Monocarbamates, derived from (S)-2-(dibenzylamino)butane-1,4-diol, and the influence of the second O-protecting group on the regioselectivity of deprotonation - Application to the synthesis of the boletus toxin (2S,4S)-γ-hydroxy-norvaline

Article abstract of DOI:10.1055/s-1998-6100

Differentially protected 1-O- and 4-O-monocarbamates, derived from (S)-2-(dibenzylamino)butane-1,4-diol are prepared and investigated with respect to their capability of being deprotonated and forming the corresponding lithium carbanions. In the 1-O-trity

Full text of DOI:10.1055/s-1998-6100

SYNTHESIS
September 1998
1287
Monocarbamates, Derived from (S)-2-(Dibenzylamino)butane-1,4-diol, and the
Influence of the Second O-Protecting Group on the Regioselectivity of Deprotonation –
Application to the Synthesis of the Boletus Toxin (2S,4S)-γ-Hydroxy-norvaline
Martin Sendzik, Walter Guarnieri, Dieter Hoppe*
Organisch-Chemisches Institut der Universität Münster, Corrensstraße 40, D-48149, Germany
Fax +49(251)83 39772
Received 6 January 1998
Abstract: Differentially protected 1-O- and 4-O-monocarbam-
ates, derived from (S)-2-(dibenzylamino)butane-1,4-diol are pre-
pared and investigated with respect to their capability of being
deprotonated and forming the corresponding lithium carbanions.
In the 1-O-trityl and methyl 4-O-monocarbamates 6a and 6b the
pro-S-4-H is removed by sec-butyllithium/(-)-sparteine with high
diastereoselectivity. The 1-O-(2-methoxyethyl) 4-O-monocarb-
amate (23e) undergoes a highly selective, substrate-controlled
abstraction of the pro-S-4-H without addition of any diamine. On
the other hand, the 4-O-methyl 1-O-monocarbamate 7a reacts
with sec-butyllithium in diethyl ether with essentially complete
stereoselectivity and forms the bicyclic chelate 33 complex with
(S)-configuration at the lithiated C-1 atom. Trapping by means of
iodomethane, CO2, and other electrophiles proceed with complete
stereoretention. The method is applied for the synthesis of Boletus
toxin (2S,4S)-γ-hydroxy-norvaline in the form of the lactone
hydrochloride. Further, evidence was found that the 2-(dimethyl-
amino) group in the 1-O-TBDMS 4-O-monocarbamate 16 induces
a highly substrate-controlled deprotonation in the (4S)-position.
Key words: stereoselective lithiation, chiral aminodiols, directed
lithiation, chiral carbanion, (–)-sparteine
Introduction
In the preceding publication we reported on the highly re-
gio- and diastereoselective lithiation of the enantiomeri-
cally pure dicarbamate 5.1 By substrate-induced chiral in-
duction, the pro-S-1-H is removed by deprotonation with
sec-butyllithium, providing a synthetic equivalent for the
chiral synthon A.
Synthon B could be approached from 5 after substitution
of the pro-S-1-H by deuterium, via the abstraction of the
pro-S-4-H by means of sec-butyllithium/(–)-sparteine
(22).1–3 For a more direct synthetic solution, a monocarb-
amate ester of type 6 is required, bearing a suitable pro-
tecting group PG at the 1-O atom which does not support
lithiation at C-1. On the other hand, monocarbamate ester
7, having the reverse protecting group pattern, may be
useful too for preparing precursors of synthon A, in cases
when the subsequent reactions require a differentiation
between the 1- and 4-oxygen function.
In principle, the ω-hydroxyalkyl carbamates 3 and 4,
which are intermediates in the preparation of dicarbamate
5 from diol 11, 4are easily accessible by monoacylation
with the oxazolidine-3-carbonyl chloride 2 (combined
yield 90%, ratio 3:1), but chromatographic separation on
a preparative scale turned out to be very cumbersome.
Scheme 1
ther approaches utilize different (S)-amino acids with a
four-carbon backbone such as (S)-methionine,5g, 6 (S)-
asparagine7 or the expensive8 (S)-homoserine for starting
materials.
Several methods have been developed in order to differ-
entiate the two carbonyl groups in (S)-aspartic acid.5 Fur-

SYNTHESIS
Papers
1288
Table 1. Differentially Protected Monocarbamates 3, 4, 6, or 7 and In-
termediates 8, 9, 10, 12, 13, 14, 15, or 16 Leading to Them
Starting from diol 1, the 4-O-TBDMS ether 8 serves as
key intermediate, which is regioselectively formed.4b, 9
Standard protecting group manipulations, followed by
acylation of the corresponding alcohols by means of
sodium hydride/2,2,6,6-tetramethyloxazolidine-3-carbo-
nyl chloride (2, CbyCl),10 led to the 4-O-carbamates 3 and
6a–f (Scheme 2, Table 1).
Producta
Substrate
(Scheme)
Yield
(%)
mpb
(°C)
3
6a
14
7a
10a
3
(2)
(3)
(5)
(2)
(2)
(2)
(2)
(2)
(2)
(5)
(5)
(2)
(2)
(2)
(2)
(2)
(2)
(3)
(3)
(3)
(4)
(4)
80–90
85
92
92
95
97
88
72
97
90
83
55
91
45
82
99
90c
37
77
92
84
82
oil
4
6a
6b
6c
6d
6e
oil
66
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
140
oil
oil
66
oil
oil
oil
oil
3
10d
10e
3
8
4
1
8
8
9a
9d
9e
11
12
13
6f
15
6f
7a
7b
8
9a
9d
10a
10d
10e
12d
13
14
15
16
a
Satisfactory elemental analyses were obtained (C ± 0.30, H ± 0.30,
N ± 0.30).
From Et2O.
Over two steps.
Ref. 6.
b
c
d
The 1-O-unprotected monocarbamate 3 was also prepared
by a shorter route, starting from (S)-methionine (11) via
the (S)-N,N-dibenzylhomoserine lactone (12) (according
to Reetz),6 aminolysis to the N,N-dimethylamide 13,
carbamoylation of the γ-hydroxy group and deaminative
reduction11 of the carbamate 14 by means of lithium tri-
ethylborohydride (Scheme 3, Table 1).12
(a) TBDMSCl (1.2 equiv), Et3N (1.2 equiv); DMAP (50 mol%),
CH2Cl2, 0°C, 10 min, then 40°C, 8 h; (b) Ph3CCl (1.2 equiv), Et3N
(1.9 equiv), DMAP (4 mol%), CH2Cl2, r.t., 14 h; (c) For 8 → 9d: NaH
(2.0 equiv), MeOCH2CH2Br (3.2 equiv), Bu4NI (11 mol%), DMAP (2
mol%), THF, 65°C, 20 h; 45%. For 8 → 9e: MEMCl (1.2 equiv),
iPr2NEt (1.2 equiv), CH2Cl2, 40°C, 24 h; (d) TBAF (2.5 equiv), THF/
Et2O, r.t., 14 h; 10a (82%); 10d (99%); 10e (90% over two steps). (e)
i. NaH (1.5 equiv), THF, r.t., 3 h; ii. + CbyCl (2, 1.3 equiv), 65°C,
16 h; 6a (92%); 6d (88%); 6e (72%); (f) TFA (21.5 equiv), MeOH/
CH2Cl2, –5°C, 0.5 h then r.t., 2 h; (g) For 3 → 6b: i. NaH (3.0 equiv),
THF, r.t., 0.5 h; ii. + MeI (4.0 equiv), 65°C, 16 h; (95%). For 3 → 6c:
MOMCl (20 equiv), CH2Cl2, r.t., 7 d; 97%. For 3 → 6f: TBDMSCl
(1.2 equiv), Et3N (5 equiv), CH2Cl2, r.t., 10 h; 97%.
(a) BnBr (3.0 equiv), K2CO3, NaOH, H2O/MeOH, reflux, 45 min; (b)
Me2NH (11.2 equiv), EtOH/BnOH, 0°C, 48 h; (c) i. NaH (1.5 equiv),
THF, r.t., 3 h; ii. + CbyCl (2, 1.5 equiv), 65°C, 16 h; (d) LiEt3BH
(4.8 equiv), THF, 0°C; r.t., 12 h.
Scheme 3
Scheme 2

SYNTHESIS
September 1998
1289
For the synthesis of the 3-(dimethylamino)butyl carbam- ucts 18a,b,e and 20a,b,d,e, respectively in good yields
ate 16, the N-benzyl groups in carbamate 6f were removed (Scheme 6, Table 3). If the deprotonation is assisted by
by Pd-catalyzed transfer hydrogenolysis,13 followed by (–)-sparteine the intermediate 17•22 has the (4S)-configu-
reductive dimethylation, utilizing sodium cyanoborohy- ration and the external electrophilic substitution at the sp3-
dride as reacting agent (Scheme 4, Table 1).14
C–Li bond will proceed with retention, since we never en-
countered an exception in an intermolecular reaction.3
The correct configurational assignment was proven for
the methylation product by its conversion into the known
(2S,4S)-4-hydroxy-norvaline lactone hydrochloride 32
(see Scheme 10).
(a) cyclohexene (15 equiv), Pd/C (6 mol%), MeOH, reflux, 12 h; (b)
i. H2C=O/H2O (5 equiv), NaBH3CN (1.6 equiv), MeCN, r.t., 0.5 h; ii.
HOAc.
Scheme 4
The 4-O-methyl- and 4-O-TBDMS-protected 1-O-
carbamates 7a and 7b, respectively, and as well the free 1-
alkanol 4, are also conveniently prepared from the
TBDMS ether 8 (Scheme 5, Table 1).
(a) i. NaH (1.2 equiv), THF, r.t., 2 h; ii. CbyCl (2, 1.2 equiv), reflux,
16 h; (b) TBAF (2.5 equiv), THF, r.t., 40 min; (c) i. NaH (2.0 equiv),
THF, r.t., 0.5 h; ii. + MeI (2.0 equiv), reflux, 15 h.
(a) s-BuLi (1.6 equiv), (–)-sparteine (22, 1.6 equiv), Et2O, –78°C, 5
h. (b) For 18: MeI (1.6 equiv), 3 h at –78°C, → r.t. For 19: i. gaseous
CO2; ii. after workup CH2N2 in Et2O.
Scheme 5
Scheme 6
The 1-O- and the 4-O-methyl derivatives 6b and 7b were The argument, outlined above, requires that no substrate-
also obtained by direct methylation of the sodium alkox- catalyzed lithiation takes place. The 1-O-methyl and the
ides of 3 and 4 (3:1) and could be separated on a small 1-O-MOM derivative 6b and 6c did not react with sec-
scale (1 g) by LC on silica gel.
butyllithium in diethyl ether (–78°C, 5 h) when
(–)-sparteine was not present. This clearly demonstrates
that neither these very donor-active γ-alkoxy groups nor
the γ-dibenzylamino group3c are capable of intervening in
the deprotonation step. The 1-O-MEM ether 6e produced
the (vinyloxymethyl) ether 24 via elimination of lithium
methoxide (Scheme 7, Table 3). A smooth substrate-in-
duced 4-deprotonation was achieved with the 1-(2-meth-
oxyethyl) ether 6d. The tentative tricyclic chelate com-
plex 23e, bearing four donor ligands for the lithium cation
in optimal positions, obviously governs the structure of
the transition state in the kinetically controlled deprotona-
tion reaction. The diastereomerically pure ester 20d was
Deprotonation and Electrophilic Substitution of 4-O-
Monocarbamates 6
The 4-O-monocarbamates 6a,b,d,e under the usual
conditions1 were smoothly deprotonated by 1.6 equiva-
lents of sec-butyllithium/(–)-sparteine (22) in diethyl
ether (reaction at –78°C, quenching the solution of the as-
sumed lithium intermediate 17•22 by iodomethane or car-
bon dioxide (followed by conversion of the crude acids),
afforded the diastereomerically pure 4-substitution prod-

SYNTHESIS
Papers
Table 2a. Selected Data of Monocarbamates 3, 4, 6, or 7a
1290
Compound
[α]D20 b
IR
1H NMR
13C NMR
(KBr/film)
(CDCl3) δ, J (Hz)
(CDCl3) δ, J (Hz)
ν (cm–1)
3
+2.5
3430, 1680
3440, 1680
1.63 (m, 3-H); 2.12 (m, 3-H); 2.96 (m, 2-H); 3.51 24.31 (C-3); 52.34 (2C, NCH2Ph); 55.10 (C-
2
(m, 2 H, 1-H); 3.54 (d, 2 H, J = 13.3, NCH2Ph); 2); 59.98c; 61.13 (C-1)c
4.12 (m, 2 H, 4-H)
4
–54.6
–62.7
–51.6
2.05 (m, 2 H, 3-H); 3.12 (m, 2-H); 3.51 (m, 4 H, 4- 31.15 (C-3); 54.04 (2C, NCH2Ph); 56.48 (C-
H, NCH2Ph); 3.89 (d, 2H, 2J = 13.5, NCH2Ph); 4.21 2); 62.26 (C-1); 63.14 (C-4)
(dd, 2J = 11.5, 3J = 4.0 Hz, 1-H); 4.39 (dd, 3J = 6.2)
6a
6b
1690, 1095,
1070, 760,
1.84 (m, 2 H, 3-H); 3.14 (m, 2 H, 1-H, 2-H); 3.41 (d, 29.00 (C-3); 54.06 (2C, NCH2Ph); 54.47 (C-
2
2 H, J = 13.7, NCH2Ph); 3.42 (m, 1-H); 3.73 (d, 2); 62.15 (C-1)c; 62.35 (C-4)c; 87.06 (CPh3)
750, 710, 700 2 H, NCH2Ph); 4.12 (m, 4-H); 4.25 (m, 4-H)
2840, 1680
1.78 (m, 3-H); 1.89 (m, 3-H); 2.95 (m, 2-H); 3.34 (s, 26.88 (C-3); 52.09 (C-2); 52.50 (2C,
3 H, OCH3); 3.48 (m, 1-H); 3.62 (m, 3 H, 1-H, NCH2Ph); 57.12 (OCH3); 60.70 (C-1);
2
NCH2Ph); 3.82 (d, 2 H, J = 13.8, NCH2Ph); 4.14 70.87 (C-4)
(m, 2 H, 4-H)
6c
6d
6e
6f
–44.3
–35.7
2915, 1688,
1095, 1065,
745, 698
1.82 (m, 3-H); 1.92 (m, 3-H); 2.97 (m, 2-H); 3.38 (s, 28.80 (C-3); 53.88 (C-2); 54.24 (2C,
3 H, OCH3); 3.59 (d, 2 H, 2J = 13.8, NCH2Ph); 3.61 NCH2Ph); 55.33 (OCH3); 62.36 (C-4)c;
(m, 1-H); 3.78 (dd, 2J = 10.0, 3J = 5.8, 1-H); 3.85 (d, 67.05 (C-1)c; 96.57 (OCH2O)
2 H, NCH2Ph); 4.20 (t, 2 H, 3J = 6.3, 4-H); 4.62 (s ,
2 H, OCH2O)
2930, 1690,
1095, 1070,
745, 700
1.81 (m, 3-H); 1.89 (m, 3-H), 2.98 (m, 2-H); 3.39 (s, 28.71 (C-3); 53.91 (C-2); 54.22 (2C,
2
3 H, OCH3); 3.61 (d, 2 H, J = 13.8, NCH2Ph); NCH2Ph); 59.56 (OCH3); 62.47 (C-4);
3.50–3.71 (m, 5 H; 1-H, OCH2CH2O); 3.75 (dd, 2J 70.52, 71.10 (2C, OCH2CH2O)c; 72.11 (C-
= 10.0, 1-H); 3.82 (d, 2 H, NCH2Ph); 4.19 (t, 2 H, 3J 1)c
= 6.3, 4-H)
–42.8
2910, 2850,
1680, 1085,
1060, 740,
690
1.80 (m, 3-H); 1.92 (m, 3-H); 2.97 (m, 2-H); 3.41 (s, 28.77 (C-3), 53.90 (C-2); 54.21 (2C,
3 H, OCH3); 3.55–3.75 (m, 5 H, 1-H, OCH2CH2O); NCH2Ph); 59.00 (OCH3); 62.63 (C-4);
2
3.69 (d, 2 H, J = 13.8, NCH2Ph); 3.81 (dd, J = 66.92, 67.18 (2C, OCH2CH2O)c; 71.80 (C-
2
10.0, J = 5.3, 1-H); 3.84 (d, 2 H, NCH2Ph); 4.19 1)c, 95.62 (OCH2O)
3
(m, 2 H, 4-H); 4.72 (s, 2 H, OCH2O)
d
2980, 1690,
740, 695
0.09 (s, 6 H, SiCH3); 0.91 [s, 9 H; C(CH3)3]; 1.74 –5.47 (2C, SiCH3); 17.99 [C(CH3)3]; 25.67
(m, 2 H, 3-H); 2.80 (m, 2-H); 3.64 (d, 2 H, 2J = 13.8, [3C, C(CH3)3]; 28.31 (C-3); 54.33 (2C,
NCH2Ph); 3.73 (dd, 2J = 10.2, 3J = 10.2, 3J = 5.5, 1- NCH2Ph); 55.67 (C-2); 62.44 (2C, C-1, C-4)
H); 3.82 (dd, 3J = 6.4, 1-H); 3.84 (d, 2 H, NCH2Ph);
4.19 (m, 2 H, 4-H)
7a
7b
16
–14.4
–28.5
–7.6
1690, 1150
2840, 1680
0.00 (s, 6 H; SiCH3); 0.82 [s, 9 H, C(CH3)3]; 1.20– –5.28 (2C, SiCH3); 18.32 [C(CH3)3]; 25.39
1.70 (m, 3-H)e; 1.94 (m, 3-H); 3.05 (m, 2-H); 3.55– [3C, C(CH3)3]; 32.04 (C-3); 54.13 (2C,
3.88 (m, 6 H, 4-H, NCH2Ph); 4.18 (dd, 2J = 10.7, 3J NCH2Ph); 54.21 (C-2); 60.98 (C-1); 63.91
= 5.4, 1-H); 4.28 (dd, 3J = 5.9, 1-H)
(C-4)
1.71 (m, 3-H); 1.92 (m, 3-H); 3.08 (m, 2-H); 3.20 (s, 29.18 (C-3); 53.97 (2C, NCH2Ph); 53.97 (C-
3 H; OCH3); 3.35 (m, 4-H); 3.45 (m, 4-H); 3.72 (d, 2); 58.47 (OCH3); 63.76 (C-4); 70.27 (C-1)
2
2 H, J = 13.4, NCH2Ph); 3.85 (d, 2 H, NCH2Ph);
4.25 (m, 2 H, 1-H)
2090, 1690,
1095, 1065
0.05 (s, 6 H, SiCH3); 0.89 [s, 9 H, C(CH3)3]; 1.79 –5.52 (2C, SiCH3); 18.15 [C(CH3)3]; 25.86
(m, 2 H, 3-H); 2.34 (s, 6 H, NCH3); 2.64 (m, 2-H); [3C, C(CH3)3]; 27.72 (C-3); 41.41 (2C,
3.60 (dd, 2J = 10.4, 3J = 5.4, 1-H); 3.74 (dd, 3J = 5.2, NCH3); 61.83 (C-2); 62.33 (C-1)c; 62.67 (C-
1-H); 4.18 (t, 2 H, 4-H)
4)c
a NMR data of the Cby group and the aromatic ring are omitted.
b c = 0.86–1.10 in CHCl3.
d Not determined.
e As part of a multiplet.
c Assignment interchangeable.
obtained by carboxylation/esterification. Fortunately, the Well-chelating diamines, such as N,N,N',N'-tetramethyl-
(–)-sparteine- and the substrate-induced stereoselectivi- ethylenediamine (TMEDA), compete successfully with
ties match and, consequently, the stereochemical outcome the intramolecular chelation. In these cases, only the steric
is not influenced by the 1-alkoxy group.
bulk of the 2-dibenzylamino group causes a small direct-

SYNTHESIS
September 1998
1291
Table 2b. Selected Data of Intermediates 8, 9, 10, 12, 13, 14, 15, or 16
Com-
pound
[α]D20 b
1H NMR (CDCl3) δ, J (Hz)
13C NMR (CDCl3) δ, J (Hz)
1-H
2-H
3-H
4-H
C-1/C-2
C-2
C-3
8
+ 43.4
–41.6
3.53
2.96 (ddt, 3J1a,2
=
1.46 (dddd,
3.63
61.07/
61.40c
56.81
28.95
3.5, 3J1b,2 = 5.9)
2J = 13.7), 2.02
9a
3.13 (dd, 2J = 9.5,
3J1,2 = 4.0), 3.29
(dd, 3J1,2 = 5.9)
3.01
1.65, 1.84
3.56
61.48/
63.36c
54.73
32.45
9d
10a
10d
–20.2
–98.0
–80.5
3.50–3.80d
3.01
1.69, 1.90
1.58, 1.92
1.53, 1.92
3.50–3.80d
61.57/
70.63
53.95
53.35
56.74
32.32
31.03
30.84
3.55 (ddd, 3J1,2
3.4), 3.73
=
3.10–3.21d
3.09
3.10–3.21d, 3.40
3.40–3.78d
62.14/
62.44c
3.40–3.78d, 3.78
(dd, 2J = 9.8, 3J1,2
= 5.7)
62.29/
70.51
10e
12e
–80.4
–37.0
3.40–3.78d, 3.85
(dd, 2J = 10.0,
3J1,2 = 5.5)
3.08
1.54, 1.93
2.28
3.40–3.78d
62.29/
67.01
56.62
57.74
30.71
24.89
3
–
3.75 (dd, J2,3
9.8)
=
4.08 (ddd, 2J = 9.3,
3J3,4 = 8.1), 4.33
(3J3a,4 = 3.6,
175.88/
65.21
3J3b,4 = 7.6)
13
14
15
+10.2
+12.3
–3.1
–
–
3.69–3.78d
3.76
2.12
3.69–3.78d
4.09, 4.21
4.23
173.10/
60.64
56.23
54.65
50.11
27.45
25.90
33.46
2.22
171.89/
62.33
3.41 (dd, 2J = 9.8,
3J1,2 = 6.8), 3.57
(dd, 3J1,2 = 4.5)
2.93
1.36–1.56a, 1.81
68.27/
61.73c
a NMR data of the Cby group and the aromatic ring are omitted.
b c = 1.00 in CHCl3.
d As part of a multiplet.
e Ref. b.
c Assignment interchangeable.
ing effect in the diastereotopic selection: when the depro-
tonations of 6a,b,e were carried out in the presence of
TMEDA, inseparable mixtures of the epimeric carboxylic
esters 20a,b,e and 21a,b,e were isolated (yields 68–89%,
dr 75–80:25–20, see Table 3).
In earlier work we experienced that γ-dimethylamino
groups are powerful ligands in alkyl carbamate lithiation,
which prevail over (–)-sparteine.15 Since the γ-dimethyl-
amino group in the 4-monocarbamate 16 is attached to a
stereogenic center, a high stereodirecting power is expect-
ed to operate. Indeed, sec-butyllithium in diethyl ether
(5 h at –78°C) and the subsequent trapping reaction fur-
nished the diastereomerically pure carboxylic ester 27,
arising from the formal substitution of the pro-S-4-H, with
52% yield (Scheme 8, Table 2). The yield increased to
92% when (–)-sparteine was used as an additive. These
experiments demonstrate that the bicyclic chelate com-
plex 25 is formed with a very good selectivity. Presum-
ably, the (–)-sparteine addition opens an additional depro-
(a) s-BuLi (1.6 equiv), Et2O, –78°C, 5 h. (b) MeI (1.6 equiv), 3 h at
–78°C, → r.t. (c) i. gaseous CO2; ii. after workup CH2N2 in Et2O.
Scheme 7

SYNTHESIS
Papers
Table 3. Substitution Products via Lithiation of Functionalized 4-Q-Monocarbamates
1292
Producta Substrate
(Scheme)
R
El
ElX
Yield (%) (dr) Diamine
mpb
(°C)
(–)-Sparteine TMEDA
Without
(Method 1)
(Method 2)
(Method 3)
d
h
h
f
18a
18b
18e
[18g]e
20a
20b
20d
20e
27
6a (6)
6b (6)
6e (6, 7)
Ph3C
Me
MEM
CH3
CH3
CH3
CH3I
CH3I
CH3I
91c
84c
63c
[25]c,e
90c
90c
59c
69c
92c
49.5
oil
85 (85 : 15)
68 (74 : 26)
oil
[oil]e
57.5
oil
g
h
h
6a (6)
6b (6)
6d (6, 7)
6e (6, 7)
16 (8)
Ph3C
Me
MeOCH2CH2
MEM
TBDMS
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2g
85 (77 : 23)
CO2g
89 (82 : 18)
d
CO2g
44 (≥ 28 : 2)
oil
oil
oil
d
CO2
76 (71 : 29)
d
ClCO2Me
52 (≥ 98 : 2)
a
e
f
Satisfactory elemental analyses were obtained (C ± 0.30, H ± 0.29,
N ± 0.29).
From Et2O.
dr ≥ 98.2.
Not carried out.
Substituted elimination product.
Only elimination product 24.
The crude acid was converted into the methyl ester by treatment
with diazomethane.
No deprotonation achieved (≥ 98 : 2).
b
c
d
g
h
have the correct array of 32 except for the oxidation state
at C-1 (Scheme 9). The 1-O-trityl derivative 18a was
deprotected (TFA in CH2Cl2/MeOH)21 to give the alcohol
28 (yield 79%) or, under more forced conditions (5 N aq
HCl in THF), to yield the diol 29 in 86% yield. Oxidation
of 29 by tris(triphenylphosphine)ruthenium(II) dichlor-
ide/sodium carbonate22 furnished the dibenzylamino-γ-
lactone 30 (yield 39%), which was debenzylated by trans-
fer hydrogenolysis,13 to give the amino lactone, isolated in
the form of the hydrochloride 31.23 Its mp and the specific
optical rotation are in good agreement with the published
data.20
(a) s-BuLi (2.0 equiv), Et2O, –78°C, 5 h. (b) s-BuLi (2.0 equiv), (–)-
sparteine (22, 2.0 equiv), Et2O, –78°C, 5 h. (c) ClCO2Me (3.0 equiv).
Scheme 8
tonation pathway via the complex 26•22, as it was ob-
served in a related case.15, 16
Conversion of 18a into (2S,4S)-γ-Hydroxy-norvaline
Lactone Hydrochloride (31)
(2S,4S)-γ-Hydroxy-norvaline (32) has been isolated from
the fruit bodies of Boletus satanas Lenz.17 Several synthe-
ses are known for other diastereomers of γ-hydroxy-nor-
valine, but only one in the form of lactone 32 or its hydro-
chloride 31.18–20 The methylation products 18 already
(a) TFA (21.5 equiv), MeOH/CH2Cl2, –5°C, 0.5 h, r.t., 2 h; (b) 5 N
HCl, THF, reflux, 16 h; (c) i. (Ph3P)3RuCl2 (1.2 equiv), C6H6, r.t.,
24 h; ii. + Na2CO3 (14 equiv), r.t., 48 h. (d) cyclohexene (15 equiv),
Pd/C (6 mol%), MeOH, reflux, 12 h.
Scheme 9

SYNTHESIS
September 1998
1293
Deprotonation of 4-O-Protected 1-O-Monocarbamates 7 In conclusion, by selecting the O- and N-protecting
groups properly, efficient routes to equivalents of the syn-
thons A and B are easily achieved.
Can selective deprotonations be achieved also at orthogo-
nally protected 1-O-carbamates, derived from 2-amino-
butane-1,4-diol?
All reactions were carried out under argon. All solvents were puri-
1
fied by distillation and dried, if necessary, prior to use. H and 13
C
The 4-O-TBDMS ether 7a, under the usual conditions
(1.6 equiv sec-butyllithium, Et2O, 5 h at –78°C), reacted
neither in the presence of (–)-sparteine nor in the absence
of diamines (Scheme 10). Good substrate-induced stereo-
selectivity was achieved with the 4-O-methyl ether 7b.
The intermediate lithium derivative, presumably the bis-
chelate 33, could be trapped by several electrophiles to
yield the diastereomerically pure substitution products
34a–e (Scheme 10, Table 4). It is expected, that this reac-
tion course is followed, independent of the 4-alkoxy
group, as long as the Lewis basicity of the 4-oxygen atom
is not diminished by an electron-withdrawing or a bulky
group. Thus, this method can be a useful extension of the
dicarbamate deprotonation.1
NMR spectra were recorded on Bruker WM 300, AM 360 or U 600
spectrometers. Optical rotations were recorded on a Perkin–Elmer
polarimeter 241. Mps were obtained on a Gallenkamp melting point
apparatus MFB-595 and are uncorrected. Products were purified by
flash-column chromatography on silica gel (40–63 µm). (+)-(S)-2-
(Dibenzylamino)butane-1,4-diol (1) was preparing according to ref.
1 and 4.
(+)-(S)-4-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)butan-1-
ol (8):4b,9
A solution of Et3N (1.21 g, 12.0 mmol), DMAP (0.61 g, 5.00 mmol),
and TBDMSCl (1.76 g, 12.0 mmol), dissolved in CH2Cl2 (60 mL),
was added to diol 1 in anhyd CH2Cl2 (40 mL). The mixture was re-
fluxed for 8 h. After cooling to r.t., water (50 mL) was added, the
organic layer was separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(MgSO4) and evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, Et2O/pentane 1:4) to yield the silyl ether
8 (2.20 g, 55%) as a colorless oil;
Rf 0.39 (Et2O/pentane 1:2); [α]D20 +39.7 (c = 1.00, CHCl3) [ref.9 [α]D23
+43 (c = 1, CHCl3)].
(–)-(S)-4-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-1-
(triphenylmethoxy)butane (9a):
To a solution of 8 (7.71 g, 19.3 mmol) in CH2Cl2 (150 mL) was added
Et3N (3.65 g, 36.1 mmol) and subsequently trityl chloride (6.46 g,
23.2 mmol) and DMAP (0.10 g, 0.80 mmol), dissolved in CH2Cl2
(10 mL). After stirring for 14 h at r.t., water (50 mL) was added. The
CH2Cl2 layer was separated and the aqueous phase was extracted with
CH2Cl2 (2 × 40 mL). The collected extracts were dried (MgSO4) and
the solvents were evaporated in vacuo. The crude product was puri-
fied by flash chromatography (silica gel, Et2O/pentane 1:3) to yield
pure 9a (9.36 g, 91%) as a viscous oil. (Data see Table 2b.)
(–)-(S)-4-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-1-(2-
methoxyethoxy)butane (9d):
(a) s-BuLi (1.6 equiv), Et2O, –78°C, 5 h. (b) s-BuLi (1.6 equiv), (–)-
sparteine (22, 1.6 equiv), Et2O, –78°C, 5 h. (c) + ElX (1.6 equiv), 3 h
at –78°C, → r.t.
A solution of 8 (7.42 g, 18.6 mmol) in anhyd THF (40 mL) was added
dropwise to a suspension of NaH (1.48 g, 37.1 mmol, 60% in mineral
oil) in THF (10 mL). The mixture was stirred at r.t for 4 h, before
2-bromoethyl methyl ether (7.74 g, 60.0 mmol), Bu4NI (0.69 g,
2.00 mmol), and DMAP (40 mg, 0.33 mmol) were added. After heat-
ing under reflux for 20 h and cooling to r.t., water (15 mL) was poured
carefully into the mixture. The organic layer was separated and the
aqueous solution extracted with Et2O (3 × 25 mL). The collected ex-
tracts were dried (MgSO4) and the solvents evaporated in vacuo. The
crude product was purified by flash chromatography (silica gel, Et2O/
pentane 1:6) to yield pure 9d (3.29 g, 44%) as a viscous oil and 8
(3.48g, 45%).(Data see Table 2b.)
Scheme 10
Table 4. Substitution Products 33 via Lithiation of Functionalized 1-
O-Monocarbamate 7a (Scheme 10)
Product
El
ElX
Yield
(%)
mp
(°C)
34a,b
c
a
b
c
d
e
CO2Me
SiMe3
(CH3)2COH
CO2
86
65
64
64
78
oil
oil
oil
oil
oil
ClSiMe3
(CH3)2C=O
C2H5(=O)Cl
C2H5(=O)
(–)-(S)-3-(tert-Butyldimethylsilyloxy)-3-(dibenzylamino)-4-(2-
methoxyethoxymethoxy)butane (9e):
e
f
a
To a solution of 8 (16.24 g, 40.6 mmol) in CH2Cl2 (50 mL) were
added MEMCl (7.58 g, 60.9 mmol) and iPr2NEt (7.87 g, 60.9 mmol).
After heating under reflux for 24 h and cooling to r.t., water (15 mL)
was added. The CH2Cl2 layer was separated and the aqueous layer
was extracted with CH2Cl2 (2 × 40 mL). The collected extracts were
dried (MgSO4). After removal of the solvent in vacuo, the residue was
used without purification.
All products with ds ≥ 98 : 2.
Satisfactory elemental analyses were obtained (C ± 0.30, H ± 0.29,
N ± 0.29).
The crude acid was converted into the methyl ester by treatment
with diazomethane.
(E)-CH3CH=CHC(=O).
b
c
d
e
(E)-CH3CH=CHC(=O)Cl.

SYNTHESIS
Papers
Table 5. Selected Data of Substituted Monocarbamates 18, 19, 27, 33a
1294
Com-
pound
[a]D20 b IR (KBr/film) 1H NMR (CDCl3)
13C NMR (CDCl3)
δ, J (Hz)
ν (cm–1)
δ, J (Hz)
18a
+37.8 2960, 1730,
745, 695
0.94 (d, 3 H, 3J4,5 = 6.0, 5-H); 1.56 (m, 3-H); 1.98 (m, 3- 19.84 (C-5); 36.41 (C-3); 54.15 (2C,
H); 2.97 (m, 2-H); 3.24 (dd, 2J = 9.5, 3J1,2 = 5.3, 1-H); 3.38 NCH2Ph); 54.39 (C-2); 62.51 (C-1); 67.08
3
2
(dd, J1,2 = 5.5, 1-H); 3.41 (d, 2 H, J = 13.7, NCH2Ph); (C-4); 87.13 (CPh3)
3.73 (d, 2 H, NCH2Ph); 5.02 (m, 4-H)
18b
18e
–12.6 2840, 1690
0.92 (d, 3 H, 5-H); 1.82 (m, 2 H, 3-H); 2.90 (m, 2-H); 3.28 20.21 (C-5); 26.88 (C-3); 52.09 (C-2);
[3.24]c (s, 3 H, OCH3); 3.48 (m, 2 H, 1-H); 3.62 (m, 2 H, 52.50 (2C, NCH2Ph); 57.12 (OCH3); 65.83
NCH2Ph); 3.82 (d, 2H, 2J = 13.8, NCH2Ph); 5.12 (m, 4-H) (C-1); 68.78 (C-4)
–15.3 2970, 2930,
2870, 1685,
1050, 1090,
765, 748,
0.97 (d, 3 H, 3J4,5 = 6.2, 5-H); 1.63 (m, 3-H); 1.98 (m, 3- 19.90 [20.93]c (C-5); 35.88 [36.57]c (C-3);
H); 2.90 [2.96]c (m, 2-H); 3.41 (s, 3 H, OCH3); 3.55–3.85 53.54 (C-2); 54.22 [54.49]c (2C, NCH2Ph);
(m, 6 H; OCH2CH2O, 1-H); 3.57 (d, 2 H, 2J = 13.6, 59.03 (OCH3); 66.98, 67.34 (2-C),
NCH2Ph); 3.83 (d, 2 H, NCH2Ph); 4.74 [4.70]c (s, 2 H, OCH2CH2)d; 68.97 (C-4); 71.84 (C-1)d;
730, 700
OCH2O); 5.08 (m, 4-H)
95.78 (OCH2O)
18g
–17.1 2970, 2890,
1700, 1065,
0.97 (d, 3 H, 3J1,2 = 6.2, 5-H); 1.65 (m, 3-H); 1.96 (m, 3- 14.06 (C-5); 35.84 (C-3); 53.37 (C-2);
H); 2.90 (m, 2-H); 3.56 (d, 2 H, 2J = 13.6, NCH2Ph); 3.72– 54.19 (2C, NCH2Ph); 67.81 (C-1); 68.87
3.87 (m, 2 H, 1-H); 3.81 (d, 2 H, NCH2Ph); 4.18 (dd, 2J = (C-4); 91.05, 94.25 (2C, OCH2O,
1.7, J = 6.6, OCHCH2); 4.52 (dd, J = 14.1, OCHCH2); OCHCH2); 149.65 (OCHCH2)
4.92 (s, 2 H, OCH2O); 5.06 (m, 4-H); 6.43 (dd, OCHCH2)
750, 700
3
3
20a
20b
20d
20e
–43.8 2950, 1750,
1090, 1070,
765, 745,
2.06 (m, 3-H); 2.13 (m, 3-H); 3.23 (m, 4-H); 3.35 (m, 2 H, 31.45 (C-3); 51.97 (OCH3); 54.36 [53.76]c
2
5-H); 3.53 (d, J = 14.1, NCH2Ph); 3.65 [3.72]c (s, 3 H, (C-4); 54.53 (2C, NCH2Ph); 62.21 (C-5);
OCH3); 3.69 (d, 2 H, NCH2Ph); 4.97 [5.32, d]c (dd, 3J2,3a
5.0, 3J2,3b = 9.3 [10.7]c 2-H)
=
70.59 [70.01]c (C-2); 86.94 (Ph3C); 171.74
[172.53]c (C-1)
700, 705
–4.3
2840, 1730,
1680
1.84 (m, 3-H); 1.92 (m, 3-H); 3.05 (m, 4-H); 3.34 (s, 3H, 27.15 (C-3); 53.11 (C-4); 54.50 (2C,
OCH3); 3.56 (s, 3 H; COOCH3); 3.62 (m, 4 H, 5-H, NCH2Ph); 56.12 (OCH3); 58.86
NCH2Ph); 3.87 (d, 2 H, 2J = 13.8, NCH2Ph); 5.14 [5.31]c (COOCH3); 69.97 (C-5); 75.04 (C-2);
(dd, 3J2,3a = 5.1, 3J2,3b = 6.5, 2-H)
170.23 (C-1)
–22.7 2890, 1750,
1700, 1095,
1070, 745,
2.04 (m, 3-H); 2.19 (m, 3-H); 3.10 (m, 4-H); 3.38 (s, 3 H; 31.10 (C-3); 51.95 (COOCH3); 53.58 (C-4);
OCH3); 3.51–3.79 (m, 8 H, NCH2Ph, 5-H, OCH2CH2); 54.52 (2C, NCH2Ph); 59.01 (OCH3); 70.43
3.65 (s, 3 H, COOCH3); 3.73 (d, 2 H, 2J = 14.3, NCH2Ph); (C-2); 70.49, 70.73, 72.05 (3C, C-5,
700
5.13 (dd, 3J2,3a = 4.6, 3J2,3a = 9.4, 2-H)
OCH2CH2); 171.72 (C-1)
–20.6 2920, 2880,
1750, 1695,
2.07 [1.86]c (m, 3-H); 2.22 (m, 3-H); 3.11 [2.97]c (m, 4-H); 31.00 [31.81]c (C-3); 51.96 (COOCH3);
3.40 [3.42]c (s, 3 H, COOCH3); 3.66 [3.72] (s, 3 H, OCH3); 53.50 [53.04]c (C-4); 54.52 [54.04]c (2C,
3.67 (d, 2J = 12.9, NCH2Ph); 3.78 [3.91]c (d, 2 H; NCH2Ph); 59.00 (OCH3); 67.02 [66.27]c
NCH2Ph); 3.53–3.85 (m, 6 H, 5-H, OCH2CH2); 4.73 [4.72, (2C, OCH2CH2)d; 70.30 [69.92]c (C-2);
s]c (d, 2 H, OCH2O); 5.13 [5.31, d]c; dd, 3J2,3a = 4.8, 3J2,3b 71.80 (C-5)d; 95.70 (OCH2); 171.64 (C-1)
= 9.5 [10.7]c 2-H)
1095, 1070,
750, 700
27
–21.6 2915, 2900,
2865, 1745,
1690, 1075,
1045
0.61 (s, s, 6 H, SiCH3); 0.89 [s, 9 H, C(CH3)3]; 2.03 (m, 2
–5.56 (2C, OSiCH3); 18.12 [C(CH3)3]; 25.84
H, 3-H); 2.31 (s, 6 H, NCH3), 2.82 (m, 4-H); 3.50–3.85 (m, [3C, C(CH3)3]; 30.09 (C-3); 41.03 (2C,
5 H, OCH3, 5-H); 5.18 (dd, 3J2,3a= 4.5, 3J2,3b = 6.0, 2-H)
NCH3); 51.58 (OCH3); 60.57 (C-4); 59.78–
61.66 (C-5)e; 70.21 (C-2); 175.75 (C-1)
34a
–27.3 2840, 1700,
1690
1.85 (m, 2 H, 4-H); 2.19 (m, 3-H); 3.30 (s, 3 H, OCH3); 24.29 (C-4); 51.76 (OCH3); 54.87 (2C,
3.35–3.50 (m, 5 H, 3-H, 5-H, NCH2Ph); 3.53 (s, 3 H, NCH2Ph); 55.77 (C-3); 58.67 (COOCH3);
COOCH3); 3.90 (m, 2 H, 2J = 13.2, NCH2Ph); 5.35 (d, 3J2,3 69.92 (C-5); 75.02 (C-2); 170.11 (C-1)
= 4.3, 2-H)
34b
34c
–27.1 2820, 1670
0.00 (s, 9 H, SiCH3); 1.28–1.85 (m, 3-H)e; 3.15 (s, 3 H, 0.00 (3C, SiCH3); 29.82 (C-3); 56.28 (2C,
OCH3); 3.18–3.80 (m, 7-H, 2-H, 4-H, 5-H, 2J = 13.9, NCH2Ph); 59.43 (C-2); 60.01 (OCH3);
NCH2Ph); 4.97 (d, 3J1,2 = 6.9, 1-H)
72.21 (C-4); 72.85 (C-1)
+1.8
3420, 2830,
1710
0.40, 1.03 [s, s, 6 H, C(CH3)2]; 1.75 (m, 2 H, 2-H); 2.18 (m, 23.51 (C-2); 26.39, 26.68 [2C, C(CH3)2];
2
3-H); 3.40 (s, 3 H, OCH3); 3.42–3.75 (m, 6 H, 1-H, J = 54.87 (2C, NCH2Ph); 55.05 (C-3); 59.05
13.2, NCH2Ph); 4.61 (OH); 4.86 (d, 3J3,4 = 3.1, 4-H)
(OCH3); 69.81 (C-1); 74.09 (C-5); 76.99
(C-4)
34d
34e
–51.2 2830, 1730,
1690
0.93 (t, 3 H, 3J1,2 = 7.2, 1-H); 1.91 (m, 6-H); 2.18 (m, 6-H); 7.01 (C-1); 23.12 (C-2); 31.64 (C-6); 54.52
2
3.37 (s, 3 H, OCH3); 3.31–3.71 (m, 6 H, 2-H, J = 13.5, (2C, NCH2Ph); 54.86 (C-5); 58.77 (OCH3);
NCH2Ph); 3.95 (m, 2 H, 7-H); 5.35 (d, 3J4,5 = 5.0, 4-H)
69.79 (C-7); 80.16 (C-4); 205.96 (C-3)
–51.2 2830, 1730,
1690
0.93 (t, 3 H, 3J1,2 = 7.2, 1-H); 1.91 (m, 6-H); 2.18 (m, 6-H); 7.01 (C-1); 23.12 (C-2); 31.64 (C-6); 54.52
2
3.37 (s, 3 H, OCH3); 3.31–3.71 (m, 6 H, 2-H, J = 13.5, (2C, NCH2Ph); 54.86 (C-5); 58.77 (OCH3);
NCH2Ph); 3.95 (m, 2 H, 7-H); 5.35 (d, 3J4,5 = 5.0, 4-H)
69.79 (C-7); 80.16 (C-4); 205.96 (C-3)
a NMR data of the Cby group and the aromatic ring are omitted.
b c = 0.96–1.02 in CHCl3, only 18a: c = 0.36.
d Assignment interchangeable.
e As a part of a overlay of signals.
c Spectroscopic data of the minor diastereomer.

SYNTHESIS
September 1998
1295
Desilylation of Silyl Ethers 7a, 9a,d,e; Preparation of the Alcohols
4, 10a,d,e; General Procedure:
Etherification of 3, 4; Preparation of Methyl Ether 6b, 7b; Gen-
eral Procedure:
To a solution of the TBDMS ether 7 or 9 (5.0 mmol) in Et2O was
added 1.0 M TBAF in THF (12.5 mL, 12.5 mmol). After stirring at r.t.
for 14 h, water (20 mL) was added. Stirring was continued for 0.5 h,
and the organic layer was separated. The aqueous layer was extracted
with Et2O (3 × 25 mL), the combined solutions were dried (MgSO4),
and evaporated in vacuo. The crude product was purified by flash
chromatography (silica gel, Et2O/pentane 1:1) to yield the pure alco-
hol 4 (92%), 10a (82%), 10d (99%), or 10e (90%, over two steps).
(Data see Table 1a, for 4, and Table 2b.)
A solution of 3 or 4 (441 mg, 1.0 mmol) in anhyd THF (5 mL) was
added dropwise to a suspension of NaH (120 mg, 3.0 mmol, 60% in
mineral oil) in THF (5 mL). The mixture was stirred at r.t for 0.5 h,
before MeI (568 mg, 4.0 mmol) was added. After heating under reflux
for 16 h and cooling to r.t., water (10 mL) was introduced carefully to
the mixture. The organic layer was separated and the aqueous solution
extracted with Et2O (3 × 20 mL). The collected extracts were dried
(MgSO4) and the solvents evaporated in vacuo. The crude product
was purified by flash chromatography (silica gel, Et2O/pentane 1:1)
to yield the pure methyl ether 6b (432 mg, 95%) or 7b (380 mg, 85%).
(Data see Table 2a.)
Carbamoylation of the Alcohols 1, 8, 10a,d,e, 13; Preparation of
the Monocarbamates 3, 4, 7a, 6a,d,e, and 14; General Procedure:
A solution of the alcohol (60 mmol) in anhyd THF (30 mL) was added
dropwise to a suspension of NaH (3.60 g, 90 mmol, 60% in mineral
oil) in THF (60 mL). The mixture was stirred for 3 h at r.t., before
2,2,4,4-tetramethyloxazolidine-3-carbonyl chloride10 (CbyCl, 2,
14.98 g, 78 mmol) in THF (20 mL) was added. After heating under
reflux for 16 h and cooling to r.t., water (50 mL) and Et2O (50 mL)
were added carefully to the mixture. The organic layer was separated
and the aqueous solution extracted with Et2O (3 × 50 mL). The col-
lected extracts were dried (MgSO4). The solvents were evaporated in
vacuo and the crude product was purified by flash chromatography
(silica gel, Et2O/pentane 1:1) to yield pure carbamates 7a (90%), 6a
(92%), 6d (88%), 6e (72%), or 1412 (92%).(Data see Table 2a, for 14
see Table 2b.) For carbamoylation of 1 (1.43 g, 5.0 mmol) in THF
(10 mL): With NaH (3.60 g, 90 mmol, 80% in mineral oil) in THF
(10 mL) and CbyCl (2, 1.15 g, 6.0 mmol) in THF (5 mL). Chromatog-
raphy (silica gel, Et2O/pentane 1:5) afforded a 1:3 mixture of 3 and 4
(1.98 g, 90%) with partial separation.
(–)-(S)-[3-(Dibenzylamino)-4-(methoxymethoxy)butyl] 2,2,4,4-
Tetramethyloxazolidine-3-carboxylate (6c):
To a solution of 3 (1.10 g, 2.50 mmol) in CH2Cl2 (15 mL) was added
MOMCl (6.46g, 50 mmol).24 The mixture was stirred at r.t. for 7 d.
The solvent was evaporated in vacuo and the crude product was puri-
fied by flash chromatography on silica gel to yield 6c (1.18 g, 97%)
as a colorless oil. (Data see Table 2a.)
(S)-[4-(tert-Butyldimethylsilyloxy)-3-(dibenzylamino)butyl]
2,2,4,4-Tetramethyloxazolidine-3-carboxylate (6f):
A solution of Et3N (3.39 g, 33.5 mmol) and TBDMSCl (1.21 g,
8.04 mmol), dissolved in CH2Cl2 (3 mL), was added to the alcohol 3
(2.96 g, 6.70 mmol) in anhyd CH2Cl2 (50 mL). After stirring the mix-
ture at r.t. for 10 h water (50 mL) was added. The organic layer was
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 25
mL). The combined organic layers were dried (MgSO4) and evaporat-
ed in vacuo. The residue was purified by flash chromatography (silica
gel, Et2O/pentane 1:2) to yield the silyl ether 6f (3.61 g, 97%) as a
colorless oil. (Data see Table 2a.)
Detritylation of 6a, 18a; Preparation of the Alcohols 3, 28; Gen-
eral Procedure:
(–)-(S)-2-(Dibenzylamino)-4-butanolide (12):6
To a solution of (S)-methionine (14.92 g, 100 mmol), K2CO3
(15.62 g, 114 mmol) and NaOH (4.55 g, 114 mmol) in MeOH/H2O
(75 mL/75 mL) at 95°C (bath temperature) was added dropwise BnBr
(51.31 g, 300 mmol); refluxing and stirring was continued for 40 min.
To the cooled mixture was added Et2O (100 mL), the aqueous layer
was extracted with Et2O (3 × 50 mL) and the collected extracts were
dried (MgSO4). After removal of the solvent in vacuo, the residue was
purified by flash chromatography (silica gel, Et2O/pentane 1:4) to af-
ford a mixture of 12 and BnOH. The pure lactone 12 (10.33 g, 37%)
was obtained by crystallization. (Data see Table 2a.)
To a solution of the trityl ether 6a (4.22 g, 6.18 mmol) in CH2Cl2
(7 mL) and MeOH (7 mL) at –5°C TFA (10.2 mL, 133 mmol) was
added dropwise.21 After stirring the yellow mixture at –5°C for 0.5 h
and 2 h at r.t. water (15 mL) was added. Sat. K2CO3 was added care-
fully to the mixture until the formation of gas stopped. The organic
layer was separated and the aqueous solution extracted with CH2Cl2
(3 × 25 mL). The collected extracts were dried (MgSO4). The solvents
were evaporated in vacuo and the crude product was purified by flash
chromatography (silica gel, Et2O/pentane 1:2 → 1:0) to yield pure
alcohol 3 (2.28 g, 84%) as a colorless oil. (Data see Table 2a.)
(+)-(S)-2-(Dibenzylamino)-4-hydroxy-N,N-dimethylbutanamide
(13):
(+)-(2S,4S)-4-(Dibenzylamino)-5-hydroxy-1-methylbutyl 2,2,4,4-
Tetramethyloxazolidine-3-carboxylate (28):
To a solution of lactone 12 (2.81 g, 10.0 mmol) containing BnOH
(1.2 g) in anhyd EtOH (40 mL) was added 5.6 M Me2NH in EtOH
(20 mL, 112 mmol) at 0°C. After stirring for 48 h at 0°C the solvent
was evaporated in vacuo at r.t. The residue was purified by flash chro-
matography (silica gel, Et2O/pentane 1:4 → MeOH/CH2Cl2 1:20) af-
ford 13 (2.50 g, 77%) as yellow oil. (Data see Table 2b.) 0.59 g (21%)
of 12 was recovered.
From 18a (166 mg, 0.24 mmol) in CH2Cl2/MeOH (1 mL/1 mL);
yield: 86 mg (79%); colorless solid; mp 124°C; Rf 0.23 (Et2O/pentane
1:1); [α]D20 +37.8 (c = 0.36, CHCl3).
IR (film): ν = 3400 (OH), 1730 (C=O), 750, 695 cm–1 (arom).
1H NMR (CDCl3, 300 MHz): δ = 1.13–1.57 (m, 12H, Cby-CH3); 1.23
3
(d, 3H, J1,2 = 6.2 Hz, 5-H); 2.10 (m, 3-H); 2.97 (m, 3-H); 3.07 (m,
OH); 3.51 (d, 2H, 2J = 13.6 Hz, NCH2Ph); 3.40–3.75 (m, 3H, 1-H, 2-
H); 3.67, 3.68 (s, s, 2H, Cby-CH2); 3.81 (d, 2H, NCH2Ph); 3.97 (m,
4-H); 7.17–7.37 (m, 10H, Ph).
Reductive Deamination of 14; Preparation of 3:
To a solution of 14 (560 mg, 1.16 mmol) in THF (12 mL) was added
1 M LiEt3BH in THF (3.6 mL, 3.60 mmol) dropwise at 0°C.11 The
mixture was stirred at r.t. for 12 h and further LiEt3BH (2.0 mL,
2.00 mmol) was added. After stirring for 1 h, the mixture was
quenched with water (10 mL) and the separated aqueous layer was
extracted with Et2O (3 × 15 mL). The collected organic layers were
dried (MgSO4) and the solvent removal in vacuo. The residue was
purified by flash chromatography (silica gel, Et2O/pentane 4:1) to
yield 3 (436 mg, 85%). (Data see Table 2a.)
13C NMR (CDCl3, 75 MHz): δ = 20.90 (C-5); 23.97, 24.20, 25.17,
25.35, 25.60, 26.53, 26.90 (4C, Cby-CH3); 32.86 (C-3); 53.48 (2C,
NCH2Ph); 55.87 (C-4); 59.52, 60.61 [NC(CH3)2CH2]; 61.42 (C-1);
68.61 (C-2); 76.03, 76.27 (Cby-CH2); 94.60, 95.87 [OC(CH3)2N];
127.15, 127.81, 128.45, 128.83, 129.30, 139.27 (12C, Ph); 152.46,
153.11 (C=O).
Anal. Calcd for C27H38N2O4 (454.61): C, 71.34; H, 8.43. Found: C,
71.66; H, 8.51.

SYNTHESIS
Papers
1296
Debenzylation of 6f, 30; Preparation of 15, 31; General Proce-
dure:
for 12 h and water (10 mL) was added. The Et2O layer was separated
and the aqueous phase was extracted with Et2O (3 × 25 mL). The
combined Et2O were dried (MgSO4) and evaporated in vacuo. The
residue was purified by flash chromatography (silica gel, Et2O/pen-
tane 1:1 to 1:4) to afford the C-1 substituted carbamate 18.
To a solution of 6f (5.95 g, 10.0 mmol) in MeOH (40 mL) was added
5% Pd/C (1.20 g, 0.56 mmol) and cyclohexene (12.3 g, 150 mmol).
After heating under reflux for 12 h and cooling to r.t. Et2O (10 mL)
was added. The mixture was stirred at r.t. for 0.5 h. The solids were
filtered off and thoroughly extracted with Et2O (50 mL). The solvents
were evaporated in vacuo and for analyses the crude product was pu-
rified by flash chromatography on silica gel with Et2O/pentane/Et3N
(4:1:0.1) to yield the amine 15 (3.76 g, 84%). (Data see Table 2b.)
(+)-(2S,4S)-2-(Dibenzylamino)pentane-1,4-diol (29):
A solution of 18a (3.48 g, 5.00 mmol) in THF (5 mL) and 5 M HCl
(25 mL) was refluxed for 16 h. After cooling to r.t., the mixture was
neutralized with 5 M NaOH (25 mL) and extracted with Et2O (5 ×
25 mL). The collected extracts were dried (MgSO4) and the solvents
were evaporated in vacuo. The crude product was purified by flash
chromatography (silica gel, Et2O/pentane 1:3 → 1:0) to yield pure
diol 29 (1.28 g, 86%) as a viscous oil; oil; Rf 0.24 (Et2O/pentane 4:1);
[α]D20 +4.8 (c = 1.00, CHCl3).
(+)-(2S,4S)-2-Amino-4-pentanolide Hydrochloride (31):
From 30 (40 mg, 0.14 mmol) with Pd/C (25 mg, 0.01 mmol) in MeOH
(2 mL). The crude product was dissolved in 6 M HCl (2 mL) and
stirred at r.t. for 1 h. The solvent was evaporated in vacuo and the
residue was crystallized from MeOH/Et2O; yield: 20 mg (94%); col-
orless solid: mp 193°C; [α]D20 –41.0 (c = 0.50, MeOH) [ref.20 mp 198–
200°C; [α]D20 –44 (c = 1.1, MeOH).
IR (film): ν = 3450 (OH), 1050 (C–O), 750, 700 cm–1 (arom).
3
1H NMR (CDCl3, 300 MHz): δ = 1.14 (d, 3H, J4,5 = 6.2 Hz, 5-H);
1.37 (ddd, 2J = 14.3 Hz, 3J2,3 = 5.8 Hz, 3-H); 1.75 (ddd, 3J2,3 = 7.6 Hz,
3J3,4 = 9.5 Hz, 3-H); 2.51 (m, OH); 3.06 (m, 2-H); 3.53–3.80 (m, 3H,
1-H, 4-H); 3.62 (d, 2H, 2J = 13.0 Hz, NCH2Ph); 3.76 (d, 2H,
NCH2Ph); 4.36 (m, OH); 7.13–7.35 (m, 10H, Ph).
(–)-(S)-[4-(tert-Butyldimethylsilyloxy)-3-(dimethylamino)butyl]
2,2,4,4-Tetramethyloxazolidine-3-carboxylate (16):
13C NMR (CDCl3, 75 MHz): δ = 23.83 (C-5); 35.18 (C-3); 53.68 (2C,
NCH2Ph); 58.15 (C-2); 61.26 (C-1); 67.36 (C-4); 127.24, 128.46,
129.25, 138.71 (12C, Ph).
To a solution of 15 (562 mg, 1.50 mmol) in MeCN (5 mL) and 37%
aq CH2O (0.7 mL) was added NaBH3CN (150 mg, 2.40 mmol).14 The
mixture was stirred at r.t. for 0.5 h and the solution neutralized with
HOAc. The solvent was evaporated in vacuo before the residue was
dissolved in 15% aq NaOH (10 mL). After extraction with Et2O (5 ×
15 mL), the combined Et2O extracts were dried (MgSO4), evaporated
and the residue purified by flash chromatography (silica gel, Et2O/
pentane/Et3N 1:2:0.1) to yield 16 (496 mg, 82%) as a colorless oil.
(Data see Table 2a.)
MS (EI) C19H25NO2 (299.41):calcd. 299.18853, found 299.18782.
(–)-(2S,4S)-2-(Dibenzylamino)-4-pentanolide (30):
To a solution of 29 (156 mg, 0.52 mmol) in anhyd benzene (10 mL)
was added (Ph3P)3RuCl2 (600 mg, 0.62 mmol).22 The mixture was
stirred for 24 h at r.t., before Na2CO3 (827 mg, 7.80 mmol) was add-
ed; stirring was continued for 48 h. The solids were filtered off over
silica gel and the solvents evaporated in vacuo. The crude product was
purified by flash chromatography (silica gel, Et2O/pentane 1:2) to af-
ford 30 (60 mg, 39%); oil; Rf 0.50 (Et2O/pentane 1:1); [α]D20 –33.1 (c
= 0.93, CHCl3).
Deprotonation of Monocarbamate 6, 7, 16 with s-BuLi and Prep-
aration of C-1 Substituted Products 9; General Procedure:
Method 1: (–)-Sparteine (22, 422 mg, 1.80 mmol) was dissolved in
anhyd Et2O (4.5 mL) under argon and 1.4 M s-BuLi in cyclohexane/
hexane (1.29 mL, 1.80 mmol) was added dropwise. After stirring for
15 min, the monocarbamate, dissolved in Et2O (2.5 mL), was added.
Stirring was continued for 5 h before the electrophile was introduced.
(See Method A or B.)
IR (film): ν = 1180 (C–O), 1769 (C=O), 740, 695 cm–1 (arom).
3
1H NMR (CDCl3, 300 MHz): δ = 1.28 (d, 3H, J4,5 = 6.5 Hz, 5-H);
1.97 (ddd, 2J = 13.1 Hz, 3J2,3 = 9.5 Hz, 3J3,4 = 3.4 Hz, 3-H); 2.41 (ddd,
3
2
3J2,3 = 8.7 Hz, J3,4 = 8.6 Hz, 3-H); 3.67 (d, 2H, J = 13.4 Hz,
NCH2Ph); 3.82 (m, 2-H); 3.87 (d, 2H, NCH2Ph); 4.66 (ddq, 4-H);
7.18–7.44 (m, 10H, Ph).
Method 2: TMEDA (209 mg, 1.80 mmol) was dissolved in anhyd
Et2O (4.5 mL) under argon and 1.4 M s-BuLi in cyclohexane/hexane
(1.29 mL, 1.80 mmol) was added dropwise. After stirring for 15 min,
the monocarbamate, dissolved in Et2O (2.5 mL), was added. Stirring
was continued for 5 h before the electrophile was introduced. (See
Method A or B.)
13C NMR (CDCl3, 75 MHz): δ = 22.03 (C-5); 31.60 (C-3); 54.75 (2C,
NCH2Ph); 57.19 (C-2); 74.30 (C-4); 127.24, 128.38, 128.69, 138.83
(12C, Ph); 175.91 (C-1).
Anal. Calcd for C19H21NO2 (295.38): C, 77.26; H, 7.17; N, 4.74.
Found: C, 76.87; H, 7.01; N, 4.89.
Method 3: Deprotonation without diamine. To a solution of the car-
bamate (1.0 mmol) in anhyd Et2O or THF (8 mL) under argon at
–78°C 1.4 M s-BuLi in cyclohexane/hexane (1.29 mL, 1.80 mmol)
was added dropwise. Stirring was continued for 5 h before the elec-
trophile was introduced. (See Method A or B.)
Generous support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
Method A:
(1) Guarnieri, W.; Sendzik, M.; Fröhlich, R.; Hoppe, D. Synthesis,
1998, 1274.
For carboxylation, after stirring at –78°C for 5 h, a stream of dry CO2
was introduced to the solution of the deprotonated carbamate via a
syringe for 10 min. After warming to r.t., hydrolysis with water
(10 mL) and extraction with Et2O (3 × 25 mL), the collected organic
layers were dried (MgSO4) and concentrated. The residue was dis-
solved in Et2O (5 mL) and treated with ethereal CH2N2 solution until
remaining yellow. After stirring for 1 h, silica gel (20 mg) was added
and the mixture was stirred for 15 min in order to destroy the excess
of CH2N2. The subsequent flash chromatographic purification (Et2O/
pentane 1:1 to 1:4) yielded the methyl ester 20 or 33a.
(2) Hoppe, D.; Paetow, M.; Hintze, F. Angew. Chem. 1993, 105,
430; Angew. Chem., Int. Ed. Engl. 1993, 32, 394.
(3) Reviews: (a) Hoppe, D.; Hense, T. Angew. Chem. 1997, 109,
2376; Angew. Chem. Int. Ed. Engl. 1997, 36, 2282.
(b) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.;
Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri, W.;
Kolczewski, S.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994,
66, 1479.
c) Hoppe, D.; Ahrens, H.; Guarnieri, W.; Helmke, H.; Kolczew-
ski, S. Pure Appl. Chem. 1996, 68, 613.
Method B:
d) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumana-
van, S. Acc. Chem. Res. 1996, 29, 552.
After stirring at –78°C for 5 h, the electrophile (1.8 mmol) was slowly
introduced with a syringe. The mixture was allowed to warm up to r.t.

SYNTHESIS
September 1998
1297
(4) 1 has independently been prepared, see:
(a) Gmeiner, P.; Kärtner, A.; Junge, D. Tetrahedron Lett. 1993,
34, 4325.
(b) Gmeiner, P.; Junge, D.; Kärtner, A. J. Org. Chem. 1994, 59,
6766.
(5) (a) Albert, R.; Denklmaier, J.; Hönig, H.; Kandolf, H. Synthesis
1987, 635.
(12) (a) The ee value of monocarbamate 3, synthesized from (S)-
methionine was found to be >98% by 1H NMR spectroscopy af-
ter reacting with (–)-(R)-α-methoxy-α-trifluoromethylphenyl-
acetyl chloride (Mosher’s reagent); ref. 12b.
(b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(13) (a) Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem.
Rev. 1985, 85, 129.
(b) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport,
H. J. Org. Chem. 1990, 55, 3068.
(c) Chevallet, P.; Garrouste, P.; Malawska, B.; Martinez, J.
Tetrahedron Lett. 1993, 34, 7409.
(d) Burger, K. Chem.-Ztg. 1990, 114, 249.
(e) Winkler, D.; Burger, K. Synthesis 1996, 1419.
(f) Stein, K. A.; Toogood. P. L. J. Org. Chem. 1995, 60, 8110.
(g) Baldwin, J. E.; North, M.; Flinn, A. Tetrahedron Lett. 1987,
28, 3167.
(b) Bajwa, H. S. Tetrahedron Lett. 1992, 33, 2299.
(14) Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673.
(15) Sommerfeld, P.; Hoppe, D. Synlett 1992, 764.
(16) Helmke, H.; Hoppe, D. Synlett 1995, 978.
(17) (a) Eugster, C. H. Fortschr. Chem Org. Naturst. 1969, 27, 262.
(b) Matzinger, P.; Catalfomo, Ph.; Eugster, C. H. Helv. Chim.
Acta 1972, 55, 1478.
(18) γ-Hydroxy-norvalines are highly biologically active molecules,
they increase insulin secretion, see: Ribes, G.; Broca, C.; Petit,
P.; Jacob, M.; Baissac, Y.; Manteghatti, M.; Roye, M.; Sauvai-
re, Y. Diabetologia 1996, 39, A234.
(h) Baldwin, J. E.; North, M.; Flinn, A. Tetrahedron 1988, 44,
637.
(i) Cooper, R. D. G.; Jose, F.; McShane, L.; Koppel, G. A.
Tetrahedron Lett. 1978, 2243.
(19) (a) Schmeck, C.; Hegedus, L. S. J. Am. Chem. Soc. 1994, 116,
9927 and references cited therein.
(j) Jefford, C. W.; Wang J. B.; Lu, Z.-H. Tetrahedron Lett.
1993, 34, 7557.
(b) Harding, K. E.; Marman, T. H.; Nam, D.-h Tetrahedron Lett.
1988, 29, 1627.
(k) McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara,
Y.; Oh, T. J. Am. Chem. Soc. 1986, 108, 4943
(6) Reetz, M. T.; Schmitz, A.; Holdgrün, X. Tetrahedron Lett.
1989, 30, 5421.
(c) For preparation of racemate 32, see: Fischer, E.; Leuchs, L.
Ber. Deutsch. Chem. Ges. 1902, 35, 3797.
(20) Jacob, M.; Roumestant, M. L.; Viallefont, P.; Martinez, J. Syn-
lett 1997, 691.
(7) Gmeiner, P. Arch. Pharm. (Weinheim) 1991, 324, 551.
(8) The costs according to Aldrich in 1996/1997 are DM 18.60/
100 g for (S)-aspartic acid, DM 64.60/100 g for (S)-asparagine,
and DM 143.20/100 g for (S)-homoserine.
(9) Guarnieri, W. Diploma Thesis, Universität Kiel 1992.
(10) Hintze, F.; Hoppe, D. Synthesis 1992, 1216.
(11) Brown, H. C.; Kim S. C. Synthesis 1977, 635.
(21) Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem.
Soc. Jpn. 1978, 51, 1577.
(22) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1981, 22, 1605.
(23) For the preparation of (2S,4S)-γ-hydroxy-norvaline (32) from
the lactone hydrochloride 31 with i. 2 N NaOH, ii. Dowex
50WX8 (100%), see ref. 19.