Chiesa, M. V.; Manzoni, L.; Scolastico, C. Synlett 1996, 441±
443.

L. Manzoni et al. / Tetrahedron 57 (2001) 249±255
255
5. Crystal dimensions: 0.65£0.5£0.2 mm3; crystal system:
monoclinic, space group: P21, Zˆ2; cell dimensions:
279, number of restraints: 54, ®nal R indices (observed
data): R(F)ˆ0.0434, wr(F2)ˆ0.1164, GoFˆ1.056.
6. All X-ray crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as deposition No.
CCDC-149629.
Ê
Ê
Ê
aˆ6.0472(4) A,
bˆ17.6124(14) A,
cˆ11.1750(9) A,
Ê 3
bˆ97.208(6)8, Vˆ 1180.6(2) A ; Dcalcˆ1.177 g cm23, linear
absorption coeff. mˆ 0.081 mm21
,
radiation MoKa,
Max
Mo
ꢀsin u=l†
ˆ 0:59 A21; number of re¯ections collected:
ꢀ
7. Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53±
60.
4442, number of independent re¯ections: 2150, number of
observed re¯ections (I.2s): 1917, number of variables: