Syn-selective Michael addition of amines to bis-enones: Synthesis of 1,3,4,7-tetrasubstituted (4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-2H-1,3- diazepin-2-ones

Article abstract of DOI:10.1021/jo970384k

O-Protected 1,3,4,7-tetrasubstituted (4R,5S,6S,7R)-hexahydro-5,6- dihydroxy-2H-1,3-diazepin-2-ones 7a-d are seven-membered cyclic ureas useful as intermediates in the synthesis of HIV-proteinase inhibitors. We succeeded in preparing them using a three-step sequence starting from diethyl isopropylidene-L-tartrate 1. In a one-pot reaction 1 was transformed via an in situ generated aldehyde and subsequent Wittig reaction into the bis- enones 2a,b. Treatment with excess of primary amines resulted in a two-fold syn-selective Michael addition at low temperature that generated predominantly the C₂-symmetric 1,4-bis(aminoalkyl) derivatives 3a-d. Here we investigated the influence of reaction temperature and configuration of the starting bis-olefin on stereoselectivity. The cyclic ureas 6a-d were formed by treatment of 3a-d with phosgene at elevated temperature. We succeeded in extending this approach to asymmetric substituted cyclic ureas by controlled monoaddition of benzylamine to 2a, providing the monoaddition product 5a in good yields. Finally, conjugate addition of a second amine to 5a followed by cyclization gave the pseudo-C₂-symmetric cyclic urea 9.

Full text of DOI:10.1021/jo970384k

5380
J . Org. Chem. 1997, 62, 5380-5384
Syn -Selective Mich a el Ad d ition of Am in es to Bis-En on es:
Syn th esis of 1,3,4,7-Tetr a su bstitu ted
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-2H-1,3-d ia zep in -2-on es†
Erwin P. Schreiner* and Arno Pruckner
NOVARTIS Forschungsinstitut, Brunner Strasse 59, A-1235 Vienna, Austria
Received February 28, 1997X
O-Protected 1,3,4,7-tetrasubstituted (4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-2H-1,3-diazepin-2-ones
7a -d are seven-membered cyclic ureas useful as intermediates in the synthesis of HIV-proteinase
inhibitors. We succeeded in preparing them using a three-step sequence starting from diethyl
isopropylidene-L-tartrate 1. In a one-pot reaction 1 was transformed via an in situ generated
aldehyde and subsequent Wittig reaction into the bis-enones 2a ,b. Treatment with excess of primary
amines resulted in a two-fold syn-selective Michael addition at low temperature that generated
predominantly the C2-symmetric 1,4-bis(aminoalkyl) derivatives 3a -d . Here we investigated the
influence of reaction temperature and configuration of the starting bis-olefin on stereoselectivity.
The cyclic ureas 6a -d were formed by treatment of 3a -d with phosgene at elevated temperature.
We succeeded in extending this approach to asymmetric substituted cyclic ureas by controlled
monoaddition of benzylamine to 2a , providing the monoaddition product 5a in good yields. Finally,
conjugate addition of a second amine to 5a followed by cyclization gave the pseudo-C2-symmetric
cyclic urea 9.
In tr od u ction
The HIV proteinase, which exists as a C2-symmetric
homodimer, is a key enzyme in the life cycle of the human
immunodeficiency virus. Thus, the inhibition of this
proteinase is an attractive target with potential useful-
ness for the chemotherapy of the acquired immune
deficiency syndrome (AIDS). Identification of 1,3-diaz-
epan-2-ones, cyclic ureas with RSSR-configuration, as
potent nonpeptidyl inhibitors of HIV-1 proteinase by Du
Pont Merck researchers1 was an important finding in the
search for such proteinase inhibitors. Several synthetic
routes toward these cyclic ureas have been reported.2a-c
Since proteinase inhibitors only suppress the replica-
tion of the HIV virus, they would have to be administered
every day over a lifetime. Therefore, we aimed at
development of inexpensive molecules accessible by short
synthetic routes. The possibility of simultaneous manipu-
lation at two sites of the molecule makes the construction
of C2-symmetric compounds very economical. For this
reason, as well as the good availability of both enanti-
omers, we focused on tartaric acid derivatives as starting
materials for preparation of C2-symmetric HIV-1 pro-
teinase inhibitors. Retrosynthetic analysis revealed that
such functionalized cyclic ureas with RSSR-configuration
should be available by two-fold syn-selective Michael
addition of amines to a bis-enone3 derived from 1, fol-
lowed by cyclization and hydrolysis of the dioxolane ring.
F igu r e 1.
It has been reported that Michael addition of 1 equiv
of benzylamine to 2a at room temperature in ethanol
gives a mixture of syn and anti addition products with a
ratio of 1:3.6.4 However, high syn-selectivity for Michael
addition of benzylamine at low temperature under neat
conditions,5 as well as for conjugate addition of lithium
enolates6 and nitromethane7 to ethyl (E)- and (Z)-(4S)-
4,5-isopropylidene-4,5-dihydroxypentenoate is known to
occur. This behavior can be rationalized using the
modified Felkin-type model A (Figure 1) with the hydro-
gen atom in the inside position, which minimizes the 1,3-
allylic strain with the carboalkoxy group in the Z-isomer.
This situation can be achieved for at least one enone
system in conformations 2A and 2B without any ad-
ditional repulsive interactions and should predict high
syn-selectivity for Michael addition of amines to the
tartaric acid derivatives 2a ,b.
† This paper is dedicated to Professor Dieter Seebach on the occasion
of his 60th birthday.
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) Lam, P. Y. S.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.; Ru,
Y.; Bacheler, L. T.; Meek, J . L.; Otto, M. J .; Rayner, M. M.; Wong, Y.
N.; Chang, C-H.; Weber, P. C.; J ackson, D. A.; Sharpe, T. R.; Erickson-
Viitanen, S. Science 1994, 263, 380-384.
(3) Krief, A.; Dumont, W.; Pasau, P.; Lecomte, P. Tetrahedron 1989,
45, 3039-3052.
(2) (a) Nugiel, D. A.; J acobs, K.; Worley, T.; Patel, M.; Kaltenbach
III R. F.; Meyer, D. T.; J adhav, P. K.; De Lucca, G. V.; Smyser, T. E.;
Klabe, R. M.; Bacheler, L. T.;Rayner, M. M.; Seitz, S. P. J . Med. Chem.
1996, 39, 2156-2169; b) Pierce, M. E.; Harris, G. D.; Islam, Q.;
Radesca, L. A.; Storace, L.; Waltermire, R. E.; Wat, E.; J adhav, P. K.;
Emmett, G. C. J . Org. Chem. 1996, 61, 444-450; c) Rossano, L. T.;
Lo, Y. S.; Anzalone, L.; Lee, Y-C; Meloni, D. J .; Moore, J . R.; Gale, T.
M. Arnett, J . F. Tetrahedron Lett. 1995, 36, 4967-4970.
(4) Saito, S.; Narahara, O.; Ishikawa, T.; Asahara, M.; Moriwake,
T. J . Org. Chem. 1993, 58, 6292-6302.
(5) Matsunaga, H.; Sakamaki, T.; Nagaoka, H.; Yamada, Y. Tetra-
hedron Lett. 1983, 24, 3009-3012.
(6) Nagaoka, H.; Shibuya, K.; Kobayashi, K.; Miura, I.; Yamada, Y.
Tetrahedron Lett. 1993, 34, 4039-4042.
(7) Patrocinio, V. L.; Costa, P. R. R.; Correia, C. R. D. Synthesis 1994,
474-476.
S0022-3263(97)00384-8 CCC: $14.00 © 1997 American Chemical Society

Syn-Selective Michael Addition of Amines to Bis-Enones
J . Org. Chem., Vol. 62, No. 16, 1997 5381
Ta ble 1. Mich a el Ad d ition of Am in es to E,E-, E,Z-, a n d /or Z,Z-Olefin s
entry
olefin
E
R
equiv of amine
temp, °C
time, d
yield (%)a
ratiob3/4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a EE
2a EZ
2a ZZ
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
Ph
Ph
Ph
Ph
Ph
Ph
Ph
c-Pr
Ph
c-Pr
Ph
Ph
Ph
Ph
8
8
8
8
8
8
8
8
8
8
3
3
3
3
-50
-50
-50
-50
-25
0
28
28
28
28
7
2
1
7
7
3a , 71; 5a , 18
3a , 81; 5a , 2
3a , 83; 5a , 5
3a , 81; 5a , 4
3a , 80
3a , 70
3a , 61
3b, 84
3c, 75; 5c, 16
3d , 86
5
7
11
9
5
3
2a mixc
2a mixc
2a mixc
2a mixc
2a mixc
2b mixd
2b mixd
2a EZ
22
2
9
-25
-25
-25
-50
-50
-50
-25
15
18
6
10
10
6
CN
7
CO2Et
CO2Et
CO2Et
CO2Et
28
28
28
4
3a , 14; 5a , 79
3a , 26; 5a , 63
3a , 15; 5a , 72
3a , 17; 5a , 68
2a ZZ
2a mixc
2a mixc
a
b
Isolated yield. determined by 1H NMR spectroscopy. c Mixture of the E,E-, E,Z-, and Z,Z-isomers of 2a (E,E:E,Z:Z,Z ) 3:32:65).
d
Mixture of the E,E-, E,Z-, and Z,Z-isomers of 2b (E,E:E,Z:Z,Z ) 10:62:28).
Sch em e 1
F igu r e 2. X-ray crystal structure of 7d .
tion temperature (see ref 5) we also observed a clear effect
of the configuration of the starting olefin: upon treatment
with benzylamine at -50 °C, the best diastereoselectivity
was obtained for (Z,Z)-2a (11:1) followed by (E,Z)-2a (7:
1) and (E,E)-2a (5:1). A conformation with the allylic
hydrogen atom in the inside position is stabilized much
more for a Z-olefin, minimizing the 1,3-allylic strain with
the carboalkoxy group, than for the corresponding E-
olefin. Therefore, this finding supports the proposed
modified Felkin-type model A.
Resu lts a n d Discu ssion
Since a reaction temperature of -50 °C for a period of
28 days is an inacceptable protocol, we performed Michael
addition by simple storage of the reaction mixtures in
the freezer at a temperature of -30 to -25 °C for one
week, to obtain the diamines 3a -d on a multigram scale.
The cyclic ureas 6a -d 9 were synthesized in 62-68% yield
by simultaneous addition of 3a -d and phosgene or
diphosgene to a solution of N-methylmorpholine in THF
at 50 °C. Finally, the free diols 7a -d were obtained from
6a -d by treatment with trifluoroacetic acid in ethanol.
The stereochemical assignment was confirmed by an
X-ray structure analysis of 7d (Figure 2).
The realization of our concept started with Wittig
olefination of the in situ generated dialdehyde by treat-
ment with ylides in a one-pot reaction according to the
protocol of Krief et al.3 The bis-enones 2a ,b were
produced as mixtures of their E,E-, E,Z-, and Z,Z-
stereoisomers in 91% (2a ) and 75% (2b) yield (Scheme
1). Treatment of these mixtures of isomers with 8 equiv
of primary amines under neat conditions8 produced, as
expected, predominantly the desired C2-symmetric 1,4-
diaminoalkyl derivatives 3a -d along with the asym-
metric stereoisomers 4a -d and, occasionally, some
monoaddition products 5a ,c (Table 1). In addition to an
increase of the diastereoselectivity with decreasing reac-
In order to expand this approach toward pseudo-C2-
symmetrical N-substituted cyclic ureas we also aimed at
(8) Reduction of viscosity of the reaction mixture to allow magneti-
cally stirring at -50 °C was achieved by addition of low amounts of
dichloromethane.
(9) 6a ,b were the starting materials for
protease inhibitors by transformation of the ester group.
a multitude of HIV-1

5382 J . Org. Chem., Vol. 62, No. 16, 1997
Schreiner and Pruckner
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ. UK.
Sch em e 2
Gen er a l P r oced u r e for Mich a el Ad d ition of Am in es.
A mixture of the bis-enones 2a ,b (5.0 mmol) and CH2Cl2 (0.5
mL) was cooled to -30 °C, and the amine (40 mmol) was slowly
added. Then the reaction mixture was stored at -30 to -25
°C for 7 d. To remove excessive amine, the solution was
diluted with Et2O/cyclohexane (1:3, 20 mL) and filtered over
silica gel (30 g) with a gradient (30-70% Et2O). For prepara-
tion of the cyclic ureas we used 3a -d (about 90-95% pure
material) without further purification. Pure 3a -d were
obtained by column chromatography with the same solvent
system.
Gen er a l P r oced u r e for F or m a tion of th e Cyclic Ur ea s.
To a solution of N-methylmorpholine (0.85 mL, 7.75 mmol) in
dry THF (100 mL) were added the amines 3a -d , 8 (3 mmol)
in THF (5 mL), and phosgene (1.93 M in toluene, 1.67 mL)
simultanously by two syringe pumps within 24 h at 50 °C.
After additional 6 h at 50 °C N-methylmorpholine (0.85 mL)
and water (1.2 mL) were added, and the mixture was stirred
for 2 h. Finally, cyclohexane (100 mL) was added, the
precipitate formed was removed by filtration, and the solvent
was evaporated. Chromatography on silica gel with Et2O/
cyclohexane (1:2) gave the pure cyclic ureas 6a -d and 9.
Gen er a l P r oced u r e for Clea va ge of th e Isop r op yl-
id en e P r otectin g Gr ou p . 6a -d (0.1 mmol) was dissolved
in ethanol (2.0 mL) and treated with TFA (0.1 mL) at rt until
no starting material was observed on TLC. After evaporation
of the solvent, the residue was redissolved in EtOAc (10 mL)
and extracted with saturated NaHCO3 solution (2 mL). The
solvent was evaporated and the residue obtained purified by
chromatography on silica gel with EtOAc.
syn-selective monoaddition of amines to the bis-enone 2a
(Scheme 2). This was achieved by treatment of 2a with
3 equivs of benzylamine at -50 °C. The E,Z-isomer gave
a better yield (79%) than the Z,Z-isomer (63%). Subse-
quent reaction of the enone system in 5a with (amino-
methyl)cyclopropane gave the asymmetric substituted
bis(aminoalkyl) derivative 8 (82%), which was trans-
formed into the cyclic urea 9 by means of phosgene (67%).
Comparison of the 1H NMR data revealed that 5a is
identical with the major isomer assigned as the anti
isomer in ref 4. To verify that 5a is indeed the syn-
product we treated it with benzylamine and again
obtained 3a (93%). This also strongly suggests that 1
equiv of benzylamine reacts with 2a by syn-addition and
not by predominant formation of the anti-product as
reported in ref 4. The structure determination via bi-
and tricyclic lactones in ref 4 can neither theoretically
nor experimentally be followed due to insufficient docu-
mentation (e.g. detailed conditions, yield and ratio of the
lactone derivatives). Due to absence of any stereochem-
ical notation of 5a in the whole manuscript, even a trivial
error in imaging cannot be excluded. Finally, missas-
signment could occur as result of Michael- and retro-
Michael reactions in course of the sequence toward these
lactones, starting from the unseparable mixture (3.6:1)
of 5a and the minor diastereomer.
(4S,5S)-1,6-Dicyan o-4,5-O-isopr opyliden eocta-2(Z),6(Z)-
d ien ed in itr ile ((ZZ)-2b) a n d (4S,5S)-4,5-O-Isop r op ylid en e-
octa -2E,6Z-d ien ed in itr ile ((EZ)-2b). The title compounds
were prepared according to the procedure described in refer-
ence 3. Instead of the Ph3PdCHCO2Et we used Ph3PdCHCN
in ethanol. A 6.48 g amount (30 mmol) of 1 gave 2.81 g (46%)
of (ZZ)-2b and 1.76 g (29%) of (EZ)-2b. (ZZ)-2b: mp 94 °C;
[R]20 +362.8° (CHCl3, c ) 1.15); 1H-NMR (250 MHz; CDCl3):
D
δ ) 6.55 (m, 2 H); 5.61 (d, J ) 11.2 Hz, 2 H); 4.67 (m, 2 H);
1.50 (s, 6 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 147.9, 114.3,
112.1, 103.8, 78.3, 26.5. Anal. Calcd for C11H12N2O2: C, 64.69;
H, 5.92; N, 13.72. Found: C, 64.48; H, 5.88; N, 13.76. (EZ)-
2b: [R]20 +96.3° (CHCl3, c ) 1.20); 1H-NMR (250 MHz;
D
CDCl3): δ ) 6.55 (dd, J ) 16.1 and 4.8 Hz, 1 H); 6.46 (dd, J )
11.2 and 8.2 Hz, 1 H); 5.78 (dd, J ) 16.1 and 1.7 Hz, 1 H);
5.62 (dd, J ) 11.2 and 1.0 Hz, 1 H); 4.63 (ddd, J ) 8.2, 8.2 and
1.0 Hz, 1 H); 4.30 (ddd, J ) 8.2, 4.8 and 1.7 Hz, 1 H); 1.48 (s,
3 H); 1.46 (s, 3 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 148.1,
147.8, 116.3, 114.5, 112.2, 103.9, 102.6, 79.4, 78.6, 26.8, 26.7.
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.56; H, 5.83; N, 13.64.
Con clu sion
A three-step synthesis of seven-membered C2-sym-
metric cyclic ureas, starting from diethyl isopropylidene-
L-tartrate 1 has been achieved. A two-fold high syn-
selective Michael addition of primary amines to bis-
enones 2a ,b, prepared from 1 by Wittig olefination, was
observed, and the dependence of stereoselectivity on
reaction temperature and configuration of the starting
olefin was investigated. Feasibility of controlled monoad-
dition of benzylamine to 2a followed by treatment with
a second amine was demonstrated thus expanding the
approach to pseudo-C2-symmetric cyclic ureas.
Diet h yl (2R,3S,4S,5R)-3,4-O-isop r op ylid en e-2,5-b is-
[(p h en ylm et h yl)a m in o]-1,6-h exa n ed ica r b oxyla t e (3a ):
1
[R]20 -31.5° (CHCl3, c ) 1.51); H-NMR (250 MHz; CDCl3):
D
δ ) 7.34-7.17 (m, 10 H); 4.16 (bs, 2 H); 4.12 (q, J ) 7.1 Hz, 4
H); 3.89 and 3.73 (AB, J ) 13.1Hz, 4 H); 3.19 (bt, J ) 6.4 Hz,
2 H); 2.56 (ABX, 4 H); 1.65 (bs, 2 H); 1.34 (s, 6 H); 1.24 (t, J )
7.1 Hz, 6 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 172.3, 140.6,
128.4, 128.2, 127.1, 79.1, 60.4, 54.7, 51.6, 36.9, 27.4, 14.4.
Anal. Calcd for C29H40N2O6: C, 67.95; H, 7.86; N, 5.46.
Found: C, 67.90; H, 7.76; N, 5.46.
Exp er im en ta l Section
Dieth yl (2R,3S,4S,5R)-2,5-bis[(cyclop r op ylm eth yl)a m i-
Solvents were reagent grade and used without further
purification. THF was distilled from potassium/benzophenone.
Analytical thin-layer chromatography was performed on 60
F254 glass plates (HPTLC, E. Merck). Preparative column
chromatography was performed on silica gel (50-63 µm). The
chemical shifts are given in units relative to TMS (0 ppm).
Elemental analyses were performed by the Analytical Depart-
ment, Novartis Basle, Switzerland.
n o]-3,4-O-isop r op ylid en e-1,6-h exa n ed ica r boxyla te (3b):
1
[R]20 -30.2° (CHCl3, c ) 1.11); H-NMR (250 MHz; CDCl3):
D
δ ) 4.12 (q, J ) 7.1 Hz, 4 H); 4.08 (dd, J ) 2.1 and 1.4 Hz, 2
H); 3.16 (dddd, J ) 6.0, 6.0, 2.1 and 1.4 Hz, 2 H); 2.30 (m, 8
H); 1.59 (bs, 2 H); 1.37 (s, 6 H); 1.24 (t, J ) 7.1 Hz, 6 H); 0.88
(m, 2 H); 0.43 (m, 4 H); 0.09 (m, 4 H). Anal. Calcd for
C23H40N2O6: C, 62.70; H, 9.15; N, 6.36. Found: C, 62.59; H,
9.04; N, 6.33.
X-r a y Cr ysta llogr a p h y. Crystals of 7d were obtained by
spontanous crystallization from EtOAc solution. Tables of
crystallographic parameters, atomic coordinates, and bond
distances and angles are available from the authors, or from
(3R,4S,5S,6R)-4,5-O-Isop r op ylid en e-3,6-b is[(p h en yl-
m eth yl)a m in o]octa n ed in itr ile (3c): [R]20 -58.9° (CHCl3,
D
1
c ) 1.26); H-NMR (250 MHz; CDCl3): δ ) 7.39-7.21 (m, 10
H); 4.26 (bs, 2 H); 3.98 and 3.73 (AB, J ) 13.3 Hz, 4 H); 2.80

Syn-Selective Michael Addition of Amines to Bis-Enones
J . Org. Chem., Vol. 62, No. 16, 1997 5383
(bdd, J ) 7.6 and 5.0 Hz, 2 H); 2.64 and 2.51 (ABX, J AB ) 16.6
Hz, J AX ) 5.0 Hz, J BX ) 7.6 Hz, 4 H); 1.66 (bs, 2 H); 1.38 (s, 6
H). 13C-NMR (62.9 MHz; CDCl3): δ ) 139.3, 128.6, 128.2,
127.4, 118.0, 109.5, 78.0, 52.7, 51.0, 27.1, 20.5. Anal. Calcd
for C25H30N4O2: C, 71.74; H, 7.22; N, 13.39. Found: C, 71.45;
H, 7.15; N, 13.25.
Anal. Calcd for C26H28N4O3: C, 70.25; H, 6.35; N, 12.60.
Found: C, 70.03; H, 6.41; N, 12.58.
(4R,5S,6S,7R)-Hexa h yd r o-4,7-bis(cya n om eth yl)-1,3-bis-
(cyclop r op ylm et h yl)-5,6-O-isop r op ylid en e-2H -1,3-d ia z-
ep in -2-on e (6d ). A 370 mg (1.06 mmol) amount of 3d gave
242 mg (63%) of 6d . [R]20D -30.5° (CHCl3, c ) 0.88); 1H-NMR
(250 MHz; CDCl3): δ ) 4.11 (dddd, J ) 8.4, 5.8, 2.3 and 1.3
Hz, 2 H); 3.92 (dd, J ) 2.3 and 1.3 Hz, 2 H); 3.62 and 3.11
(ABX, J AB ) 14.2 Hz, J AX ) 7.4 Hz, J BX ) 6.7 Hz, 4 H); 2.83
and 2.75 (ABX, J AB ) 16.8 Hz, J AX ) 8.4 Hz, J BX ) 5.8 Hz, 4
H); 1.46 (s, 6 H); 1.04 (m, 2 H); 0.60 (m, 4 H); 0.28 (m, 4 H).
13C-NMR (62.9 MHz; CDCl3): δ ) 159.6, 150.7, 116.8, 111.8,
74.4, 56.9, 54.5, 26.6, 15.4, 10.4, 4.1, 3.5. Anal. Calcd for
C20H28N4O3: C, 64.49; H, 7.58; N, 15.04. Found: C, 64.25; H,
7.53; N, 14.98.
(3R,4S,5S,6R)-3,6-Bis[(cyclop r op ylm eth yl)a m in o]-4,5-
O-isopr opyliden eoctan edin itr ile (3d): [R]20D -57.7° (CHCl3,
1
c ) 2.00); H-NMR (250 MHz; CDCl3): δ ) 4.23 (dd, J ) 1.3
and 1.2 Hz, 2 H); 3.16 (dddd, J ) 7.6, 5.0, 1.3 and 1.2 Hz, 2
H); 2.58 (m, 8 H); 1.45 (bs, 2 H); 1.41 (s, 6 H); 0.92 (m, 2 H);
0.49 (m, 4 H); 0.13 (m, 4 H). 13C-NMR (62.9 MHz; CDCl3): δ
) 118.0, 109.5, 78.1, 54.4, 52.3, 27.1, 20.5, 11.3, 3.4, 3.1. Anal.
Calcd for C19H30N4O2: C, 65.87; H, 8.73; N, 16.17. Found: C,
65.94; H, 8.66; N, 15.94.
Diet h yl (2R,3S,4S,5S)-3,4-O-isop r op ylid en e-2,5-b is-
[(p h en ylm et h yl)a m in o]-1,6-h exa n ed ica r b oxyla t e (4a ):
(4R,5S,6S,7R)-Hexa h ydr o-5,6-dih ydr oxy-4,7-bis[(eth ox-
ycar bon yl)m eth yl]-1,3-bis(ph en ylm eth yl)-2H-1,3-diazepin -
[R]20 -181.6° (CHCl3, c ) 0.98); 1H-NMR (500 MHz; CDCl3):
D
2-on e (7a ). A 49 mg (0.09 mmol) amount of 6a gave 35 mg
δ ) 7.31-7.17 (m, 10 H); 4.12 (m, 5 H); 3.91 and 3.72 (AB, J
) 13.1 Hz, 2 H); 3.77 and 3.71 (AB, J ) 13.0 Hz, 2 H); 3.29
(dt, J ) 6.4 and 3.3 Hz, 1 H); 3.09 (dt, J ) 6.8 and 4,9 Hz, 1
H); 2.63-2.50 (2 ABX, 4 H); 1.64 (bs, 2 H); 1.36 (s, 3 H); 1.31
(s, 3 H); 1.24 (t, J ) 7.1 Hz, 6 H). 13C-NMR (62.9 MHz;
CDCl3): δ ) 172.3, 172.2, 140.4, 140.1, 128.2, 128.1, 128.0,
126.8, 108.6, 82,0, 78.2, 60.4, 60.3, 56.9, 54.4, 51.3, 51.0, 37.1,
35.7, 27.2, 27.1, 14.1. Anal. Calcd for C29H40N2O6: C, 67.95;
H, 7.86; N, 5.46. Found: C, 67.98; H, 8.03; N, 5.40.
1
(78%) of 7a . [R]20 +174.1° (CHCl3, c ) 0.58); H-NMR (250
D
MHz; CDCl3): δ ) 7.41-7.22 (m, 10 H); 4.96 and 3.96 (AB, J
) 14.1 Hz, 4 H); 4.12 (q, J ) 7.1 Hz, 4 H); 3.87 (m, 2 H); 3.25
(bs, 2 H); 2.82 (bs, 2 H); 2.63 (ABX, 4 H); 1.27 (t, J ) 7.1 Hz,
6 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 172.4, 162.0, 137.9,
129.5, 128.7, 127.7, 70.8, 61.1, 56.9, 54.4, 32.0, 14.1. Anal.
Calcd for C27H34N2O7: C, 65.04; H, 6.87; N, 5.62. Found: C,
64.89; H, 6.94; N, 5.58.
(4R,5S,6S,7R)-Hexa h yd r o-1,3-bis(cyclop r op ylm eth yl)-
5,6-d ih yd r oxy-4,7-b is[(et h oxyca r b on yl)m et h yl]-2H -1,3-
(4S,5S,6R)-4,5-O-isopr opyliden e-6-[(ph en ylm eth yl)am i-
n o]oct-2(E)-en ed in itr ile (5c). Treatment of 2b (400 mg,
1.96 mmol) with benzylamine (0.64 mL, 5.88 mmol) according
the general procedure gave 445 mg (73%) of 5c. [R]20D -81.7°
(CHCl3, c ) 0.60); 1H-NMR (500 MHz; CDCl3): δ ) 7.38-7.29
(m, 5 H); 6.50 (dd, J ) 16.2 and 5.3 Hz, 1 H); 5.41 (dd, J )
16.2 and 1.7 Hz, 1 H); 4.67 (ddd, J ) 5.3, 2.4 and 1.7 Hz, 1 H);
4.05 and 3.77 (AB, J ) 13.3 Hz, 2 H); 3.85 (dd, J ) 8.2 and 2.4
Hz, 1 H); 2.92 (ddd, J ) 8.3, 7.9 and 5.0 Hz, 2 H); 2.73 and
2.59 (ABX, J AB ) 16.7 Hz, J AX ) 5.0 Hz, J BX ) 7.9 Hz, 2 H);
1.69 (bs, 1 H); 1.43 (s, 3 H) 1.39 (s, 3 H). 13C-NMR (125.8 MHz;
CDCl3): δ ) 150.0, 139.0, 128.7, 128.4, 127.7, 117.5, 116.4,
110.7, 101.5, 81.3, 76.0, 51.5, 50.7, 29.7, 26.9, 26.8, 26.6, 20.3.
Anal. Calcd for C18H21N3O2: C, 69.43; H, 6.80; N, 13.49.
Found: C, 69.54; H, 6.82; N, 13.41.
d ia zep in -2-on e (7b). A 50 mg (0.11 mmol) amount of 6b gave
1
37 mg (68%) of 7b. [R]20 -31.8° (CHCl3, c ) 0.73); H-NMR
D
(250 MHz; CDCl3): δ ) 4.27 (dddd, J ) 7.4, 6.8, 2.0 and 1.6
Hz, 2 H); 4.12 (q, J ) 7.1 Hz, 4 H); 4.01 (m, 2 H); 3.61 and
2.94 (ABX, 4 H, J AB ) 14.1 Hz, J AX ) 7.4 Hz, J BX ) 6.8 Hz);
2.79 and 2.69 (ABX, J AB ) 15.8 Hz, J AX ) 8.3 Hz, J BX ) 5.5
Hz, 4 H); 1.40 (s, 6 H,); 1.24 (t, J ) 7.1 Hz, 6 H); 1.05 (m, 2 H);
0.54 (m, 4 H); 0.26 (m, 4 H). 13C-NMR (62.9 MHz; CDCl3): δ
) 172.5, 161.5, 71.3, 61.0, 58.6, 55.8, 32.1, 14.1, 10.5, 4.1, 3.4.
Anal. Calcd for C21H34N2O7: C, 59.14; H, 8.04; N, 6.57.
Found: C, 59.21; H, 8.07; N, 6.52.
(4R,5S,6S,7R)-Hexa h yd r o-4,7-bis(cya n om eth yl)-5,6-d i-
h ydr oxy-1,3-bis(ph en ylm eth yl)-2H-1,3-diazepin -2-on e (7c).
A 20 mg (0.05 mmol) amount of 6c gave 15 mg (82%) of 7c.
(4R,5S,6S,7R)-H exa h yd r o-4,7-b is[(et h oxyca r b on yl)-
m eth yl]-5,6-O-isop r op ylid en e-1,3-bis(p h en ylm eth yl)-2H-
1,3-d ia zep in -2-on e (6a ). A 15.0 g (29.26 mmol) amount of
1
[R]20 -13.8° (CHCl3, c ) 0.82); H-NMR (250 MHz; CDCl3):
D
δ ) 7.41-7.27 (m, 10 H); 5.09 and 4.13 (AB, J ) 14.3 Hz, 4
H); 3.73 (bd, J ) 7.8 Hz, 2 H); 3.25 (bs, 2 H); 3.21 (bs, 2 H);
2.72 and 2.57 (ABX, J AB ) 17.0 Hz, J AX ) 4.3 Hz, J BX ) 7.8
Hz, 4 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 160.3, 136.7,
129.2, 129.1, 128.4, 117.7, 69.7, 57.5, 55.4, 14.7. Anal. Calcd
for C23H24N4O3: C, 68.30; H, 5.98; N, 13.85. Found: C, 68.02;
H, 5.86; N, 13.72.
3a gave 10.6 g (68%) of 6a . [R]20 +43.7° (CHCl3, c ) 1.26);
D
1H-NMR (250 MHz; CDCl3): δ ) 7.42-7.25 (m, 10 H); 5.08
and 4.08 (AB, J ) 13.1 Hz, 4 H); 4.12 (q, J ) 7.1 Hz, 4 H);
4.10 (m, 2 H); 3.48 (m, 2 H); 2.57 (ABX, 4 H); 1.28 (t, J ) 7.1
Hz, 6 H); 1.19 (s, 6 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 171.0,
161.8, 138.0, 129.1, 128.6, 127.6, 110.4, 74.7, 60.9, 55.2, 53.8,
32.1, 26.4, 14.1. Anal. Calcd for C30H38N2O7: C, 66.90; H,
7.11; N, 5.20. Found: C, 66.54; H, 7.02; N, 5.26.
(4R,5S,6S,7R)-Hexa h yd r o-4,7-bis(cya n om eth yl)-1,3-bis-
(cyclop r op ylm et h yl)-5,6-d ih yd r oxy-2H -1,3-d ia zep in -2-
on e (7d ). A 31 mg (0.08 mmol) amount of 6d gave 16 mg
(60%) of 7d . Mp 217-222 °C; 1H-NMR (250 MHz; CDCl3/
CD3OD; 60 °C): δ ) 3.87 (m, 2 H); 3.75 (m, 2 H); 3.71 and
2.98 (ABX, J AB ) 14.2 Hz, J AX ) 7.4 Hz, J BX ) 6.8 Hz, 4 H);
2.95 (ABX, 4 H); 1.03 (m, 2 H); 0.61 (m, 4 H); 0.29 (m, 4 H).
13C-NMR (62.9 MHz; CDCl3/CD3OD; 60 °C): δ ) 161.2, 119.2,
70.7, 60.0, 57.4, 15.6, 11.4, 4.8, 4.3. Anal. Calcd for
C17H24N4O3: C, 61.43; H, 7.28; N, 16.85. Found: C, 61.24; H,
7.32; N, 16.76.
(4R,5S,6S,7R)-Hexa h yd r o-1,3-bis(cyclop r op ylm eth yl)-
4,7-b is[(et h oxyca r b on yl)m et h yl]-5,6-O-isop r op ylid en e-
2H-1,3-d ia zep in -2-on e (6b). A 1.75 g (4.13 mmol) amount
of 3b gave 1.07 g (62%) of 6b. [R]20D +33.9° (CHCl3, c ) 0.76);
1H-NMR (250 MHz; CDCl3): δ ) 4.27 (dddd, J ) 7.4, 6.8, 2.0
and 1.6 Hz, 2 H); 4.12 (q, J ) 7.1 Hz, 4 H); 4.01 (m, 2 H); 3.61
and 2.94 (ABX, 4 H, J AB ) 14.1 Hz, J AX ) 7.4 Hz, J BX ) 6.8
Hz); 2.79 and 2.69 (ABX, J AB ) 15.8 Hz, J AX ) 8.3 Hz, J BX
)
5.5 Hz, 4 H); 1.40 (s, 6 H); 1.24 (t, J ) 7.1 Hz, 6 H); 1.05 (m,
2 H); 0.54 (m, 4 H); 0.26 (m, 4 H). 13C-NMR (62.9 MHz;
CDCl3): δ ) 171.1, 161.2, 110.7, 75.4, 60.8, 56.3, 54.8, 32.3,
26.6, 14.1, 10.6, 4.6, 3.3. Anal. Calcd for C24H38N2O7: C,
61.78; H, 8.21; N, 6.00. Found: C, 61.63; H, 8.25; N, 6.03.
(4R,5S,6S,7R)-Hexa h yd r o-4,7-bis(cya n om eth yl)-5,6-O-
isop r op ylid en e-1,3-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-
on e (6c). A 444 mg (1.06 mmol) amount of 3c gave 300 mg
Dieth yl (2R,3S,4S,5R)-5-[(cyclop r op ylm eth yl)a m in o]-
3,4-O-isop r op ylid en e-2-[(p h en ylm eth yl)a m in o]-1,6-h ex-
a n ed ica r boxyla te (8): [R]20 -29.9° (CHCl3, c ) 0.94); 1H-
D
NMR (500 MHz; CDCl3): δ ) 7.34-7.02 (m, 5 H); 4.14 (m, 6
H); 3.92 and 3.77 (AB, J ) 13.1 Hz, 2 H); 2.60 (ABX, J AB
)
15.1 Hz, J AX ) 6.3 Hz, J BX ) 6.5 Hz, 2 H); 3.21 (dt, J ) 6.4
and 3.3 Hz, 1 H); 3.16 (ddd, J ) 6.9, 6.0 and 3.6 Hz, 1 H);
2.53-2.42 (m, 4 H); 1.39 (s, 3 H); 1.66 (bs, 2 H); 1.36 (s, 3 H);
1.26 (t, J ) 7.1 Hz, 3 H); 1.25 (t, J ) 7.1 Hz, 3 H); 0.88 (m, 1
H); 0.43 (ABXY, 2 H); 0.08 (ABXY, 2 H); 13C-NMR (125.8 MHz;
CDCl3): δ ) 172.3, 172.2, 140.5, 128.3, 128.1, 126.9, 108.6,
79.1, 78.8, 60.5, 60.4, 54.9, 54.6, 52.5, 51.5, 36.8, 36.7, 27.2,
14.2, 11.4, 3.3, 3.1. Anal. Calcd for C26H40N2O6: C, 65.52; H,
8.46; N, 5.88. Found: C, 65.61; H, 8.43; N, 5.89.
(64%) of 6c. Mp 142-144 °C; [R]20 -32.4° (CHCl3, c ) 0.51);
D
1H-NMR (250 MHz; CDCl3): δ ) 7.45-7.27 (m, 10 H); 5.02
and 4.37 (AB, 4 H, J ) 14.4 Hz); 3.94 (dddd, J ) 8.6, 5.4, 2.2
and 1.4 Hz, 2 H); 3.48 (dd, J ) 2.2 and 1.4 Hz, 2 H); 2.59 and
2.47 (ABX, J AB ) 16.9 Hz, J AX ) 5.4 Hz, J BX ) 8.6 Hz, 4 H);
1.29 (s, 6 H). 13C-NMR (62.9 MHz; CDCl3): δ ) 159.7, 137.3,
129.2, 129.0, 128.5, 116.8, 111.5, 73.9, 56.0, 53.4, 26.4, 15.3.

5384 J . Org. Chem., Vol. 62, No. 16, 1997
Schreiner and Pruckner
(4R,5S,6S,7R)-H exa h yd r o-3-(cyclop r op ylm et h yl)-4,7-
b is[(e t h oxyca r b on yl)m e t h yl]-5,6-O-isop r op ylid e n e -1-
127.6, 110.6, 75.2, 75.0, 60.9, 56.7, 55.0, 53.8, 32.6, 31.9, 26.6,
26.5, 14.1, 10.7, 4.1, 3.3. Anal. Calcd for C27H38N2O7: C,
64.52; H, 7.62; N, 5.57. Found: C, 64.34; H, 7.58; N, 5.52.
(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (9): [R]20 -11.3°
D
(CHCl3, c ) 1.14); 1H-NMR (500 MHz; CDCl3): δ ) 7.40-7.28
(m, 5 H); 4.97 and 4.04 (AB, J ) 14.2 Hz, 2 H); 4.27 (ddd, J )
9.0, 5.0, and 4.3 Hz, 1 H); 4.13 (m, 5 H); 3.96 (dd, J ) 9.7 and
4.3 Hz, 1 H); 3.72 and 2.98 (ABX, J AB ) 14.2 Hz, J AX ) 7.4
Hz, J BX ) 6.8 Hz, 2 H); 3.58 (dd, J ) 9.7 and 4.3 Hz, 1 H);
2.70 and 2.61 (ABX, J AB ) 15.8 Hz, J AX ) 9.0 Hz, J BX ) 5.0
Hz, 2 H); 2.67 (ABX, 2 H); 1.34 (s, 3 H); 1.27 (m, 9 H); 1.08 (m,
1 H); 0.56 (ABXY, 2 H); 0.29 (ABXY, 2 H); 13C-NMR (125.8
MHz; CDCl3): δ ) 171.1, 171.0, 161.4, 138.2, 129.2, 128.7,
Ack n ow led gm en t. Erwin P. Schreiner thanks Di-
eter Scholz for highly fruitful discussions and Peter
Nussbaumer for his assistance in manuscript prepara-
tion. We also thank Hans Peter Weber for the X-ray
structure analysis of 7d and Ewald Haidl, Edgar Mark,
and Gerhard Schulz for carrying out NMR spectroscopy.
J O970384K