Facile and highly stereoselective synthesis of the C2-symmetrical diamino diol core-unit of HIV-1 protease inhibitors and of their symmetrical and unsymmetrical analogs from lithiated 2-(dibenzylamino)alkyl carbamates: Oxidative dimerization

Article abstract of DOI:10.1055/s-1999-3576

The lithio derivatives of (S)-and (R)-2-(N,N-dibenzylamino)alkyl carbamates 3 and ent-3, generated by substrate-directed deprotonation from the precursors 2 and ent-2, add with high diastereoselectivity to (S)-2-(N,N- dibenzylamino)alkanals. The (S)-aminoaldehyde 5a, derived from (S)- phenylalanine, is produced in situ from the lithium compound 3a by the controlled addition of dioxygen to the reaction mixture affording the protected anti,syn,anti-α,δ-diamino-β,γ-diol 6aa which is the core unit of anti-HIV 1 protease agents. Several symmetric and unsymmetric structure analogs, differing in the substitution pattern and the configurations, have been synthesized. A further approach to the title compound is given by the acylation of lithium derivatives 3/4, followed by a hydride reduction. The reaction of the lithium derivatives 3a/4a with CuCl leads to an eliminative oxidative coupling with formation of (3 E/Z, 2S,5S)-2,5-dibenzylamino-1,6- diphenylhex-3-enes (E)- and (Z)-26.

Full text of DOI:10.1055/s-1999-3576

PAPER
1593
Facile and Highly Stereoselective Synthesis of the C2-Symmetrical Diamino
Diol Core-Unit of HIV-1 Protease Inhibitors and of Their Symmetrical and
Unsymmetrical Analogs from Lithiated 2-(Dibenzylamino)alkyl Carbamates:
Oxidative Dimerization
B. Weber, S. Kolczewski, R. Fröhlich, D. Hoppe*
Institut für Organische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
Fax +49(251)83 39772; E-mail: dhoppe@uni-muenster.de
Received 25 February 1999
Dedicated to Professor Armin de Meijere on the occasion of his 60th birthday.
al and simple route leading to C2-symmetric diamino diols
Abstract: The lithio derivatives of (S)- and (R)-2-(N,N-diben-
10 and 13 (R1 = R2), to the configurational unsymmetrical
zylamino)alkyl carbamates 3 and ent-3, generated by substrate-di-
diastereomers 11 and 12, and as well, to the constitutional
rected deprotonation from the precursors 2 and ent-2, add with high
analogs 10–13 (R1 ≠ R2) is obvious: It consists in the ad-
diastereoselectivity to (S)-2-(N,N-dibenzylamino)alkanals. The (S)-
aminoaldehyde 5a, derived from (S)-phenylalanine, is produced in dition of the lithium reagents 3 and 4 onto (S)-2-(N,N-
situ from the lithium compound 3a by the controlled addition of di-
dibenzylamino)alkanals 5.
oxygen to the reaction mixture affording the protected anti,syn,anti-
α,δ-diamino-β,γ-diol 6aa which is the core unit of anti-HIV 1 pro-
tease agents. Several symmetric and unsymmetric structure analogs,
Taking into account the ratio of epimers 3 and 4 and the
Re-facial selectivity predicted by the Felkin–Anh model5
of (S)-2-(N,N-dibenzylamino)alkanals 5, which are easily
prepared from natural L-amino acids,6 the adducts 6 and 8
are expected to be the major isomers. The efficient synthe-
sis of the diastereomers 7 and 9, which are not found as
byproducts, should require more indirect approaches. We
present in this paper a flexible brick-box system for the
preparation of different stereoisomers and analogs of 1 by
reliable and predictable routes, including oxidative dimer-
ization of 3 and 4.
differing in the substitution pattern and the configurations, have
been synthesized. A further approach to the title compound is given
by the acylation of lithium derivatives 3/4, followed by a hydride re-
duction. The reaction of the lithium derivatives 3a/4a with CuCl
leads to an eliminative oxidative coupling with formation of (3E/Z,
2S,5S)-2,5-dibenzylamino-1,6-diphenylhex-3-enes (E)- and (Z)-26.
Key words: 2,5,-diamino-1,6-diphenylhexane-3,4-diols, dioxygen,
oxidative coupling, TMEDA-mediated deprotonation, lithiation,
HIV-1 protease inhibitors
Introduction
Results and Discussion
C2-Symmetric 2,5-diamino-1,6-diphenylhexane-3,4-diols
1 find application as core-units of pseudopeptides capable
of very efficient HIV-1 protease inhibition.1 Several ap-
proaches for their synthesis have been published,2 among
them pinacol-type homo- and cross-coupling reactions of
α-aminoalkanals with low-valent metal salts2a–c or by ela-
boration of compounds from the “chiral pool” such as D-
mannitol2d,e or D-tartrate.2f,g
Aldehyde Addition Reactions
The addition of 3a/4a (approx. 90:10), prepared by the
TMEDA-assisted deprotonation3b of the (S)-phenyl-
alaninol carbamate 2a, to the amino aldehyde 5a yielded
6aa as a single product in 61% yield, besides some start-
ing material 2a (Scheme 1, Table 1). Another diastere-
omer could not be detected. The same procedure for
homo-coupling, starting from the (S)-leucinol derivatives
2b (via 3b/4b, 80:20) and 5b, afforded a separable mix-
ture of 6bb and 8bb (88:12) in 79% yield. The appropriate
(S)-phenylglycinol pair 2c/5c - via 3c/4c (40:60) - yielded
the epimers 6cc and 8cc (52%, 33:67). In the latter two ex-
amples, the diastereomer ratio roughly reflects the epimer
ratio in the carbanionic intermediates 3/4.
Figure 1 2,5-Diamino-1,6-diphenyl-3,4-hexanediols 1
When performing cross-coupling reactions we were sur-
prised when an apparently lower selectivity was observed.
The reaction of 2a and 5b gave after usual workup, which
includes warming-up the reaction mixture before neutral-
ization to room temperature, in addition to the expected
product 6ab (48%), another unknown isomer in 25% yield
(ratio 66:34) (Scheme 2). When the reaction mixture was
neutralized by formic acid at −78°C, the ratio shifted to
We found recently,3 that the carbamates 2, derived from
(S)-2-(N,N-dibenzylamino)alkanols, are easily deproto-
nated by sec-butyllithium/TMEDA adjacent to the car-
bamate moiety4 to form the epimeric lithium compounds
3 and 4 with good diastereoselectivities (90:10 for 2a,
R1 = CH2Ph, Scheme 1).3b From this observation, a gener-
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B. Weber et al.
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Scheme 1
Scheme 1
83:17. After deblocking the hydroxy group in both iso- rangement proceeds on the stage of the originally pro-
mers the same diol 10ab was obtained. On the basis of duced lithium alcoholates 14ab/15ab. Further support
these results it became clear, that the unknown compound comes from the deblocking of the constitutionally inverse
differs from 6ab only in the position of the O-carbamoyl mixture 6ba/16ba [R1 = (CH3)2CHCH2, R2 = C6H5CH2] to
group and has to be assigned the structure 16ab. The rear- give also the diol 10ab. This feature already excludes the
Table 1 Coupling Products 6, 8, and 16 Prepareda
Products
Starting
Materials
R1
R2
Yield (%)
(Ratio)
mpb
(°C)
[a]2D2c
6aa
6ab (=16ba),
16ab (=6ba)
2a,5a
2a,5b
C6H5CH2
C6H5CH2
C6H5CH2
(CH3)2CHCH2
61
72–73
58–62,
56–61
+17.7
–28.5
–24.9
48, 25 (66:34)d
77 (83:17)e
45
47, 36 (57:43)
6ac
6ad,16ad
2a,5c
2a,5d
C6H5CH2
C6H5CH2
C6H5
(CH3)2CH
71–75
49–51,
51–54
48–50,
50–52
48–50
–f,
+31.4
– 4.0
–22.6
–53.8
–23.4
–53.8
–f,
6bb,8bb
2b,5b
(CH3)2CHCH2
(CH3)2CHCH2
68, 11 (86:14)
6ba,16ba,8ba
6cc,8cc
2b,5a
2c,5c
(CH3)2CHCH2
C6H5
C6H5CH2
C6H5
44, 22, 17 (53:27:20)
13, 39 (33:67)
84–88
+63.4
a All new compounds gave correct C,H-analyses (C 0.4, H 0.4).
b From Et2O/pentane.
c (c = 1, CH2Cl2).
d Hydrolysis at room temperature.
e Hydrolysis at –78°C.
f Mixture of 6cc and 2c, which is not separable by flash chromatography.
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Stereoselective Synthesis of C2-Symmetrical Diamino Diol Core-Unit of HIV-1 Protease Inhibitors
1595
ium salts of hemiacetals 21, and elimination of the lithium
carbamate (LiOCby) furnishes the intermediate aldehydes
5 which undergo addition to the remaining lithium com-
pounds 3. Surprisingly the diastereomeric purity of 6bb is
higher than in the two-step process described above. We
assume that the minor epimer 4b has a higher reactivity in
the oxidation process and is removed preferentially.
Scheme 2
structures 7 and 8 to be the major isomers, since here dif-
ferent diols must be formed from constitutionally inverse
isomers.
As Scheme 3 demonstrates, further series of diastere-
omers can be synthesized by selecting both starting mate-
rials with different absolute configurations. From the (R)-
2-(N,N-dibenzylamino)butyl carbamate ent-2e,3d via
TMEDA-mediated deprotonation and addition to (S)-
N,N-dibenzylalaninal (5f), the adduct 18 was prepared to
give a single all-anti-diol 19 on O-deprotection.
Scheme 4
We also undertook some experiments for accomplishing a
“true” oxidative coupling of the carbanionic intermediates
3a/4a by means of copper(II)8 and copper(I)9 salts
(Scheme 5). After treating 3a/4a with 1 equivalent of
CuBr2 and finally with dioxygen, from the multicompo-
nent reaction mixture, the dimer 23aa (30%) and again
6aa (10%) could be isolated. Thus, minor amounts of fur-
ther diastereomers can not be excluded. Presumably the
(configurationally labile) radical 22 is the intermediate,
which dimerizes with pronounced substrate-induced dia-
stereoselectivity.
Using CuCl as the oxidation reagent, a surprising result
was obtained. An E/Z-mixture of the diaminoalkenes 26
was isolated; the relative configuration of (Z)-26 was elu-
cidated by a single crystal X-ray analysis10 (Figure 2). We
assume the copper(I) carbene complex 25 to be the essen-
tial intermediate.11
Scheme 3
anti,anti,syn-Diols 11 via Acylation/Reduction
An efficient, selective approach to the anti,anti,syn-diols
11 consists in the acylation of the lithiocarbamates 3/4 by
(S)-N,N-dibenzylamino acid benzyl esters 27 and reduc-
tion of the ketones 28 (Scheme 6, Table 2). When the re-
duction is performed with LiAlH4 in refluxing THF, the
carbamate group is removed simultaneously to give di-
rectly the pure alcohols 11 via the carbamates 7. Obvious-
ly, the stereodirecting power of the chiral centers in 3 and
28 is extremely high, since no other diastereomers could
be detected by TLC or 1H NMR spectroscopy. The prize
Oxidative Coupling
When dioxygen was introduced to the ethereal solution of
the lithium/TMEDA complexes 3a/4a or 3b/4b in a con-
trolled way, the aldehyde adducts 6aa (48%) or 6bb
(44%) could be isolated as the sole diastereomers besides
some starting material 2a (23%) or 2b (14%) (Scheme 4).
It is quite likely that the reaction starts with the formation
of the lithium peroxides7 20, which oxidize 3/4 to the lith-
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B. Weber et al.
PAPER
Scheme 6
Scheme 5
Figure 2 X-ray structure of (Z)-2610
to pay for the high selectivity is in some cases the low
yield, which arises from the low reactivity of the benzyl
esters 27.
Similarly, from the (R)-aminoalkyl carbamate ent-2e and
benzyl (S)-N,N-dibenzylalaninate (27f), the “mixed” ke-
tone 29 was obtained (Scheme 7). The reduction of 29
could be directed by the selection of the reducing agent:
LiAlH4 in diethyl ether at 0°C yielded the all-anti-mono-
carbamate 18 in excess, whereas lithium triethylboronate
furnished the anti,syn,syn-diastereomer 31. Monocarbam-
ate 18, on deprotection with excess LiAlH4, led to the
crystalline diol 19, from which an X-ray analysis12 was
performed (Figure 3).
Scheme 7
is the most convenient procedure on a laboratory scale4
(Method A, Scheme 8, Table 3). The usual procedure,
which consists in the acid-catalyzed cleavage of the ox-
azolidine ring and subsequent base-catalyzed cleavage of
the intermediate N-hydroxyalkylcarbamate4,13 was ap-
Deprotection and Configurational Assignment
The reductive decarbamoylation of monocarbamates 6, 7,
or 8 to form the free bis(dibenzylamino)diols 10, 11, or 12
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Stereoselective Synthesis of C2-Symmetrical Diamino Diol Core-Unit of HIV-1 Protease Inhibitors
1597
Figure 3 X-ray structure of diol 1912
Scheme 9
plied (Method B, Scheme 8). 1,3-Propanedithiol was
used14 for deblocking the dicarbamate 23aa by transace-
talization and the bis(N-monoalkyl)carbamate 32 formed
was then treated with K2CO3/MeOH.
Finally, diols 10aa and 11aa were separately converted to
the known bis-Boc derivatives2a 37aa and 38aa via the di-
aminodiols 35aa and 36aa, respectively (Scheme 10).
Reagents and conditions: a) LiAlH4 (4 equiv)/THF, reflux, 5 h (Me-
thod A); b) i. MeSO3H (5 equiv)/MeOH, reflux, ii. K2CO3 (8 equiv)/
MeOH, reflux (Method B)
Scheme 10
Scheme 8
In conclusion, several methods are now available for the
synthesis of the enantiopure title compounds, differing in
the substitution pattern and the relative configuration by a
simple “brick-box system“.
Evidence for the correct stereochemical assignment of di-
ols 10aa, 10bb, and 10cc, in addition to the presented ar-
1
guments, comes from the H NMR spectra. As expected
from their C2-symmetry, the appropriate signals of the
“left hand” and the “right hand” side coincide. Com-
pounds 10aa, 10bb, 10ab and 10ad, bearing a syn-diol All reactions which are sensitive to moisture were carried out under
argon. All solvents were purified by distillation and dried, if neces-
unit, easily cyclized on treatment with dimethyl
sary, prior to use. 1H and 13C NMR spectra were recorded on Bruker
WM300, AM 360 or U600 spectrometer. Optical rotations were re-
corded on a Perkin-Elmer polarimeter 241 at 20°C. Mps were ob-
tained on Gallenkamp melting point apparatus MFB-595 and are
carbonate15 to give the trans-disubstituted 1,3-dioxolan-2-
ones 33 (J4,5 = 7.0–7.2 Hz)3b,16, whereas the diastereomers
7 failed to give the highly stericly encumbered cis-isomers
34.
uncorrected. Products were purified by flash column chromatogra-
phy on silica gel (40–63 µm).
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Table 2 Acylation Products 28, Diols 11, and Derivatives 7 Prepareda
Product
Starting
Materials
R1
R2
Yield (%)
mp
[a]2D2c
(°C)b
28aa
28ab
28bb
28ba
7aa
2a, 27a
2a, 27b
2b, 27b
2b, 27a
28aa
28bb
28aa
28ab
28bb
C6H5CH2
C6H5CH2
C6H5CH2
59
50
26
29
89e
93e
76
77
81
86
58–62
45–48
45–50
+35.1
+43.0
+14.3
(CH3)2CHCH2
(CH3)2CHCH2
C6H5CH2
C6H5CH2
(CH3)2CHCH2
C6H5CH2
(CH3)2CHCH2
(CH3)2CHCH2
C6H5CH2
(CH3)2CHCH2
(CH3)2CHCH2
C6H5CH2
(CH3)2CHCH2
C6H5CH2
C6H5CH2
(CH3)2CHCH2
(CH3)2CHCH2
d
d
–
–
68–72
46–49
53–56
47–50
46–49
57–59
–17.4
–32.2
+48.6
+32.2
+17.9
+52.4
7bb
11aa
11ab
11bb
11ba
28ba
a All new compounds gave correct C,H-analyses (C 0.4, H 0.4).
b From Et2O/pentane.
c (c = 1, CH2Cl2).
d Mixture of 28ba and 2b, which is not separable by flash column chromatography.
e Reduction with NaBH4 in EtOH.
Deprotonation of Carbamates 2 and ent-2 with s-BuLi/TMEDA
and Preparation of Substituted Products 6, 8, 16, 18, 28, and 29;
General Procedure
yields and physical data of substituted carbamates 6, 8 or 16 see Ta-
bles 1 and 4. For yields and physical data of substituted carbamates
28 see Tables 2 and 4.
Carbamate 2 or ent-2 (1.00 mmol) and TMEDA (232 mg, 2.00
mmol) were dissolved in anhyd Et2O (15 mL) under argon in a
dry ice/acetone bath and s-BuLi (1.3 M) in cyclohexane/hexane
(1.50 mL, 2.00 mmol) was added to the solution dropwise. After
stirring for 4 h (ent-2) or 6 h (2) the electrophile (3.00 mmol) was
slowly introduced with a syringe. The mixture was allowed to warm
up to r. t. for 12 h and H2O (10 mL) was added. The Et2O layer was
separated and the aqueous phase was extracted with Et2O (3 × 10
mL). The combined Et2O phases were dried (MgSO4) and evaporat-
ed in vacuo. The residue was purified by flash chromatography
(Et2O/pentane, 1:1 to 1:8) to afford the substituted carbamate. For
(2S,3S,4R,5R)-2,5-Bis(N,N-dibenzylamino)-4-O-(2,2,4,4-tetra-
methyl-1,3-oxazolidine-3-carbonyl)-3,4-heptanediol (18)
The reaction of ent-2e with (S)-N,N-dibenzylalaninal as electrophile
yielded 18 (583 mg, 86%, dr >95:<5) as a colorless solid; Rf 0.56
(Et2O/pentane, 1:1); mp 54–56°C (Et2O/pentane); [α]D +28.6
(c = 1, acetone).
Anal. Calcd. for C43H55N3O4 (677.9): C, 76.18; H, 8.18; Found C,
76.13; H, 8.23.
For 1H, 13C NMR, and IR data of 18, see Table 4.
Table 3 Deblocking of Monocarbamates 6, 7, 8, 18, and 30a
Product
Starting
Material
R1
R2
Method
Yield (%)
mp
[a]2D0c
(∞C)b
10aa
11aa
10ab
11ab
10ac
10ad
10dae
10bb
6aa
7aa
6ab
7ab
6ac
6ad
6da
6bb
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
(CH3)2CH
(CH3)2CHCH2
C6H5CH2
C6H5CH2
A
B
B
B
C
A
B
A
B
B
A
B
A
B
A
B
72
75
91
47
73
74
90
83
94
83
43
86
36
74
69
89
46–49
–
+ 2.0
–
d
d
(CH3)2CHCH2
(CH3)2CHCH2
C6H5
(CH3)2CH
C6H5CH2
43–47
–12.0
d
d
–
–
61–63
39–43
+43.4
–19.1
e
e
–
–
(CH3)2CHCH2
36–41
–23.2
d
d
11bb
12bbf
10cc
12cc
7bb
8bb
6cc
8cc
(CH3)2CHCH2
(CH3)2CHCH2
C6H5
(CH3)2CHCH2
(CH3)2CHCH2
C6H5
–
–
–
–
d
d
77–81
76–79
+83.6
+83.2
C6H5
C6H5
19
31
18
30
–
–
–
–
212–214
98–99
+11.4
+50.5
a All new compounds gave correct C,H-analyses (C 0.4, H 0.4).
b From Et2O/pentane.
c (c = 1, CH2Cl2).
d See Table 2.
e Compound 10da corresponds to 10ad.
f Compound 12bb corresponds to 11bb in Table 2.
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Stereoselective Synthesis of C2-Symmetrical Diamino Diol Core-Unit of HIV-1 Protease Inhibitors
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(2S,4R,5R)-2,5-Bis(N,N-dibenzylamino)-4-O-(2,2,4,4-tetrame-
thyl-1,3-oxazolidine-3-carbonyloxy)-3-heptanone (29)
ed with Et2O (3 × 20 mL). The combined organic layers were dried
(MgSO4) and the solvents were removed in vacuo. The residue was
purified by flash chromatography (Et2O/pentane, 1:8) to give 7aa or
7bb as pure product.
Benzyl (S)-N,N-dibenzylalaninate 27f was used as electrophile after
deprotonation of ent-2e. Purification of the crude product by flash
chromatography (Et2O/pentane 1:10→1:6) gave 29 (372 mg, 55%,
dr >95:<5) as a colorless solid; Rf 0.69 (Et2O/pentane, 1:1); mp
124–126°C (Et2O/pentane); [α]D −106.0 (c = 1, acetone).
For yields and physical data of 7aa and 7bb see Tables 2 and 4.
Reduction of Ketone 29; Preparation of Monocarbamates 18
and 30
Anal. Calcd. for C43H53N3O4 (675.9): C, 76.41; H, 7.90; Found C,
76.39; H, 7.94.
For 1H, 13C NMR, and IR data of 29 see Table 4.
R e d u c t i o n w i t h L i A l H 4 : A solution of ketone 29 (600 mg,
0.88 mmol) in anhyd Et2O (20 mL) was added dropwise to a suspen-
sion of LiAlH4 (57 mg, 1.50 mmol) in anhyd Et2O (10 mL) at 0°C.
The suspension was stirred for 1 h and then hydrolyzed with succes-
sively H2O (57 µL), 15% NaOH solution (57 µL), and H2O (171
µL). The precipitate was filtered off and washed with Et2O (20 mL).
The filtrate was dried (MgSO4) and the solvent was evaporated in
vacuo. The crude product was purified by flash chromatography
(Et2O/pentane, 1:8) to give 18 (440 mg, 74%) and 30 (110 mg,
18%) as colorless solids; diastereomeric ratio 80:20.
Dimerization of 2a in the Presence of CuBr2; (2S,3S,4S,5S)-2,5-
Bis(N,N-dibenzylamino)-1,6-diphenyl-3,4-bis(2,2,4,4-tetrame-
thyl-1,3-oxazolidine-3-carbonyloxy)hexane (23aa)
To a solution of carbamate 2a (486 mg, 1.00 mmol) and TMEDA
(232 mg, 2.00 mmol) in anhyd Et2O (15 mL) was added dropwise
s-BuLi (1.3 M) in cyclohexane/hexane (1.50 mL, 2.00 mmol) at
−78°C. Stirring was continued for 6 h and subsequently anhyd
CuBr2 (223 mg, 1.00 mmol) was added to the mixture under an ar-
gon stream. The slurry was allowed to warm up to r.t., oxygen
(12 mL, 0.5 mmol) was introduced via syringe during 30 min, and
finally H2O (10 mL) was added. The two layers were separated and
the aqueous phase was extracted with Et2O (3 × 10 mL). The com-
bined organic layers were washed with satd EDTA-solution, dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography (Et2O/pentane, 1:6→1:3) to yield 23aa
(291 mg, 30%) as a colorless solid and 6aa (82 mg, 10%) beside
some starting material 2a (44 mg, 9%); Rf 0.31 (Et2O/pentane, 1:2);
mp 94–98°C (Et2O/pentane); [α]D +22.2 (c = 1, CH2Cl2).
R e d u c t i o n w i t h L i E t 3 B H : To a solution of 29 (450 mg,
0.67 mmol) in THF (20 mL) was added LiEt3BH (2.60 mL, 2.60
mmol, 1.0M in THF) at 0°C. The mixture was refluxed for 2 d and
then hydrolyzed with H2O (5 mL). The aqueous layer was separated
and extracted with Et2O (3 × 15 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Purification of the
residue by flash chromatography (EtOAc/cyclohexane, 1:15) af-
forded the diastereomers 18 (20 mg, 4%) and 30 (310 mg, 69%) in
a ratio of 6:94 beside some starting material 29 (52 mg, 12%).
(2S,3R,4R,5R)-2,5-Bis(N,N-dibenzylamino)-4-O-(2,2,4,4-tetra-
methyl-1,3-oxazolidine-3-carbonyl)-3,4-heptanediol (30)
Rf 0.60 (Et2O/pentane, 1:1); mp 134–135°C (Et2O/pentane); color-
less solid; [α]D +64.2 (c = 1, acetone).
Anal. Calcd. for C62H74N4O6 (971.3): C, 76.67; H, 7.68; Found C,
76.67; H, 7.91.
For 1H, 13C NMR and IR data of 23aa see Table 4.
Anal. Calcd. for C43H55N3O4 (677.9): C, 76.18; H, 8.18; Found C,
75.93; H, 8.09.
For 1H, 13C NMR, and IR data of 30 see Table 4.
Conversion of 2a in the Presence of CuCl; cis- and trans-
(2S,5S)-2,5-Bis(N,N-dibenzylamino)-1,6-diphenyl-3-hexene (Z-
26 and E-26)
To a solution of carbamate 2a (486 mg, 1.00 mmol) and TMEDA
(232 mg, 2.00 mmol) in anhyd Et2O (15 mL) was added dropwise
s-BuLi (1.3 M) in cyclohexane/hexane (1.50 mL, 2.00 mmol) at −
78°C. After stirring for 5 h anhyd CuCl (150 mg, 1.50 mmol) was
added under an argon stream and the mixture was allowed to warm
up to r.t. Oxygen (12 mL, 0.5 mmol) was slowly introduced via sy-
ringe and then H2O (10 mL) was added. The two layers were sepa-
rated and the aqueous phase was extracted with Et2O (3 × 10 mL).
The combined organic layers were washed with satd EDTA-solu-
tion, dried (MgSO4) and the solvents were evaporated in vacuo. Pu-
rification of the crude product by flash chromatography (Et2O/
pentane, 1:12) afforded a mixture of (Z)-26 and (E)-26 (170 mg,
54%) as colorless crystals; ratio 47:53. (Z)-26 could be obtained as
pure diastereomer by recrystallization from CH2Cl2/pentane.
Simultaneous Reduction and Decarbamoylation of 28aa, 28bb,
28ab, and 28ba with LiAlH4; Preparation of Diols 11aa, 11bb,
11ab, and 11ba
LiAlH4 (0.5 mL, 0.5 mmol, 1M in Et2O) was added dropwise to a
solution of 28 (0.1 mmol) in THF or Et2O (5 mL) at 0°C. The ice
bath was removed and the suspension was refluxed for 24 h. After
successive hydrolysis with H2O (20 µL), aq NaOH (20 µL, 15%),
and H2O (60 µL) the slurry was heated under reflux for 30 min. The
solid materials were filtered off and washed with CH2Cl2 (10 mL).
The filtrate was dried (MgSO4) and the solvents were evaporated in
vacuo. Purification of the residue by flash chromatography (Et2O/
pentane, 1:8) yielded analytically pure diol 11.
For yields and physical data of diols 11aa, 11bb, 11ab, and 11ba
see Tables 2 and 4.
(Z)-26
Decarbamoylation of Monocarbamates 6, 7, 8, 18, and 30; Prep-
aration of Diols 10, 11, 12, 19, and 31; General Procedures
Method A: To a suspension of LiAlH4 (76 mg, 2.00 mmol) in anhyd
THF (7 mL), was added dropwise a solution of the monocarbamate
6 or 8 (0.50 mmol) in THF (8 mL) at 0°C. After heating under re-
flux for 6 h, the mixture was hydrolyzed successively with H2O (76
µL), 15% NaOH solution (76 µL), and H2O (228 µL) at 0°C. After
heating under reflux for further 30 min the precipitate was filtered
off and washed with THF (15 mL). The filtrate was dried (MgSO4)
and concentrated in vacuo. Flash chromatography of the residue
(Et2O/pentane, 1:4 to 1:8) afforded the free diol 10 or 12.
Rf 0.66 (Et2O/pentane, 1:2); mp 165–167°C (Et2O/pentane), color-
less crystals; [α]D +83.1 (c = 1, CH2Cl2).
Anal. [Mixture of (Z)-26 and (E)-26] Calcd. for C46H46N2 (626.9):
C, 88.14; H, 7.40; Found C, 88.05; H, 7.40.
For 1H, 13C NMR, and IR data of Z-26 and E-26 see Table 4.
Reduction of Ketones 28aa and 28bb with NaBH4 in EtOH;
Preparation of Monocarbamates 7aa and 7bb
NaBH4 (114 mg, 3.00 mmol) was added to a solution of ketone 28aa
(488 mg, 0.60 mmol) or 28bb (448 mg, 0.60 mmol) in EtOH (10
mL). The solution was stirred for 3 h at r.t. and then refluxed for
24 h. After addition of H2O (20 mL) the aqueous phase was extract-
Method B: A solution of the monocarbamate 6, 7, or 8 (1.00 mmol)
and MeSO3H (324 µL, 480 mg, 5.00 mmol) in MeOH (15 mL) was
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

1600
B. Weber et al.
PAPER
Table 4 Selected Data of Compounds 6, 7, 8, 10, 11, 12, 18, 19, 23, Z-26, E-26, 28, 29, 30, 31, and 33a
Product IR (KBr/
1H NMR (300 MHz, CDCl3), δ, J (Hz)
1’-H 2-H 2’-H N-CH2Ph
13C NMR (75 MHz, CDCl3), δ
film)
ν
1-H
C-1 C-1’ C-2 C-2’ N-CH2
Ph
(cm-1)
6aa
6bb
3420, 5.49 (dd,
1675
4.42 3.26– 2.93– 3.60, 3.82
(br s) 3.39 3.18b (2 d, 2JBn
(m) (m)
14.5), 3.68, 2.93–3.18b (m, 3-Hb,
2.58–2.73 (m, 3'-Ha),
2.74–2.88 (m, 3-Ha),
75.5 71.4 58.9 61.4 53.8, 32.7 (C-3'),
54.6 33.4 (C-3)
3J1,1’, 3J1,2
=
=
=
5.4, 8.3)
3.69 (2 d,
3'-Hb)
2JBn = 10.4)
3430, 5.36 (dd,
4.15 2.83– 2.62– 3.61, 3.89
(br s) 2.97 2.74 (2 d, 2JBn
(m) (m)
0.40, 0.49 (2 d, 3J4,5
= 6.4, 5-H3, 5'-H3),
14.3), 3.70, 0.84, 0.89 (2 d,
,
75.8 71.8 55.6 57.2 54.0,, 20.8, 21.0,
4’,5’
1680
3J1,1’, 3J1,2
=
54.7 23.8, 23.9
(C-5, C-5',
4-CH3, 4'-
CH3), 23.8,
23.9 (C-4,
C-4'), 34.9
(C-3'), 36.7
(C-3)
5.1, 10.1)
3.82, 3.84
3J4,4-
,
3 = 6.7,
CH
CH
4’4’-
(2 d, 2JBn
=
4-CH3,34'-CH3), 0.85–
0.96, 1.67–1.88b (2 m,
3'-Ha, 3'-Hb), 0.97–
1.12, 1.67–1.88b (2 m,
3-Ha, 3-Hb), 1.89–2.12
(m, 4-H, 4'-H)
13.8)
6ab
3430, 5.40 (dd,
4.34 1.83– 2.65– 3.55, 3.89
(br s) 2.00 2.85b (2 d, 2JBn
0.34, 0.82 (2 d,
75.6 71.0 59.1 57.2 53.8, 20.6, 23.9
(=16ba) 1685
3J1,1’, 3J1,2
=
=
3J4’4’-
,
4’,5’= 6.4, 6.7,
54.7 (C-5', 4'-
CH3), 23.8
(C-4'), 33.4
(C-3), 35.2
(C-3')
CH
3
4.8, 7.4)
(m)
(m)
14.3), 3.62- 5'-H3, 4'-CH3), 0.84–
3.78b (m,
4 H)
0.95, 1.65–1.80 (2 m,
3'-Ha, 3'-Hb), 1.83–2.00
(m, 4'-H), 2.65–2.85b,
2.95–3.10 (2 m, 3-Ha,
3-Hb)
6ba
3430, 5.46 (dd,
4.21 2.90– 2.90– 3.55–3.90b 0.47, 0.89 (2 d,
(br s) 3.10b 3.10b (m, 8 H) 3J4,4-
4,5 = 6.4, 6.9,
(m) (m)
75.6 72.3 55.4 61.4 54.0, 21.0, 24.0
(=16ab) 1680
3J1,1’, 3J1,2
=
,
54.7 (C-5,
4-CH3), 24.2
(C-4), 32.5
(C-3'), 36.7
(C-3)
CH
3
4.5, 9.1)
5-H3, 4-CH3), 1.00–
1.20, 1.70–1.90b (2 m,
3-Ha, 3-Hb), 1.70–1.90b
(m, OH), 1.90–2.05 (m,
C-4), 2.60–2.73, 2.90–
3.10b (2 m, 3'-Ha, 3'-
Hb)
6ad
6da
3430, 5.62 (dd,
4.35 3.40– 2.64 3.40–3.85b 0.96, 0.97 (2 d, 3J3,3-
74.8 70.1 64.7 58.7 54.0, 20.3, 22.3
CH
3
1680
3J1,1’ = 6.8, (dd, 3.85b (dd, (m, 8 H)
= 3J 3’,4’= 6.4, 4'-H3, 3'-
CH3), 1.84–1.92 (m, 3'-
55.6 (C-4',
3'-CH3),
3J1,2 = 3.5) 3J1’,2’ = (m)
3J2’,3’
=
3.3)
7.4)
H), 2.94 (dd, 2J3a,3b
=
28.4 (C-3'),
33.2 (C-3)
14.4, 3J2,3a = 3.4, 3-Ha),
3.22 (dd, 3J2,3b = 9.9, 3-
Hb)
3430, 5.41 (br s) 4.34 2.64 3.12– 3.45, 3.72
(br s) (br s) 3.24 (2 d, 2JBn
1.09, 1.13 (2 d, 3J3,3-
75.0 71.5 64.4 61.5 54.4, 21.2, 21.5
CH
3
(=16ad) 1680
=
= 3J3,4 = 6.7, 4-H3, 3-
56.0 (C-4,
3-CH3), 28.2
(C-3), 32.2
(C-3')
(m)
13.8), 3.58, CH3), 1.98–2.16 (m, 3-
3.88 (2 d,
H), 2.94 (dd, 2J3’a,3’b
=
2JBn = 14.3) 14.1, 3J2’,3’a = 3.6, 3'-
Ha), 3.07 (dd, 3J2’,3’b
=
9.5, 3'-Hb)
6ccc
8cc
–
5.93 (br s)
–
–
–
–
–
–
–
–
–
–
–
–
3450, 5.90 (br s) 4.50– 3.95– 3.35 2.94, 3.95- 6.49 (br s, OH)
1680
4.65 4.20b (d, 4.20b (d and
(m) (m)
75.1 74.4 63.4* 65.6* 54.7,
55.4
3J1’,2’= m, 2JBn
=
8.6) 13.6), 3.09,
3.80 (2 d,
2JBn = 13.4)
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of C2-Symmetrical Diamino Diol Core-Unit of HIV-1 Protease Inhibitors
1601
Table 4 (continued)
Product IR (KBr/
film)
1H NMR (300 MHz, CDCl3), δ, J (Hz)
1’-H 2-H 2’-H N-CH2Ph
13C NMR (75 MHz, CDCl3), δ
1-H
C-1 C-1’ C-2 C-2’ N-CH2
ν
Ph
(cm-1)
6ac
7aa
3400, 5.49 (d, 3J1,2 4.55 3.50– 3.84/ 3.18, 3.94
2.84 (bd, 2J3a,3b = 14.5, 74.0 70.8 59.7 65.5 54.0, 33.1 (C-3)
1680
= 7.9)
(d,
3.68 3.87 (2 d, 2JBn
=
3-Ha), 3.13 (dd, 3J2,3b
=
55.1
3J1’,2’ = (m)
(d)
13.9), 3.42, 12.6, 3-Hb)
3.77 (2 d,
7.2)
2JBn = 13.8)
3380, 5.66 (br s) 4.91 3.30– 2.80- 3.35, 3.70– 2.80–3.26 (m, 3-H2,
1680
(br s) 3.42 3.26b 3.82b (d and 3'-H2, 2'-H), 3.30–3.42
(m) (m) (m, 2-H)
m, 2JBn
72.7* 73.3* 60.5+ 61.6+ 53.8, 34.2, 35.2
53.9 (C-3, C-3')
=
13.6), 3.45,
3.70–3.82b
(d and m,
2JBn = 14.5)
7bb
3430, 5.43 (br s) 3.32 2.75– 2.75- 3.41, 3.97- 0.46, 0.84 (2 d, 3J4,5
=
73.7 73.7 56.7* 59.0* 54.4, 21.2, 22.3,
3
1680
(d,
2.95b 2.95b 4.18 (d + m, J 4’,5’= 6.4, 5-H3, 5'-
54.4 24.4 (C-5,
C'-5, 4-CH3,
4'-CH3),
3J1’,2’ = (m)
(m)
2JBn = 14.1), H3), 1.03 (d, 6H,
8.1)
3.69, 3.89
(2 d,
3J4,4-
,
= 6.4,
CH
CH
4’4’-
4-CH3,34'-CH33), 1.30–
24.5, 25.6
(C-4, C-4'),
38.3, 38.4
2JBn = 14.6) 1.80 (m, 3-H2,
3'-H2), 1.80–2.10 (m,
4-H, 4'-H), 4.52 (br s,
OH)
(C-3, C-3')
8bb
3430, 5.08 (dd,
1680
4.50– 3.06– 2.71 3.41, 3.97- 0.70, 0.87 (2 d, 3J4,5
,
73.8 71.2 56.1 57.2 55.3, 21.6, 21.8,
4’,5’
3J1,2, 3J1,1’
=
4.70 3.19 (br d, 4.18 (d and = 6.7, 5-H3, 5'-H3),
55.5 24.3, 24.4
(C-5, C'-5,
4-CH3, 4'-
CH3), 24.1,
24.2 (C-4,
C-4'), 31.6
(C-3'), 34.6
(C-3)
3.3, 7.6)
(m)
(m)
3J2’,3b’=m, 2JBn
=
0.86, 0.91 (2 d,
3
11.2) 14.1), 3.69, J4,4-
,
3 = 6.4,
CH
CH
4’4’-
3.89 (2 d, 2JBn 4-CH3,34'-CH3), 1.05–
= 14.6)
1.15 (m, 3'-Ha), 1.20–
1.60b (m, 3-H2), 1.63–
1.79 (m, 4-H), 1.71
(ddd, 2J3a’,3b’ = 14.3,
3J3b’,4’ = 3.1,
3'-Hb), 1.90–2.05
(m, 4'-H)
8bad
–
5.15–5.28 4.45– –
–
–
–
–
–
–
–
–
–
(m)
4.65
(m)
23aae
1680
6.01 (br s)
3.26
3.65, 3.87
2.66 (br d, 2J3a,3b = 14.5, 71.8
3-Ha), 3.02 (dd, 3-Hb)
58.0
52.3 33.2 (C-3)
(br d,
3J2,3b
12.0)
(2 d, 2JBn
=
=
14.3)
28aa
28bb
1710, 6.05 (br s)
1680
-
-
3.57– 3.70– 3.43, 3.92
3.68 3.88b (2 d, 2JBn
(m) (m)
14.3), 3.70- (dd, 2J3’a,3’b = 15.0,3J2’,3’a
2.74 (dd, 2J3a,3b = 14.1, 75.5 206.9 65.7 58.5 53.8, 33.8, 34.0
=
3J2,3a = 3.3, 3-Ha), 2.77
53.8 (C-3, C-3')
3.88b (m)
= 8.4, 3'-Ha), 3.00–3.09
(m, 3-Hb), 3.19 (dd,
3J2’,3’b = 6.9, 3'-Hb)
1710, 6.05 (d, 3J1,2
3.18– 3.47 3.50, 3.76
3.29 (dd, (2 d, 2JBn
0.47, 0.48 (2 d, 3J4,5
,
75.7 208.4 55.0 63.7 54.1, 20.9, 23.3,
4’,5’
1680
= 1.4)
=
= 6.4, 5-H3, 5'-H3),
54.6 24.2 (C-5,
C-5', 4-CH3,
4'-CH3),
(m)
3J2’,3a’, 14.3), 3.70- 0.86, 0.93 (2 d,
3J2’,3b’=3.82b (m)
3J4,4-
,
3 = 6.7, 4-
CH
CH
4’4’-
5.3,
9.8)
CH3, 4'3-CH3), 0.79–
1.11 (m, 3-Ha,
23.9, 24.3
(C-4, C-4'),
36.6, 37.5
3'-Ha), 1.35–2.12 (m,
3-Hb, 3'-Hb, 4-H, 4'-H)
(C-3, C-3')
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

1602
B. Weber et al.
PAPER
Table 4 (continued)
Product IR (KBr/
film)
1H NMR (300 MHz, CDCl3), δ, J (Hz)
1’-H 2-H 2’-H N-CH2Ph
13C NMR (75 MHz, CDCl3), δ
1-H
C-1 C-1’ C-2 C-2’ N-CH2
ν
Ph
(cm-1)
28ab
1710, 6.08 (d,
1680
-
3.45– 3.45– 3.54, 3.99
3.63b 3.63b (2 d, 2JBn
0.50 (d, 3J4’,5’ = 6.4,
75.6 207.9 58.6 63.4 53.9, 21.1, 23.1
3J1,2 = 1.4)
=
5'-H3), 0.85 (d,
54.4 (C-5', 4'-
CH3), 24.4
(C-4'), 34.0
(C-3), 37.2
(C-3')
3
(m)
(m)
14.6), 3.70– J4’4’-
= 6.7,
CH
3
3.85b (m)
4'-CH3), 1.40–1.95b
(m, 3'-H2, 4'-H), 2.83
(d, 2J3a,3b = 13.2, 3-Ha),
3.06, 3.15 (d,
3-Hb)
28baf
10aae
–
6.05 (br s)
-
–
–
–
–
–
–
–
–
–
–
3540, 4.05 (d,
3440
2.90–
3.12b
(m)
3.53, 3.66
2.03 (br s, OH), 2.90–
72.1
61.5
54.6 33.0 (C-3)
3J1,2 = 5.7)
(2 d, 2JBn
=
3.12b (m, 3-H2)
13.8)
11aa
3420
4.07 (dd,
3J1,1’
3J1,2 = 8.5) (m)
2.85– 2.85– 2.85– 3.38, 3.79
3.24b 3.24b 3.24b (2 d, 2JBn
(m) (m)
2.18 (br s, OH), 2.85–
70.1 74.7 64.2 59.2 54.8, 28.2 (C-3'),
55.7 32.6 (C-3)
=
=
3.24b (m, 3-H2, 3'-H2),
13.0), 3.52, 5.78 (br s, OH)
4.31 (d and
br s, 2JBn
=
13.6)
10ab
3550, 4.01 (dd,
3.92 2.98– 2.72 3.54, 3.72
0.76 (d, 3J4’,5’ = 6.7,
72.0* 72.1* 62.0 57.4 54.6, 23.0, 23.1
3440
3J1,1’ = 1.9, (dd, 3.13b (ddd, (2 d, 2JBn
=
5'-H3), 0.88 (d,
54.6 (4'-CH3,
C-5'), 25.5
(C-4'), 32.8
(C-3), 36.4
(C-3')
3J1,2 = 4.8) 3J1’,2’ = (m)
3J2’,3’a = 13.8), 3.58, J4’4’-
= 6.7,
CH
3
3
6.7)
3J2’,3’b =3.65 (2 d,
4'-CH3), 1.37 (ddd,
6.4) 2JBn = 13.6) J3’a,3’b = 13.8, 3J3’a,4’
=
2
6.7, 3'-Ha), 1.58 (ddd,
3J3’b,4’= 6.7, 3'-Hb), 1.79
(ddqq, 4'-H), 2.18 (br s,
2 H, OH), 2.98–3.13b
(m, 3-H2)
11ab
(=12ba)
3380
3.99 (dd,
3J1’,1’
3J1,2 = 8.0) (m)
2.88– 3.09– 2.68– 3.39, 4.15
0.77 (d, 3J4’,5’ = 5.7,
70.6 75.2 64.1 54.7 54.8, 21.9, 24.4
=
3.08b 3.24b 2.80 (d and br s, 5'-H3), 0.98 (d,
55.6 (4'-CH3,
C-5'), 24.8
(C-4'), 30.5
(C-3'), 32.7
(C-3)
3
(m)
(m)
2JBn = 13.1), J4’4’- 3 = 6.0,
CH
3.43, 3.77
4'-CH3), 1.35–1.55 (m,
(2 d, 2JBn
=
3'-Ha, 4'-H), 1.88 (dd,
2J3’a,3’b = 9.9, 3J2’,3’b or
3J3’b,4’ = 9.9, 3'-Hb),
2.88–3.08b (m, 3-Ha),
3.09–3.24b (m, 3-Hb)
12.9)
10ac
10ad
10bbe
3550, 4.49 (d,
3400
4.56 3.13– 3.76 3.00, 3.75
3J1,2 = 7.2) (d, 3.25b (d) (2 d, 2JBn
3J1’,2’ = (m)
10.0)
2.27, 2.55 (2 br s, OH), 71.0 70.4 61.5 64.0 54.6, –
=
3.02–3.12 (m, 3-Ha),
54.7
13.8), 3.58, 3.13–3.25b (m, 3-Hb)
3.72 (2 d,
2JBn = 13.8)
3550, 4.20 (d,
4.20 3.00– 2.54 3.43, 3.55
3.22b (dd, (2 d, 2JBn
3J1’,2’ = (m)
9.6)
1.06 (d, 3J3’,4’ = 7.2,
71.4* 69.8* 61.8+ 61.0+ 54.6, 19.3, 24.2
3430
3J1,2 = 8.1) (d,
=
4'-H3), 1.08 (d,
54.7 (3'-CH3,
C-4'), 24.9
(C-3'), 33.2
(C-3)
3J2’,3’ = 13.4), 3.46, J3’3’-
= 7.7,
3
CH
3
1.9) 3.66 (2 d,
3'-CH3), 3.00–3.22b
2JBn = 13.8) (m, 3-H2)
3550, 3.91 (d,
2.72
(ddd,
3J2,3a
3J2,3b
6.2)
3.69, 3.71
0.76 (d, 3J4,5 = 6.4,
5-H3), 0.89 (d, 3J4,4-
71.6
57.9
54.6 22.9, 23.1
(4-CH3,
3430
3J1,2 = 5.9)
(2 d, 2JBn
=
CH
3
=
=
13.6)
= 6.7, 4-CH3), 1.40
C-5), 25.3
(C-4), 36.0
(C-3)
(ddd, 2J3a,3b = 13.6,
3J3a,4 = 6.5, 3-Ha), 1.61
(ddd, 3J3b,4 = 6.5, 3-Hb),
1.79 (ddqq, 4-H), 2.49
(br s, OH)
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of C2-Symmetrical Diamino Diol Core-Unit of HIV-1 Protease Inhibitors
1603
Table 4 (continued)
Product IR(KBr/
film)
1H NMR (300 MHz, CDCl3), δ, J (Hz)
1’-H 2-H 2’-H N-CH2Ph
13C NMR (75 MHz, CDCl3), δ
1-H
C-1 C-1’ C-2 C-2’ N-CH2
ν
Ph
(cm-1)
11bb
(=12bb) 3400
3550, 3.94 (dd,
3.13 2.70– 2.70– 3.39, 4.22
0.79, 1.00 (2 d, 3J4,5
=
71.3 75.5 59.8 54.6 54.4, 22.1, 23.2,
3
3J1’,1’
=
(dd, 2.80b 2.80b (d and br s, J4’,5’= 6.2, 5-H3, 5'-H3),
55.6 23.3, 24.4
(C-5, C-5',
4-CH3, 4'-
CH3), 25.1,
26.0 (C-4,
C-4'), 30.6
(C-3'), 36.8
(C-3)
3J1,2 = 8.2) 3J1’,2’ = (m)
(m)
2JBn = 13.4), 0.83, 0.88 (2 d, 3J4,4-
CH
3
3.8)
3.49, 3.75
= 3J4’4’-
= 6.5, 4-
CH
3
(2 d, 2JBn
=
CH3, 4'-CH3), 1.35–
1.65 (m, 3-H2, 3'-H2),
1.80–1.95 (m, 4-H, 4'-
H)
13.6)
11ba
3550, 4.02 (dd,
3410
3J1,1’
3J1,2 = 8.4) (m)
2.88– 2.57– 2.88– 3.39, 4.32
0.75–0.85 (m, 5-H3,
71.3 75.1 59.2 60.2 54.3, 22.9, 23.6
=
3.27b 2.68b 3.27b (d and br s, 4-CH3), 1.35–1.58 (m,
55.8 (4-CH3,
C-5) 26.3
(C-4), 28.2
(C-3'), 36.8
(C-3)
(m)
(m)
2JBn = 13.1), 3-H2), 1.70–1.80 (m,
3.52, 3.77
4-H), 2.08, 6.04 (2 br s,
OH), 2.88–3.27b (m,
3'-H2)
(2 d, 2JBn
=
13.4)
10cce
12cc
3550, 5.03 (d,
3400
–
3.83
(d)
–
2.96, 3.82
4.12 (br s, OH)
69.2
64.1
54.4
–
3J1,2 = 9.8)
(2 d, 2JBn
=
13.8)
3550, 4.02 (dd,
4.29 3.82 3.72 2.94, 4.09
–
70.3* 74.7* 63.2+ 66.7+ 54.7,
54.9
–
3400
3J1,1’ = 7.0, (dd, (d)
(d)
(2 d, 2JBn
=
3J1,2 = 3.9) 3J1’,2’
=
13.4), 3.09,
3.80 (2 d,
8.0)
2JBn = 13.6)
33aae
33ab
1790
1795
4.27 (br s)
2.87–
3.10b
(m)
3.43, 3.63
2.79 (dd, 2J3a,3b = 12.9, 80.7
3J2,3a = 6.2, 3-Ha), 2.87–
3.10b (m, 3-Hb)
61.7
54.7 31.0 (C-3),
154.5 (C=O)
(2 d, 2JBn
=
14.2)
4.52 (dd,
3J1,1’ = 7.2, (dd, (ddd, (ddd, (2 d, 2JBn
3J1,2 =1.2) 3J1’,2’ = 3J2,3a = 3J2’,3a’=14.0), 3.68, 13.9, 3J3’a,4’ = 9.8, 3'-
1.7) 6.7, 3.3, 3.80 (2 d,
Ha), 0.91 (d, 3J4’4’-
4.26 3.06 2.53 3.10, 3.68
0.61 (d, 3J4’,5’ = 6.4, 5'- 80.7 78.2 61.8 57.9 54.5, 21.5, 23.7
=
H3), 0.90 (ddd, 2J3’a,3’b
=
54.7 (4'-CH3,
C-5') 24.2
=
(C-4'), 30.9
(C-3), 34.0
(C-3'), 154.7
(C=O)
CH
3
3J2,3b = 3J2’,3b’=2JBn = 14.3) 6.7, 4'-CH3), 1.67 (ddd,
6.4) 9.8)
3J3’b,4’ = 3.7, 3'-Hb),
1.75–1.95 (m, 4'-H),
2.89 (dd, 2J3a,3b = 13.4,
3-Ha), 3.15 (dd, 3-Hb)
33ad
33bbe
Z-26e
1790
1800
4.73 (d,
4.14 3.08– 2.38 3.14, 3.60
0.74 (d, 3J3’,4’ = 6.7,
4'-H3), 0.98 (d,
82.4 78.2 64.9 62.7 54.7, 20.4, 22.0
3J1,1’ = 7.0) (dd, 3.21b (dd, (2 d, 2JBn
=
55.1 (3'-CH3, 4'-
H3), 26.6
3J1’,2’ = (m)
3J2’,3’ = 14.1), 3.76 3J3’3’- 3 = 6.7,
CH
3.3)
6.9) (br s)
3'-CH3), 1.96 (dqq,
(C-3'), 30.7
(C-3), 154.8
(C=O)
3'-H), 2.94 (dd, 2J3a,3b
=
15.5, 3J2,3a = 9.3, 3-Ha),
3.08–3.21b (m, 3-Hb)
4.53 (br s)
2.68
(dd,
3.40, 3.90
0.68 (d, 3J4,5 = 6.4, 5-
78.2
57.9
57.2
54.5 21.6, 23.8
(4-CH3,
(2 d, 2JBn
=
H3), 0.98 (d, 3J4,4-
=
CH
3
3J2,3a
3.0,
=
=
14.2)
6.7, 4-CH3), 0.99 (ddd,
C-5), 24.2
(C-4), 34.0
(C-3), 154.8
(C=O)
2J3a,3b = 14.3, 3J3a,4
=
3J2,3b
10.2)
10.0, 3-Ha), 1.81 (ddd,
3J3b,4 = 3.6, 3-Hb), 2.00
(ddqq, 4-H)
1590g 5.87 (dd,
3J1,2 = 9.3,
3.57
3.28, 3.71
2.71 (dd, 2J3a,3b = 14.1, 131.6
3-Ha), 2.97 (dd, 3-Hb)
53.6 39.8 (C-3)
(dddd,
(2 d, 2JBn
=
4J1,2’ = 2.4)
3J2,3a
5.7,
=
14.3)
3J2,3b
9.3)
=
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

1604
B. Weber et al.
PAPER
Table 4 (continued)
Product IR (KBr/
film)
1H NMR (300 MHz, CDCl3), δ, J (Hz)
1’-H 2-H 2’-H N-CH2Ph
13C NMR (75 MHz, CDCl3), δ
1-H
C-1 C-1’ C-2 C-2’ N-CH2
ν
Ph
(cm-1)
g
E-26e
–
5.40 (dd, 3J1,2
3.34–
3.48
(m)
3.42, 3.82
2.68 (dd, 2J3a,3b = 13.9, 130.9
61.6
53.8 38.7 (C-3)
= 5.0, 4J1,2’
=
(2 d, 2JBn
=
3J2,3a = 7.6, 3-Ha), 2.96
(dd, 3J2,3b = 6.8, 3-Hb)
2.4)
13.8)
18
3300– 5.23 (dd,
3510, 3J1,1’, 3J1,2
3.45– 2.98– 2.73– 3.45–3.90b 1.01 (d, 3J2’,3’ = 7.4, 3'-
72.1+ 71.9+ 61.2 54.4 55.0, 8.5 (C-4),
54.0 12.9 (C-3'),
=
3.90b 3.10 2.98 (m)
(m) (m)* (m)*
H3), 1.18 (t, 3J3,4 = 7.2,
4-H3), 1.40–1.60 (m,
3-Ha), 1.60–1.80 (m, 3-
Hb)
1680
4.8, 7.9)
19.9 (C-3)
19
29
3250– 3.40 (dd,
3.25 2.77 2.98 3.28, 3.82
1.15 (t, 3J3,4 = 7.4,
4-H3), 1.16 (d, 3'-H3),
74.5* 74.4* 59.8 64.9 54.1, 7.9 (C-4),
54.5 14.4 (C-3'),
3550
3J1,1’ = 8.7, (dd, (ddd, (dq, (2 d, 2JBn
=
3J1,2 = 9.3) 3J1’,2’ = J2,3a = 3J2’,3’ = 12.9), 3.41, 1.53 (br s, OH), 1.63–
18.4 (C-3)
3
9.3) 3J2,3b = 6.7) 3.80 (2 d,
4.5)
2JBn = 12.9)
1.85 (m, 3-H2)
1700, 5.88 (br s)
1680
–
2.60– 3.56 3.13, 3.72– 0.75–0.90 (m, 3'-H3,
2.70 (q,
3.84b (d and 4-H3), 1.20–1.34 (m,
(m) 3-Ha), 1.70–1.75 (m,
3J2’,3’ = m, 2JBn
77.5 208.9 58.2 56.4 54.0, 12.2, 12.8
54.1 (C-4, C-3'),
=
20.2 (C-3)
6.7) 13.8), 3.72– 3-Hb)
3.84b (m,
4 H)
30
31
3340- 5.01 (dd, (dd, 3.50– 3.02 2.55 3.18, 3.71
3520, 3J1,1’ = 12.2, 3.77b (ddd, (dq, (2 d, 2JBn
1.00/1.01 (t, 3J3,4 = 7.3, 71.9, 70.0, 62.4 55.2, 53.0, 7.6 (C-4),
=
4-H3), 1.08, 1.10 (d,
72.1* 70.2*
55.4 54.5 12.6 (C-3'),
20.8 (C-3)
1680
3J1,2 = 5.6) (m)
3J2,3 3J1’,2’ = 13.2), 3.50- 3'-H3), 1.60–1.85 (m,
=
9.7, 3J2’,3’ = 3.77b (m, 4H)3-H2), 4.15 (br s, OH)
5.6) 6.6)
3300– 3.38 (d, 3J1,2 3.57 2.62 2.87 3.31, 3.78
1.01 (t, 3J3,4 = 7.1,
4-H3), 1.03 (d, 3'-H3),
70.6* 69.7* 54.6 62.3 53.4, 8.2 (C-4),
54.6 13.3 (C-3'),
3520
= 7.1)
(d,
(ddd, (dq, (2 d, 2JBn
=
3
3J1’,2’ = J2,3a = 3J2’,3’ = 12.9), 3.62, 1.62–1.75 (m, 3-H2)
19.7 (C-3)
9.7) 3J2,3b = 6.6) 3.68 (2 d, 2JBn
7.1)
= 13.4)
a NMR data of the Cby group and the aromatic rings are omitted. * or + NMR data, signed by these symbols, are interchangeable.
b As part of a multiplett.
c Data from a mixture of 6cc and 2c.
d Data from a mixture of 8ba and 8b.
e Compound is C2-symmetrical. The 1H and 13C NMR data are only given for one half of the molecule.
f Data from mixture of 28ba and 2b.
g Z-26 could be obtained diastereomerically pure from a diastereomeric mixture of E-26 and Z-26 by recrystallization.
refluxed for 12 h. After the addition of solid K2CO3 (1.11 g,
8.00 mmol) the suspension was refluxed for 4 h. The inorganic salts
were removed by filtration over silica gel (1 g) and washed with
MeOH (30 mL). The solvent was evaporated in vacuo and the resi-
due was purified by flash chromatography (Et2O/pentane, 1:4 to
1:8) to give the pure diol.
concentrated in vacuo. Purification of the crude product by flash
chromatography (Et2O/pentane, 1:6 to 1:8) yielded the diol 10ac
(71 mg, 73%) or 10aa (36 mg, 68%).
For yields and physical data of diols 10, 11, 12, 19, and 31 see Ta-
bles 3 and 4.
Method C: Monocarbamate 6ac (120 mg, 0.15 mmol) or dicarbam-
ate 23aa (78 mg, 0.08 mmol), 1,3-propanedithiol (59 µL, 64 mg,
0.60 mmol), and MeSO3H (48 µL, 72 mg, 0.75 mmol) were dis-
solved in CH2Cl2 (3 mL) and the solution was stirred for 24 h at r.t.
After addition of solid K2CO3 (207 mg, 1.50 mmol) stirring was
continued for 30 min and subsequently the inorganic salts were fil-
tered off and washed with CH2Cl2 (10 mL). The solvent was re-
moved in vacuo and the residue was dissolved in MeOH (10 mL).
Solid K2CO3 (207 mg, 1.50 mmol) was added and the suspension
was refluxed for 24 h. The solid materials were filtered off and
washed with CH2Cl2 (10 mL). The filtrate was dried (MgSO4) and
Cyclic Carbonates 33aa, 33ab, 33ad, and 33bb; General
Procedure15
A suspension of diol 10 (0.40 mmol) in excess dimethyl or diethyl
carbonate (10 mL) and K2CO3 (280 mg, 2.00 mmol) was heated at
80 °C, until the substrate could not longer be detected by TLC (ap-
prox. 2–3 d). The solids were filtered off and washed with Et2O (30
mL). The filtrate was concentrated in vacuo and the residue was pu-
rified by flash chromatography (Et2O/pentane, 1:6 to 1:10) to give
the cyclic carbonate 33 as pure compound. For 1H, 13C NMR, and
IR data of 33aa, 33ab, 33ad, and 33bb, see Table 4.
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of C2-Symmetrical Diamino Diol Core-Unit of HIV-1 Protease Inhibitors
1605
[4S,4S(1S),5S,5S(1S)]-4,5-Bis[1-(N,N-dibenzylamino)-2-phe-
nylethyl]-1,3-dioxolan-2-one (33aa)
References
Yield: 193 mg (72%); colorless crystals; mp 199–201°C (Et2O/pen-
tane); Rf 0.52 (Et2O/pentane, 1:2); [α]D −32.2 (c = 1, CH2Cl2).
(1) (a) Kempf, D. J.; Norbeck, D. W.; Codacovi, L.; Wang, X. C.;
Kohlbrenner, W. E.; Wideburg, N. E.; Paul, D. A.; Knigge, M.
F.; Vasavanonda, S.; Craig-Kennard, A.; Saldivar, A.;
Rosenbrook, Jr., W.; Clement, J. J.; Plattner, J. J.; Erickson, J.
J. Med. Chem. 1990, 33, 2687.
(b) Kempf, D. J.; Norbeck, D. W.; Codacovi, L.; Wang, X. C.;
Kohlbrenner, W. E.; Wideburg, N. E.; Saldivar, A.; Craig-
Kennard, A.; Vasavanonda, S.; Clement, J. J.; Erickson,
J. Spec. Publ., Royal Soc. of Chem., London 1993, 119, 297.
(2) (a) Kempf, D. J.; Sowin, T. J.; M. Doherty, E.; Hannick, S. M.;
Codavoci, L.; Henry, R. F.; Green, B. E.; Spanton, S. G.;
Norbeck, D. W. J. Org. Chem. 1992, 57, 5692.
(b) Konradi, A. W.; Pedersen, S. F. J. Org. Chem. 1992, 57,
28.
Anal. Calcd. for C47H46N2O3 (686.9): C, 82.18; H, 6.75; Found C,
82.29; H, 8.78.
[4S,4S(1S),5S,5S(1S)]-5-[1-(N,N-dibenzylamino)-3-methylbu-
tyl]-4-[1-(N,N-dibenzylamino)-2-phenylethyl]-1,3-dioxolan-2-
one (33ab)
Yield: 225 mg (88%); colorless solid; mp 138–140°C (Et2O/pen-
tane); Rf 0.57 (Et2O/pentane, 1:2); [α]D −66.0 (c = 0.5, CH2Cl2).
Anal. Calcd. for C44H48N2O3 (652.9): C, 80.95; H, 7.41; Found C,
80.98; H, 7.61.
[4S,4S(1S),5S,5S(1S)]-5-[1-(N,N-dibenzylamino)-2-methylpro-
pyl]-4-[1-(N,N-dibenzylamino)-2-phenylethyl]-1,3-dioxolan-2-
one (33ad)
Yield: 209 mg (83%); colorless solid; mp 53–55°C (Et2O/pentane);
Rf 0.55 (Et2O/pentane, 1:2); [α]D −50.0 (c = 1, CH2Cl2).
(c) Kammermeier, B.; Beck, G.; Holla, W.; Jacobi, D.;
Napierski, B.; Jendralla, H. Chem. Eur. J. 1996, 2, 307.
(d) Ghosh, A. K.; McKee, S. P.; Thompson, W. J. Tetrahedron
Lett. 1991, 32, 5729.
(e) Chenera, B.; Boehm, J. C.; Dreyer, G. B.; Bioorg. Med.
Chem. Lett. 1991, 1, 219.
Anal. Calcd. for C43H46N2O3 (638.8): C, 80.48; H, 7.40; Found C,
80.63; H, 7.36.
(f) Baker, W. R.; Condon, S. L. J. Org. Chem. 1993, 58, 3277.
(g) Kang, S. H.; Ryu, D. H. Chem. Commun. 1996, 355.
(h) Rama Rao, A. V.; Gurjar, M. K.; Pal, S.; Pariza, R. J.;
Chorghade, M. S. Tetrahedron Lett. 1995, 36, 2505.
(i) Gurjar, M. K.; Pal, S.; Rama Rao, A. V.; Pariza, R. J.;
Chorghade, M. S. Tetrahedron 1997, 53, 4769.
(j) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.;
Zlatoidzky, P. J. Org. Chem. 1997, 62, 9348.
[4S,4S(1S),5S,5S(1S)]-4,5-Bis[1-(N,N-dibenzylamino)-3-me-
thylbutyl]-1,3-dioxolan-2-one (33bb)
Yield: 176 mg (71%); colorless solid; mp 147–150°C (Et2O/pen-
tane); Rf 0.77 (Et2O/pentane, 1:2); [α]D −112.3 (c = 1, CH2Cl2).
Anal. Calcd. for C41H50N2O3 (618.9): C, 79.57; H, 8.14; Found C,
79.57; H, 8.34.
Debenzylation17 of Diol 10aa and Subsequent Conversion to the
Bis-N-Boc-Protected Derivative 37; (2S,3S,4S,5S)-2,5-
Bis{[(tert-butyloxy]carbonyl)amino}-3,4-dihydroxy-1,6-
diphenylhexane
(3) (a) Preliminary communication: Schwerdtfeger, J.; Hoppe, D.
Angew. Chem. 1992, 104, 1547; Angew. Chem., Int. Ed. Engl.
1992, 31, 1505.
(b) Schwerdtfeger, J.; Kolczewski, S.; Weber, B.; Fröhlich R.;
Hoppe, D. Synthesis 1999; preceding paper.
A suspension of diol 10aa (182 mg, 0.27 mmol) and palladium (180
mg, 60 mol%, 10% on charcoal) in MeOH/HCO2H (20 mL, 95:5)
was stirred under a H2 atmosphere for 48 h at r.t. The solids were
filtered over Celite (500 mg) and washed with MeOH (10 mL). The
solvents were removed in vacuo and the residue was dissolved in
MeOH (10 mL) without any further purification. After addition of
di-tert-butyl dicarbonate (219 mg, 1.00 mmol) and Et3N (0.17 mL,
121 mg, 1.20 mmol) the solution was stirred for 4 d at r.t. The sol-
vent was evaporated in vacuo and the residue was purified by flash
chromatography (Et2O/pentane, 1:8→1:3) to give 37 (110 mg,
81%, two steps) as a colorless solid. The 1H NMR data were identi-
cal to those from the literature;2a [α]D −6.0 (c = 1, CHCl3); mp
211°C (Et2O/pentane) (Lit.2a mp 172–173°C).
(c) Schwerdtfeger, J. Dissertation, University of Kiel, 1993.
(d) Kolczewski, S. Dissertation, University of Münster, 1995.
(e) Weber, B. Diploma Thesis, University of Münster, 1995.
(f) Weber, B. Dissertation, University of Münster, 1998.
(4) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. 1990,
102, 1457; Angew. Chem., Int. Ed. Engl. 1990, 29, 1422.
(b) Hintze, F.; Hoppe, D. Synthesis 1992, 1216.
(c) Hoppe, D.; Hense, T. Angew. Chem. 1997, 109, 2353;
Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
(5) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
1968, 2199.
(b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145.
(6) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem.
1987, 99, 1186; Angew. Chem., Int. Ed. Engl. 1987, 26, 1141,
and references cited therein.
(7) (a) Müller, E.; Töpel, T. Ber. Dtsch. Chem. Ges. 1939, 72,
273.
Debenzylation of Diol 11aa and Conversion to the Bis-N-Boc-
Protected Derivative 38 in a One-Pot Synthesis;18
(2S,3S,4R,5S)-2,5-Bis{[(tert-butyloxy]carbonyl)amino}-3,4-di-
hydroxy-1,6-diphenylhexane
A suspension of diol 11aa (80 mg, 0.12 mmol), di-tert-butyl dicar-
bonate (33 mg, 0.33 mmol), and Pd(OH)2 (32 mg, 20% on charcoal,
50% neat) in EtOAc (3 mL) was stirred under a H2 atmosphere for
24 h at r.t. The solid materials were filtered off and washed with
EtOAc (10 mL). The filtrate was concentrated in vacuo and the
crude product was purified by flash chromatography (Et2O/pentane,
(b) Soznovsky, G.; Brown, J. H. Chem. Rev. 1966, 66, 529.
(c) Boche, G.; Bosold, F.; Lohrenz, J. C. W. Angew. Chem.
1994, 106, 1228; Angew. Chem. Int. Ed. Engl. 1994, 33, 1161.
(d) Julia, M.; Pfeuty-Saint Jalmes, V.; Verpeaux, J.-N. Synlett
1993, 233.
(e) Julia, M.; Pfeuty-Saint Jalmes, V.; Verpeaux, J.-N.;
Hollingworth, G. Bull. Soc. Chim. Fr. 1996, 133, 15.
(f) Schöllkopf, U. Houben–Weyl: Methoden der Organischen
Chemie, Müller, E., (Ed.); Georg Thieme Verlag: Stuttgart
1970, Vol. 13, No. 1, p 170.
1
1:6) to afford 38 (54 mg, 92%) as a colorless solid. The H NMR
data are identical to those from the literature;2a [α]D −53.2 (c = 1,
CHCl3); mp 171°C (Et2O/pentane).
(g) Wade, P. A.; D’Ambrosio, S. G.; Murray, Jr., J. K. J. Org.
Chem. 1995, 60, 4258.
Acknowledgement
(8) For copper(II) salts:
Generous support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged
(a) Langer, T.; Illich, M.; Helmchen, G. Tetrahedron Lett.
1995, 36, 4409.
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York

1606
B. Weber et al.
PAPER
space group P21 (No. 4), λ = 1.54178 Å, T = 223 K, ω/2θ
scans, 3436 reflections collected (+h, –k, ±l), [(sinθ)/λ] = 0.62
Å–1, 3240 independent and 2713 observed reflections [I ≥ 2
σ(I)], 357 refined parameters, R = 0.052, wR2 = 0.131, max.
residual electron density 0.37 (–0.32) e Å–3, hydrogens
calculated and refined as riding atoms.
(b) Corey, E. J.; Chen, Z.; Tanoury, G. J. J. Am. Chem. Soc.
1993, 115, 11000.
(c) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.;
Sato, K. J. Am. Chem. Soc. 1990, 112, 5244.
(d) Maryanoff, C. A.; Maryanoff, B. E.; Tang, R.; Mislow, K.
J. Am. Chem. Soc. 1973, 95, 5839.
(e) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93,
4605.
(9) For copper(I) salts:
Data sets were collected with an Enraf Nonius CAD4
diffractometer. Programs used: data reduction MolEN,
structure solution SHELXS-86, structure refinement
SHELXL-97, graphics SCHAKAL-92.
(a) Posner, G. H. Org. React. 1975, 22, 253.
(b) Whitesands, G. M.; SanFilippo, Jr., J.; Casey, C. P.; Panek,
E. J. J. Am. Chem. Soc. 1967, 89, 5302.
(c) Garber, T.; Rillema, D. P. Synth. Commun. 1990, 20, 1233.
(d) Kauffmann, T.; Schönfelder, M.; Legler, J. Liebigs Ann.
Chem. 1970, 731, 37.
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-114412 (19) and CCDC-114413 (Z-
26). Copies of the data can be obtained free of charge on
application to The Director, CCDC, 12 Union Road,
CambridgeCB2 1EZ, UK [fax +44(1223)336033, e-mail:
deposit@ccdc.cam.ac.uk].
(e) Walborsky, H. M.; Banks, R. B.; Banks, M. L. A.;
Duraisamy, M. Organometallics 1982, 1, 667.
(10) X-ray crystal structure analysis of Z-26: formula C46H46N2,
M = 626.85, colourless crystal, 0.25 × 0.20 × 0.10 mm,
a = 9.608(1), c = 40.315(3) Å, V = 969.0(2) Å3, ρcalc = 1.119 g
cm–3, F(000) = 1344 e, µ = 4.85 cm–1, empirical absorption
correction via ϕ scan data (0.954 ≤ C ≤ 0.999), Z = 4,
tetragonal, space group P41212o. 92), λ = 1.54178 Å, T = 223
K, ω scans, 4260 reflections collected (+h,+k,+l), [(sinθ)/
λ] = 0.62 Å–1, 3771 independent and 2208 observed
reflections [I ≥ 2 σ(I)], 218 refined parameters, R = 0.046,
wR2 = 0.106, max. residual electron density 0.14 (–0.14) e Å–
3, hydrogens calculated and refined as riding atoms.
(11) (a) Lohse, P.; Loner, H.; Acklin, P.; Sternfeld, F.; Pfaltz, A.
Tetrahedron Lett. 1991, 32, 615.
(b) Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345.
(12) X-ray crystal structure analysis of 19: formula C35H42N2O2,
M = 522.71, colourless crystal, 0.7 × 0.3 × 0.1 mm,
a = 9.510(1), b = 9.649(1), c = 16.386(2) Å, β = 91.84(1)°,
V = 1502.8(3) Å3, ρcalc = 1.155 g cm–3, F(000) = 564 e,
µ = 5.49 cm–1, no absorption correction, Z = 2, monoclinic,
(13) (a) Tomooka, K.; Shimizu, H.; Nakai, T. 70th Annual Meeting
of Chemical Society of Japan, Tokyo April 1996.
(b) van Bebber, J.; Ahrens, H.; Fröhlich, R.; Hoppe, D. Chem.
Eur. J. 1999, 5, in press.
(14) Kotthaus, M. Dissertation, University of Münster, 1996.
(15) Takano, S.; Yanase, M.; Ogasawa, K. Heterocycles 1989, 29,
1849.
(16) For coupling constants of further cis,trans-carbonates see:
Iida, T.; Itaya, T. Tetrahedron 1993, 49, 10511.
(17) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G.
E. J. Org. Chem. 1979, 44, 3442.
Pastò, M.; Castejòn, P.; Moyano, A.; Pericàs, M. A.; Riera, A.
J. Org. Chem. 1996, 61, 6033.
Article Identifier:
1437-210X,E;1999,0,09,1593,1606,ftx,en;Z02099SS.pdf
Synthesis 1999, No. 9, 1593–1606 ISSN 0039-7881 © Thieme Stuttgart · New York