A versatile synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones

Article abstract of DOI:10.1016/S0040-4020(03)00583-0

A mild and general strategy for the synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones is described. The seven-membered lactam is prepared by intramolecular amide bond formation from the intermediate amino acid, which is obtained e

Full text of DOI:10.1016/S0040-4020(03)00583-0

Tetrahedron 59 (2003) 4421–4432
A versatile synthesis of 2-substituted
4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones
a
Karolien Van Rompaey, Isabelle Van den Eynde, Norbert De Kimpe and Dirk Tourwe
a
b
a
,
*
´
aDepartment of Organic Chemistry (ORGC), Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 18 September 2002; revised 19 March 2003; accepted 9 April 2003
Abstract—A mild and general strategy for the synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones is described. The
seven-membered lactam is prepared by intramolecular amide bond formation from the intermediate amino acid, which is obtained either by
reductive alkylation of a variety of amines with N-Boc,N-Me-ortho-formyl-Phe and Phth-ortho-formyl-Phe, or by reductive amination of a
variety of aldehydes with N-Boc-ortho-aminomethyl-Phe. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Two synthetic routes for Aba-Gly 3 have been described so
far in the literature (Scheme 1). In the first one, the aromatic
ring reacts with an N-acyliminium intermediate which is
generated by treating the dipeptide oxazolidinone 2 with a
strong acid.6,7 A similar synthesis has been reported for the
Tyr-derived 8-hydroxy-substituted analogue Hba-Gly 4.5,8
The partial racemisation which has been observed is the
drawback of this strategy.7
The 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-one (Aba)
structure has attracted attention as a conformationally
constrained Phe analogue. It constrains the Ca–Cb dihedral
angle (x1) to þ608 or 1808, which corresponds to a
gauche(þ) and a trans conformation, respectively.1 It has
been shown to influence receptor selectivity in opioid
peptides1,2 and to provide selective enzyme inhibitors3,4 and
antigenic peptides.5
The second route uses the amide bond formation for
Scheme 1. Retrosynthetic pathways for Phth-Aba-Gly 3 and Phth-Hba-Gly 4.
Keywords: 2-benzazepine-3-ones; constrained amino acids; peptidomimetics.
*
Corresponding author. Tel.: þ32-2-629-32-95; fax: þ32-2-629-33-04; e-mail: datourwe@vub.ac.be
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00583-0

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K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
cyclisation,3 a strategy that was previously reported as
unsuccessful.6 The key step in this synthesis is the formation
of ortho-formyl-Phe 6 by ozonolysis of the ortho-vinyl-Phe
precursor.3 Partial epimerization at the a-carbon was also
observed. Both routes use a phthaloyl group for protection
of the a-nitrogen.
quantitative yield from 13 by catalytic hydrogenation over
Raney nickel in aqueous pyridinium acetate. Similar to the
Warshawsky strategy,3 carboxylic acid 14 was protected by
esterification with 2-(trimethylsilyl)ethanol using DCC and
pyridine.14 The ester 16 was obtained in a rather low yield
(42%), due to the formation of a considerable amount of
N-acylurea (37%).
In this paper, we report on the synthesis of 2-substituted
4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones, by for-
mation of the amide bond (pathway b in Scheme 1). The
method is optimized to give access to a large variety of
substituents on the heterocyclic nitrogen.
On the other hand, protection of carboxylic acid 13 under
these conditions resulted in remarkably better yields (74%).
Reduction of nitrile 15 to aldehyde 16 under the above
mentioned conditions was then accomplished in a com-
parable yield as for the conversion of 13 to 14.
Both Gly-OBn (R¼CH2COOBn) and Val-OMe (R¼
CH(iPr)COOMe) were used in a reductive amination of
aldehyde 16. The crude products 17a,b were treated
subsequently with TBAF15 and DCC/pyridine to give the
bicyclic products 18a,b in a yield of 26 and 30%,
respectively (yields calculated from 16). The overall yield
calculated from 13 is 18% for 18a, and 20% for 18b
(Table 1, Scheme 3).
2. Results and discussion
To provide the widest versatility for the introduction of 2-N
substituents in the precursor 10 which will be ring closed to
11, two approaches were elaborated, both starting from Boc-
ortho-cyano-Phe 7 (Scheme 2).
The nitrile function in 7 may be reduced to the correspond-
ing aldehyde 8.9 Reductive amination of this aldehyde with
a primary amine would lead to amino acid 10, which may be
cyclised to lactam 11. As an alternative, compounds 10 can
also be obtained by reductive alkylation of the benzylic
amine 9 with aldehydes.
These low yields prompted us to use aldehyde 14 directly in
the reductive amination with Gly-OBn. Compound 19a was
isolated in 71% crude yield, with some loss in the acidic
aqueous wash phases (pH 4). Cyclisation of amino acids 19
was accomplished with 2-(1H-benzotriazole-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate (TBTU). Lactam 18a
was obtained in a 45% yield (32% calculated from 14).
The racemic Boc-protected ortho-cyano-Phe 7 was obtained
in excellent yields by phase transfer alkylation10 of ethyl
N-(diphenylmethylene)glycinate11 and ortho-cyanobenzyl
bromide, followed by hydrolysis of the ester and Boc-
protection of the nitrogen.
The same reactions were performed with Val-OMe. Only
53% of amino acid 19b was isolated, with again some
compound being lost in the aqueous wash phases. The cyclic
product 18b was isolated in a 36% yield (19% calculated
from 14).
The product isolated from the reduction of nitrile 7 under
conditions to generate the aldehyde9 was identified as the
Boc-protected Tic 12, rather than the desired aldehyde 8,
indicating a rapid reductive cyclisation (Scheme 3). The
latter undesired reaction should be prevented by the
introduction of a second nitrogen substituent. Compound 7
was N-methylated by deprotonation with sodium
hydride and substitution with iodomethane.12,13 N-Boc,N-
Me-ortho-formyl-Phe 14 was indeed obtained in an almost
In order to avoid losses due to the solubility of amino acids
19 in water, the cyclisation was performed immediately
after completion of the reductive amination, without
isolation of the intermediates 19. After formation of
products 19a,b, the solvent was removed from the reaction
mixture and the residue was treated with DCC and pyridine
Scheme 2. Pathways towards 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones 11. RCHO¼Fmoc-D-Phe-H (a), Fmoc-Leu-H (b), Fmoc-Trp-H
(c), iPrCHO (d), PhCHO (e).

K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4423
Scheme 3. (a) RaNi, H2 (50 psi), H2O–Py–AcOH 1:1:1, 508C, overnight; (b) NaH, MeI, THF, 24 h, rt; (c) HO(CH2)2SiMe3, DCC, Py, CH3CN, 4 h, rt;
(d) RNH2, NaCNBH3, MgSO4, MeOH or CH2Cl2, NMM or AcOH, rt; (e) (1)TBAF, THF, rt, (2) DCC, Py, CH3CN, H2O, rt; (f) DCC, Py, CH3CN, o.n., rt;
(g) Boc2O, DMAP, CH3CN, o.n., rt; (h) TBAF, THF, rt, 30 min.
in acetonitrile. The cyclisation to benzazepines 18a,b was
completed after an overnight reaction. After purification, a
yield of 49 and 45% was obtained for 18a,b (calculated
from 14), respectively, which is quite an improvement
compared to the yields obtained before (Table 1).
Using the same conditions, the Phe-OBn derived benz-
azepine 18f was isolated in 45% yield (calculated from 14).
Similarly, isopropylamine, cyclohexylamine and methyl
5-aminovalerate were used with comparable results, in order
to demonstrate the generality of the method.
Moreover, using this method, the trimethylsilylethyl ester
protection is avoided.
It is worth mentioning that it is not possible to prepare the

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K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
Table 1. Yields of benzazepinones 18 obtained from N-Boc,N-Me-ortho-
cyano-Phe 13 by different pathways as shown in Scheme 3
The racemic ortho-cyano-Phe 24 was reacted with
N-carbethoxyphthalimide which resulted in the phthaloyl
protected ortho-cyano-Phe 25. Using the same conditions
mentioned above, nitrile 25 was successfully converted into
the aldehyde 26. Reductive amination with Gly-OBn
followed by ring closure led to the formation of benz-
azepinone 27a (44% yield calculated from 26). Clearly, the
phthaloyl group represents a suitable alternative for the
N-Boc,N-Me protection applied in benzazepinones 18.
Entry
Yield from
13 to 18 via
2-(TMS)ethyl
ester 17
Yield from
14 to 18
via 19
(19 isolated)
(%)
Yield from
14 to 18
via 19
(19 not
isolated)
(%)
(%)
18a (R¼CH2COOBn)
18b (R¼CH(iPr)COOMe)
18c (R¼iPr)
18
20
32
19
49
45
42
37
27
45
In order to determine the potential of the method for the
preparation of homochiral compounds, enantiopure Phth-
(R)-Aba-Gly-OBn 27b was prepared starting from
(R)-ortho-cyano-Phe. The homochiral (R)- and (S)-ortho-
cyano-Phe were obtained by enzymatic resolution of
N-Ac-(R,S)-ortho-cyanophenylalanine ethyl ester with
a-chymotrypsin.17 After hydrogenolysis of benzazepinone
27b and phthaloyl deprotection with hydrazine the so
obtained (R)-Aba-Gly-OH was reacted with Marfey’s
reagent,18 resulting in one peak on HPLC analysis.
Treatment of (R,S)-Aba-Gly-OH, derived from 27a, with
Marfey’s reagent resulted in two well separated peaks. In
case of 27b, the absence of the peak corresponding to
(S)-Aba-Gly-OH is a clear proof that no racemisation at the
Ca of the benzazepinone occurs. This result differs from the
strategy described by Warshawsky3 where 6% racemisation
at the Ca stereocenter was observed.
18d (R¼cHx)
18e (R¼(CH2)4COOMe)
18f (R¼CH(Bn)COOBn)
Aba-Phe analogue 18f by the oxazolidinone method,
because in that case the more favourable 6-membered
tetrahydroisoquinoline ring will be formed by reaction with
the acyliminium intermediate rather than the 7-membered
benzazepine structure.
Although this strategy is quite general with respect to the
2-N substituents, the use of the irreversible methyl group as
a nitrogen protection to prevent cyclisation to Boc-Tic (7 to
12, Scheme 3) limits the accessible diversity of the
benzazepinones.
Therefore, a reversible double nitrogen protection such as a
double Boc-protection would be preferable. Boc-ortho-
cyano-Phe 7 was converted into its trimethylsilylethyl
ester,14 and the second Boc-group was introduced by
reaction with dimethylaminopyridine and Boc2O
(Scheme 3).16 Ester 20 was subjected to the reductive
conditions. A very slow reduction of the nitrile was
observed in addition to an insufficient stability of the bis-
Boc protection. Under the reaction conditions one Boc-
group was cleaved and the trimethylsilylethyl ester of
Boc-Tic was formed instead of aldehyde 22. The same result
was obtained in an attempt to perform the reduction on
carboxylic acid 21, leading to Boc-Tic 12, rather than the
corresponding aldehyde 23.
Potential racemisation at the Ca of the 2-N substituents was
examined by the synthesis of Phth-(R)-Aba-(S)-Ala-OBn
27c (49% yield). HPLC analysis showed the presence of
1.5% of the Phth-(R)-Aba-(R)-Ala-OBn, an indication of
minor racemisation at the Ca of Ala.
It was also demonstrated that during the Boc-protection of
ortho-cyano-Phe and the subsequent N-methylation no
racemisation occurred. Homochiral (S)-ortho-cyano-Phe
was Boc-protected and N-methylated. After Boc-deprotec-
tion of (S)-N-Boc,N-Me-ortho-cyano-Phe a GITC19
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl isothiocyanate)
derivatisation was performed. The detection of only one
peak on HPLC analysis in comparison to two peaks for the
racemic product demonstrates the absence of the
(R)-enantiomer.
Because of these disappointing results we switched the
phthaloyl group for double nitrogen protection (Scheme 4).
Scheme 4. Synthesis of phthaloyl protected benzazepinones.

K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4425
In an alternative strategy (path b, Scheme 2), Boc-ortho-
cyano-Phe 7 was reduced to the corresponding amine 9 by
catalytic hydrogenation. The synthesis of 9 proceeded
smoothly (95%), provided the reaction time of 4 h was not
exceeded, which caused the formation of the hydrogenolysis
product N-Boc-ortho-methylphenylalanine.
The racemisation at the stereocenter of the 2-N substituent
was studied by the synthesis of the (S,S)-benzazepinone 11f,
prepared from (S)-ortho-cyano-Phe and Fmoc-(S)-Tyr-
(OtBu)-H. In this case 17% of the (S,R)-diastereomer was
detected by HPLC, an indication of racemisation at the
stereocenter of Tyr, either during the synthesis of the
aminoaldehyde or during the reductive amination.
Reductive alkylation of 9 was performed with Fmoc-
protected a-aminoaldehydes, which were prepared by the
reduction of the corresponding hydroxamates.20 Using
NaCNBH3 as described above,21,22 no conditions could be
found for a clean reductive alkylation of 9. The use of a
small excess (1.2–1.5 equiv.) of aldehyde to avoid double
alkylation resulted in an incomplete transformation of 9
with competing reduction of the Fmoc-aminoaldehyde to
the alcohol. Changing from pH 5 to pH 8, neither the use of
trimethyl orthoformate23 as a cosolvent, neither switching
from dichloromethane to the protic solvent methanol22
could avoid this side reaction. The use of a larger excess of
aldehyde resulted in a contamination with double alkylated
product.
3. Conclusion
The formation of ortho-formyl-phenylalanine was per-
formed in excellent yields by reduction with RaNi/H2 of
the nitrile, provided a double nitrogen protection was used.
The N-Boc,N-Me and the phthaloyl protection were both
suitable. Initially, the carboxylic acid was protected as a
trimethylsilylethyl ester, but it was observed that this was
unnecessary and higher yields were obtained without it.
Since isolation of the reductive amination products 19
proved to be difficult, a procedure for the ring closure using
the crude reaction mixture was developed.
However, the use of Na(OAc)3BH24 as reductant resulted in
a clean reductive mono-alkylation, with less than 5% of
alcohol being formed. This reaction was also performed
with isobutyraldehyde and benzaldehyde with good yields.
Cyclisation of the crude v-amino acids 10 was executed
using TBTU activation. Overall yields of compounds 11
after flash column chromatography purification are reported
in Table 2.
The alternative method in which Boc-ortho-aminomethyl-
phenylalanine 9 was reacted with various aldehydes was
also successful. In this case the use of Na(OAc)3BH as
reductant resulted in higher yields and less impurities
compared to NaCNBH3.
Both methods allow a rapid assembly of the 4-amino-
1,2,4,5-tetrahydro-2-benzazepine-3-one skeleton with a
variety of 2-N substituents. Whereas compounds 18a,b,f
represent constrained dipeptide analogues, the benzazepines
11a,b,c,f are diamines having a differential nitrogen
protection which can be further elaborated into pepti-
domimetic structures.
For this second strategy, the extent of racemisation was also
examined. The racemic benzazepinone 11d was Boc-
deprotected, and two peaks were detected on HPLC after
derivatisation with Marfey’s reagent. The same lactam was
prepared as its (S)-enantiomer, starting from enantiopure
(S)-ortho-cyano-Phe. In this case, FDAA derivatisation led
to only one peak on HPLC, demonstrating, as in the first
strategy, that no racemisation occurred at the Ca of the
benzazepinone.
In both strategies no racemisation occurs at the Ca of the
benzazepinone, but some racemisation is detected at the
stereocenter of the 2-N substituents.
Table 2. Yields of benzazepinones 11 obtained from N-Boc-ortho-aminomethylphenylalanine 9 as shown in Scheme 2
Entry 11 (n¼1)
Yield from 9 to 11 (%)
Entry 11 (n¼1)
Yield from 9 to 11 (%)
11a, RCHO¼Fmoc-D-Phe-H
49
11d, RCHO¼iPrCHO
48
11b, RCHO¼Fmoc-Leu-H
25
49
11e, RCHO¼PhCHO
64
50
11c, RCHO¼Fmoc-Trp-H
11f, RCHO¼Fmoc-Tyr(OtBu)-H

4426
K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4. Experimental
dissolved in a minimum amount of EtOH, and the dropwise
addition of Et2O led to the formation of white crystals
(23.84 g, 85%). Mp 155.9–159.98C; HPLC (grad. 1)
tret¼13.0 min; Rf (EtOAc–MeOH 1:1) 0.51; MS 145
(100%), 191 (40%), 219 (100%); dH (D2O) 1.18 (3H, t,
4.1. General
RP-HPLC was performed using a RP C-18 column (Vydac
218TP54, ID¼0.46 cm, L¼25 cm, PS¼5 m). The mobile
phase (water–acetonitrile) contained 0.1% TFA. Gradient 1
or 2 was used (grad. 1: t¼0 min, 0% CH3CN; t¼30 min,
80% CH3CN; t¼35 min, 80% CH3CN; grad. 2: t¼0 min,
0% CH3CN; t¼30 min, 80% CH3CN; t¼40 min, 100%
CH3CN), flow rate: 1.0 mL min21, l¼215 nm. Preparative
HPLC was performed using a RP C-18 column (Vydac
218TP152022, ID¼2.5 cm, L¼25 cm, PS¼15–20 m).
1 ,
was used, flow rate: 13.0 mL min21
3
2
0
CH3, J¼7.2 Hz), 3.49 (1H, dd, Hb, J(Hb, Hb )¼14.5 Hz,
3J(Ha, Hb)¼7.1 Hz), 3.55 (1H, dd, Hb , 2J(Hb,
0
3
0
0
Hb )¼14.5 Hz,
J(Ha, Hb )¼8.1 Hz), 4.25 (2H, q,
COOCH2, 3J¼7.2 Hz), 4.48 (1H, pseudo t, Ha, 3J(Ha,
3
0
Hb)< J(Ha, Hb )¼7.6 Hz), 7.53–7.85 (4H, M, Harom); dC
(D2O) 12.96 (CH3), 34.39 (CH2b), 53.18 (CHa), 63.79
(CH2 ester), 111.89 (Cquat arom), 118.10 (CN), 128.70,
130.66, 133.61, 134.10 (CH arom), 137.76 (Cquat arom),
168.88 (CO).
Gradient
l¼215 nm. TLC analysis was performed on a plastic
sheet precoated with silicagel 60F254 (Merck). Silica gel 60
(0.040–0.063 mm) from Merck was used for flash column
chromatography (w/w 60/1 or 120/1). Melting points were
measured on a Bu¨chi B 540 melting point apparatus. 1H and
13C NMR spectra were recorded at 250 and 63 MHz,
respectively, on a AC 250 Bruker spectrometer in D2O or
MeOH-d4, using the residual solvent signal as internal
reference or in CDCl3 with TMS as an internal standard.
Mass spectra were recorded on a VG QuattroII spectrometer
using electrospray ionisation (positive ion mode).
(R,S)-ortho-cyano-phenylalanine hydrochloride 24. A
solution of (R,S)-ortho-cyano-phenylalanine ethyl ester
hydrochloride (2 g, 7.87 mmol) in 5 M HCl–acetone (1:1,
40 mL) was refluxed for 21 h and subsequently cooled down
to room temperature. The dark red solution was washed with
CH2Cl2 until a colourless aqueous layer was obtained.
Water was evaporated from the aqueous phase and the
residue was lyophilized from acetonitrile–water (1:1) to
yield a white powder (1.64 g, 92%). Mp 336–3378C; HPLC
(grad. 2) tret¼10.8 min; Rf (CH3CN–CH3OH–H2O 4:1:1)
0.31; MS 145 (100%), 191 (40%); dH (D2O) 3.26 (1H, dd,
Enantiomeric purities were determined by GITC19 (2,3,4,6-
tetra-O-acetyl-b-D-glucopyranosyl isothiocyanate) or
FDAA18 (Na-(2,4-dinitro-5-fluorophenyl)-L-alaninamide)
using the RP-HPLC gradients mentioned above.
Hb, J(Hb, Hb )¼14.6 Hz, J(Ha, Hb)¼7.7 Hz), 3.41 (1H, dd,
2
3
0
2
3
0
0
3
0
Hb , J(Hb, Hb )¼14.6 Hz, J(Ha, Hb )¼7.2 Hz), 4.17 (1H,
3
0
pseudo t, Ha, J(Ha, Hb)< J(Ha, Hb )¼7.4 Hz), 7.37–7.69
(4H, M, Harom); dC (D2O) 32.24 (CH2b), 51.19 (CHa), 109.88
(Cquat arom), 116.11 (CN), 126.79, 128.70, 131.89, 132.23
(CH arom), 135.50 (Cquat arom), 167.91 (CO).
For the GITC method a stock solution of 22.5 mM GITC in
acetonitrile was prepared. The analyte (1 mg) was dissolved
in 1 mL CH3CN–H2O 1:1þ0.4% NEt3. Two molar
equivalents of the stock solution were added to 100 ml of
the analyte solution and the sample was incubated at room
temperature for 2 h. The sample was diluted four times
before injection on the HPLC (l¼250 nm).
(R,S)-Boc-ortho-cyano-phenylalanine 7. (R,S)-ortho-cyano-
phenylalanine hydrochloride 24 (1 g, 4.4 mmol) was
dissolved in dioxane–H2O (1:1, 50 mL) and the pH was
adjusted to 8 with 1 M NaOH. After the addition of Boc2O
(1.8 mL, 8.85 mmol), the mixture was stirred overnight and
more NaOH was added portionwise to keep a constant pH.
The dioxane was evaporated in vacuo, followed by an
extraction of the aqueous layer with pentane (2£50 mL).
The organic phase was washed with saturated NaHCO3
(3£40 mL). All aqueous phases were combined and
acidified to pH 1–1.5 with 10% KHSO4, followed by
extraction with diethyl ether (4£100 mL). The organic layer
was washed with water (2£100 mL), dried (MgSO4),
filtered and evaporated in vacuo. After crystallisation from
EtOAc–hexane a white product was obtained (1.08 g,
84%). Mp 137.8–138.38C; HPLC (grad. 2) tret¼20.7 min;
Rf (EtOAc–MeOH 2:1þ1% AcOH) 0.56; MS 191 (100%),
235 (50%), 291 (15%); dH (CD3OD) 1.34 (9H, s, tBu), 3.09
For the FDAA method a stock solution of 20.0 mM FDAA
in acetone was prepared. The analyte (1 mg) was dissolved
in 1 mL NaHCO3. Two molar equivalents of the stock
solution were added to 100 ml of the analyte solution and the
sample was incubated at 408C for 2 h. After quenching with
2 M HCl the sample was diluted 10 times before injection
on the HPLC (l¼340 nm).
4.1.1. (R,S)-Boc-ortho-cyano-Phe 7. (R,S)-Ortho-cyano-
phenylalanine ethyl ester hydrochloride. To a solution of
ethyl
93.6 mmol),
N-(diphenylmethylene)glycinate
ortho-cyanobenzyl bromide
(25.00 g,
(20.19 g,
103 mmol) and nBu4NþHSO24 (1.59 g, 4.68 mmol) in
CH2Cl2 (200 mL), a 10% aqueous NaOH solution was
added (200 mL). After 24 h of vigourous stirring, the layers
were separated and the aqueous phase was washed with
CH2Cl2 (2£200 mL). The combined organic layers were
washed with water until neutral. The organic phase was
dried (MgSO4), filtered and evaporated to yield a pale
yellow oil of N-(diphenylmethylene)-ortho-cyano-phenyl-
alanine ethyl ester. The diphenylmethylene protection at
nitrogen was removed by hydrolysis in 1N HCl–acetone
(1:1, 600 mL). After 3 h stirring the solvent was evaporated
and the residue was triturated with ether. The product was
(1H, dd, Hb, J(Hb, Hb )¼14.0 Hz, J(Ha, Hb)¼9.7 Hz),
2
3
0
3.45 (1H, dd, Hb , J(Hb, Hb )¼14.0 Hz, 3J(Ha,
2
0
0
Hb )¼5.0 Hz), 4.49 (1H, dd, Ha, 3J(Ha, Hb)¼9.4 Hz,
0
3
0
J(Ha, Hb )¼5.0 Hz), 7.37–7.70 (4H, M, Harom); dC
(CD3OD) 28.41 and 28.65 (CH3 Boc), 37.51 and 38.49
(CH2b), 54.44 and 55.24 (CHa), 80.92 and 82.50 (Cquat
Boc), 113.88 (Cquat arom), 118.27 (CN), 127.99, 131.03,
131.61 and 133.35 (CH arom), 140.93 (Cquat arom), 155.69
and 156.93 (COOtBu), 174.99 and 175.65 (COOH).
4.1.2. Preparation of enantiopure (R)- and (S)-ortho-
cyano-phenylalanine by enzymatic resolution. Synthesis

K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4427
of N-acetyl-(R,S)-ortho-cyano-phenylalanine ethyl ester.
(R,S)-ortho-cyano-phenylalanine ethyl ester hydrochloride
(5 g, 19.7 mmol) was dissolved in CH2Cl2 (100 mL),
followed by the addition of NEt3 (9.94 g, 98.4 mmol) and
acetic anhydride (10.04 g, 98.4 mmol). The mixture was
stirred at room temperature for 1 h. The mixture was
extracted with H2O (2£75 mL). The organic layer was dried
(MgSO4), filtered and evaporated. The product was crystal-
lised from CHCl3–Et2O to yield white crystals (4.09 g,
88%). Mp 74.5–75.58C; HPLC (grad. 2) tret¼18.6 min; Rf
(CH3CN–MeOH–H2O 4:1:1) 0.90; MS 261 (100%); dH
removed in vacuo. Enantiopure (R)- and (S)-ortho-cyano-
Phe·HCl was obtained as a white solid after lyophilisation
from H2O (81%).
Characterisation: see 24. Optical purity was determined by
FDAA analysis (HPLC (grad. 2) tret¼19.60 min for (S)-
ortho-cyano-Phe and tret¼20.48 min for (R)-ortho-cyano-
Phe).
4.1.3. (R,S)-N-Boc,N-Me-ortho-cyano-Phe 13. (R,S)-Boc-
ortho-cyano-Phe 7 (12.00 g, 41.3 mmol) was dissolved in
THF (120 mL), followed by the addition of CH3I (20.6 mL,
0.33 mol). The reaction mixture was cooled in an ice bath,
after which NaH (55–65% dispersion in oil, 5.41 g,
124 mmol) was added. After removal of the ice bath the
mixture was stirred for 24 h. EtOAc (150 mL) was added,
followed by the dropwise addition of water. The solvent was
evaporated and the residue was divided between water
(200 mL) and ether (60 mL). The aqueous phase was
extracted with ether (2£60 mL), and the combined organic
layer was extracted with saturated aqueous NaHCO3
(2£40 mL). The combined aqueous layer was acidified
with 10% KHSO4 until pH 3, followed by extraction with
EtOAc (4£100 mL). The organic layer was subsequently
washed with 5% Na2S2O3 (2£100 mL) and water
(2£100 mL). The solution was dried (MgSO4), filtered and
evaporated. After crystallisation (EtOAc–hexane) white
crystals were obtained (10.66 g, 85%). Mp 115.1–115.88C;
HPLC (grad. 1) tret¼20.8 min; Rf (EtOAc–MeOH 3:1þ1%
AcOH) 0.55; MS 205 (100%), 249 (30%), 305 (15%); dH
3
(CDCl3) 1.30 (3H, t, CH3, J¼7.2 Hz), 2.00 (3H, s, CH3–
2
CO), 3.26 (1H, dd, Hb, J(Hb, Hb )¼14.1 Hz, 3J(Ha,
0
2
0
0
Hb)¼7.2 Hz), 3.41 (1H, dd, Hb , J(Hb, Hb )¼14.1 Hz,
3
0
J(Ha, Hb )¼5.8 Hz), 4.20 (2H, M, COOCH2), 4.90 (1H, m,
Ha), 6.10 (1H, d, J¼7.7 Hz, NH), 7.2–7.7 (4H, M, arom. H);
dC (CDCl3) 13.86 (CH3 Et), 22.87 (CH3 Ac), 36.65 (CH2b),
52.80 (CHa), 61.84 (CH2 Et), 113.20 (Cquat arom next to
CN), 117.84 (CN), 127.49–132.73 (CH arom.), 140.34
(Cquat arom next to CH2b), 169.76 (NHCO), 170.92
(COOEt).
Resolution of N-acetyl-(R,S)-ortho-cyano-phenylalanine
ethyl ester by a-chymotrypsin. N-acetyl-(R,S)-ortho-
cyano-phenylalanine ethyl ester (5 g, 19.2 mmol) was
suspended in milliQ H2O (100 mL) and the mixture was
brought to 378C. After adjusting the pH to 5 with 0.2 M
LiOH, a-chymotrypsin (0.190 g, 41 units/mg) was added.
The pH was kept at 5 with 0.2 M LiOH. The enzymatic
resolution was monitored by HPLC and stopped at an acid–
ester ratio of 50:50 by the addition of active charcoal
(0.190 g). The mixture was filtered over dicalite, followed
by lyophilisation of the filtrate. The product was dissolved
in a minimal amount of 0.2 M NaHCO3 and N-Ac-(R)-
ortho-cyano-Phe-OEt was extracted with CHCl3. Then the
aqueous layer was acidified to pH 1 with 1N HCl and N-Ac-
(S)-ortho-cyano-Phe was extracted with EtOAc
(10£75 mL). The organic layers containing respectively
the ester and the acid were dried (MgSO4), filtered and
evaporated. The acid N-Ac-(S)-ortho-cyano-Phe was
obtained as a white solid (1.88 g, 85%). The ester N-Ac-
(R)-ortho-cyano-Phe-OEt was recrystallised from CHCl3–
Et2O to yield white crystals (2.15 g, 86%).
(CDCl3) 1.35 and 1.38 (9H, 2 s, tBu), 2.79 (3H, s, N-Me),
2
0
0
3.31 (1H, m, Hb), 3.58 (1H, dd, Hb , J(Hb, Hb )¼14.6 Hz,
3
0
J(Ha, Hb )¼5.1 Hz), 4.84 (1H, m, Ha), 7.31–7.64 (4H, M,
Harom); dC (CDCl3) 28.60 (CH3 Boc), 33.48 (N-Me), 33.83
and 34.50 (CH2b), 59.99 and 60.89 (CHa), 81.22 and 81.73
(Cquat Boc), 113.37 (Cquat arom), 118.07 and 118.24 (CN),
127.77 and 127.94, 130.84 and 131.12, 133.29 and 133.40
(CH arom), 141.90 (Cquat arom), 155.31 and 156.39
(COOtBu), 175.69 (COOH).
4.1.4. (R,S)-N-Boc,N-Me-ortho-formyl-Phe 14. Wet RaNi
(50 m pore, Aldrich, 1.5 g) was washed with milliQ water
(15£10 mL) and suspended with 13 (350 mg, 1.15 mmol) in
Py–AcOH–H2O (1:1:1, 30 mL). The suspension was
hydrogenated in a Parr apparatus (50 psi, 508C, overnight).
The mixture was filtered over dicalite and rinsed with water.
After evaporation of the solvent, the residue was redissolved
in EtOAc (100 mL) and washed with 1 M HCl (3£50 mL).
The organic layer was dried (MgSO4), filtered and
evaporated. A yellowish paste was obtained (343 mg,
97%); HPLC (grad. 1) tret¼20.2 min; Rf (EtOAc–MeOH
3:1þ1% AcOH) 0.63; MS 208 (60%), 252 (40%), 308
(60%); dH (CDCl3) 1.27 and 1.36 (9H, 2 s, tBu), 2.71 (3H, s,
N-Ac-(S)-ortho-cyano-Phe. Mp 175.0–177.08C; HPLC
(grad. 2) tret¼12.7 min; Rf (CH3CN–MeOH–H2O 4:1:1)
0.63; MS 233 (100%); dH (DMSO) 1.7 (3H, s, CH3–CO),
2
0
2
3.02 (1H, dd, Hb,
J(Hb, Hb )¼14.1 Hz, 3J(Ha,
0
0
Hb)¼9.6 Hz), 3.27 (1H, dd, Hb , J(Hb, Hb )¼14.1 Hz,
3
0
J(Ha, Hb )¼5.3 Hz), 4.5 (1H, m, Ha), 7.4–7.7 (4H, M,
arom. H); dC (DMSO) 22.3 (CH3), 35.5 (CH2b), 52.1
(CHa), 112.1 (Cquat arom next to CN), 117.7 (CN), 127.5–
132.9 (CH arom), 141.2 (Cquat arom), 169.2 (CONH), 172.5
(COOH).
0
N-Me), 3.20 and 3.48 (1H, m, Hb), 3.85 (1H, m, Hb ), 4.72
(1H, m, Ha), 7.71–7.82 (4H, M, Harom), 10.16 (1H, s,
Haldehyde); dC (CDCl3) 28.59 (CH3 Boc), 33.34 and 33.75
(CH2b), 34.45 and 34.71 (N-Me), 61.09 and 61.22 (CHa),
80.97 and 81.26 (Cquat Boc), 127.99, 132.91, 134.36 and
135.17 (CH arom), 140.32 (Cquat arom), 155.47 and 156.35
(COOtBu), 175.55 and 177.72 (COOH), 193.82 (HCvO).
N-Ac-(R)-ortho-cyano-Phe-OEt. Characterisation: see
N-Ac-(R,S)-ortho-cyano-Phe-OEt.
(S)-ortho-cyano-Phe and (R)-ortho-cyano-Phe. In order to
remove the acetyl groups of N-Ac-(S)-ortho-cyano-Phe or
N-Ac-(R)-ortho-cyano-Phe-OEt, 16.8 mmol was dissolved
in a minimal amount of 6N HCl. After refluxing for 4 h, the
reaction mixture was cooled down to rt and the solvent was
4.1.5. (R,S)-N-Boc,N-Me-ortho-cyano-Phe 2-(trimethyl-
silyl)ethyl ester 15. A solution of 13 (150 mg, 0.49 mmol),

4428
K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
pyridine (80 ml, 0.99 mmol) and 2-(trimethylsilyl)ethanol
(84 ml, 0.59 mmol) in CH3CN (6 mL) was cooled in an ice
bath for 10 min, followed by the addition of DCC (111 mg,
0.54 mmol). After 1 h reaction the ice bath was removed,
and the reaction mixture was stirred for 4 h. Oxalic acid
(0.3 mL of a 5 M solution in DMF) was added, and after
30 min stirring the precipitate was filtered and rinsed with
EtOAc. The filtrate was washed with 1N HCl (3£10 mL)
and with saturated aqueous NaHCO3 (3£10 mL). After
drying (MgSO4), filtration and evaporation the product was
purified by flash column chromatography (hexane–EtOAc
7:1) to yield a colourless oil (147 mg, 74%); HPLC (grad. 1)
tret¼31.2 min; Rf (hexane–EtOAc 4:1) 0.29; MS 405
(15%), 427 (100%); dH (CDCl3) 0.03 (9H, s, SiMe3), 1.00
(4 mL) and TBAF·3H2O (1.35 mmol) was added. The
reaction mixture turned immediately yellow. When the
deprotection was complete (2 h for Val-OMe, overnight for
Gly-OBn, monitored by HPLC) the solvent was removed
under reduced pressure. The product was redissolved in
acetonitrile–water (27:10), pyridine (73 ml, 0.898 mmol)
was added and the mixture was cooled in an ice bath. After
the addition of DCC (101 mg, 0.494 mmol) the reaction
mixture was stirred for 1 h at 08C, and overnight at room
temperature. Oxalic acid (5 M solution in DMF, 1 mL) was
added and after 30 min stirring the precipitate was filtered,
the filtrate was evaporated and redissolved in EtOAc
(100 mL). After washing with 1N HCl and saturated
aqueous NaHCO3 (3£50 mL), the organic layer was dried
(MgSO4), filtered and evaporated. A paste containing small
DCU particles was isolated. The paste was dissolved in
toluene, and the particles were removed by filtration. After
purification by flash column chromatography a yield of 26%
was obtained for 18a, and 30% for 18b (calculated from 16).
(2H, t, 3J¼8.5 Hz, CH2Si), 1.28 and 1.33 (9H, 2 s, tBu), 2.75
3
0
(3H, s, N-Me), 3.25 (1H, m, Hb), 3.52 (1H, dd, Hb , J(Ha,
2
0
0
Hb )¼4.9 Hz,
J(Hb, Hb )¼14.5 Hz), 4.23 (2H, m,
COOCH2), 4.72 and 4.90 (1H, 2£dd, Ha, 3J(Ha,
3
0
Hb)¼10.3 Hz, J(Ha, Hb )¼4.9 Hz), 7.26–7.63 (4H, M,
Harom); dC (CDCl3) -1.56 (SiMe3), 17.31 (CH2Si), 28.06
(CH3 Boc), 32.33 and 32.60 (N-Me), 33.53 and 34.10
(CH2b), 59.37 and 60.32 (CHa), 63.80 and 63.90 (OCH2),
80.07 and 80.49 (Cquat Boc), 112.93 (Cquat arom), 117.63
and 117.85 (CN), 127.06 and 127.28, 130.30 and 130.63,
132.66 and 132.77 (CH arom), 141.79 (Cquat arom), 154.69
and 155.56 (COOtBu), 170.26 and 170.55 (COOCH2–).
4.3. General procedure for the synthesis of 2-substituted
4-(Boc-methyl-amino)-1,2,4,5-tetrahydro-2-benzazepine-
3-ones 18
To a solution of aldehyde 14 (655 mg, 2.13 mmol) in
CH2Cl2 (puriss. p.a. 30 mL) the amine RNH2 (free amine,
hydrochloric acid or p-toluenesulfonic acid salt, 2.24 mmol)
was added. The pH was adjusted to 6 with N-methyl-
morpholine or AcOH, followed by the addition of MgSO4
(20 wt%) and NaCNBH3 (5.33 mmol). When the reaction
was completed (typically 2 h to overnight according to
HPLC) the solvent was removed under reduced pressure.
The residue was redissolved in acetonitrile (130 mL) and
pyridine (4.26 mmol) was added. The mixture was cooled in
an ice bath for 10 min and DCC (2.34 mmol) was added.
After 1 h stirring at 08C the reaction continued overnight at
room temperature. Oxalic acid (5 M solution in DMF,
5 mL) was added and after 30 min stirring the abundant
precipitate was filtered. The filtrate was evaporated and
redissolved in EtOAc (200 mL). After washing with 1N HCl
and saturated aqueous NaHCO3 (3£50 mL), the organic
layer was dried (MgSO4), filtered and evaporated. The small
particles of DCU in the obtained paste could be removed by
filtration after dissolving the paste in toluene. The product
was further purified by flash column chromatography or
preparative HPLC to yield colourless pastes.
4.1.6. (R,S)-N-Boc,N-Me-ortho-formyl-Phe 2-(trimethyl-
silyl)ethyl ester 16. Wet RaNi (1.8 g, 50 m pore, Aldrich)
was washed with milliQ water (15£10 mL) and suspended
with 15 (400 mg, 0.989 mmol) in Py–AcOH–H2O (1:1:1,
40 mL). The suspension was hydrogenated as described for
14. A yellowish paste was obtained (367 mg, 91%); HPLC
(grad. 1) tret¼32.5 min; Rf (hexane–EtOAc 4:1) 0.29; MS
352 (20%), 408 (100%); dH (CDCl3) 0.03 (9H, s, SiMe3),
0.99 (2H, t, 3J¼8.4 Hz, CH2Si), 1.23 and 1.33 (9H, 2 s, tBu),
2.63 and 2.69 (3H, 2 s, N-Me), 3.19 and 3.42 (2£0.5H, 2m,
3
2
0
0
0
Hb), 3.82 (1H, dd, Hb , J(Ha, Hb )¼4.5 Hz, J(Hb, Hb )¼
13.4 Hz), 4.24 (2H, m, COOCH2), 4.70 (1H, dd, Ha, 3J(Ha,
3
0
Hb)¼4.7 Hz, J(Ha, Hb )¼10.6 Hz), 7.20–7.80 (4H, M,
Harom), 10.17 (1H, s, aldehyde H); dC (CDCl3) -1.54 (SiMe3),
17.35 (CH2Si), 28.09 (CH3 Boc), 31.88 and 32.79 (CH2b),
32.59 and 33.55 (N-Me), 60.50 and 60.73 (CHa), 63.56
(OCH2), 79.87 and 80.11 (Cquat Boc), 126.88–134.20 (CH
arom), 140.17 (Cquat arom), 154.88 and 155.45 (COOtBu),
170.81 and 171.02 (COOCH2-), 192.87 (H–CvO).
4.2. Synthesis of 18a and 18b starting from 16
4.3.1. [4(R,S)-(Boc-methylamino)-1,2,4,5-tetrahydro-2-
benzazepine-3-one-2-yl] acetic acid benzyl ester 18a.
Purification by flash column (EtOAc–hexane 12:20). Yield:
49% (Calcd from 14); HPLC (grad. 1) tret¼27.2 min; Rf
(hexane–EtOAc 1:1) 0.43. Accurate MS (ES) [MþH]þ
found 439.2252, calcd 439.2233; dH (CDCl3) 1.45 (9H, s,
tBu), 2.96–3.02 (4H, overlapping s with m, N-MeþHb),
Aldehyde 16 (242 mg, 0.60 mmol) was dissolved in dry
MeOH (12 mL), to which the amine (211 mg p-toluene
sulfonic acid salt of Gly-OBn, 108 mg hydrochloric acid salt
of Val-OMe, 0.624 mmol) was added. After adjusting the
pH to 6 with N-methylmorpholine, MgSO4 (50 mg, 20 wt%)
was added, as well as NaCNBH3 (94 mg, 1.49 mmol). When
the reaction was finished (2.5 h for Gly-OBn, overnight for
Val-OMe, monitored by HPLC), methanol was evaporated
and the residue was redissolved in EtOAc (50 mL). After
washing with 10% KHSO4 (3£20 mL), the organic layer
was dried (MgSO4), filtered and evaporated to yield crude
products 17a,b (80–90%).
3
3
0
0
3.38 (1H, pseudo t, Hb , J(Ha, Hb)< J(Ha, Hb )¼14.4 Hz),
0
4.15 (2H, m, Ha GlyþH1), 4.35 (1H, m, Ha Gly), 5.17
0
(3.5H, m, 0.5HaþH1 þCH2 Bn ester), 5.52 (0.5H, m,
0.5Ha), 7.04–7.45 (9H, M, Harom); dC (CDCl3) 28.35 (CH3
Boc), 31.07 (N-Me), 34.41 (CH2b), 50.37 (CH21), 53.54
(CH2 Gly), 54.44 and 56.05 (CHa), 66.96 (CH2 Bn ester),
80.14 (Cquat Boc), 126.51, 128.26, 128.53, 130.41 (CH
arom), 134.01, 135.25, 135.75 (Cquat arom), 155.56
(COOtBu), 168.92 (COOBn), 172.78 (N-CvO).
Compounds 17a,b (0.450 mmol) were dissolved in THF

K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4429
0
4.3.2. 2(S)-[4(R,S)-(Boc-methylamino)-1,2,4,5-tetra-
hydro-2-benzazepine-3-one-2-yl]-3-methyl-butyric acid
methyl ester 18b. Purification by flash column (EtOAc–
hexane 10:45); yield: 45% (Calcd from 14); HPLC (grad. 1)
tret¼26.5 and 26.8 min; Rf (hexane–EtOAc 1:1) 0.53.
Accurate MS (ES) [MþH]þ found 405.2386, calcd
acidþHb ), 3.60 (3H, s, COOMe), 4.03 (1H, m, H1), 4.80
0
(1H, m, H1 ), 5.06–5.47 (1H, 2 m, Ha), 7.08–7.62 (4H, M,
Harom); dC (CDCl3) 21.89 (CH2), 27.39 (CH2), 28.30 (CH3
Boc), 31.12 (N-Me), 33.37 (CH2), 34.13 (CH2b), 47.75
(CH21), 51.31 (CH3 ester), 52.03 (CH2), 53.88 and 55.46
(CHa), 79.92 (Cquat Boc), 126.38, 127.93, 128.29, 130.47
(CH arom), 134.48, 135.57 (Cquat arom), 156.31 (COOtBu),
172.17 (COOMe), 173.65 (N–CvO).
3
405.2389; dH (CDCl3) 0.92 (3H, d, CH3 Val, J¼6.7 Hz),
0
3
1.01 (3H, d, CH3 Val, J¼6.4 Hz), 1.47 (9H, s, tBu), 2.32
(1H, m, HbVal), 3.18 and 3.35 (7H, 2 s, N-MeþMe
esterþHb), 3.41 (1H, pseudo t, Hb , 3J(Ha, Hb)< J(Ha,
4.3.6. 2(S)-[4(R,S)-(Boc-methylamino)-1,2,4,5-tetra-
hydro-2-benzazepine-3-one-2-yl]-3-phenylpropionic
acid benzyl ester 18f. Purification by flash column
(EtOAc–hexane 1:2). Yield: 45% (Calcd from 14); HPLC
(grad. 1) tret¼31.4 and 31.8 min; Rf (hexane–EtOAc 1:1)
0.53. Accurate MS (ES) [MþH]þ found 529.2696, calcd
529.2702; dH (CDCl3) 1.45 (9H, broad singlet, tBu), 2.05–
5.65 (13H, M, 2 singlets at 2.82 and 2.96 ppm), 6.70–7.40
(14H, M, Harom); dC (CDCl3) 28.27 (CH3 Boc), 30.54
(N-Me), 34.17 (CH2b), 35.74–36.41 (CH2 Phe), 49.40
(CH21), 53.31 (CHa), 59.70 (CHa Phe) 66.5 (CH2 Bn
ester), 79.85 (Cquat Boc), 126.24–130.27 (CH arom),
133.59–136.65 (Cquat arom), 156.07 (COOtBu), 170.33
(COOBn), 172.57–173.10 (N–CvO).
3
0
2
0
0
Hb )¼14.8 Hz), 4.20 (1H, d, H1, J(H1, H1 )¼16.7 Hz), 4.90
0
(2H, M, H1 þHa Val), 5.45–5.74 (1H, 2 m, Ha), 7.02–7.27
0
(4H, M, Harom); dC (CDCl3) 18.65 (CH3 Val), 19.52 (CH3
Val), 27.12 (CHbVal), 28.32 (CH3 Boc), 30.21 (N-Me),
34.08 (CH2b), 47.06 (CH21), 51.26 (CH3 ester), 53.06
and 54.18 (CHa), 60.95 (CHa Val), 79.97 (Cquat Boc),
126.06, 127.78, 129.21, 130.37 (CH arom), 133.33, 135.24
(Cquat arom), 156.33 (COOtBu), 170.80 (COOMe), 173.31
(N–CvO).
4.3.3. 4(R,S)-(Boc-methylamino)-2-isopropyl-1,2,4,5-
tetrahydro-2-benzazepine-3-one 18c. Purification by
preparative HPLC; yield: 42% (Calcd from 14); HPLC
(grad. 1) tret¼24.2 min; Rf (hexane–EtOAc 1:1) 0.33.
Accurate MS (ES) [MþH]þ found 333.2180, calcd
4.3.7. (R,S)-Phth-ortho-cyano-Phe 25. (R,S)-ortho-cyano-
phenylalanine hydrochloride 24 (3 g, 13.2 mmol) was
dissolved in CH3CN–H2O (20:12, 120 mL), to which
NEt3 was added (4.61 mL, 35 mmol) as well as N-
carbethoxyphthalimide (3.92 g, 17.9 mmol). After 1 h
stirring (rt) the acetonitrile was removed in vacuo and
satd. NaHCO3 (100 mL) was added. The aqueous layer was
washed with EtOAc (3£50 mL), acidified with 1N HCl (pH
2) and extracted with EtOAc (3£100 mL). The organic layer
was dried (MgSO4), filtered and evaporated to yield a white
powder which was recrystallised from EtOH–hexane
(3.27 g, 77%, white needles). Mp 198.8–200.78C; HPLC
(grad. 2) tret¼19.9 min; Rf (EtOAc–EBAW 15:1 (EBAW¼
EtOAc–nBuOH–AcOH–H2O 1:1:1:1)) 0.46; MS 275
(10%), 321 (15%), 343 (100%), 359 (20%), 663 (30%),
3
333.2178; dH (CDCl3) 0.99 (3H, d, CH3 iPr, J¼6.6 Hz),
0
3
1.19 (3H, d, CH3 iPr, J¼6.6 Hz), 1.47 (9H, s, tBu), 3.06
0
(4H, s with broad base, N-MeþHb), 3.41 (1H, pseudo t, Hb ,
3
3
2
0
J(Ha, Hb)< J(Ha, Hb )¼14.1 Hz), 4.09 (1H, d, H1, J(H1,
0
0
H1 )¼16.9 Hz), 4.90 (2H, M, H1 þCH iPr), 5.20–5.60 (1H,
2 m, Ha), 7.12–7.27 (40H, M, Harom); dC (CDCl3) 19.92
(CH3 iPr), 20.55 (CH3 iPr), 28.39 (CH3 Boc), 31.09
(N-Me), 34.34 (CH2b), 45.10 (CH21þCH iPr), 53.68 and
55.19 (CHa), 79.96 (Cquat Boc), 126.46, 127.47, 128.24,
130.54 (CH arom), 135.22, 135.75 (Cquat arom), 156.35
(COOtBu), 173.31 (N–CvO).
4.3.4. 4(R,S)-(Boc-methylamino)-2-cyclohexyl-1,2,4,5-
tetrahydro-2-benzazepine-3-one 18d. Purification by
preparative HPLC; yield: 47% (Calcd from 14); HPLC
(grad. 1) tret¼28.2 min; Rf (hexane–EtOAc 1:1) 0.47.
Accurate MS (ES) [MþH]þ found 373.2487, calcd
373.2491; dH (CDCl3) 0.94–1.81 (19H, M overlapping
with s at 1.44 ppm, 5 CH2 cyclohexylþtBu), 3.02 (4H,
679 (5%); dH (CD3OD) 3.65 (1H, dd, Hb, 2J(Hb,
3
0
0
Hb )¼14.4 Hz, J(Ha, Hb)¼11.4 Hz), 3.81 (1H, dd, Hb ,
2
3
0
0
J(Hb, Hb )¼14.4 Hz, J(Ha, Hb )¼4.6 Hz), 5.20 (1H, dd,
3
3
0
Ha, J(Ha, Hb)¼11.4 Hz, J(Ha, Hb )¼4.6 Hz), 7.28–7.99
(8H, M, Harom); dC (CD3OD) 34.60 (CH2b), 53.37 (CHa),
113.82 (CquatCN), 118.49 (CN), 124.42, 128.68, 131.21,
134.10, 134.25 and 135.75 (CH arom), 132.72 (Cquat arom
Phth), 142.55 (CquatCH2b), 168.72 (CO), 171.24 (CO).
broad s, N-MeþHb), 3.37 (1H, pseudo t, Hb , 3J(Ha,
0
3
Hb)< J(Ha, Hb )¼14.8 Hz), 4.09 (1H, d, H1, 2J(H1,
0
0
H1 )¼17.0 Hz), 4.41 (1H, m, CH cyclohexyl), 4.71 (1H,
0
m, H1 ), 5.23–5.58 (1H, 2 m, Ha), 7.08–7.30 (4H, M,
Harom); dC (CDCl3) 25.45 (CH2), 25.63 (CH2), 28.34 (CH3
Boc), 30.23 and 31.15 (2 CH2þN-Me), 34.22 (CH2b), 46.08
(CH21), 53.74 and 55.00 (CH cyclohexylþCHa), 80.40
(Cquat Boc), 126.45, 127.75, 128.27, 130.51 (CH arom),
135.09, 135.59 (Cquat arom), 156.41 (COOtBu), 172.47
(N–CvO).
4.3.8. (R,S)-Phth-ortho-formyl-Phe 26. The product was
prepared from 25 using the same procedure as described for
14. The reaction time was 38 h. A white sticky foam was
obtained (78%); HPLC (grad. 2) tret¼19.7 min; Rf (EtOAc–
EBAW (EBAW¼EtOAc–nBuOH–AcOH–H2O 1:1:1:1)
15:1) 0.42; MS 278 (90%), 324 (85%), 349 (100%), 362
2
0
(20%); dH (CDCl3) 3.65 (1H, dd, Hb, J(Hb, Hb )¼13.6 Hz,
3J(Ha, Hb)¼11.3 Hz), 4.24 (1H, dd, Hb , 2J(Hb,
0
4.3.5. 5-[4(R,S)-(Boc-methylamino)-1,2,4,5-tetrahydro-
2-benzazepine-3-one-2-yl] pentanoic acid methyl ester
18e. Purification by preparative HPLC. Yield: 27% (Calcd
from 14); HPLC (grad. 1) tret¼23.9 min; Rf (hexane–EtOAc
1:1) 0.27. Accurate MS (ES) [MþH]þ found 405.2390,
calcd 405.2389; dH (CDCl3) 1.09–1.73 (13H, M, 2 CH2
pentanoic acidþtBu), 2.23 (2H, m, CH2CO pentanoic acid),
3.01 (4H, M, N-MeþHb), 3.37 (3H, M, NCH2 pentanoic
3
0
0
Hb )¼13.6 Hz, J(Ha, Hb )¼4.7 Hz), 5.43 (1H, dd, Ha,
3
3
0
J(Ha, Hb)¼11.1 Hz, J(Ha, Hb )¼4.7 Hz), 7.01–8.07 (8H,
M, Harom), 10.15 (1H, s, H aldehyde); dC (CDCl3) 32.58
(CH2b), 51.75 (CHa), 123.50, 127.77, 132.08, 133.66,
134.13 and 135.27 (CH arom), 131.42 (Cquat arom), 138.55
(CquatCH2b), 167.33 (CO), 173.66 (CO), 193.44 (CH
aldehyde).

4430
K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4.3.9. [4(R,S)-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-
1,2,4,5-tetrahydro-2-benzazepine-3-one-2-yl] acetic
acid benzyl ester 27a. The procedure used for benzaze-
pinones 18 was applied, starting from aldehyde 26.
Purification by flash column (EtOAc–hexane 12:20).
Yield: 44% (Calcd from 26); HPLC (grad. 1) tret¼27.0
min; Rf (hexane–EtOAc 1:2) 0.49; MS 455 (50%), 477
(100%), 493 (90%), 931 (70%), 947 (20%); dH (CDCl3)
4.4. General procedure for the synthesis of N-Fmoc
protected aminoaldehydes
Synthesis of the Weinreb amides. To a solution of a N-Fmoc-
amino acid (10.32 mmol) in CH2Cl2 (160 mL), Et3N
(1.04 g, 10.32 mmol) and TBTU (3.98 g, 12.39 mmol)
were added. After 5 min N,O-dimethylhydroxylamine
hydrochloride (1.1 g, 11.36 mmol) and Et3N (3.12 g,
30.94 mmol) were added and the reaction mixture was
stirred at room temperature for 2 h. If necessary the pH was
adjusted to 8 with Et3N. When the reaction was complete
the mixture was diluted with CH2Cl2 (100 mL) and
extracted with 1N HCl (3£80 mL), saturated NaHCO3
(4£100 mL) and brine (3£50 mL). The organic layer was
dried (MgSO4), filtered and evaporated. The resulting
Weinreb amide was purified by column chromatography
(EtOAc–cyclohexane 2:1).
2
3.12 (1H, dd, Hb,
J(Hb, Hb )¼15.8 Hz, 3J(Ha,
0
0
0
Hb)¼4.3 Hz), 4.24 (2H, M, Hb þH1), 4.43 (1H, d, H1 ,
J(H1, H1 )¼17.3 Hz), 4.59 (1H, d, Ha Gly, 2J(Ha,
2
0
Ha )¼16.1 Hz), 4.85 (1H, d, Ha Gly, 2J(Ha,
0
0
0
Ha )¼16.1 Hz), 5.15 (2H, s, CH2 Bn ester), 5.44 (1H,
3
3
0
dd, Ha, J(Ha, Hb)¼4.4 Hz, J(Ha, Hb )¼13.0 Hz), 7.11–
8.20 (13H, M, Harom); dC (CDCl3) 34.20 (CH2b), 51.0
(CH21), 51.73 (CHa), 53.36 (CH2 Gly), 67.0 (CH2 Bn
ester), 123.48, 126.98, 128.25, 128.53, 129.98, 134.04
(CH arom), 132.0, 134.67, 135.25, 135.88 (Cquat arom),
167.77, 168.69, 169.37 (CO).
Reduction to the aldehydes. To a solution of the Weinreb
amide (4.30 mmol) in dry Et2O, LiAlH4 (0.245 g,
6.45 mmol) was added at 08C over 15 min. Then the ice
bath was removed and the reaction was stirred for 30 min.
EtOAc (100 mL) and 10% KHSO4 (100 mL) were added
and the two phases were separated. The aqueous phase was
washed with Et2O (100 mL), and the combined organic
layers were extracted with 1N HCl (3£100 mL), saturated
NaHCO3 (3£100 mL) and brine (3£50 mL). The organic
layer was dried (MgSO4), filtered and evaporated. No
further purification was performed.
4.3.10. 2(S)-[4(R)-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-
1,2,4,5-tetrahydro-2-benzazepine-3-one-2-yl] propionic
acid benzyl ester 27c. The procedure used for benza-
zepinones 18 was applied, starting from aldehyde 26.
Purification by flash column (EtOAc–hexane 12:20),
followed by prep. HPLC. Yield: 49% (Calcd from 26);
HPLC (grad. 1) tret¼26.37 min (1.5% (R,R) diastereomer)
and 26.66 min; Rf (hexane–EtOAc 1:2) 0.36; MS 361
(80%), 469 (100%), 491 (55%), 507 (15%); dH (CDCl3)
1.43 (3H, d, CH3 Ala, 3J¼7.3 Hz), 3.17 (1H, dd, Hb,2J(Hb,
3
0
0
Hb )¼16.2 Hz, J(Ha, Hb)¼4.2 Hz), 4.26 (1H, dd, Hb ,
4.5. General procedure for the synthesis of benzazepines
11
2
3
0
0
J(Hb, Hb )¼16.1 Hz, J(Ha, Hb )¼13.3 Hz), 4.37 (1H, d,
H1, J(H1, H1 )¼16.4 Hz), 4.81 (1H, d, H1 , 2J(H1,
2
0
0
0
H1 )¼16.4 Hz), 5.14 (2H, s, CH2 Bn ester), 5.40 (1H,
(R,S)-Boc-ortho-aminomethyl phenylalanine 9 (0.5 g,
1.70 mmol) was dissolved in 1,2-dichloroethane (50 mL)
and the aldehyde (0.122 g, 1.70 mmol), Et3N (0.172 g,
1.70 mmol), Na(OAc)3BH (0.505 g, 2.38 mmol) and
MgSO4 (30 wt%) were added. The reaction was stirred at
room temperature. RP-HPLC indicated reaction times
between 2 and 4 h. The mixture was quenched with
saturated NaHCO3 (50 mL) and extracted with EtOAc
(3£70 mL). The organic layer was dried (MgSO4), filtered
and evaporated. The obtained products 10 were used
without further purification.
q, Ha Ala, 3J¼7.3 Hz), 5.58 (1H, dd, Ha benzazepine,
3J(Ha, Hb)¼4.4 Hz, J(Ha, Hb )¼13.2 Hz), 7.11–7.89
3
0
(13H, M, Harom); dC (CDCl3) 15.68 (CH3 Ala), 34.50
(CH2b), 48.65 (CH21), 51.96 (CHa benzazepine), 53.96
(CHa Ala), 67.92 (CH2 Bn ester), 123.91, 127.36, 128.48,
128.70, 128.76, 128.99, 130.50, 134.50 (CH arom), 132.42,
135.20, 135.84, 136.42 (Cquat arom), 168.35, 169.84, 171.90
(CO).
4.3.11. (R,S)-Boc-ortho-aminomethyl-Phe 9. (R,S)-Boc-
ortho-cyano-Phe 7 (2.00 g, 6.89 mmol) was dissolved in
EtOH–H2O (3:1, 70 mL), to which a 0.1M AcOH
solution (2 mL) was added, as well as 10% Pd on C
(0.4 g, 20 wt%). After hydrogenation in a Parr apparatus
(50 psi, rt, 4 h), the reaction mixture was filtered over
dicalite and rinsed with EtOH. The filtrate was evaporated
and the residue was crystallised from EtOH (1.93 g, 95%,
white crystals). Mp 165.5–166.38C; HPLC (grad. 2)
tret¼14.7 min; Rf (CH3CN–CH3OH–H2O 4:1:1) 0.58; MS
A 17 mM solution of product 10 in CH2Cl2 (puriss. p.a.) was
prepared, to which TBTU (1 equiv.) and NMM (2.5 equiv.)
were added. The reaction was stirred overnight at room
temperature, after which the reaction mixture was extracted
with saturated NaHCO3 (3£), 1N HCl (1£) and brine (1£).
The organic layer was dried (MgSO4), filtered and
evaporated. The benzazepines 11 were purified by flash
column chromatography.
178 (50%), 195 (15%), 239 (40%), 295 (100%); dH (D2O)
2
0
1.41 (9H, s, tBu), 3.06 (1H, dd, Hb, J(Hb, Hb )¼14.1 Hz,
4.5.1. 3-[4(R,S)-(Boc-amino)-1,2,4,5-tetrahydro-2-benza-
zepine-3-one-2-yl]-2(R)-Fmoc-amino-1-phenyl-propane
11a. Purification by flash column (Et2O–hexane 1:2, then
Et2O–CH2Cl2 2:1). Yield: 48.5% (white solid). Mp 106.4–
113.28C; HPLC (grad. 2) tret¼32.8 and 33.3 min; Rf
(hexane–EtOAc 1:2) 0.10; Rf (Et2O–CH2Cl2 1:1) 0.65.
Accurate MS (ES) [MþH]þ found 632.3136, calcd
632.3124; dH (CDCl3) 1.47 (9H, s, CH3 Boc), 2.70–2.72
(2H, m, 2Hb Phe), 2.82–2.88 (1H, m, Hb benzazepine),
3J(Ha, Hb)¼8.9 Hz), 3.34 (1H, dd, Hb , 2J(Hb,
0
3
0
0
Hb )¼14.4 Hz, J(Ha, Hb )¼5.5 Hz), 4.27 (1H, dd, Ha,
3J(Ha, Hb)¼8.4 Hz, J(Ha, Hb )¼5.9 Hz), 4.40 (2H, s,
3
0
CH2N), 7.31–7.51 (4H, M, Harom); dC (CD3OD) 28.69 (CH3
Boc), 37.36 (CH2b), 41.63 (CH2g), 58.26 (CHa), 80.46
(Cquat Boc), 128.30, 130.21, 131.44 and 132.87 (CH arom),
133.18 and 139.22 (Cquat arom), 157.45 (COOtBu), 178.06
(COOH).

K. Van Rompaey et al. / Tetrahedron 59 (2003) 4421–4432
4431
3.24–3.28 (1H, m, NCH), 3.32–3.41 (1H, m, Hb
benzazepine), 3.63–3.69 (1H, m, H1 benzazepine), 3.82–
3.90 (2H, M, NCH0þHa Phe), 4.02–4.09 (1H, m, CH
Fmoc), 4.17–4.24 (2H, m, CH2 Fmoc), 4.88 (1H, m, NH
6.05 (1H, d, NH, 3J¼5.9 Hz), 7.13–7.38 (4H, M, H arom.);
0
0
dC (CDCl3) 20.17 (CH3 iBu), 20.59 (CH3 iBu), 27.94 (CH
iBu), 28.86 (CH3 Boc), 37.82 (Cb), 49.85 (Ca), 53.18 (C1),
55.88 (CH2 iBu), 79.98 (CquatBoc), 126.52–131.37 (CH
arom.), 133.90þ136.35 (Cquatarom.), 155.61 (COOtBu),
172.14 (N–CvO).
0
Fmoc), 4.89–5.13 (2H, M, Ha benzazepineþH1 benza-
zepine), 6.04–6.07 (1H, d, NH Boc), 6.90–7.84 (17H, M,
CH arom.); dC (CDCl3) 28.4 (CH3 Boc), 37.12 (CH2b),
38.89 (CH2 Phe), 47.38 (CH Fmoc), 49.38 (CHa), 50.69
(CH21), 52.33 (CHa Phe), 53.00 (CH2), 66.25 (CH2 Fmoc),
79.73 (Cquat Boc), 119.96–130.75 (CH arom), 132.90–
143.98 (Cquat arom), 155.07 (COOFm), 155.33 (COOtBu),
173.05 (N–CvO).
4.5.5. 4-(Boc-amino)-2-benzyl-1,2,4,5-tetrahydro-2-
benzazepine-3-one 11e. Purification by crystalisation
(hexane–Et2O). Yield: 64%; white crystals. Mp 144.7–
144.98C; HPLC (grad. 2) tret¼28.6 min; Rf (EtOAc–hexane
1:2) 0.11; Rf (Et2O–CH2Cl2 1:1) 0.48. Accurate MS (ES)
[MþH]þ found 367.2025, calcd 367.2021, dH (CDCl3) 1.46
3
4.5.2. 1-[4(R,S)-(Boc-amino)-1,2,4,5-tetrahydro-2-benza-
zepine-3-one-2-yl]-2(S)-Fmoc-amino-4-methyl-pentane
11b. Purification by flash column (aceton–hexane 1:3).
Yield: 45%; white solid. Mp 101.5–102.58C; HPLC (grad.
2) tret¼33.5 and 33.8 min; Rf (EtOAc–hexane 1:2) 0.14; Rf
(Et2O–CH2Cl2 1:1) 0.53. Accurate MS (ES) [MþH]þ
found 598.3255, calcd 598.3281; dH (CDCl3) 0.86 (3H, m,
CH3 Leu), 1.41 (2H, m, CH2 Leu), 1.46 (9H, s, tBu), 1.73
(1H, m, CH Leu), 2.73–2.95 (1H, m, Hb), 3.20–3.40 (1H,
(9H, s, CH3 Boc), 2.96 (1H, dd, Hb, J(Ha, Hb)¼12.7 Hz,
2
J(Hb, Hb )¼17.1 Hz), 3.48 (1H, dd, Hb , 3J(Ha,
0
0
2
0
0
Hb )¼4.4 Hz,
J(Hb, Hb )¼16.7 Hz), 3.79 (1H, d,
H1b0 enzazepine
,
3J¼16.7 Hz), 4.25 0(1H, d, CHbenzyl
,
3J¼14.9 Hz), 4.97–5.03 (2H, M, H1benzazepineþCHbenzyl0),
5.21 (1H, dd, Ha, 3J(Ha, Hb)¼12.4 Hz, 3J(Ha,
Hb )¼4.3 Hz), 5.94 (1H, d, NH, 3J¼5.9 Hz), 6.81–7.51
0
(9H, M, Harom); dC (CDCl3) 28.36 (CH3 Boc), 37.36
(CH2b), 49.38 (CHa), 50.46 (CH21), 51.01 (CH2benzyl),
79.56 (Cquat Boc), 125.87–1310.80 (CH arom),
132.89þ135.81þ136.45 (Cquat arom), 155.08 (COOtBu),
171.76 (N–CvO).
0
m, Hb ), 3.44–3.47 (1H, m, H1), 3.71–3.74 (2H, m, CH2),
4.06 (1H, m, CH Fmoc), 4.09 (1H, m, Ha Leu), 4.31–4.34
(2H, m, CH2 Fmoc), 4.72–4.75 (1H, d, NH, J¼8.6 Hz),
0
5.02–5.09 (2H, M, HaþH1 ), 5.82–5.85 (1H, d, NH,
J¼5.9 Hz), 6.97–7.76 (12H, M, CH arom); dC (CDCl3)
28.38 (CH3 Boc), 37.14 (CH2b), 41.76 (CH2 Leu), 47.41
(CHa Leu), 48.32 (CH Fmoc), 49.36 (CHa), 51.74 (CH21),
53.06 (CH2), 66.48 (CH2 Fmoc), 79.64 (Cquat Boc), 120–
130 (CH arom), 155.06 (COOFm), 155.47 (COOtBu),
172.71 (N–CvO).
4.5.6. 3-[4(S)-(Boc-amino)-1,2,4,5-tetrahydro-2-benza-
zepine-3-one-2-yl]-2(S)-Fmoc-amino-1-phenyl-(4-tert-
butoxy)-propane 11f. Purification by flash column (Et2O–
hexane 1:2). Yield: 50% (white solid). Mp 119–1248C;
HPLC (grad. 2) tret¼34.4 (S,R) and 34.9 min (S,S); Rf
(Et2O–CH2Cl2 1:2) 0.65. Accurate MS (ES) [MþH]þ
found 704.3676, calcd 704.3699; dH (CDCl3) 1.31 (9H, s,
CH3 Boc), 1.47 (9H, s, (CH3)3OtBu), 2.67 (2H, m, 2Hb
Tyr), 2.83–2.89 (1H, m, Hb benzazepine), 3.20–3.28 (1H,
4.5.3. 3-[4(R,S)-(Boc-amino)-1,2,4,5-tetrahydro-2-benza-
zepine-3-one-2-yl]-2(S)-Fmoc-amino-1-(indol-3-yl)-pro-
pane 11c. Purification by flash column (acetone–hexane
1:1). Yield: 49%; pale yellow solid. Mp 112.3–113.28C;
HPLC (grad. 2) tret¼34.3 and 34.8 min; Rf (EtOAc–hexane
1:2) 0.06; Rf (Et2O–CH2Cl2 1:1) 0.39. Accurate MS (ES)
[MþH]þ found 671.3202, calcd 671.3233; Due to the
presence of two diastereomers not all the signals could be
assigned: dH (CDCl3) 1.48 (9H, s, CH3 Boc), 2.89 (3H),
3.32–3.59 (3H), 3.82–3.88 (1H), 4.03–4.26 (4H), 4.94–
5.16 (2H), 5.83–5.91 (1H, NH), 6.83–7.75 (17H, M, CH
arom), 8.20–8.24 (1H, NH indole); dC (CDCl3) 28.38 (CH3
Boc), 37.05 (CH2b), 47.20 (CH Fmoc), 49.37 (CHa), 50.66
(CH2 Trp), 51.01 (CH21), 51.60 (CHa Trp), 52.74 (CH2),
66.34 (CH2 Fmoc), 79.74 (Cquat Boc), 110.80 (CH arom),
118.60–130.87 (CH arom), 132.96–143.95 (Cquat arom),
155.01 (COOFm), 156.17 (COOtBu), 173.02 (N–CvO).
0
m, NCH2), 3.33–3.42 (1H, m, Hb benzazepine), 3.62–3.69
(1H, m, H1 benzazepine), 3.86–3.89 (1H, m, Ha Tyr),
4.03–4.10 (1H, m, CH Fmoc), 4.20–4.24 (2H, m, CH2
Fmoc), 4.89–4.91 (1H, m, NH Fmoc), 5.03–5.15 (2H, M,
0
Ha benzazepineþH1 benzazepine), 5.81–6.84 (1H, m, NH
Boc), 6.87–8.04 (16H, M, CH arom.); dC (CDCl3) 28.4
(CH3 Boc),28.8 ((CH3)3OtBu), 37.11 (CH2b), 38.16 (CH2
Tyr), 47.28 (CH Fmoc), 49.39 (CHa), 50.71 (CHa Tyr),
52.33 (CH21), 53.04 (CH2), 66.25 (CH2 Fmoc), 79.72 (Cquat
BocþCquat OtBu), 125.94–130.85 (CH arom), 132.85–
136.41 (Cquat arom), 152.57 (COOFmocþCOOtBu), 155.16
(Cquat arom next to OtBu), 171.89 (N–CvO).
Acknowledgements
4.5.4. 4(R,S)-(Boc-amino)-2-isobutyl-1,2,4,5-tetrahydro-
2-benzazepine-3-one 11d. Purification by flash column
(EtOAc–hexane 1:2). Yield: 48%; white solid. Mp 126.1–
126.88C; HPLC (grad. 2) tret¼27.6 min; Rf (EtOAc–hexane
1:2) 0.29; Rf (Et2O–CH2Cl2 1:1) 0.64. Accurate MS (ES)
[MþH]þ found 333.2187, calcd 333.2178; dH (CDCl3) 0.85
K. Van Rompaey is a Research Assistant of the Fund
for Scientific Research-Flanders (Belgium) (F.W.O.-
Vlaanderen), which the authors thank for financial support.
0
(3H, d, CH3 iBu, 3J¼6.6 Hz), 0.96 (3H, d, CH3 iBu,
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