Chiral 1,3-diamines from a lithiated isocyanide and chiral aziridines

Article abstract of DOI:10.1016/S0957-4166(99)00075-0

Reaction of lithiated 4-methoxybenzylisocyanide with homochiral amino acid derived N-tosyl- and N-diphenylphosphinoylaziridines proceeds diastereoselectively to provide N-protected 3-isocyanoamines. Separation of the diastereomers of these adducts or the

Full text of DOI:10.1016/S0957-4166(99)00075-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1001–1014
Chiral 1,3-diamines from a lithiated isocyanide and chiral
aziridines
Alexander Kaiser ∗ and Miriam Balbi
Institut für Pharmazie, Pharmazeutische Chemie I, Universität Regensburg, D-93040 Regensburg, Germany
Received 15 February 1999; accepted 2 March 1999
Abstract
Reaction of lithiated 4-methoxybenzylisocyanide with homochiral amino acid derived N-tosyl- and N-
diphenylphosphinoylaziridines proceeds diastereoselectively to provide N-protected 3-isocyanoamines. Separation
of the diastereomers of these adducts or the corresponding formamides, and subsequent transformations, lead to
1,3-diamines and their monoprotected and differentially bisprotected derivatives. © 1999 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Although the number of reports on the synthesis of 1,3-diamines1 has grown over the last few years,
this class of compounds is not receiving the attention which has been devoted to its 1,2-analogues.2
In connection with our interest in the preparation and use of 1,3-diamines as ligands for cytostatic
cis-platinum complexes,3 we required a method for the preparation of diastereo- and enantiomerically
pure 1,3-diamines. Our approach is based on the retrosynthetic cleavage of the target molecule to an
α-amino carbanion and a 2-aminoethyl cation (Scheme 1). We anticipated that lithiated isocyanides
and N-activated aziridines as synthetic equivalents for the above-mentioned synthons should provide
diastereomeric N-protected 3-isocyanoamines, which, after separation of the diastereomers, should
afford enantiomerically pure4 1,3-diamines in few steps. Lithiated isocyanides5,6 as well as N-activated
aziridines7,8 have been widely employed as synthetic building blocks, but to the best of our knowledge,
this approach to 1,3-diamines has not been explored up to now.
Homochiral-activated aziridines are easily prepared from chiral amino alcohols, which in turn are
obtained by reduction of α-amino acids.8 As aziridine activators, we chose the p-toluenesulfonyl group
(Ts) and the more easily removed diphenylphosphinoyl group (Dpp).9,10 Here, we report the results
∗
Corresponding author. E-mail: alexander.kaiser@chemie.uni-regensburg.de
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00075-0

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A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
Scheme 1.
obtained with N-Ts and N-Dpp aziridines derived from L-phenylalanine, L-valine, L-leucine and lithiated
4-methoxybenzylisocyanide.
2. Results and discussion
We started with the L-phenylalanine derived N-tosylaziridine 2a (Scheme 2). 4-Methoxybenzyl-
isocyanide 1 was treated with n-BuLi at −78°C,11 and the resulting anion was reacted with aziridine 2a for
3 h at −78°C followed by aqueous work-up. 1H NMR analysis of the crude material showed the presence
of two diastereoisomers in a 60:40 syn:anti ratio. Chromatographic separation gave diastereomerically
pure syn-3a and anti-3a in 38% and 17% yield, respectively, and 36% of a diastereomeric mixture. Use
of aziridines 2b and c resulted in the formation of diastereomeric mixtures with syn:anti ratios of 70:30
and 60:40, respectively, from which only the syn-isomers (syn-3b: 34%; syn-3c: 20%) could be isolated
diastereomerically pure by column chromatography. The anti-isomers were obtained contaminated with
syn-isomers (anti-3b: 12% chemical yield, d.e. 86%; anti-3c: 15% chemical yield, d.e. 82%). In addition,
about 30% of diastereomeric mixtures were obtained.
Scheme 2.
The N-Dpp aziridines turned out to be less reactive towards the lithiated isocyanide 1 than their N-Ts
counterparts. Applying the conditions found effective in the reaction with N-Ts aziridines, adduct 5a was
isolated in only 40% yield along with the starting aziridine 4a (Scheme 3). The use of two equivalents
of isocyanide 1 and modified temperature protocol was found essential for complete disappearance of
the starting aziridine from the reaction mixture. Thus, 5a was obtained in 81% yield after column
chromatography as a diastereomeric mixture (syn:anti, 60:40) from which the syn-isomer could be
isolated diastereomerically pure by recrystallization from CH2Cl2/petroleum ether in 30% yield. Under
the same reaction conditions, L-valine derived aziridine 4b gave the syn- and anti-diastereomer of 5b as
an 80:20 diastereomeric mixture. Column chromatography provided diastereomerically pure syn-5b and
anti-5b in 30% and 10% yield, respectively, and 20% of a diastereomeric mixture. Reaction of lithiated
isocyanide 1 with aziridine 4c resulted in formation of a 1:1 diastereomeric mixture of syn-5c and anti-5c,
inseparable by column chromatography or recrystallization.

A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
1003
Scheme 3.
In the case of adducts 5a and c, where pure diastereoisomers could not be obtained by column
chromatography, we found that chromatographic separation worked very efficiently after conversion
into 3-phosphinamido-formamides 6a and b by short treatment of Et2O/THF solutions of 5a and c,
respectively, with a small amount of conc. HCl12 (Scheme 3). In this manner, syn-6a and syn-6b were
obtained in 42% and 34% yield, and anti-6a and anti-6b in 35% and 34% yield, respectively.
Then we turned our attention to the transformation of the obtained diastereomerically pure compounds
into monoprotected 1,3-diamines, thereby allowing further selective manipulation of the two amino
groups. Reflux of the pure diastereoisomers of 3-isocyano-tosylamides 3a in 2 N HCl/dioxane and
subsequent evaporation of the reaction mixtures gave the hydrochloride salts of 3-amino-tosylamides
syn-8 and anti-8 in high yields (95% and 93%), from which the free bases were liberated with an
Na2CO3 solution (Scheme 4). Isolation of the hydrochloride salts was of no benefit for purification
and characterization, since no solvent for recrystallization of the hydrochloride salts could be found,
whereas crystalline free bases 8 could be recrystallized from toluene. Alternatively, monoprotected 1,3-
diamines can be obtained by alkaline hydrolysis of 3-tosylamido-formamides, prepared by acid-catalyzed
addition of water to the isocyano functionality. This was demonstrated by the conversion of syn-7 to syn-
8 by treatment with ethanolic KOH (Scheme 4). This protocol also worked for the diastereomers of
3-phosphinamido-formamides 6a providing the Dpp-monoprotected 1,3-diamine derivatives syn-9 and
anti-9 in 68% and 63% yield, respectively.
Reductive removal of the tosyl group from 3-amino-toluenesulfonamides 8 by exposure to sodium
naphthalenide13 gave diastereomeric 1,3-diamines only in modest yield (syn-10: 39%; anti-10: 35%;
Scheme 5). Higher yields were achieved starting from Dpp-derivatives as shown by the one-step double
deprotection of 3-phosphinamido-formamide syn-6a and by the deprotection of 3-amino-phosphinamide
anti-9: treatment with conc. HCl gave the diastereomeric 1,3-diamines syn-10 and anti-10 in 60% and
91% yield, respectively. The conversion of 3-isocyano-phosphinamide syn-5b into the corresponding
1,3-diamine syn-11 in a three-step one-pot process in 75% yield is worth noting. These examples
demonstrate that our approach allows preparation of diastereo- and enantiomerically pure 1,3-diamines
in only two (separation of diastereoisomers of 3-isocyano-phosphinamides) or three steps (separation of
diastereoisomers of 3-isocyano-sulfonamides or of 3-phosphinamido-formamides) from easily available
isocyanides and aziridines.

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A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
Scheme 4.
Scheme 5.
2.1. Stereochemical assignment
1
The relative stereochemistry of the phenylalanine derived products was determined from the H
NMR data of cyclic ureas 12 (Scheme 6), which were prepared by treatment of the diamines with
carbonyldiimidazole.14 Since the absolute configuration of the amino acid derived stereogenic center was
known, assignment of the relative stereochemistry allowed determination of the absolute configuration
of the newly created stereogenic center. The ∆δ (1H) values for diastereotopic protons 5-HA and 5-

A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
1005
HB and the differences between the vicinal coupling constants J5-H(A),4-H or J5-H(A),6-H on the one
side and J5-H(B),4-H or J5-H(B),6-H on the other side are known to be small, if existing at all, in anti-
perhydropyrimidine and anti-perhydro-1,3-oxazine systems and relatively large in the corresponding
syn-systems.14–17 Therefore, we assigned cis-configuration to the isomer of 12 with a shift difference
of 0.41 ppm and the coupling constants of 11.4, 3.5 and 3.3 Hz and trans-configuration to the isomer of
12 with a shift difference of 0.05 ppm and the coupling constants of 6.9, 5.5, 5.2 and 5.0 Hz.
Scheme 6.
The absolute and relative stereochemistries of L-valine- and L-leucine-derived products were esta-
1
blished by comparing their H NMR data with that of the L-phenylalanine derived products at the 3-
isocyano- or 3-formamido adduct stage. Signals of the benzylic proton at the isocyanide-bearing carbon
were observed at a higher field in the syn-isomers of 3-isocyano-amides 3 and 5 than in the anti-isomers.
The coupling constants between these protons and the diastereotopic protons of the adjacent methylene
group were identical (J=7.2 Hz) in the syn-diastereoisomers and different (J1=10.7–11.0 Hz, J2=2.3–3.3
Hz) in the anti-diastereoisomers.
3. Conclusion
This methodology is an easy way to prepare homochiral 1,3-diamines from readily available starting
materials. Selective manipulation of the N-functionalities in the 3-isocyano-amides allows the synthesis
of differentially bisprotected diamines as well as monoprotected derivatives. Also, since R-amino acids
are commercially available, our approach allows for the preparation of all four stereoisomers of 1,3-
diamines.
4. Experimental
4.1. General methods
Compounds 1,11 2a–c18–20 and 4a–c9 were prepared according to literature procedures. Commercial
reagent grade solvents and chemicals were used as obtained except as indicated below. THF was distilled
from sodium benzophenone ketyl. Pyridine and Et3N were stored over KOH pellets. Petroleum ether
refers to the 40–60°C boiling fraction. Solvents used for column chromatography were distilled prior
to use. All oxygen- or moisture-sensitive reactions were run in flame-dried glassware under nitrogen.
Organic extracts were dried over anhydrous Na2SO4. For thin-layer chromatography (TLC) analysis,
precoated TLC plates (Merck Kieselgel 60 F254 and Merck aluminum oxide 60 F254 neutral) were
used, and column chromatography was performed using Merck Kieselgel 60. Spots were visualized with
ultraviolet light (254 nm) or detected by exposure to iodine fumes. Infrared spectra were recorded with a
FT-IR spectrometer; only representative bands are given. 1H and 13C NMR spectra were obtained at 250
and 62 MHz, respectively. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter with

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A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
a thermally jacketed 10 cm cell at 20°C (concentration c is given as g/100 ml). Diastereomeric ratios
were established by the integration of well separated signals of the diastereomers in the crude reaction
mixtures. Compounds which were not submitted for, or did not pass elemental analysis, were judged to
be of >95% purity based on TLC homogenity and 1H NMR analyses.
4.2. 3-Isocyano-p-toluenesulfonamides 3a–c. General procedure
To a solution of isocyanide 1 (1.19 g, 8 mmol) in dry THF (30 ml), n-BuLi (1.6 M in hexane, 5.3 ml,
8.5 mmol) was added dropwise at −78°C under nitrogen. After stirring for 40 min at −78°C, a solution
of aziridine 2a–c (8 mmol) in dry THF (40 ml) was added, and stirring was continued for 3 h at −78°C.
Half saturated NH4Cl solution (40 ml) was added, the layers were separated, and the aqueous layer was
extracted with Et2O (2×100 ml). The combined organic layers were washed with brine (2×10 ml), dried
and evaporated.
4.2.1. (2S,4S)- and (2S,4R)-N-[4-Isocyano-4-(4-methoxyphenyl)-1-phenyl-2-butyl]-p-toluenesulfon-
amide (syn-3a; anti-3a)
Colorless oil (diastereomeric mixture; syn:anti, 60:40). The diastereomers were separated by column
chromatography (CH2Cl2:EtOAc, 95:5). In addition to 1.25 g (36%) of a pale yellow oil (diastereomeric
mixture; syn:anti, 60:40), the following were obtained.
syn-3a (2S,4S): Colorless crystals (1.32 g, 38%); m.p. 107°C; IR (KBr): 3243 (NH), 2155 (NC), 1315,
1
1153 cm−1 (S_O). H NMR (CDCl3): δ (ppm)=1.99–2.21 (m, 2H, CH2), 2.43 (s, 3H, ArCH3), 2.57,
2.70 (ABX, JAB=13.8 Hz, JAX=6.4 Hz, JBX=6.4 Hz, 2H, ArCH2), 3.30–3.43 (m, 1H, CHNHTs), 3.82
(s, 3H, OCH3), 4.39 (d, J=8.0 Hz, 1H, NH, exchangeable), 4.71 (dd, J=7.2 Hz, 1H, CHNC), 6.86, 7.13
(AA0BB0, J=8.7 Hz, 4H, ArH), 6.82–6.89 (m, 2H, ArH), 7.09–7.22 (m, 3H, ArH), 7.24, 7.58 (AA0BB0,
J=8.7 Hz, 4H, ArH). Anal. calcd for C25H26N2O3S (434.5): C, 69.10; H, 6.03; N, 6.45. Found: C, 68.94;
20
D
H, 6.12; N, 6.29. [α] =−81.0 (c=0.51, MeOH).
anti-3a (2S,4R): Colorless crystals (0.59 g, 17%); m.p. 119°C; IR (KBr): 3228 (NH), 2135 (NC), 1321,
1157 cm−1 (S_O). 1H NMR (CDCl3): δ (ppm)=1.62–1.77 (m, 1H, HCH), 1.98 (ddd, J=14.1, 11.0, 2.9
Hz, 1H, HCH) 2.44 (s, 3H, ArCH3), 2.67 (d, J=6.2 Hz, 2H, ArCH2), 3.70–3.85 (m, 1H, CHNHTs),
3.80 (s, 3H, OCH3), 4.44 (d, J=8.9 Hz, 1H, NH, exchangeable), 4.79 (dd, J=10.9, 3.1 Hz, 1H, CHNC),
6.87, 7.15 (AA0BB0, J=8.7 Hz, 4H, ArH), 6.90–6.98 (m, 2H, ArH), 7.12–7.26 (m, 3H, ArH), 7.29, 7.74
(AA0BB0, J=8.2 Hz, 4H, ArH). Anal. calcd for C25H26N2O3S (434.5): C, 69.10; H, 6.03; N, 6.45. Found:
20
D
C, 68.81; H, 6.01; N, 6.34. [α] =−12.1 (c=0.28, MeOH).
4.2.2. (1S,3R)- and (1R,3R)-N-[1-Isocyano-1-(4-methoxyphenyl)-4-methyl-3-pentyl]-p-toluenesulfon-
amide (syn-3b; anti-3b)
Pale yellow oil (diastereomeric mixture; syn:anti, 70:30). The diastereomers were separated by column
chromatography (CH2Cl2:EtOAc, 95:5). In addition to 0.97 g (31%) of a colorless oil (diastereomeric
mixture; syn:anti, 85:15), the following were obtained.
syn-3b (1S,3R): Colorless foam (1.07 g, 34%); IR (KBr): 3284 (NH), 2138 (NC), 1327, 1161 cm−1
(S_O). 1H NMR (CDCl3): δ (ppm)=0.64 (d, J=6.9 Hz, 3H, CH3), 0.71 (d, J=6.9 Hz, 3H, CH3), 1.59–1.71
(m, 1H, CH(CH3)2), 1.96 (dd, J=6.9 Hz, 2H, CH2), 2.44 (s, 3H, ArCH3), 3.00–3.10 (m, 1H, CHNH), 3.82
(s, 3H, OCH3), 4.57 (d, J=9.3 Hz, 1H, NH, exchangeable), 4.66 (dd, J=7.2 Hz, 1H, CHNC), 6.88, 7.19
(AA0BB0, J=8.7 Hz, 4H, ArH), 7.31, 7.74 (AA0BB0, J=8.2 Hz, 4H, ArH). Anal. calcd for C21H26N2O3S
20
D
(386.5): C, 65.26; H, 6.78; N, 7.25. Found: C, 65.17; H, 6.93; N, 7.12. [α] =−49.0 (c=1.15, CHCl3).

A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
1007
anti-3b (1R,3R): Colorless foam (0.38 g, 12%), contaminated with 7% of syn-3b; IR (KBr): 3286
(NH), 2138 (NC), 1326, 1160 cm−1 (S_O). 1H NMR (CDCl3): δ (ppm)=0.71 (d, J=6.8 Hz, 3H, CH3),
0.80 (d, J=6.9 Hz, 3H, CH3), 1.53–1.80 (m, 2H, HCH and CH(CH3)2), 1.91 (ddd, J=14.1, 11.5, 2.4 Hz,
1H, HCH), 2.44 (s, 3H, ArCH3), 3.38–3.49 (m, 1H, CHNH), 3.81 (s, 3H, OCH3), 4.70 (d, J=9.2 Hz, 1H,
NH, exchangeable), 4.73 (dd, J=10.8, 2.8 Hz, 1H, CHNC), 6.88, 7.18 (AA0BB0, J=8.7 Hz, 4H, ArH),
7.34, 7.84 (AA0BB0, JAB=8.2 Hz, 4H, ArH). Anal. calcd for C21H26N2O3S (386.5): C, 65.26; H, 6.78;
20
D
N, 7.25. Found: C, 65.16; H, 6.99; N, 7.16. [α] =−9.5 (c=1.05, CHCl3).
4.2.3. (1S,3S)- and (1R,3S)-N-[1-Isocyano-1-(4-methoxyphenyl)-5-methyl-3-hexyl]-p-toluenesulfon-
amide (syn-3c; anti-3c)
Pale yellow oil (diastereomeric mixture; syn:anti, 60:40). The diastereomers were separated by column
chromatography (CH2Cl2:EtOAc, 95:5). In addition to 0.97 g (30%) of a colorless oil (diastereomeric
mixture; syn:anti, 65:35), the following were obtained.
syn-3c (1S,3S): Colorless foam (0.64 g, 20%); IR (KBr): 3280 (NH), 2138 (NC), 1333, 1161 cm−1
(S_O). 1H NMR (CDCl3): δ (ppm)=0.59 (d, J=6.4 Hz, 6H, 2CH3), 1.04–1.18 and 1.20–1.49 (m, 3H, CH2
and CH(CH3)2), 1.87–2.13 (m, 2H, CH2CHNC), 2.43 (s, 3H, ArCH3), 3.13–3.27 (m, 1H, CHNH), 3.82
(s, 3H, OCH3), 4.44 (d, J=8.4 Hz, 1H, NH, exchangeable), 4.71 (dd, J=7.2 Hz, 1H, CHNC), 6.84, 7.22
(AA0BB0, J=8.7 Hz, 4H, ArH), 7.31, 7.74 (AA0BB0, J=8.3 Hz, 4H, ArH). Anal. calcd for C22H28N2O3S
20
D
(400.5): C, 65.97; H, 7.05; N, 6.99. Found: C, 65.74; H, 7.04; N, 6.85. [α] =−9.2 (c=0.76, CHCl3).
anti-3c (1R,3S): Colorless foam (0.48 g, 15%), contaminated with 9% of syn-3c; IR (KBr): 3270
(NH), 2138 (NC), 1331, 1161 cm−1 (S_O). 1H NMR (CDCl3): δ (ppm)=0.65 (d, J=6.5 Hz, 3H, CH3),
0.74 (d, J=6.5 Hz, 3H, CH3), 1.10–1.30 (m, 2H, CH2), 1.33–1.51 (m, 1H, CH(CH3)2), 1.60–1.77 (m, 1H,
HCHCHNC), 1.97 (ddd, J=14.1, 11.0, 3.0 Hz, 1H, HCHCHNC), 2.44 (s, 3H, ArCH3), 3.40–3.54 (m,
1H, CHNHTs), 3.81 (s, 3H, OCH3), 4.38 (d, J=8.7 Hz, NH, exchangeable), 4.86 (dd, J=10.7, 3.3 Hz, 1H,
CHNC), 6.88, 7.20 (AA0BB0, J=8.7 Hz, 4H, ArH), 7.33, 7.81 (AA0BB0, J=8.0 Hz, 4H, ArH). Anal. calcd
20
D
for C22H28N2O3S (400.5): C, 65.97; H, 7.05; N, 6.99. Found: C, 65.89; H, 7.30; N, 6.74. [α] =−71.1
(c=0.65, CHCl3).
4.3. 3-Isocyano-phosphinamides 5a–c. General procedure
To a solution of isocyanide 1 (1.48 g, 10 mmol) in dry THF (30 ml), n-BuLi (1.6 M in hexane, 6.6 ml,
10.5 mmol) was added dropwise at −78°C under nitrogen. After stirring for 40 min at −78°C, a solution
of aziridine 4a–c (5 mmol) in dry THF (40 ml) was added, and stirring was continued for 5 h at −78°C.
The cooling bath was removed, and stirring was continued for 15 min. Half saturated NH4Cl solution (40
ml) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×60 ml).
The combined organic layers were washed with brine (2×20 ml), dried and evaporated.
4.3.1. (2S,4S)- and (2S,4R)-N-[4-Isocyano-4-(4-methoxyphenyl)-1-phenyl-2-butyl]-diphenylphosphin-
amide (syn-5a; anti-5a). Diastereomeric mixture
The crude product was purified by column chromatography (EtOAc): colorless crystals (1.96 g, 81%,
diastereomeric mixture; syn:anti, 60:40); IR (KBr): 3434 (NH), 2138 (NC), 1179 cm−1 (P_O). 1H NMR
(CDCl3): δ (ppm)=1.70–1.87 (m, 1H, HCH, anti-diastereomer), 2.00–2.28 (m, 3H, HCH, anti- and CH2
syn-diastereomer), 2.71–3.03 (m, 3H, PhCH2 and NH, exchangeable), 3.10–3.29 (m, CHN, 0.6H, syn-
diastereomer), 3.48–3.66 (m, CHN, 0.4H, anti-diastereomer), 3.78 (s, 1.8H, OCH3, syn-diastereomer),
3.79 (s, 1.2H, OCH3, anti-diastereomer), 5.07 (dd, J=7.2 Hz, 0.6H, CHNC, syn-diastereomer), 5.43
(dd, J=10.9, 3.1 Hz, 0.4H, CHNC, anti-diastereomer), 6.78, 7.21 (AA0BB0, J=8.7 Hz, 2.4H, ArH, syn-

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A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
diastereomer), 6.85, 7.29 (AA0BB0, J=8.7 Hz, 1.6H, ArH, anti-diastereomer), 7.00–7.07 (m, 1H, ArH),
7.13–7.74 (m, 12H, ArH), 7.80–7.94 (m, 2H, ArH). Anal. calcd for C30H29N2O2P (485.5): C, 74.98;
H, 6.08; N, 5.83. Found: C, 74.57; H, 5.98; N, 5.97. Recrystallization from CH2Cl2/petroleum ether
afforded pure syn-5a (2S,4S) (0.72 g, 30%) as colorless crystals: m.p. 188°C; IR (KBr): 3434, 3251
(NH), 2137 (NC), 1184 cm−1 (P_O). 1H NMR (CDCl3): δ (ppm)=2.19–2.25 (m, 2H, CH2), 2.76–2.86
(m, 3H, PhCH2 and NH, exchangeable), 3.10–3.25 (m, 1H, CHN), 3.78 (s, 3H, OCH3), 5.07 (dd, J=7.2
Hz, 1H, CHNC), 6.78, 7.21 (AA0BB0, J=8.7 Hz, 4H, ArH), 6.98–7.07 (m, 2H, ArH), 7.15–7.70 (m, 11H,
ArH), 7.80–7.91 (m, 2H, ArH). Anal. calcd for C30H29N2O2P (485.5): C, 74.98; H, 6.08; N, 5.83. Found:
20
D
C, 74.65; H, 5.81; N, 5.98. [α] =−23.7 (c=0.12, EtOAc).
4.3.2. (1S,3R)- and (1R,3R)-N-[1-Isocyano-1-(4-methoxyphenyl)-4-methyl-3-pentyl]-diphenylphos-
phinamide (syn-5b; anti-5b)
Pale yellow oil (diastereomeric mixture; syn:anti, 80:20). The diastereomers were separated by column
chromatography (EtOAc) and recrystallized from Et2O. In addition to 0.42 g (20%) of a colorless oil
(diastereomeric mixture; syn:anti, 70:30), the following were obtained.
syn-5b (1S,3R): Colorless crystals (0.64 g, 30%); m.p. 156°C; IR (KBr): 3434, 3174 (NH), 2132 (NC),
1
1185 cm−1 (P_O). H NMR (CDCl3): δ (ppm)=0.70 (d, J=6.9 Hz, 3H, CH3), 0.88 (d, J=6.9 Hz, 3H,
CH3), 1.78–1.94 (m, 1H, CH(CH3)2), 2.06–2.18 (m, 2H, CH2), 2.68–2.95 (m, 2H, CHNH and NH,
exchangeable), 3.79 (s, 3H, OCH3), 5.09 (dd, J=7.2 Hz, 1H, CHNC), 6.83, 7.30 (AA0BB0, J=8.7 Hz,
4H, ArH), 7.38–7.60 (m, 6H, ArH), 7.80–8.00 (m, 4H, ArH). Anal. calcd for C26H29N2O2P (432.5): C,
20
D
72.20; H, 6.76; N, 6.48. Found: C, 72.24; H, 6.78; N, 6.42. [α] =−30.8 (c=1.13, CHCl3).
anti-5b (1R,3R): Colorless crystals (0.21 g, 10%); m.p. 130°C; IR (KBr): 3425, 3160 (NH), 2138 (NC),
1
1187 cm−1 (P_O). H NMR (CDCl3): δ (ppm)=0.90 (d, J=6.6 Hz, 3H, CH3), 0.92 (d, J=6.5 Hz, 3H,
CH3), 1.60–1.78 (m, 1H, CH(CH3)2), 1.83–2.07 (m, 2H, CH2), 2.72–2.91 (m, 1H, NH, exchangeable),
3.10–3.25 (m, 1H, CHNH), 3.80 (s, 3H, OCH3), 5.51 (dd, J=11.0, 2.3 Hz, 1H, CHNC), 6.88, 7.30
(AA0BB0, J=8.7 Hz, 4H, ArH), 7.40–7.60 (m, 6H, ArH), 7.89–8.07 (m, 4H, ArH). Anal. calcd for
20
D
C26H29N2O2P (432.5): C, 72.20; H, 6.76; N, 6.48. Found: C, 72.00; H, 6.66; N, 6.35. [α] =−24.6
(c=0.69, CHCl3).
4.3.3. (1S,3S)- and (1R,3S)-N-[1-Isocyano-1-(4-methoxyphenyl)-5-methyl-3-hexyl]-diphenylphosphin-
amide (syn-5c; anti-5c). Diastereomeric mixture
The crude product was purified by column chromatography (EtOAc): pale yellow foam (1.78 g,
80%, diastereomeric mixture syn:anti, 50:50); IR (KBr): 3425, 3149 (NH), 2138 (NC), 1178 cm−1
1
(P_O). H NMR (CDCl3): δ (ppm)=0.52 (d, J=6.5 Hz, 1.5H, CH3), 0.69–0.82 (m, 4.5H, CH3),
1.30–1.87 (m, 4H, CH2CHCH3)2, CH(CH3)2 and HCH), 1.96–2.28 (m, 1H, HCH), 2.70–2.81 (m,
0.5H, NH, exchangeable), 2.85–3.08 (m, 0.5H, CHNH, syn-diastereomer), 3.17–3.38 (m, 0.5H, CHNH,
anti-diastereomer), 3.78 and 3.80 (s, 3H, OCH3, syn- and anti-diastereomer), 5.07 (dd, J=7.2 Hz,
0.5H, CHNC, syn-diastereomer), 5.41 (dd, J=10.6, 3.3 Hz, 0.5H, CHNC, anti-diastereomer), 6.83,
7.33 (AA0BB0, J=8.8 Hz, 2H, ArH, syn-diastereomer), 6.87, 7.28 (AA0BB0, J=8.9 Hz, 2H, ArH, anti-
diastereomer), 7.36–7.59 (m, 6H, ArH), 7.81–8.02 (m, 4H, ArH). Anal. calcd for C27H31N2O2P (447.5):
C, 72.63; H, 7.00; N, 6.27. Found: C, 72.66; H, 7.08; N, 6.19.
4.4. 3-Phosphinamido-formamides 6. General procedure
At 0°C, to a stirred solution of 3-isocyano-phosphinamides 5a,c (3 mmol) in Et2O:THF 1:1 (80 ml)
concd HCl (1 ml) was added. The cooling bath was removed, and stirring was continued for 3 min. The

A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
1009
mixture was shaken with saturated NaHCO3 solution (25 ml), the layers were separated, and the aqueous
layer was extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine (2×15
ml), dried and evaporated.
4.4.1. (1S,3S)- and (1R,3S)-N-[3-Diphenylphosphinamido-1-(4-methoxyphenyl)-4-phenyl-1-butyl]-
formamide (syn-6a; anti-6a)
Pale yellow oil (diastereomeric mixture syn:anti, 60:40). The diastereomers were separated by column
chromatography (CH2Cl2:MeOH, 95:5). syn-6a was recrystallized from toluene.
syn-6a (1S,3S): Pale yellow crystals (1.06 g, 42%); m.p. 95°C; IR (KBr): 3211 (NH), 1665 (C_O),
1
1179 cm−1 (P_O). H NMR (CDCl3): δ (ppm)=1.93 (ddd, J=14.2, 8.2, 4.1 Hz, 1H, HCH), 2.39 (ddd,
J=14.2, 11.1, 3.7 Hz, 1H, HCH), 2.61 (s, 1H, NH, exchangeable), 2.62–2.80 [m, 1H, HCHPh, after H/D-
exchange: 2.66 (dd, J=13.5, 8.2 Hz)], 2.93–3.06 (m, 1H, HCHPh), 3.19–3.34 (m, 1H, CHNHPO), 3.75
(s, 3H, OCH3), 4.96–5.05 [m, 1H, CHNHCHO, after H/D-exchange: 5.09 (dd, J=11.1, 3.7 Hz)], 6.78,
7.16 (AA0BB0, J=8.7 Hz, 4H, ArH), 7.12–7.21 (m, 1H, ArH), 7.23–7.51 (m, 12H, ArH), 7.67–7.80 (m,
3H, NHCHO, exchangeable and 2H, ArH), 8.07 (s, 1H, NCHO). Anal. calcd for C30H31N2O3P (503.5):
20
D
C, 72.27; H, 6.27; N, 5.62. Found: C, 72.02; H, 6.47; N, 5.42. [α] =−77.15 (c=0.15, CHCl3).
anti-6a (1R,3S): Colorless crystals (0.88 g, 35%); m.p. 75°C; IR (KBr): 3210 (NH), 1665 (C_O),
1
1179 cm−1 (P_O). H NMR (CDCl3): δ (ppm)=1.91–2.07 (m, 1H, HCH), 2.25–2.49 (m, 1H, HCH),
2.78 (d, J=6.6 Hz, 2H, PhCH2), 2.96–3.07 (m, 1H, NH, exchangeable), 3.14–3.31 (m, 1H, CHNHPO),
3.77 (s, 3H, OCH3), 5.20–5.28 [m, 1H, CHNHCHO, after H/D-exchange: 5.23 (dd, J=7.0, 5.2 Hz)],
6.76, 7.16 (AA0BB0, J=8.7 Hz, 4H, ArH), 6.94–7.03 (m, 2H, ArH), 7.21–7.57 (m, 11H, ArH), 7.72–7.85
(m, 2H, ArH), 8.10 (d, J=7.7 Hz, 1H, NHCHO, exchangeable), 8.14 (s, 1H, NCHO). Anal. calcd for
20
D
C30H31N2O3P (503.5): C, 72.27; H, 6.27; N, 5.62. Found: C, 72.12; H, 6.49; N, 5.43. [α] =−11.8
(c=0.45, CHCl3).
4.4.2. (1S,3S)- and (1R,3S)-N-[3-Diphenylphosphinamido-1-(4-methoxyphenyl)-5-methyl-1-hexyl]-
formamide (syn-6b; anti-6b)
Pale yellow oil (diastereomeric mixture; syn:anti, 50:50). The diastereomers were separated by column
chromatography (CH2Cl2:MeOH, 95:5). In addition to 0.13 g (9%) of a colorless oil (diastereomeric
mixture; syn:anti, 50:50), the following were obtained.
syn-6b (1S,3S): Colorless foam (0.48 g, 34%); IR (KBr): 3433 (NH), 1665 (C_O), 1181 cm−1 (P_O).
1H NMR (CDCl3): δ (ppm)=0.69 (d, J=6.6 Hz, 3H, CH3), 0.81 (d, J=6.6 Hz, 3H, CH3), 1.41 (dd, J=7.0
Hz, 2H, CH2CH(CH3)2), 1.67–1.97 (m, 2H, CH(CH3)2 and HCH), 2.40 (ddd, J=14.2, 10.8, 3.8 Hz, 1H,
HCH), 2.78–2.89 (m, 1H, NH, exchangeable), 3.05–3.21 (m, 1H, CHNH), 3.76 (s, 3H, OCH3), 4.90–5.01
[m, 1H, CHNHCHO, after H/D-exchange: 4.98 (dd, J=10.8, 4.0 Hz)], 6.80, 7.22 (AA0BB0, J=8.7 Hz, 4H,
ArH), 7.40–7.58 (m, 6H, ArH), 7.70 (d, J=7.6 Hz, NH, exchangeable), 7.77–7.99 (m, 4H, ArH), 8.14 (s,
1H, NCHO). Anal. calcd for C27H33N2O3P (464.5): C, 69.81; H, 7.16; N, 6.03. Found: C, 69.76; H, 7.21;
20
D
N, 5.99. [α] =−98.0 (c=1.34, CHCl3).
anti-6b (1R,3S): Colorless foam (0.48 g, 34%); IR (KBr): 3205 (NH), 1669 (C_O), 1181 cm−1
1
(P_O). H NMR (CDCl3): δ (ppm)=0.60–0.69 (m, 6H, 2CH3), 1.23–1.70 (m, 3H, CH2CH(CH3)2 and
CH(CH3)2), 1.88 (ddd, J=14.6, 5.0, 4.9 Hz, 1H, HCH), 2.32 (ddd, J=14.6, 8.4, 4.7 Hz, 1H, HCH),
2.90–3.08 (m, 2H, CHNH and NH, exchangeable), 3.77 (s, 3H, OCH3), 5.13–5.21 [m, 1H, CHNHCHO,
after H/D-exchange: 5.16 (dd, J=8.4, 4.7 Hz)], 6.80, 7.25 (AA0BB0, JAB=8.7 Hz, 4H, ArH), 7.38–7.60
(m, 6H, ArH), 7.79–7.99 (m, 4H, ArH), 8.14 (s, 1H, NCHO), 8.35 (d, J=7.9 Hz, 1H, NH, exchangeable).
Anal. calcd for C27H33N2O3P (464.5): C, 69.81; H, 7.16; N, 6.03. Found: C, 69.80; H, 7.33; N, 5.97.
20
D
[α] =−30.3 (c=1.14, CHCl3).

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A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
4.5. (1S,3S)- and (1R,3S)-N-[1-(4-Methoxyphenyl)-4-phenyl-3-p-toluenesulfonamido-1-butyl]form-
amide (syn-7; anti-7)
syn-7 (1S,3S): At 0°C, to a stirred solution of 3-isocyano-p-toluenesulfonamide syn-3a (0.22 g, 0.5
mmol) in Et2O (100 ml), concd HCl (1.1 ml) was added. The cooling bath was removed, and stirring
was continued for 5 min. The mixture was shaken with saturated NaHCO3 solution (30 ml), the layers
were separated, and the aqueous layer was extracted with Et2O (2×30 ml). The combined organic layers
were washed with brine (2×15 ml), dried and evaporated. Recrystallization from CH2Cl2/petroleum ether
afforded syn-7 (0.19 g, 84%) as colorless crystals: m.p. 72°C; IR (KBr): 3344 (NH), 1665 (C_O), 1315,
1
1153 cm−1 (S_O). H NMR (CDCl3): δ (ppm)=1.90–2.02 (m, 1H, HCH), 2.09–2.23 (m, 1H, HCH),
2.41 (s, 3H, CH3), 2.64, 2.89 (ABX, JAB=13.7 Hz, JAX=6.3 Hz, JBX=6.7 Hz, 2H, PhCH2), 3.25–3.40
(m, 1H, CHNHTs), 3.79 (s, 3H, OCH3), 4.77 (d, J=7.0 Hz, 1H, NHTs, exchangeable), 4.93 (dd, J=7.2
Hz, 1H, ArCHN), 5.83 (d, J=7.8 Hz, 1H NHCHO, exchangeable), 6.78, 6.93 (AA0BB0, J=8.7 Hz, 4H,
ArH), 6.90–7.04 (m, 2H, ArH), 7.10–7.28 (m, 5H, ArH), 7.49–7.60 (m, 2H, ArH), 8.16 (s, 1H, NCHO).
Anal. calcd for C25H28N2O4S (452.6): C, 66.35; H, 6.24; N, 6.19. Found: C, 66.13; H, 6.31; N, 6.30.
20
[α] =−4.1 (c=0.32, EtOH).
D
anti-7 (1R,3S): Starting from anti-3a (0.22 g, 0.5 mmol), and following the procedure described for
the preparation of syn-7, using half amounts of Et2O (50 ml) and concd HCl (0.55 ml); anti-7 (0.20 g,
88%) was obtained after recrystallization from CH2Cl2/petroleum ether as colorless crystals: m.p. 70°C;
1
IR (KBr): 3377 (NH), 1670 (C_O), 1324, 1156 cm−1 (S_O). H NMR (CDCl3): δ (ppm)=1.74–1.86
(m, 1H, HCH), 2.04–2.29 (m, 1H, HCH), 2.39 (s, 3H, CH3), 2.59, 2.76 (ABX, JAB=13.9 Hz, JAX=6.1
Hz, JBX=7.3 Hz, 2H, PhCH2), 3.20–3.32 (m, 1H, CHNHTs), 3.82 (s, 3H, OCH3), 4.64 (d, J=7.0 Hz, 1H,
NHTs, exchangeable), 5.09 (dd, J=7.2 Hz, 1H, ArCHN), 6.07 (d, J=7.8 Hz, 1H NHCHO, exchangeable),
6.88, 7.18 (AA0BB0, J=8.7 Hz, 4H, ArH), 6.79–6.93 (m, 2H, ArH), 7.05–7.34 (m, 5H, ArH), 7.36–7.48
(m, 2H, ArH), 8.14 (s, 1H, NCHO). Anal. calcd for C25H28N2O4S (452.6): C, 66.35; H, 6.24; N, 6.19.
20
D
Found: C, 66.14; H, 6.39; N, 6.26. [α] =+5.8 (c=0.38, EtOH).
4.6. (2S,4S)- and (2S,4R)-N-[4-Amino-4-(4-methoxyphenyl-1-phenyl-2-butyl]-p-toluenesulfonamide
hydrochloride (syn-8·HCl; anti-8·HCl)
syn-8·HCl (2S,4S): A solution of syn-3a (1.52 g, 3.5 mmol) in 2 N HCl (70 ml) and dioxane (140 ml)
was stirred for 1 h at room temperature and then refluxed for 6 h. The mixture was evaporated in vacuo to
dryness, and the residue was triturated with Et2O to afford syn-8·HCl (1.54 g, 95%) as colorless crystals:
1
m.p. 236°C; IR (KBr): 3423 (NH), 1325, 1148 cm−1 (S_O). H NMR (CDCl3): δ (ppm)=2.28–2.70
[m, 4H, PhCH2 and CH2CHNHTs, after H/D-exchange: 2.48 (d, J=7.2 Hz, PhCH2)], 2.33 (s, 3H, CH3),
3.10–3.28 (m, 1H, CHNHTs), 3.71 (s, 3H, OCH3), 4.60 [m, 1H, CHNH+3 , after H/D-exchange: 4.52 (dd,
J=8.7, 4.6 Hz)], 6.65–6.73 (m, 2H, ArH), 6.77, 7.28 (AA0BB0, J=8.7 Hz, 4H, ArH), 6.91–7.03 (m, 3H,
ArH), 7.09, 7.53 (AA0BB0, J=8.2 Hz, 4H, ArH), 7.43 (d, J=7.9 Hz, 1H, NHTs, exchangeable), 8.34 (s,
20
3H, NH+, exchangeable). [α] =−70.2 (c=0.50, CHCl3).
D
3
anti-8·HCl (2S,4R): The same procedure as described above for the preparation of syn-8·HCl was used
to afford anti-8·HCl (1.51 g, 93%) as colorless crystals: m.p. 222°C; IR (KBr): 3423 (NH), 1304, 1156
1
cm−1 (S_O). H NMR (CDCl3): δ (ppm)=2.29–2.79 (m, 4H, PhCH2 and CH2CHNHTs), 2.33 (s, 3H,
CH3), 3.35–3.51 (m, 1H, CHNHTs), 3.73 (s, 3H, OCH3), 4.58 [m, 1H, CHNH+3 , after H/D-exchange:
4.55 (dd, J=8.1, 6.5 Hz)], 6.23 (d, J=7.9 Hz, 1H, NHTs, exchangeable), 6.71–6.80 (m, 2H, ArH), 6.8+3,
7.44 (AA0BB0, J=8.6 Hz, 4H, ArH), 6.90–7.08 (m, 5H, ArH), 7.30–7.41 (m, 2H, ArH), 8.63 (s, 3H, NH3 ,
20
D
exchangeable). [α] =−73.7 (c=0.70, CHCl3).

A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
1011
4.7. (2S,4S)- and (2S,4R)-N-[4-Amino-4-(4-methoxyphenyl)-1-phenyl-2-butyl]-p-toluenesulfonamide
(syn-8; anti-8)
syn-8 (2S,4S): To syn-8·HCl (1.38 g, 3 mmol) a saturated Na2CO3 solution was added and the
resulting mixture was extracted with CH2Cl2 (3×100 ml). The combined CH2Cl2 layers were dried and
evaporated. Recrystallization from toluene gave syn-8 (1.12 g, 87%) as colorless crystals: m.p. 106°C;
1
IR (KBr): 3367, 3297 (NH), 1324, 1157 cm−1 (S_O). H NMR (CDCl3): δ (ppm)=1.46–1.75 (m, 5H,
CH2CHNH, NHTs and NH2, exchangeable), 2.44 (s, 3H, CH3), 2.66, 2.98 (ABX, JAB=13.5 Hz, JAX=3.9
Hz, JBX=8.3 Hz, 2H, PhCH2), 3.33–3.50 (m, 2H, CHNHTs and CHNH2), 3.76 (s, 3H, OCH3), 6.77, 6.89
(AA0BB0, J=8.7 Hz, 4H, ArH), 7.00–7.10 (m, 2H, ArH), 7.12–7.19 (m, 3H, ArH), 7.32, 7.80 (AA0BB0,
J=8.1 Hz, 4H, ArH). Anal. calcd for C24H28N2O3S (424.57): C, 67.90; H, 6.65; N, 6.60. Found: C, 67.91;
20
D
H, 6.56; N, 6.48. [α] =+37.5 (c=0.48, CHCl3).
anti-8 (2S,4R): Starting from anti-8a·HCl and following the same procedure as described above for the
preparation of syn-8, anti-8 (1.01 g, 79%) was obtained as colorless crystals: m.p. 108°C; IR (KBr): 3450,
3340, 3301 (NH), 1306, 1148 cm−1 (S_O). 1H NMR (CDCl3): δ (ppm)=1.51–1.80 (m, 5H, CH2, NHTs
and NH2, exchangeable), 2.41 (s, 3H, CH3), 2.60–2.71 (m, 2H, PhCH2), 3.60–3.71 (m, 1H, CHNHTs),
3.78 (s, 3H, OCH3), 4.06 (dd, J=9.3, 4.3 Hz, 1H, CHNH2), 6.82, 7.08 (AA0BB0, J=8.7 Hz, 4H, ArH),
6.90–7.00 (m, 2H, ArH), 7.12–7.20 (m, 3H, ArH), 7.24, 7.68 (AA0BB0, J=8.1 Hz, 4H, ArH). Anal. calcd
20
D
for C24H28N2O3S (424.57): C, 67.90; H, 6.65; N, 6.60. Found: C, 67.83; H, 6.66; N, 6.53. [α] =+15.2
(c=0.54, CHCl3).
4.7.1. syn-8 From 3-toluenesulfonamido-formamide syn-7
A solution of syn-7 (0.45 g, 1 mmol) in 10% ethanolic KOH (50 ml) was stirred overnight at
50°C. EtOH was removed in vacuo, water (30 ml) was added, and the mixture was extracted with
EtOAc (3×50 ml). The combined organic layers were washed with brine, dried and evaporated. Column
chromatography (EtOAc:MeOH, 9:1) and recrystallization from toluene afforded syn-8 (0.31 g, 74%).
4.8. (2S,4S)- and (2S,4R)-N-[4-Amino-4-(4-methoxyphenyl)-1-phenyl-2-butyl]-diphenylphosphinamide
(syn-9; anti-9)
syn-9 (2S,4S): A solution of syn-6a (0.75 g, 1.5 mmol) in 10% ethanolic KOH (80 ml) was stirred for
6.5 h at 50°C. EtOH was removed in vacuo, water (80 ml) was added, and the mixture was extracted
with EtOAc (3×100 ml). The combined organic layers were washed with brine (2×15 ml), dried and
evaporated. Column chromatography (CH2Cl2:MeOH, 9:1) and recrystallization from toluene afforded
syn-9 (0.48 g, 68%) as colorless crystals: m.p. 131°C; IR (KBr): 3386 (NH and NH2), 1180 cm−1 (P_O).
1H NMR (CDCl3): δ (ppm)=1.67 (s, 2H, NH2, exchangeable), 1.85 (dd, J=6.7 Hz, 2H, CH2), 2.70–2.90
(m, 2H, PhCH2), 3.25–3.94 (m, 2H, CHN and NH, exchangeable), 3.77 (s, 3H, OCH3), 4.10 (dd, J=7.0
Hz, 1H, CHNH2), 6.76, 7.09 (AA0BB0, J=8.7 Hz, 4H, ArH), 6.97–7.04 (m, 4H, ArH), 7.15–7.53 (m,
7H, ArH), 7.61–7.90 (m, 4H, ArH). Anal. calcd for C29H31N2O2P (470.5): C, 74.02; H, 6.64; N, 5.95.
20
D
Found: C, 73.86; H, 6.70; N, 6.02. [α] =−23.75 (c=0.56, CHCl3).
anti-9 (2S,4R): Starting from anti-6a, and following the procedure described for the preparation of syn-
9, anti-9 (0.44 g, 63%) was obtained as colorless crystals: m.p. 163°C; IR (KBr): 3423 (NH and NH2),
1179 cm−1 (P_O). 1H NMR (CDCl3): δ (ppm)=1.69–1.81 (m, 1H, HCH), 1.83–2.03 (m, 3H, HCH and
NH2, exchangeable), 2.86 (d, J=6.3 Hz, 2H, PhCH2), 3.32–3.51 (m, 1H, CHN), 3.64–3.72 (m, 1H, NH,
exchangeable), 3.77 (s, 3H, OCH3), 4.18 (dd, J=9.5, 4.7 Hz, 1H, CHNH2), 6.80, 7.16 (AA0BB0, J=8.7
Hz, 4H, ArH), 7.00–7.56 (m, 11H, ArH), 7.60–7.72 (m, 2H, ArH), 7.80–7.91 (m, 2H, ArH). Anal. calcd

1012
A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
20
D
for C29H31N2O2P (470.5): C, 74.02; H, 6.64; N, 5.95. Found: C, 73.72; H, 6.81; N, 5.94. [α] =−10.7
(c=0.88, CHCl3).
4.9. (1S,3S)- and (1R,3S)-1-(4-Methoxyphenyl)-4-phenyl-1,3-diaminobutane (syn-10; anti-10)
4.9.1. From 3-amino-p-toluenesulfonamides 8
syn-10 (1S,3S): To a solution of syn-8 (0.78 g, 1.83 mmol) in dry THF (20 ml) a solution of
sodium naphthalenide [31 ml; prepared by stirring naphthalene (3.96 g, 31.2 mmol) and small pieces
of sodium (1.92 g, 83.8 mmol) in dry THF (120 ml) for 3 h at room temperature under nitrogen] was
added over 10 min at −78°C. After 6.5 h at −78°C, water (5 ml) was added, and THF was removed
under reduced pressure. The mixture was diluted with water (10 ml) and extracted with EtOAc (3×30
ml). The combined EtOAc layers were washed with brine (2×20 ml), dried and evaporated. Column
chromatography (CH2Cl2:MeOH, 90:10) afforded syn-10 (0.17 g, 39%) as a colorless oil: IR (NaCl):
3357 cm−1 (NH). 1H NMR (CDCl3): δ (ppm)=1.76–2.05 (m, 2H, CH2), 2.80 [d, J=6.9 Hz, 2H, PhCH2,
after H/D-exchange: 2.52, 2.75 (ABX, JAB=13.3 Hz, JAX=5.1 Hz, JBX=8.3 Hz)], 3.10–3.26 (m, 1H,
CHCH2Ph, after H/D-exchange: 2.89–3.00), 3.72 (s, 3H, OCH3), 4.00 [dd, J=9.4, 4.5 Hz, 1H, ArCHCH2,
after H/D-exchange: 4.01 (dd, J=7.1 Hz)], 4.22 (s, 4H, 2 NH2, exchangeable), 6.85, 7.12 (AA0BB0, J=8.3
20
D
Hz, 4H, ArH), 7.15–7.22 (m, 5H, ArH). [α] =+14.15 (c=0.53, CHCl3).
anti-10 (1R,3S): Starting from anti-8, and following the procedure described for the preparation of syn-
10, anti-10 (0.15 g, 35%) was obtained as a colorless oil: IR (NaCl): 3357 cm−1 (NH). 1H NMR (CDCl3):
δ (ppm)=1.68–1.95 (m, 2H, CH2), 2.37 (s, 4H, 2NH2, exchangeable), 2.61, 2.83 (ABX, JAB=13.4 Hz,
J
AX=5.3 Hz, JBX=8.4 Hz, 2H, PhCH2), 3.10–3.22 (m, 1H, CHCH2Ph), 3.79 (s, 3H, OCH3), 4.23 [dd,
J=8.2, 5.1 Hz, 1H, ArCHNH2, after H/D-exchange: 4.10 (dd, J=8.5, 5.5 Hz)], 6.86, 7.14 (AA0BB0, J=8.4
20
D
Hz, 4H, ArH), 7.18–7.31 (m, 5H, ArH). [α] =+4.0 (c=0.15, CHCl3).
4.9.2. From 3-phosphinamido-formamide syn-6a
syn-10 (1S,3S): syn-6a (0.50 g, 1 mmol) was stirred with concd HCl (12 ml) for 15 min at room
temperature and for 4 h at 50°C. The suspension was allowed to cool to room temperature and filtered.
The filter cake was washed with 2 N HCl (2×10 ml), the combined filtrates were basified with 6 N
NaOH and extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried and evaporated.
Column chromatography (CH2Cl2:MeOH, 90:10) afforded syn-10 (0.16 g, 60%) as a colorless oil.
4.9.3. From 3-amino-phosphinamide anti-9
anti-10 (1R,3S): Starting from anti-9 (1.88 g, 4.0 mmol), and following the procedure described for
the preparation of syn-10, using 20 ml of concd HCl and a reaction time of 2.5 h at 50°C, anti-10 (0.99
g, 91%) was obtained as a colorless oil.
4.10. (1S,3R)-1-(4-Methoxyphenyl)-4-methyl-1,3-diaminopentane (syn-11)
Starting from syn-5b (0.37 g, 0.8 mmol), and following the procedure described for the preparation
of syn-10, using 4 ml of concd HCl, syn-11 (0.13 g, 75%) was obtained as a colorless oil: IR (NaCl):
3359 cm−1 (NH). 1H NMR (CDCl3): δ (ppm)=0.82 (d, J=6.8 Hz, 3H, CH3), 0.85 (d, J=6.8 Hz, 3H, CH3),
1.49–1.82 (m, 7H, CH2, CH(CH3)2 and 2NH2, exchangeable), 2.40–2.50 (m, 1H, CHNH2), 3.80 (s, 3H,
20
OCH3), 4.03 (dd, J=7.0 Hz, 1H, ArCHCH2), 6.87, 7.25 (AA0BB0, J=8.3 Hz, 4H, ArH). [α] =+8.9
D
(c=0.12, CHCl3).

A. Kaiser, M. Balbi / Tetrahedron: Asymmetry 10 (1999) 1001–1014
1013
4.11. (4S,6S)- and (4R,6S)-4-(4-Methoxyphenyl)-6-(phenylmethyl)hexahydropyrimidin-2-one (cis-12;
trans-12)
cis-12 (4S,6S): To a stirred solution of syn-10 (0.27 g, 1 mmol) in CH2Cl2 (15 ml), carbonyldiimidazole
(0.20 g, 1.1 mmol) was added, and stirring was continued for 0.5 h. The solution was washed with 2 N
HCl (10 ml), saturated NaHCO3 solution (2×10 ml) and brine (2×10 ml), dried and evaporated. The
crude product was purified by column chromatography (CH2Cl2:MeOH, 95:5): Colorless crystals (0.12
1
g, 40%); m.p. 149°C (toluene); IR (KBr): 3425, 3236 (NH), 1677 cm−1 (C_O). H NMR (CDCl3): δ
(ppm)=1.64 (dd, J=13.1, 11.4 Hz, 1H, HCH), 2.00–2.11 [m, 1H, HCH, after H/D-exchange: 2.04 (ddd,
J=13.1, 3.5, 3.3 Hz)], 2.69, 2.83 (ABX, JAB=13.4 Hz, JAX=7.9 Hz, JBX=6.2 Hz, 2H, PhCH2), 3.70–3.76
[m, 1H, CHBn, after H/D-exchange: 3.75 (dddd, J=11.3, 7.9, 6.2, 3.3 Hz)], 3.80 (s, 3H, OCH3), 4.43 (dd,
J=11.4, 3.5 Hz, CHPh-4-OMe), 4.93 (s, 1H, NH, exchangeable), 5.01 (s, 1H, NH, exchangeable), 6.88,
7.21 (AA0BB0, J=8.8 Hz, 4H, ArH), 7.11–7.39 (m, 5H, ArH). Anal. calcd for C18H20N2O2 (296.4): C,
20
D
72.95; H, 6.80; N, 9.45. Found: C, 72.39; H, 6.81; N, 9.20. [α] =−36.25 (c=0.24, CHCl3).
trans-12 (4R,6S): Starting from anti-10, and following the procedure described for the preparation of
cis-12, trans-12 (0.13 g, 43%) was obtained as colorless crystals: m.p. 192°C (EtOH); IR (KBr): 3255
(NH), 1682 cm−1 (C_O). 1H NMR (CDCl3): δ (ppm)=1.94–2.05 [m, 2H, CH2, after H/D-exchange: 1.97
(ddd, J=13.2, 5.5, 5.2 Hz, HCH)], 2.03 (ddd, J=13.2, 6.9, 5.0 Hz, HCH)], 2.69, 2.83 (ABX, JAB=13.4
Hz, JAX=9.0 Hz, JBX=5.1 Hz, 2H, PhCH2), 3.42–3.59 [m, 1H, CHBn, after H/D-exchange: 3.49 (dddd,
J=9.0, 6.9, 5.2, 5.1 Hz)], 3.81 (s, 3H, OCH3), 4.60–4.73 [m, 2H, CHPh-4-OMe and NH, exchangeable,
after H/D-exchange: 4.64 (dd, J=5.5, 5.0 Hz)], 4.93 (s, 1H, NH, exchangeable), 6.89, 7.20 (AA0BB0,
J=8.7 Hz, 4H, ArH), 7.10–7.34 (m, 5H, ArH). Anal. calcd for C18H20N2O2 (296.4): C, 72.95; H, 6.80;
20
D
N, 9.45. Found: C, 72.53; H, 7.07; N, 9.39. [α] =−11.7 (c=0.29, CHCl3).
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