A solid-phase synthesis of functionalized 6-, 7- and 8-membered azacycles via olefin metathesis

Article abstract of DOI:10.1055/s-1999-3681

A modular solid-phase synthesis of functionalized azacycles is described. The approach is based on a ring-closing metathesis to form heterocycles of different ring sizes. Furthermore, the epoxidation of the primarily formed cyclic double bond has been inv

Full text of DOI:10.1055/s-1999-3681

138
PAPER
A Solid-Phase Synthesis of Functionalized 6-, 7- and 8-Membered Azacycles
via Olefin Metathesis
Josef Pernerstorfer, Matthias Schuster, Siegfried Blechert*
Institut fŸr Organische Chemie der Technischen UniversitŠt, Stra§e des 17. Juni 135, D-10623 Berlin, Germany
Fax +49(30)31423619; E-mail:sibl@wap0105.chem.tu-berlin.de
Received 9 February 1998; revised 22 June 1998
CHO, an allyl anion equivalent and an acyl moiety R2-X.
Abstract: A modular solid-phase synthesis of functionalized aza-
We decided to use polystyrene/2% divinylbenzeneÐtrityl
cycles is described. The approach is based on a ring-closing me-
chloride9 as the solid support since cleavage conditions
are exceptionally mild.
tathesis to form heterocycles of different ring sizes. Furthermore,
the epoxidation of the primarily formed cyclic double bond has
been investigated.
The viability of the synthetic concept was first confirmed
by synthesizing 6-membered compound 9 in solution us-
ing trityl chloride as a soluble trityl resin equivalent
(Scheme 2). N-(Trichloroacetyl)vinylglycinol 4a, which
was easily accessed from (Z)-but-2-ene-1,4-diol and
trichloroacetonitrile according to established pro-
cedures10 (Scheme 3) was O-tritylated to get a solution-
phase analog 5 of the corresponding polymer-bound sub-
strate. Cleavage of the trichloroacetamide using KOH/
isopropyl alcohol and subsequent formation of the imine
6 with benzaldehyde proceeded quantitatively. Addition
of allyllithium to the imine moiety produced the dialke-
nyl amine 7.11 Although olefin metatheses of unprotect-
ed amines have been described,12 we decided to acylate
the nitrogen of 7 since metathesis reactions of amides
usually proceed more reliably. Moreover, the acylation
comprises an additional source for molecular diversity.
Consequently, N-trifluoroacetylation of 7 gave the olefin
metathesis precursor 8. RCM using 2.5 mol% [Ru] pro-
ceeded smoothly to give 97% of six-membered 9. En-
couraged by this result, we attempted the synthesis of 6-,
7- and 8-membered azacycles on the solid phase, re-
quiring the synthesis of the homologous N-trichloroacetyl-
ated amino alcohols 4b and 4c (Scheme 3). Reduction of C-
allylglycine and reaction of the crude amino alcohol with
trichloroacetyl chloride yielded 4b in 62% over two steps.
Hex-5-ene-1,2-diol was selectively O-monotritylated to
give 10. The secondary hydroxy function was then trans-
Key words: metathesis, solid-phase synthesis, nitrogen heterocy-
cles, epoxidation
Natural, as well as synthetic, nitrogen heterocycles of dif-
ferent ring sizes represent an important class of bioactive
compounds. For example, iminocyclitols are potent inhib-
itors of glycosidic enzymes, since their protonated forms
closely resemble the transition states of the latter.1 They
have also found widespread medical application.2 Due to
their structural diversity iminocyclitols have been the tar-
get of considerable synthetic efforts. Recently, efficient
syntheses of iminocyclitols3 and other azacycles4 employ-
ing ring-closing olefin metathesis as the key step have
been reported. We wish to present a solid-phase synthesis
towards functionalized 6-, 7- and 85-membered azacycles.
The modular character of our concept should also enable
a combinatorial application.
Olefin metathesis has emerged as a powerful tool in or-
ganic synthesis during the last few years, especially be-
cause of the development of a new generation of
metathesis catalysts which are highly active even in the
presence of a wide range of functional groups.6 A well-es-
tablished catalyst is GrubbsÕ ruthenium based
Cl2(PCy3)2Ru=CHPh ([Ru], Cy = cyclohexyl).7 Until now
only a few authors have described applications of olefin
metathesis in combination with solid-phase chemistry.8
Our retrosynthetic strategy contains a ring-closing olefin
metathesis (RCM) as the key step, whereby azacycles 1
are formed from the polymer-supported diolefinic acyclic
precursors 2 (Scheme 1). These precursors are readily pre-
pared from olefinic amino alcohols 3, which are tethered
to the solid phase via the alcohol function, an aldehyde R1-
(a) TrCl, pyridine, r.t., 12 h (84%); (b) 1. KOH, iPrOH, r.t., 1 h; 2.
PhCHO, toluene, r.t., 10 min (100%); (c) CH2=CHCH2Li, benzene,
r.t., 2 h (91%); (d) TFAA, pyridine, r.t., 5 min (96%); (e) 2.5 mol%
[Ru], CH2Cl2, reflux (97%)
Scheme 1
Scheme 2
Synthesis 1999, No. 1, 138Ð144 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
Solid-Phase Synthesis of Functionalized Azacycles
139
Table Cyclization Reactions on the Solid Phase
Product
[Ru]a mg (mol%)
Yieldb (%)
14a
14b
14c
14d
30 (15)
23 (11)
17 (8)
85
89
87
88
30 (15)
on the nitrogen, which turned out to be stable to the cleav-
age procedure as we demonstrated for the 7-membered
ring 14d, thus enabling the solid-phase synthesis of acy-
lated azacycles. The further functionalizability of the
polymer-bound metathesis products was exemplarily
demonstrated by epoxidation of the double bond of 14d
with Cl3CCN/H2O214 to give 16. For characterization pur-
poses the oxidation product 16 was cleaved using the stan-
dard conditions described above. Obviously, acidic
cleavage was accompanied by 5-exo-tet-recyclization of
the epoxide, resulting in the formation of bicyclic prod-
ucts 17 in 70% overall yield15 (Scheme 5). The further
functionalization of the solid-phase supported epoxides is
currently under investigation in our laboratory.
(a) 1. Cl3CCN, Na (cat,), 70¡C, 3 h; 2. tBuPh, reflux, 2 h; (b) 1.
LiAlH4, THF, reflux, 4 h; 2. CCl3COCl, NEt3, 0¡C, 30 min (62%); (c)
TrCl, pyridine, 45¡C, 12 h (99%); (d) DEAD, PPh3, (PhO)2P(O)N3,
r.t., 12 h (77%); (e) LiAlH4, THF, reflux, 1 h (73%); (f) CCl3COCl,
tBuOMe, sat. NaHCO3, r.t. (95%); (g) TFA, CH2Cl2 (95%)
Scheme 3
formed into azide 11 by a Mitsunobu reaction. Reduction of
11 yielded amine 12, which was N-trichloroacetylated to
give 13. Acidic cleavage of the trityl group afforded 4c in
51% overall yield starting from hex-5-ene-1,2-diol.
These homologous N-acylated amino alcohols 4aÐc were
tethered to chlorotrityl resin (approximately 0.6 mmol gÐ1)
(Scheme 4). Cleavage of the trichloroacetyl moieties pro-
ceeded smoothly with KOH in a mixture of isopropyl al-
cohol/dichloromethane (1:3).13 The polymer-bound
amines were reacted with benzaldehyde to the corre-
sponding imines. Subsequent addition of allyllithium re-
sulted in the formation of the solid-phase-bound dialkenyl
amines.11 N-Trifluoroacetylation gave the corresponding
(a) Cl3CCN, CH2Cl2, H2O2, K2HPO4, reflux, 3 h; (b) CH2Cl2, 2%
TFA (70%)
Scheme 5
metathesis precursors. The RCM using 8Ð15 mol% of In summary, we have presented a modular solid-phase
[Ru] proceeded well to give 14aÐc in good yields (Table). synthesis approach towards functionalized azacycles of
The cyclic products were cleaved by treating the resins different ring sizes.
with dichloromethane/2% trifluoroacetic acid. The triflu-
oroacetyl groups were found to be partially removed dur-
All chemicals were obtained from commercial suppliers, solvents
ing cleavage, but treatment of the crude cleavage products were distilled prior to use. Only if indicated, they were dried as fol-
lows. THF: distillation over K; Et2O: distillation over Na; CH2Cl2,
pyridine: distillation over CaH2. The following stationary phases
were used for chromatography. TLC: aluminum foils Merck 60 F
with K2CO3/MeOH (or KOH/MeOH in the case of 14c)
afforded the amino alcohols 15aÐc as exclusive products.
When using benzoyl chloride instead of trifluoroacetic an-
hydride as the acylating agent we obtained an acyl residue
254, flash chromatography: 0.0040Ð0.0063 mm Merck silica. Ana-
lytical and semi-preparative HPLC was performed with a Knauer
HPLC-64 equipped with a Waters-C18 reverse-phase column
(8 mm × 300 mm) using a MeOH/H2O gradient (50:50 to 95:5 over
25 min, flow rate 2.5 mL minÐ1) with a mass sensitive Sedere
SEDEX-55 Evaporative Light Scattering Detector. The following
spectrometers were used to record physical data. NMR: Bruker AM
400 (1H: 400 MHz), Bruker AC 200 (13C: 50 MHz) at 25¡C, unless
otherwise stated, vs. TMS as external standard. MS and HRMS:
Finnigan MAT 95 SQ or Varian MAT 711. MS spectra are EI spec-
tra (70 eV) unless otherwise noted. FAB-MS spectra were recorded
using a 3-nitrobenzyl alcohol matrix. IR: Nicolet 750 FT-IR spec-
trophotometer, resins: in KBr on a PerkinÐElmer IR 881. Mps: Le-
ica Galen III microscope (uncorrected).
(a) 1. styrene/2% divinylbenzeneÐTrCl, pyridine, 70¡C, 3 h; 2.
KOH, iPrOH, CH2Cl2, 40 ûC, 12 h; 3. R1-CHO, toluene, r.t., 3 h; 4.
CH2=CHCH2Li, benzene, r.t., 12 h (85Ð95%); 5. R2-X (R2 = acyl),
pyridine; 6. [Ru], CH2Cl2, reflux; (b) CH2Cl2, 2% TFA (85Ð89%)
2,2,2-Trichloro-N-[1-(trityloxymethyl)allyl]acetamide (5)
Alcohol 4a (3.8 g, 15 mmol) and trityl chloride (4.5 g, 16 mmol)
were dissolved in a mixture of CH2Cl2 (90 mL) and pyridine
Scheme 4
Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York

140
J. Pernerstorfer et al.
PAPER
(3.5 mL). The resulting solution was stirred at r.t. overnight, then
washed with 20% aq citric acid (50 mL) and water (25 mL), dried
(MgSO4) and evaporated to dryness in vacuo. Recrystallization of
the residue from EtOH afforded 5 as colorless crystals (5.8 g, 84%);
mp 120¡C.
1H NMR (CDCl3): d = 3.32 (d, 1H, J = 4 Hz, CH2O), 4.55Ð4.65 (m,
1H, CH-N), 5.30 (d, 1H, J = 10 Hz, CH2=CH), 5.32 (d, 1H, J = 17
Hz, CH2=CH), 5.92 (ddd, 1H, J = 17/10/5 Hz, CH2=CH), 7.15 (d,
1H, J = 8 Hz, NH), 7.23Ð7.35 (m, 9H, Ar-H), 7.41Ð7.45 (m, 6H, Ar-
H).
13C NMR (CDCl3): d = 53.1 (CH, CH-N), 64.2 (CH2, CH2O), 86.5
(Cq, CPh3), 92.5 (Cq, CCl3), 116.9 (CH2, CH2=CH), 127.1 (CH),
127.8 (CH), 128.3 (CH), 134.0 (CH, CH2=CH), 143.1 (Cq), 161.0
(Cq, C=O).
a solution of 6 (460 mg, 1.1 mmol) in anhyd benzene (100 mL). Af-
ter stirring for 2 h MeOH (1 mL) was added and the mixture was
evaporated to dryness in vacuo. The residue was partitioned be-
tween water (25 mL) and hexanes (3 × 25 mL), the combined organ-
ic layers were dried (MgSO4), the solvent was removed by
distillation and the residue was purified by flash chromatography
(silica gel, tBuOMe/hexanes 3:97) to yield 7 (460 mg, 91%) as a
pale yellow oil (inseparable mixture of two diastereomers; ratio 1:4,
as determined by 1H NMR).
1H NMR (CDCl3): d = 2.33Ð2.43 (m, 2H, Ph-CHCH2), 3.01Ð3.19
(m, 3H, CHCH2O,), 3.60 (dd, 0.8H, J = 7/7 Hz, Ph-CHmajor), 3.73
(dd, 0.2H, J = 7/7 Hz, Ph-CHminor), 4.93Ð5.23 (m, 4H, 2 CH2=CH),
5.58Ð5.78 (m, 2H, 2 CH2=CH), 7.16Ð7.47 (m, 20H, Ar-H).
13C NMR (major isomer, CDCl3): d = 42.9 (CH2, Ph-CHCH2), 58.7
(CH), 59.7 (CH), 65.2 (CH2, CH2O), 86.4 (Cq, CPh3), 115.5 (CH2),
117.6 (CH2), 126.6Ð128.8 (6 CH), 135.4 (CH, CH2=CH), 139.4
(CH, CH2=CH), 144.1 (Cq, Trityl), 144.4 (Cq).
IR (CCl4): n = 3430 (NÐH), 1725 cmÐ1 (C=O).
Anal. (C25H22Cl3NO2): calcd: C, 63.24; H, 4.67; N, 2.95. Found: C,
63.70; H, 4.75; N, 2.94.
HRMS (FAB, C33H33NO, M+): calcd 459.2562, found 459.2562.
IR (CCl4): n = 992, 920 cmÐ1 (Alkene CÐH).
N-Benzylidene-1-(trityloxy)but-3-en-2-amine (6)
2,2,2-Trichloro-N-[1-(trityloxymethyl)allyl]acetamide (5) (1.5 g,
3.1 mmol) was added to a solution of KOH (1 g) in iPrOH (10 mL)
and stirred for 1 h at r.t. The mixture was evaporated to dryness in
vacuo, the residue was dissolved in water (25 mL) and extracted
with EtOAc (3 × 25 mL). The combined organic extracts were dried
(MgSO4) and the solvent was evaporated to yield 1-(trityloxy)but-
3-en-2-amine (1.0 g, 100%) as pale yellow oil.
1H NMR (CDCl3): d = 3.02 (dd, 1H, J = 9/8 Hz, CH2O), 3.17 (dd,
1H, J = 9/4.5 Hz, CH2O), 3.53Ð3.61 (m, 1H, CH-N), 5.09 (d, 1H, J
= 10.5 Hz, CH2=CH), 5.20 (d, 1H, J = 17 Hz, CH2=CH), 5.83 (ddd,
1H, J = 17/10.5/6 Hz, CH2=CH), 7.21Ð7.27 (m, 3H, Ar-H), 7.28Ð
7.34 (m, 6H, Ar-H), 7.43Ð7.50 (m, 6H, Ar-H).
2,2,2-Trifluoro-N-(1-phenylbut-3-enyl)-N-[1-(trityloxymeth-
yl)allyl]acetamide (8)
N-(1-Phenylbut-3-enyl)-1-(trityloxymethyl)allylamine (7) (460 mg,
1.0 mmol) was dissolved in a mixture of anhyd CH2Cl2 (5 mL) and
pyridine (1 mL). TFAA (0.26 mL, 1.8 mmol) was added and the
mixture was stirred for 5 min, diluted with CH2Cl2 (25 mL), washed
with 20% aq citric acid (25 mL) and water (10 mL). The organic
layer was dried (MgSO4) and evaporated. The residue was purified
by flash chromatography (silica gel, tBuOMe/hexanes 3:97) to
yield 8 (530 mg, 96%) as colorless crystals (inseparable mixture of
two diastereomers, NMR indicates the presence of rotamers).
1H NMR (DMSO-d6, 423 K, major isomer): d = 2.75Ð2.84 (m, 1H,
Ph-CHCH2), 2.96 (dd, 1H, J = 9/5 Hz, CH2O), 2.97Ð3.07 (m, 1H, Ph-
CHCH2), 3.35 (dd, 1H, J = 9/7 Hz, CH2O), 4.26Ð4.35 (m, 1H,
CHCH2O), 4.80Ð4.99 (m, 1H, Ph-CH), 5.03 (d, 1H, J = 10 Hz,
CH2=CH), 5.08 (d, 1H, J = 17 Hz, CH2=CH), 5.28 (d, 1H, J = 10 Hz,
CH2=CH), 5.29 (d, 1H, J = 17 Hz, CH2=CH), 5.53Ð5.76 (m, 1H,
CH2=CH), 6.04Ð6.12 (m, 1H, CH2=CH), 7.10Ð7.40 (m, 20H, Ar-H).
13C NMR (CDCl3, not coalesced): d = 35.6/38.1 (CH2, Ph-CHCH2),
59.8/60.1/60.3/60.4/61.3 (2 CH, Ph-CH, CHCH2O), 63.3/63.5
(CH2, CH2O), 86.2/87.1/87.3 (Cq, CPh3), 116.6 (q, J = 287 Hz,
CF3), 117.7Ð120.1 (2 CH2, CH2=CH), 126.7Ð129.0 (CH), 132.7Ð
134.8 (2 CH, CH2=CH), 135.7/135.8 (Cq), 139.3 (Cq), 143.3Ð143.8
(Cq, Trityl), 155.9 (Cq, q, J = 35 Hz, C=O).
13C NMR (CDCl3): d = 54.2 (CH, CH-N), 68.2 (CH2, CH2O), 86.4
(Cq, CPh3), 115.0 (CH2, CH2=CH), 127.0 (CH), 127.8 (CH), 128.6
(CH), 139.5 (CH, CH2=CH), 144.0 (Cq).
MS (FI): m/z (%) = 330 (MH+, 100), 260 (45), 245 (35), 243 (77).
IR (CCl4): n = 3393 (NÐH), 988, 925 cmÐ1 (Alkene CÐH).
Freshly distilled benzaldehyde (840 mg, 7.9 mmol) was added to a
solution of crude 1-(trityloxy)but-3-en-2-amine (2.6 g, 7.9 mmol) in
toluene (6 mL). After 10 min the volatiles were evaporated in vac-
uo. To remove residual water, the residue was dissolved twice in
toluene (5Ð6 mL each) and subsequently evaporated to yield 6
(3.3 g, 100%) as a yellow oil.
1H NMR (CDCl3): d = 3.21 (dd, 1H, J = 9/5 Hz, CH2O), 3.42 (dd,
1H, J = 9/9 Hz, CH2O), 4.06 (ddd, 1H, J = 9/6.5/5 Hz, CH-N), 5.13
(ddd, 1H, J = 10.5/1.5/1.5 Hz, CH2=CH), 5.22 (ddd, 1H, J = 17/1.5/
1.5 Hz, CH2=CH), 6.00 (ddd, 1H, J = 17/10.5/6.5 Hz, CH2=CH),
7.10Ð7.55 (m, 18H, Ar-H), 7.62Ð7.66 (m, 2H, Ar-H), 8.43 (s, 1H,
Ph-CH).
HRMS (FAB, C33H33NO, M+): calcd 556.24634, found 556.2463.
IR (film): n = 1692 (C=O), 1215 (CÐF), 993, 926 cmÐ1 (Alkenyl CÐH).
Anal. (C35H32F3NO2): calcd: C, 75.57; H, 5.80; N, 2.52. Found: C,
75.47; H, 5.79; N, 2.55.
13C NMR (CDCl3): d = 66.8 (CH2, CH2O), 73.4 (CH, CH-N), 86.5
(Cq, CPh3), 116.4 (CH2, CH2=CH), 126.9Ð128.8 (5 CH), 130.7
(CH), 136.4 (Cq), 137.2 (CH, CH2=CH), 144.1 (Cq), 161.6 (Cq, Ph-
CH).
HRMS (FAB, C30H28NO, MH+): calcd 418.2171, found 418.2171.
IR (film): n = 1647 (C=N), 922 cmÐ1 (Alkene CÐH).
2-Phenyl-1-(trifluoroacetyl)-6-(trityloxymethyl)-1,2,3,6-tet-
rahydropyridine (9)
2,2,2-Trifluoro-N-(1-phenylbut-3-enyl)-N-[1-(trityloxymethyl)al-
lyl]acetamide (8) (87 mg, 0.16 mmol) was dissolved in CH2Cl2 (2 mL)
under argon. [Ru] (3.0 mg, 3.6 µmol) was added and the solution was
refluxed overnight. The solvent was evaporated and the residue was pu-
rified by flash chromatography (silica gel, tBuOMe/hexanes 3:97) to
yield 9 (80 mg, 97%) as colorless wax (inseparable mixture of two di-
astereomers, NMR indicates the presence of rotamers).
1H NMR (C6D6, 348 K, major isomer): d = 2.13Ð2.25 (m, 1H, H-
3a), 2.57Ð2.75 (m, 1H, H-3b), 3.53 (dd, 1H, J = 9/4 Hz, CH2O), 3.75
(dd, 1H, J = 9/5 Hz, CH2O), 4.78Ð4.90 (m, 1H, H-6), 5.22Ð5.30 (m,
1H, H-2), 5.40Ð5.53 (m, 1H, H-4), 5.75 (ddd, 1H, J = 10/7/3 Hz, H-
5), 6.90Ð7.41 (m, 14H, Ar-H), 7.50Ð7.60 (m, 6H, Ar-H).
N-(1-Phenylbut-3-enyl)-1-(trityloxymethyl)allylamine (7)
A solution of allyllithium16 was prepared by addition of PhLi in
hexane (3.8 mmol) to a solution of allyltriphenylstannane (1.5 g,
3.8 mmol) in anhyd Et2O (20 mL) at r.t. under exclusion of moisture
and air. After stirring for 20 min the clear supernatant (10 mL) was
collected using a syringe, the residue was washed with Et2O (2 ×
10 mL). The combined clear ethereal solutions were added at r.t. to
Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid-Phase Synthesis of Functionalized Azacycles
141
13C NMR (CDCl3, major isomer): d = 26.8 (CH2, C-3), 54.3 (CH,
C-2 or C-6), 55.6 (CH, C-2 or C-6), 63.0 (CH2, CH2O), 86.8 (Cq,
CPh3), 116.1 (Cq, q, J = 288 Hz, CF3), 125.4 (CH), 126.8Ð128.7 (5
CH), 143.3 (Cq), 143.7 (Cq, Trityl).
phenylphosphoryl azide (320 mg, 1.2 mmol) were added slowly.
This mixture was stirred overnight at r.t. in the darkness. The sol-
vent was removed, and the residue was purified by flash chromatog-
raphy (silica gel, hexanes/tBuOMe 98:2) to yield 11 (310 mg, 77%)
as yellow oil.
1H NMR (CDCl3): d = 1.46Ð1.55 (m, 2H, CH2, CH2CH2CHOH),
1.98Ð2.16 (m, 2H, CH2=CHCH2), 3.15 (dd, 1H, J = 10/7 Hz,
CH2O), 3.21 (dd, 1H, J = 10/4 Hz, CH2O), 3.39Ð3.48 (m, 1H, CH-
N3), 4.97 (ddd, 1H, J = 10.5/3.5/2 Hz, CH2=CH), 4.98 (ddd, 1H, J
= 17/3.5/1.5 Hz, CH2=CH), 5.71 (dddd, 1H, J = 17/10.5/7/6.5 Hz,
CH2=CH), 7.19Ð7.34 (m, 9H, Ar-H), 7.42Ð7.49 (m, 6H, Ar-H).
IR (film): n = 1688 (C=O), 1209, 1190 cmÐ1 (CÐF).
Anal. (C33H28F3NO2): calcd: C, 75.13; H, 5.35; N, 2.66. Found: C,
75.17; H, 5.41; N, 2.75.
2,2,2-Trichloro-N-[1-(hydroxymethyl)but-3-enyl]acetamide
(4b)
C-Allylglycine (1.5 g, 13 mmol) was added to a suspension of
LiAlH4 (1.2 g, 32 mmol) in THF (50 mL). The resulting mixture
was heated under reflux for 4 h. After cooling, Et2O (150 mL) was
added, followed by water (10 mL) until the aluminum salts precip-
itated. The supernatant was collected and the remainder washed
with tBuOMe (5 × 100 mL). NEt3 (5 mL) was added to the com-
bined organic extracts. At 0¡C trichloroacetic chloride (3.5 g,
20 mmol) was added slowly. After stirring for another 30 min, the
mixture was washed with aq K2CO3 (50 mL), 1 M HCl (50 mL) and
water (50 mL) and dried (MgSO4). The solvent was evaporated and
the residue was purified by flash chromatography (silica gel,
tBuOMe/hexanes 1:2) to yield 4b (1.9 g, 62%) as a pale yellow oil.
1H NMR (CDCl3): d = 2.37Ð2.51 (m, 2H, CH2=CHCH2), 3.74Ð3.81
(m, 2H, CH2O), 4.02 (dddd, 1H, J = 17/7.5/7.5/4 Hz, CH-N), 5.17
(br d, 1H, J = 10 Hz, CH2=CH), 5.19 (br d, 1H, J = 17 Hz, CH2=CH)
5.81 (dddd, 1H, J = 17/10/7/7 Hz, CH2=CH), 6.84Ð7.06 (br s, 1H,
NH).
13C NMR (CDCl3): d = 29.9 (CH2), 30.0 (CH2), 61.7 (CH, CH-N3),
66.2 (CH2, CH2O), 87.0 (Cq, CPh3), 115.5 (CH2, CH2=CH), 127.0
(CH), 127.8 (CH), 128.6 (CH), 137.1 (CH, CH2=CH), 143.6 (Cq, Tri-
tyl).
IR (film): n = 2099 cmÐ1 (N3).
¥
Anal. (C25H25N3O 0.5 H2O): calcd: C, 76.50; H, 6.68; N, 10.70.
Found: C, 76.42; H, 6.75; N, 10.38.
1-(Trityloxy)hex-5-en-2-amine (12)
5-Azido-6-(trityloxy)hex-1-ene (11) (3.7 g, 9.6 mmol) was dis-
solved in anhyd THF (10 mL) and added to a refluxing suspension
of LiAlH4 (1.8 g, 48 mmol) in THF (20 mL). After 1 h, the mixture
was cooled, and after addition of Et2O (100 mL), water was added
slowly until the white aluminum salts precipitated. The supernatant
was collected, the precipitate was extracted with tBuOMe (5 ×
100 mL). The combined organic layers were evaporated to dryness,
and the residue was purified by flash chromatography (silica gel,
MeOH/tBuOMe/NEt3 0:99:1Ð2:97:1) to yield 12 (2.5 g, 73%) as
yellow oil.
13C NMR (CDCl3): d = 34.9 (CH2, CH2=CHCH2), 52.5 (CH, CH-
N), 62.7 (CH2, CH2O), 92.4 (CCl3), 118.6 (CH2, CH2=CH), 133.0
(CH, CH2=CH), 162.0 (Cq, C=O).
HRMS (C6H7Cl3NO, M+ Ð CH2OH): calcd 213.9593, found
213.9589.
1H NMR (CDCl3): d = 1.25Ð1.40 (m, 1H, CH2, CH2CH2CHOH),
1.44Ð1.59 (m, 1H, CH2, CH2CH2CHOH), 1.94Ð2.14 (m, 2H,
CH2=CHCH2), 2.90 (dd, 1H, J = 8.5/7 Hz, CH2O), 2.92Ð3.00 (m,
1H, CH-N), 3.13 (dd, 1H, J = 8.5/4 Hz, CH2O), 4.93 (dm, 1H, J =
10 Hz, CH2=CH), 4.97 (dm, 1H, J = 18 Hz, CH2=CH), 5.76 (dddd,
1H, J = 18/10/13/3 Hz, CH2=CH), 7.21Ð7.33 (m, 9H, Ar-H), 7.41Ð
7.43 (m, 6H, Ar-H).
13C NMR (CDCl3): d = 30.2 (CH2), 33.4 (CH2), 50.9 (CH, CH-N),
68.5 (CH2, CH2O), 86.3 (Cq, CPh3), 114.6 (CH2, CH2=CH), 126.9
(CH), 127.7 (CH), 128.6 (CH), 138.3(CH, CH2=CH), 144.1 (Cq, Tri-
tyl).
IR (film): n = 3410, 3334 (OÐH, NÐH), 1695 (C=O), 1042, 921 cmÐ
1 (Alkenyl CÐH).
1-(Trityloxy)hex-5-en-2-ol (10)
Hex-5-ene-1,2-diol (600 mg, 5.2 mmol) was dissolved in pyridine
(5 mL), trityl chloride (1.5 g, 5.3 mmol) was added and the mixture
was stirred overnight at 45¡C. After distillation in vacuo, the resi-
due was dissolved in water (25 mL) and extracted with tBuOMe
(3 × 25 mL). The combined organic extracts were washed with 20%
aq citric acid (25 mL) and water (25 mL), dried (MgSO4), the sol-
vent was removed, and the residue was purified by flash chromatog-
raphy (silica gel, tBuOMe/hexanes 1:9Ð1:1) to yield 10 (1.8 g, 99%)
as a pale yellow oil.
IR (film): n = 995 cmÐ1 (Alkenyl CÐH).
2,2,2-Trichloro-N-[1-(trityloxymethyl)pent-4-enyl]acetamide
(13)
1H NMR (CDCl3): d = 1.42Ð1.58 (m, 2H, CH2), 2.00Ð2.21 (m, 2H,
CH2=CHCH2), 2.33 (d, 1H, J = 3.5 Hz, OH), 3.05 (dd, 1H, J = 9.5/
7.5 Hz, CH2O), 3.19 (dd, 1H, J = 9.5/3.5 Hz, CH2O), 3.77Ð3.85 (m,
1H, CH-OH), 4.91 (ddd, 1H, J = 10.5/3.5/1 Hz, CH2=CH), 4.99
(ddd, 1H, J = 17/3.5/2 Hz, CH2=CH), 5.78 (dddd, 1H, J = 17/10.5/
7/7 Hz, CH2=CHCH2), 7.22Ð7.34 (m, 9H, Ar-H), 7.42Ð7.48 (m, 6H,
Ar-H).
13C NMR (CDCl3): d = 29.6 (CH2), 32.4 (CH2), 67.6 (CH2, CH2O),
70.3 (CH, CH-OH), 86.7 (Cq, CPh3), 114.7 (CH2, CH2=CH), 127.0
(CH), 127.8 (CH), 128.6 (CH), 138.2 (CH, CH2=CH), 143.8 (Cq,
Trityl).
1-(Trityloxy)hex-5-en-2-amine (12) (90 mg, 0.25 mmol) was dis-
solved at r.t. in a mixture of tBuOMe (2 mL) and aq NaHCO3
(5 mL). Trichloroacetyl chloride (70 mg, 0.38 mmol) was added
slowly under vigorous stirring. After no starting material was de-
tectable by TLC, the mixture was extracted with tBuOMe (2 ×
5 mL). The combined organic extracts were dried (MgSO4), the sol-
vent was removed in vacuo and the residue was purified by flash
chromatography (silica gel, tBuOMe/hexanes 1:1) to yield 13
(120 mg, 95%) as colorless crystals; mp 88Ð91¡C (hexanes).
1H NMR (CDCl3): d = 1.72Ð1.89 (m, 2H, CH2, CH2CH2CHOH),
1.98Ð2.08 (m, 2H, CH2=CHCH2), 3.18 (dd, 1H, J = 10/4 Hz,
CH2O), 3.29 (dd, 1H, J = 10/4 Hz, CH2O), 3.98Ð4.09 (m, 1H, CH-
N), 4.97 (br d, 1H, J = 11 Hz, CH2=CH), 4.98 (br d, 1H, J = 17 Hz,
CH2=CH), 5.77 (dddd, 1H, J = 17/11/7/6 Hz, CH2=CH), 7.19Ð7.34
(m, 9H, Ar-H), 7.36Ð7.43 (m, 6H, Ar-H).
MS (FAB): m/z (%) = 281 (2), 243 (100).
IR (film): n = 3426 cmÐ1 (OÐH).
5-Azido-6-(trityloxy)hex-1-ene (11)
13C NMR (CDCl3): d = 30.0 (CH2), 30.9 (CH2), 51.2 (CH, CH-N),
63.7 (CH2, CH2O), 86.6 (Cq, CPh3), 92.8 (Cq, CCl3), 115.6 (CH2,
CH2=CH), 127.2 (CH), 127.9 (CH), 128.5 (CH), 137.1 (CH,
CH2=CH), 143.4 (Cq, Trityl), 161,2 (Cq, C=O).
1-(Trityloxy)hex-5-en-2-ol (10) (380 mg, 1.1 mmol) was dissolved
in THF (5 mL) and PPh3 (320 mg, 1.2 mmol) was added. After cool-
ing in an ice bath, DEAD (200 mg, 1.2 mmol) and subsequently di-
Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York

142
J. Pernerstorfer et al.
PAPER
MS (FAB): m/z (%) = 501 (M+, 1 isotope, 100).
IR (film): n = 3343 (NÐH), 1705 cmÐ1 (C=O).
mL each) and dried in vacuo. The IR showed no C=N absorption at
1645 cmÐ1.
N-Acylation; General Procedure
2,2,2-Trichloro-N-[1-(hydroxymethyl)pent-4-enyl]acetamide
(4c)
Dialkenylamine resin (1 g, about 0.5 mmol) was swollen in anhyd
CH2Cl2 (9 mL) and pyridine (1 mL). After addition of TFAA
(0.29 mL, 2.0 mmol) (for 14aÐc) or benzoyl chloride (0.23 mL,
2.0 mmol) (for 14d) the mixture was shaken at r.t. (for 14aÐc) or at
50¡C (for 14d) for 4 h. The polymer was filtered, repeatedly washed
with CH2Cl2 and Et2O (3 × 10 mL each) and dried in vacuo. The IR
showed a characteristic C=O absorption at 1685Ð1690 cmÐ1.
TFA (3.6 g, 32 mmol) was added to a solution of 13 (3.2 g,
6.4 mmol) in CH2Cl2 (15 mL). After 10 min MeOH (3 mL) and water
(20 mL) were added and the mixture was stirred for another 30 min.
The mixture was diluted with CH2Cl2 (50 mL) and washed with sat.
NaHCO3 (25 mL). The combined organic extracts were dried
(MgSO4), the solvent was evaporated and the residue was purified by
flash chromatography (silica gel, tBuOMe/hexanes 1:1Ð1:0) to yield
4c (1.6 g, 95%) as colorless crystals, mp 46Ð50¡C (hexanes).
Olefin Metathesis; General Procedure
Dialkenylamide resin (0.5 g) was swollen in CH2Cl2 (5 mL) in an
argon atmosphere. [Ru] was added in two equivalent portions (for
amounts, see the Table) and the suspension was refluxed intermedi-
ately for 4 h. After refluxing overnight the mixture was filtered, re-
peatedly washed with CH2Cl2 and Et2O (3 × 0.5 mL each) and dried
in vacuo.
1H NMR (CDCl3): d = 1.72Ð1.79 (m, 2H, CH2, CH2CH2CHOH),
1.98 (br s, 1H, OH), 2.12Ð2.19 (m, 2H, CH2=CHCH2), 3.73 (dd, 1H,
J = 11/4 Hz, CH2O), 3.79 (dd, 1H, J = 11/4 Hz, CH2O), 3.94Ð4.03
(m, 1H, CH-N), 5.02 (ddd, 1H, J = 10/3/1.5 Hz, CH2=CH), 5.07
(ddd, 1H, J = 17/3/1.5 Hz, CH2=CH), 5.81 (dddd, 1H, J = 17/10/7.5/
7.5 Hz, CH2=CH), 6.92 (br s, 1H, NH).
13C NMR (CDCl3): d = 29.8 (2 CH2), 52.8 (CH, CH-N), 63.4 (CH2,
CH2O), 92.5 (Cq, CCl3), 115.6 (CH2, CH2=CH), 137.0 (CH,
CH2=CH), 162.1 (Cq, C=O).
Isolation of 15aÐd from the Solid Phase
14aÐd (200 mg each) were treated according to the general cleavage
procedure.
IR (film): n = 3410, 3329 (OÐH, NÐH), 1693 cmÐ1 (C=O).
(6-Phenyl-1,2,5,6-tetrahydropyridin-2-yl)methanol (15a)
The crude cleavage product was dissolved in MeOH (0.3 mL), some
K2CO3 was added, after 2 min the mixture was dissolved in water
(2 mL) and extracted with EtOAc (3 × 2 mL). The combined organ-
ic layers were dried (MgSO4) and concentrated. The residue was
purified by flash chromatography (MeOH/tBuOMe/NEt3 0:99:1Ð
1:98:1) to obtain 15a (14 mg, 85%) (mixture of 2 diastereomers, cis/
trans 2:3).
Anal. (C8H12Cl3NO2): calcd: C, 36.88; H, 4.64; N, 5.38. Found: C,
37.15; H, 4.69; N, 5.39.
Attachment of 4aÐc to Chlorotrityl Resin; General Procedure
Chlorotrityl resin (1 g) was swollen in a solution of benzene (4 mL)
and pyridine (1 mL). After addition of 4a, 4b or 4c (0.6 mmol) the
mixture was shaken at 70¡C for 3 h. MeOH (0.5 mL) was added and
shaking was continued at 70¡C for 2 h. The mixture was filtered off,
washed with MeOH, CH2Cl2 and Et2O (3 × 10 mL each) and dried
in vacuo. For all of 4aÐc the loading was found to be approximately
0.5 mmol gÐ1 by quantitative GC analysis of the product isolated
from a sample of resin. The IR of the polymers as pellets in KBr
showed a characteristic C=O absorption at 1720 cmÐ1.
cis-15a: Rf 0.26 (tBuOMe/NEt3 99:1).
1H NMR (CDCl3): δ = 2.15Ð2.31 (m, 2H, H-5), 3.60 (dd, 1H, J =
11/5 Hz, CH2O), 3.69 (dd, 1H, J = 11/3.5 Hz, CH2O), 3.76Ð3.82 (m,
1H, H-2), 3.97 (dd, 1H, J = 9.5/4.5 Hz, H-6), 5.64 (ddd, 1H, J = 10/
4.5/1.5 Hz, H-3), 5.98 (dddd, 1H, J = 10/5/2.5/2.5 Hz, H-4), 7.28
(m, 1H, Ar-H), 7.31Ð7.43 (m, 4H, Ar-H). NOE (400 MHz, CDCl3):
δ = 3.76Ð3.82 (H-2) ↔ 3.97 (H-6) (1.5%).
13C NMR (CDCl3): δ = 34.5 (CH2, C-5), 57.1 (CH, C-2 or C-6), 57.4
(CH, C-2 or C-6), 65.8 (CH2, CH2O), 126.7 (CH), 127.0 (CH),
127.4 (CH), 128.0 (CH), 128.5 (CH), 144.5 (Cq, Ar-C).
HRMS (C12H14NO, M+ Ð H): calcd 188.1075, found 188.1075.
IR (CCl4): ν = 3400, 3247 cmÐ1 (OÐH, NÐH).
trans-15a: Rf 0.15 (tBuOMe/NEt3 99:1).
1H NMR (CDCl3): δ = 2.19Ð2.38 (m, 2H, H-5), 3.49Ð3.60 (m, 3H,
H-1, H-2), 3.97 (dd, 1H, J = 9.5/4.5 Hz, H-6), 5.70 (ddd, 1H, J = 10/
4/2.5 Hz, H-3), 5.97Ð6.05 (m, 1H, H-4), 7.24Ð7.42 (m, 5H, Ar-H).
Cleavage of Products and Intermediates from the Solid Phase;
General Procedure
The resin (200 mg) was placed into a porous glass filter frit and
treated with CH2Cl2/TFA (4 mL/0.1 mL) in three portions. The
combined eluents were evaporated to dryness in vacuo.
Hydrolysis of the Trichloroacetamides; General Procedure
N-Trichloroacetamide resin (1 g) was swollen in CH2Cl2 (25 mL).
After addition of a solution of KOH (0.8 g) in iPrOH (8 mL) the re-
sulting mixture was shaken at 40¡C overnight. The mixture was fil-
tered, repeatedly washed with MeOH, water, MeOH, CH2Cl2 and
Et2O (3 × 10 mL each) and dried in vacuo. The IR showed no C=O
absorption at 1720 cmÐ1.
13C NMR (CDCl3): δ = 32.9 (CH2, C-5), 50.9 (CH, C-2 or C-6), 55.1
(CH, C-2 or C-6), 62.9 (CH2, CH2O), 126.1 (CH), 126.6 (CH),
127.2 (CH), 127.9 (CH), 128.5 (CH), 143.7 (Cq, Ar-C).
Formation of the Imines; General Procedure
Amine resin (1 g) was swollen in CH2Cl2 (10 mL). After addition of
benzaldehyde (1.0 g) and HC(OMe)3 (0.2 mL) the mixture was
shaken at r.t. for 4 h. The mixture was filtered, repeatedly washed
with CH2Cl2 and Et2O (3 × 10 mL each) and dried in vacuo. The IR
showed a characteristic C=N absorption at 1645 cmÐ1.
HRMS (C12H14NO, M+ Ð H): calcd 188.1075, found 188.1075.
IR (CCl4): ν = 3400, 3299 cmÐ1 (OÐH, NÐH).
(7-Phenyl-2,3,6,7-tetrahydro-1H-azepin-2-yl)methanol (15b)
The crude cleavage product was dissolved in MeOH (0.3 mL), some
K2CO3 was added, after 2 min the mixture was dissolved in water
(2 mL) and extracted with EtOAc (3 × 2 mL). The combined organ-
ic layers were dried (MgSO4) and concentrated. This crude material
was purified by flash chromatography (MeOH/tBuOMe/hexanes/
NEt3 0:66:33:1Ð1:98:0:1) to obtain 15b (20 mg, 89%) (mixture of 2
diastereomers, cis/trans 1:1).
Allylation; General Procedure
Allyllithium (0.45 mmol) in Et2O (35 ml) was prepared16 by the
procedure described above. This ethereal solution was added at r.t.
to a suspension of the imine resins (1 g each) in anhyd benzene
(80 mL) under exclusion of moisture and air. This mixture was
shaken at r.t. overnight. MeOH (1 mL) was added, the polymer was
filtered, repeatedly washed with MeOH, CH2Cl2, and Et2O (3 × 10
Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid-Phase Synthesis of Functionalized Azacycles
143
cis-15b: Rf 0.35 (tBuOMe/NEt3 99:1).
HRMS (C14H19NO, M+): calcd 217.1466, found 217.1478.
1H NMR (CDCl3): δ = 2.06Ð2.25 (m, 2H, H-3), 2.38Ð2.59 (m, 2H,
H-6), 2.84 (dddd, 1H, J = 10/9/4/2.5 Hz, H-2), 3.33 (dd, 1H, J = 10/
10 Hz, CH2O), 3.61 (dd, 1H, J = 10/4 Hz, CH2O), 3.71 (dd, 1H, J =
10/2.5 Hz, H-7), 5.81Ð5.91 (m, 2H, H-4, H-5), 7.20Ð7.48 (m, 5H,
Ar-H).
IR (film): ν = 3351 cmÐ1 (br, OÐH, NÐH).
(1-Benzoyl-7-phenyl-2,3,6,7-tetrahydro-1H-azepine-2-yl)meth-
anol (15d)
The crude cleavage product was purified by flash chromatography
(CH2Cl2/tBuOMe 9:1) to obtain 15d (28 mg, 88%) as a separable
mixture of two diastereomeric products. To assign the stereochem-
istry of the diastereomers, about 0.5 mg each were dissolved in
MeOH (0.1 mL), KOH (10 mg) was added, the mixture was heated
to 50¡C for 15 min, diluted with water and extracted with tBuOMe.
The TLC of the two extracts were compared with authentic samples
of 15b.
NOE (400 MHz, CDCl3): δ = 2.84 (H-2) ↔ 3.71 (H-7) (4%).
13C NMR (CDCl3): δ = 34.1 (CH2, C-6), 39.8 (CH2, C-3), 59.5 (CH,
C-2 or C-7), 62.8 (CH, C-2 or C-7), 66.2 (CH2, CH2O), 126.4 (CH),
127.1 (CH), 128.5 (CH), 129.7 (CH), 130.3 (CH), 145.8 (Cq, Ar-C).
HRMS (C13H17NO, M+): calcd 203.1310, found 203.1313.
IR (film): ν = 3400, 3281 cmÐ1 (OÐH, NÐH).
trans-15b: Rf 0.17 (tBuOMe/NEt3 99:1).
1H NMR (CDCl3): δ = 2.19Ð2.27 (m, 1H, H-3), 2.29Ð2.39 (m, 1H, H-
3), 2.43Ð2.51 (m, 1H, H-6), 2.76Ð2.85 (m, 1H, H-6), 3.36Ð3.45 (m, 2H,
CH2O, H-2), 3.52 (dd, 1H, J = 15/9 Hz, CH2O), 4.33 (dd, 1H, J = 11/3
Hz, H-7), 5.70Ð5.79 (m, 2H, H-4, H-5), 7.20Ð7.48 (m, 5H, Ar-H).
cis-15d: Rf 0.42 (CH2Cl2/tBuOMe 3:1).
trans-15d: Rf 0.48 (CH2Cl2/tBuOMe 3:1).
1H NMR (CDCl3, 55¡C): δ = 2.06Ð2.16 (m, 1Hcis, H-3a), 2.26 (ddd,
1Hcis, J = 16/7/6 Hz, H-3b), 2.34Ð2.45 (m, 1Htrans, H-3a), 2.54 (ddd,
1Htrans, J =15/8/6 Hz, H-6a), 2.72Ð2.81 (m, 1Hcis, H-6a; m, 1Htrans
,
H-6b), 2.92 (ddd, 1Hcis, J = 17/6/6 Hz, H-6b), 3.18Ð3.27 (m, 1Hcis,
CH2O; 1Htrans, H-3b), 3.43 (dd, 1Hcis, J = 11/8 Hz, CH2O), 3.99 (dd,
1Htrans, J = 12.5/6 Hz, CH2O), 4.06Ð4.16 (m, 1Htrans, H-2), 4.21 (d,
1Htrans, J = 12.5 Hz, CH2O), 4.45Ð4.60 (m, 2Hcis, H-7, H-2), 5.04
(dd, 1Htrans, J = 11/6 Hz, H-7), 5.64Ð5.74 (m, 1Htrans, =CH), 5.76Ð
5.83 (m, 1Htrans, =CH), 5.79Ð5.86 (m, 1Hcis, =CH), 5.95Ð6.03 (m,
1Hcis, =CH), 7.21Ð7.53 (m, 10H, Ar-H)
13C NMR (CDCl3): δ = 31.9 (CH2, Ph-CHCH2), 37.3 (CH2,
CH2CHCH2O), 55.5 (CH), 56.4 (CH), 65.4 (CH2, CH2O), 126.5
(CH), 126.9 (CH), 128.4 (CH), 128.5 (CH), 129.2 (CH), 145.4 (Cq,
Ar-C).
HRMS (C13H17NO, M+): calcd 203.1310, found 203.1322.
IR (film): ν = 3400, 3276 cmÐ1 (OÐH, NÐH).
13C NMR (CDCl3, not coalesced, mixture of stereoisomers): δ =
28.9 (CH2), 32.3 (CH2), 56.7 (CH), 59.1 (CH), 63.8 (CH), 64.6
(CH2), 123.7Ð130.8 (8 CH), 136.9 (Cq), 137.5 (Cq), 141.4 (Cq),
174.9 (Cq).
HRMS (C20H21NO2, M+): calcd 307.15723, found 307.1577.
IR (film): ν = 3402 (OÐH), 1615 cmÐ1 (C=O).
(8-Phenyl-1,2,3,4,7,8-hexahydroazocin-2-yl)methanol (15c)
The crude cleavage product was dissolved in MeOH (0.3 mL), some
KOH was added, after 2 min the mixture was dissolved in water
(2 mL) and extracted with EtOAc (3 × 2 mL). The combined organ-
ic layers were dried (MgSO4) and concentrated. This crude product
was purified by flash chromatography (EtOAc/tBuOMe 1:1) to ob-
tain 15c (20 mg, 87%) (mixture of 2 diastereomers, cis/trans 1:2).
Epoxidation
cis-15c: Rf 0.45 (tBuOMe/NEt3 99:1).
14d (200 mg) was suspended in CH2Cl2 (4 mL) and Cl3CCN (1.7 g,
12 mmol). A solution of K2HPO4 (0.5 g) in 30% aq H2O2 (1 mL)
was added and the resulting mixture was shaken under reflux for
3 h. The polymer was filtered, washed with water, MeOH, CH2Cl2,
and Et2O (2 mL each) and dried in vacuo.
1H NMR (CDCl3): δ = 1.32 (dddd, 1H, J = 14.5/10.5/9/4 Hz, H-3a),
1.69 (dddd, 1H, J = 14.5/6/6/3 Hz, H-3b), 2.19Ð2.29 (m, 1H, H-4a),
2.35Ð2.44 (m, 1H, H-4b), 2.48 (ddd, 1H, J = 13.5/10/5 Hz, H-7a),
2.68 (ddd, 1H, J = 13.5/9.5/5 Hz, H-7b), 2.86 (dddd, 1H, J = 10.5/
10/5/3 Hz, H-2), 3.03 (dd, 1H, J = 10/10 Hz, CH2O), 3.48 (dd, 1H,
J = 10/5 Hz, CH2O), 3.85 (dd, 1H, J = 5/5 Hz, H-8), 5.66 (ddd, 1H,
J = 10/9.5/8 Hz, H-6), 5.94 (ddd, 1H, J = 10/8/8 Hz, H-5), 7.21Ð7.39
(m, 5H, Ar-H).
2-Benzoyl-5-hydroxy-3-phenyl-7-oxa-2-azabicyc-
lo[4.2.1]nonane (17)
Isolation from the solid phase: resin 16 (100 mg) was treated ac-
cording to the general cleavage procedure. The crude product was
purified by flash chromatography (tBuOMe/MeOH 100:0Ð98:2) to
yield 17 (12 mg, 70%) as mixture of two diastereomeric products.
NOE (400 MHz, CDCl3): δ = 2.86 (H-2) ↔ 3.85 (H-8) (3%).
13C NMR (CDCl3): δ = 24.4 (CH2, C-3), 33.8 (CH2, C-4 or C-7),
34.9 (CH2, C-4 or C-7), 59.0 (CH, C-2 or C-8), 62.6 (CH, C-2 or C-
8), 66.3 (CH2, CH2O), 126.2 (CH), 126.8 (CH), 127.0 (CH), 128.4
(CH), 132.9 (CH), 144.7 (Cq, Ar-C).
HRMS (C14H19NO, M+): calcd 217.1466, found 217.1460.
IR (film): ν = 3400, 3330 cmÐ1 (OÐH, NÐH).
trans-15c, Rf 0.35 (tBuOMe/NEt3 99:1).
1H NMR (CDCl3): δ = 1.13 (dddd, 1H, J = 14/12.5/11/2.5 Hz, H-
3a), 1.68 (dddd, 1H, J = 14/6/2.5/2 Hz, H-3b), 2.17Ð2.27 (m, 1H, H-
4a), 2.29Ð2.38 (m, 2H, H-4b, H-7), 2.61Ð2.69 (m, 1H, H-2), 2.86
(dd, 1H, J = 10/9 Hz, CH2O), 2.87 (dddd, 1H, J = 13/12/10/1 Hz, H-
7), 3.14 (dd, 1H, J = 10/5 Hz, CH2O), 3.89 (dd, 1H, J = 12.5/3.5 Hz,
H-8), 5.76 (dddd, 1H, J = 11/7/7/2 Hz, H-6), 6.05 (dddd, 1H, J = 11/
7.5/7.5/1 Hz, H-5), 7.23Ð7.29 (m, 1H, Ar-H), 7.33Ð7.39 (m, 2H, Ar-
H), 7.42Ð7.47 (m, 2H, Ar-H).
13C NMR (CDCl3): δ = 25.4 (CH2, C-3), 29.9 (CH2, C-4 or C-7),
33.8 (CH2, C-4 or C-7), 54.0 (CH, C-2 or C-8), 58.1 (CH, C-2 or C-
8), 66.3 (CH2, CH2O), 127.3 (CH), 127.9 (CH), 128.5 (CH), 128.8
(CH), 133.0 (CH), 143.3 (Cq, Ar-C).
Diastereomer A: Rf 0.42 (tBuOMe).
1H NMR (CDCl3): δ = 2.01 (ddd, 1H, J = 15/8/7 Hz, H-9a), 2.27Ð
2.31 (m, 1H, H-4a), 2.45 (d, 1H, J = 15 Hz, H-9b), 2.81 (br d, 1H, J
= 16 Hz, H-4b), 4.07 (dd, 1H, J = 7/5 Hz, H-5), 4.14 (d, 1H, J =
10 Hz, H-8a), 4.19Ð4.24 (m, 1H, H-8b), 4.28 (dd, 1H, J = 8/5 Hz,
H-6), 5.07Ð5.22 (m, 1H, H-1), 5.36Ð5.60 (m, 1H, H-3), 7.19Ð7.42
(m, 10H, Ar-H).
13C NMR (CDCl3): δ = 28.0 (CH2, C-4 or C-9), 34.0 (CH2, C-4 or
C-9), 56.2 (CH, C-1), 71.2 (CH, C-5), 77.2 (CH2, C-8), 80.7 (CH,
C-6), 125.6 (CH), 125.8 (CH), 127.1 (CH), 128.5 (CH), 128.8 (CH),
129.5. (CH), 136.8 (Cq, Ar-C), 141.2 (Cq, Ar-C).
MS (EI): m/z (%) = 323 (M+, 24), 252 (16, M+ Ð C4H7O), 105 (100),
77 (44).
HRMS (C20H21NO3, M+): calcd 323.15215, found 323.15214.
IR (film): ν = 3423 (OÐH), 1614 cmÐ1 (C=O).
Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York

144
J. Pernerstorfer et al.
PAPER
Diastereomer B: Rf 0.32 (tBuOMe).
(6) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109, 2124; An-
gew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(7) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem. 1995, 107, 2179; Angew. Chem., Int. Ed. Engl. 1995,
34, 2039.
1H NMR (CDCl3): δ = 1.95 (ddd, 1H, J = 16/6/3 Hz, H-4a), 2.01
(dd, 1H, J = 14/7.5 Hz, H-9a), 2.39 (d, 1H, J = 14 Hz, H-9b), 2.44
(ddd, 1H, J = 16/11/4 Hz, H-4b), 4.07 (dd, 1H, J = 10/7 Hz, H-8a),
4.16 (d, 1H, J = 10 Hz, H-8b), 4.18Ð4.23 (m, 1H, H-5), 4.32 (dd, 1H,
J = 7.5/4.5 Hz, H-6), 4.97 Ð5.07 (m, 1H, H-1), 5.42 (dd, 1H, J = 11/
3 Hz, H-3), 7.12Ð7.43 (m, 10H, Ar-H).
(8) For example, see:
Schuster, M.; Pernerstorfer, J.; Blechert, S. Angew. Chem.
1996, 108, 2111; Angew. Chem., Int. Ed. Engl. 1996, 35,
1979.
van Maarseveen, J. H.; den Hartog, J. A. J.; Engelen, V.; Fin-
ner, E.; Visser, G.; Kruse, C. G. Tetrahedron Lett. 1996, 37,
8249.
13C NMR (CDCl3): δ = 31.8 (CH2, C-4 or C-9), 38.9 (CH2, C-4 or
C-9), 55.4 (CH, C-1), 58.5 (CH, C-3), 69.3 (CH, C-5), 73.6 (CH2,
C-8), 80.3 (CH, C-6), 125.5 (CH), 126.4 (CH), 127.5 (CH), 128.4
(CH), 128.6 (CH), 130.0. (CH), 137.0 (Cq, Ar-C), 144.6 (Cq, Ar-C),
173.6 (Cq, C=O).
MS (EI): m/z (%) = 323 (M+, 24), 252 (26, M+ Ð C4H7O), 105 (100),
77 (28).
Peters, J.; Blechert, S. Synlett 1997, 348;
Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sa-
rabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannaka-
kou, P.; Hamel, E. Nature 1997, 387, 268;
HRMS (C20H21NO3, M+): calcd 323.15215, found 323.15214.
Nicolaou, K. C.; Vourloumis, D.; Li, T.; Pastor, J.; Winssin-
ger, N.; He, Y.; Ninkovic, S.; Sarabia, F.; Vallberg, H.; Ro-
schangar, F.; King, N. P.; Finlay, M. R. V.; Giannakakou, P.;
Verdier-Pinard, P.; Hamel, E. Angew. Chem. 1997, 109, 2181;
Angew. Chem., Int. Ed. Engl. 1997, 36, 2097.
Boger, D. L.; Chai, W.; Ozer, R. S.; Anderson, C.-M Bioorg.
Med. Chem. Lett. 1997, 7, 463.
IR (film): ν = 3398 (OÐH), 1625 cmÐ1 (C=O).
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Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York