Enantioselective entry to the Homalium alkaloid hoprominol: Synthesis of an (R,R,R)-hoprominol derivative

Article abstract of DOI:10.1002/hlca.200390016

The diastereoselective synthesis of the N- and O-protected hoprominol derivative (R,R,R)-6 is described. The building up of the bicyclic O-silylated and di(N-tosylated) asymmetric scaffold 6 succeeded by convergent preparation of the two basic chiral azalactam units 7a and 7b and their subsequent iterative linking by a known method (Scheme 5). Both 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 7a and 7b were prepared from the chiral β-amino acid portions 10a and 10b, respectively, by application of a set of reactions (e.g., N-alkylation of 10a,b and Sb(OEt)₃-assisted cyclization of the resulting open-chain intermediates) already known. In comparison with the total syntheses of homaline (1) and homoprine (2), the newness of the described synthesis lies in the asymmetric approach to the difunctionalized fatty acid derivative 10b starting from (-)-(S)-malic acid (9) (Schemes 3 and 4). Key step in the preparation of 10b was the diastereoselective amination of the optically pure α,β-unsaturated δ-hydroxy homoallylic ester 14 via conjugate intramolecular aza-Michael cyclization of the acylic δ-(carbamoyloxy) intermediate 11.

Full text of DOI:10.1002/hlca.200390016

Helvetica Chimica Acta Vol. 86 (2003)
233
Enantioselective Entry to the Homalium Alkaloid Hoprominol:
Synthesis of an (R,R,R)-Hoprominol Derivative
by Corinne Ensch1) and Manfred Hesse*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
(tel.: ‡41-1-6354281; fax: ‡41-1-6356812; e-mail: mtbohley@oci.unizh.ch)
The diastereoselective synthesis of the N- and O-protected hoprominol derivative (R,R,R)-6 is described.
The building up of the bicyclic O-silylated and di(N-tosylated) asymmetric scaffold 6 succeeded by convergent
preparation of the two basic chiral azalactam units 7a and 7b and their subsequent iterative linking by a known
method (Scheme 5). Both 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 7a and 7b were prepared from the chiral
b-amino acid portions 10a and 10b, respectively, by application of a set of reactions (e.g., N-alkylation of 10a,b
and Sb(OEt)3-assisted cyclization of the resulting open-chain intermediates) already known. In comparison with
the total syntheses of homaline (1) and homoprine (2), the newness of the described synthesis lies in the
asymmetric approach to the difunctionalized fatty acid derivative 10b starting from (À)-(S)-malic acid (9)
(Schemes 3 and 4). Key step in the preparation of 10b was the diastereoselective amination of the optically pure
a,b-unsaturated d-hydroxy homoallylic ester 14 via conjugate intramolecular aza-Michael cyclization of the
acylic d-(carbamoyloxy) intermediate 11.
Introduction. Isolated from the leaves of the New Caledonian plant Homalium
pronyense Guillaum. (Flacourtiaceae) [2], the four Homalium alkaloids homaline
(1), hopromine (2), hoprominol (3), and hopromalinol (4) constitute a small family of
optically active natural products characterized by a unique bis-eight-membered lactam
structure incorporating a spermine (5) backbone (Fig.). The structures of the
Homalium alkaloids were elucidated in the seventies by Pais and co-workers [3],
and the correctness of the proposed formulae was confirmed by several total syntheses
since then.
A single-crystal X-ray analysis [4] as well as manifold asymmetric syntheses [5][6]
allowed the determination of the absolute (S,S)-configuration of the major alkaloid
homaline (1). In a preceding paper [1], we presented a new, potent synthetic entry to
the Homalium scaffold that enabled us to prepare (Æ)-homaline (1) and (À)-
hopromine (2) and, hence, to determine the absolute configuration of the natural
hopromine (2) as being (R,R). Since, hitherto, all the syntheses of the remaining,
unsymmetrically substituted parent molecules hoprominol (3) and hopromalinol (4)
are nonstereospecific [7], the absolute configurations of the alkaloids 3 and 4 are still
unknown. Hereafter, we now wish to report the application of our previously described
synthetic strategy for building up the bicyclic Homalium core by the preparation of the
N- and O-protected (R,R,R)-hoprominol precursor 6 (Fig.), with the higher aim of
elucidating the yet-undefined configuration of the natural product (À)-homprominol
(3).
1
)
Part of the Ph.D. thesis of C. E., University of Z¸rich, 2002.

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Helvetica Chimica Acta Vol. 86 (2003)
CH3
O
N
N
R
R'
N
N
O
H3C
1
2
3
4
R = Ph
R' = Ph
R' = Me(CH2)6
R' = Me(CH2)4CH(OH)CH2
R' = Me(CH2)4CH(OH)CH2
homaline
R = Me(CH2)4
R = Me(CH2)4
R = Ph
hopromine
hoprominol
hopromalinol
H
N
NH2
H2N
N
H
5
O
NTs
C5H11
H
H11C5
N
N
H
tBuPh2SiO
TsN
O
6
Figure. The Homalium alkaloids 1 4, their spermine backbone 5, and the hoprominol derivative 6
One chiral structural unit of the bis-eight-membered structure, namely the N-
tosylated, 4-pentyl-substituted hexahydro-1,5-diazocin-2(1H)-one 7a (Scheme 1) could
be efficiently prepared from (‡)-l-aspartic acid (8) according to [1], whereas the
second building block 7b, carrying a supplementary OH group at the C7 side chain, was
synthesized starting from (À)-(S)-malic acid (9). The choice of 9 as chiral starting
material for the construction of 10b was motivated on the one hand by the supposition
that all the members of the Homalium family share the same three-dimensional
orientation of the residues at their corresponding stereogenic centers of the lactam
rings (i.e., (4S)-configuration for the phenyl-substituted lactams and (4R)-configura-
tion for the alkyl-substituted ring systems). On the other hand, it resulted from the idea
(Scheme 2) to introduce the chiral N-functional group in 10b via the key step of an 1,3-
syn-selective intramolecular conjugate aza-Michael-cyclization reaction of the optically
pure a,b-unsaturated d-(carbamoyloxy) ester 11. This plan involved that, to be able to
generate a (4R)-configured stereogenic center at the ring system 7b, the later OH group
at C(2) of the C7-alkyl side chain had to have the absolute (R)-configuration. The set of
reaction methods elaborated for the preparation of different 4-substituted hexahydro-
1,5-diazocin-2(1H)-ones, and optimized earlier in the course of our homaline (1) and
hopromine (2) syntheses, proved to remain valid for the preparation of the eight-
membered lactam system 7b from the doubly functionalized linear precursor 10b.
Results and Discussion. Analogously to the retrosynthetic analysis of homaline
(1) and hopromine (2), the parent hoprominol (3) might be fragmented into two 4-
alkyl-substituted eight-membered lactam rings 7a and 7b bridged by a C4 chain
(Scheme 1). The azalactams 7a and 7b, then, can be decomposed into a nonchiral C3-N

Helvetica Chimica Acta Vol. 86 (2003)
235
Scheme 1. Retrosynthetic Analysis of Hoprominol (3)
R
O
N
H
5''
H
N
1'
H11C5
N 1''
O
2'"
R'O
C5H11
N
1
4'
5
R
3
6
R = CH3 R' = H
t
R = Ts
R' = SiPh2 Bu
O
O
O
H
tBuPh2SiO
H11C5
OMe
NHTs
R''
OEt
NHTs
H
H
7b
4
1NH
7a
TsN5
H11C5
10b
10a
7a R'' = Me(CH2)4
b R'' = Me(CH2)4CH(OSiPh2 Bu)CH2
t
O
OCONH2
O
OEt
OEt
H
I
11
NHTs
12
OH
O
OEt
COOH
13
H
HOOC
NH2
O
O
8
OEt
15
COOH
OH
H
HOOC
9
chain and two b-alkyl-b-amino acid portions 10a and 10b, respectively, as the
asymmetric structural units. The b-amino fatty acid unit 10a, on the one hand, was
divided into a linear C5-alkyl rest and the chiral iodoester 12, easily obtainable from
(‡)-l-aspartic acid (8) by modification of the a-carboxylic acid group [8] through
intramolecular condensation, regioselective NaBH4 reduction [9], and EtOH/trime-
thylsilyl iodide-mediated lactone cleavage [10]. Based on 10a, the corresponding
enantiomerically pure N-tosylated 4-pentyl-substituted azalactam 7b was prepared
according to the procedures described in [1].

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2. Plan for the Construction of the Difunctionalized Fatty Acid Derivative 10b
O
TBDPSO
OMe
NHTs
OH
(R)
O
H
OEt
(5R) (3R)
10b
13
O
OR
(R)
O
O
NH
O
key step:
OEt
OEt
1,3-syn cyclization
(3R)
(5R)
14
11
R = H
R = CONH2
22
TBDPS = tBuPh2Si = (tert-butyl)diphenylsilyl
The doubly functionalized C10 moiety 10b, in turn, was traced back in a first step to
the chiral b-hydroxy ester 13 (Scheme 2), which, after a simple C2 homologation to the
corresponding a,b-unsaturated d-hydroxy ester 14, should serve as a basis for the
diastereoselective introduction of the required amino function. The b-hydroxy ester 13
belongs to a class of valuable chiral precursors commonly prepared by the reac-
tion of organocuprates with optically pure b,g-epoxy esters, like 15 in our case.
The synthesis of the first key intermediate 15 was planned to involve the chemo-
selective modification of a commercially available chiral-pool material, (À)-(S)-malic
acid (9).
An efficient chemical method for the preparation of the chiral synthon 15 was
√
elaborated by Larcheveque and Henrot [11b,c]: it is achieved (Scheme 3) by chemo-
selective ring opening of the b-hydroxybutyrolactone 16 (without any supplementary
protection of the free OH function) with trimethylsilyl iodide [10b] in the presence of
an excess of EtOH in CH2Cl2, followed by stereoselective cyclization of the resulting
iodohydrin 17 with 1.2 equiv. of silver oxide at room temperature in dry MeCN. In our
hands, the silver-mediated epoxidation of 17 gave the epoxybutanoate 15 in 82%
chemical yield and ca. 93% optical purity (determined by comparison of the optical-
rotation value of 15 with the data of the optically pure product given in [11c]).
The required lactone 16 was easily prepared in three steps from (À)-(S)-malic acid
(9) according to [12] by quantitative acylation of the starting material in boiling acetyl
chloride, methanolysis of the anhydride 18 to the intermediate half-ester 19, and
subsequent reduction with NaBH4 in tBuOH/MeOH into a transitional dihydroxy acid
that cyclized spontaneously to the desired lactone 16 under acidic conditions.
The prolongation of the C4 chain present in the key element 15 to the C8 backbone
of 13 was accomplished by submitting the oxirane-acetate 15 to the action of a twofold

Helvetica Chimica Acta Vol. 86 (2003)
237
Scheme 3. Synthesis of the b,g-Unsaturated d-Hydroxy Ester 14 from (À)-(S)-Malic Acid (9)
O
O
COOMe
OAc
COOH
OH
a)
b)
c)
H
H
O
O
HOOC
HOOC
HO
AcO
O
9
18
19
16
d)
O
e)
OR
O
f)
O
OEt
O
H
I
OEt
OEt
HO
13 R = H
g)
15
17
20 R = THP
h)
OR
O
OH
O
i)
H
OEt
21 R = THP
14
a) AcCl, reflux, 3 h; 99%. b) MeOH, r.t., overnight; quant. c) 1. NaBH4, tBuOH/MeOH, reflux, 2 h; 2. AcCl,
MeOH, 08 ! r.t., 1 h; 76%. d) Me3SiI, EtOH, CH2Cl2, 3 ä mol. sieves, r.t., overnight; 89%. e) Ag2O, MeCN, r.t.,
4 h; 81.5%. f) BuLi, CuBr¥ Me2S, Et2O/THF 1.5 :1, À 658 !À 358, 3.5 h; 61%. g) 3,4-dihydro-2H-pyran,
TsOH ¥ H2O (1 mol-%), CH2Cl2, r.t., 3 h; 96%. h) 1. LiAlH4, THF, r.t. ! 558, 2.5 h; 2. PDC, CH2Cl2, reflux, 4 h;
76%. i) 1. (EtO)2P(O)CH2CO2Et, DBU, LiCl, MeCN, r.t., 1 h; 2. TsOH ¥ H2O (10 mol-%), MeOH, r.t., 1 h;
62%.
excess of the lithiocuprate Bu2CuLi under anhydrous conditions in dry Et2O/THF
1.5 :1 between À 65 and À 358. The necessary cuprate reagent was successfully
generated in situ from commercially available BuLi and CuBr¥ Me2S in Et2O/THF at
À 658 in an analogous manner to that described in [1]. As expected from the previously
√
reported results of Larcheveque and co-workers [11], the attack of the cuprate
nucleophile occurred exclusively at the less-substituted C-atom of the oxirane ring of
15 to give the desired (R)-configured b-hydroxy ester 13 in 61% chemical yield and
near enantiomeric purity (e.e. ca. 98%).
To obtain the final C-chain length of the doubly functionalized C10 moiety 10b, the
enantiomerically pure b-hydroxy ester 13 had to undergo a classical C2 homologation.
Since the attempted direct half-reduction of ester 13 with diisobutylaluminium hydride
to the corresponding aldehyde was always accompanied by considerable amounts of
over-reduction products, a complete reduction of the ester function to the primary
alcohol followed by re-oxidation to the aldehyde was employed. Therefore, the OH
group of 13 was first quantitatively THP-protected (THP ˆ tetrahydro-2H-pyran-2-yl)
by treatment with cat. TsOH ¥ H2O (Ts ˆ tosyl ˆ p-toluenesulfonyl) and dihydro-2H-
pyran in CH2Cl2 at room temperature to give 20, then the ester function was totally

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Helvetica Chimica Acta Vol. 86 (2003)
reduced with LiAlH4 in dry THF under reflux, and, finally, the primary alcohol was
oxidized with pyridinium dichromate (PDC) in boiling CH2Cl2, thus yielding the
aldehyde 21 in 76% yield (from 20). A very mild olefination procedure developed by
Roush, Masamune, and co-workers [13], which involves a phosphonate in combination
with chelating LiCl and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base in dry
MeCN, allowed a very rapid Horner-Wadsworth-Emmons transformation of aldehyde
21 into the corresponding THP-protected a,b-unsaturated d-hydroxy ester, which was
immediately deprotected with cat. TsOH ¥ H2O in MeOH to give the desired
homoallylic d-hydroxy ester 14 in 62% chemical yield.
For the planned diastereoselective amination of the (E)-olefinic C10 framework by
intramolecular conjugate addition of a carbamate group (Scheme 4), the key
intermediate 14 was transformed into the d-(carbamoyloxy) ester 11 according to the
standard procedure of Graf [14]: by treatment of the d-hydroxy ester 14 with
chlorosulfonyl isocyanate in CH2Cl2 for 1 h at À 788 and subsequent hydrolysis of the
chlorosulfonyl group, the carbamoylation of the homoallylic group was achieved in
94% yield. In the next step, cooled 0.1m tBuOK in dry THF was added dropwise at 08 to
0.1m d-(carbamoyloxy) ester 11 in THF, and the mixture was kept at 08 for 2.5 h. In
accordance with the related studies made by Hirama and co-workers [15], the
thermodynamically controlled, base-catalyzed aza-Michael cyclization of 11 to the 6-
membered oxazinone system 22 succeeded with 80% chemical yield and remarkably
Scheme 4. Preparation of 10b by Conjugate aza-Michael Cyclization of the d-(Carbamoyloxy) Ester 11,
Cleavage of the Oxazinone Ring, and Protection of the Functional Groups
O
OCONH2
O
O
NH
O
a)
b)
14
OEt
OEt
(5R) (3R)
11
22
c)
O
O
OH NH2
O
H
NHTs
d)
OH
25
23
g)
+
O
TBDPSO
OMe
NHTs
OH NHTs O
H
e) f)
OH
10b
24
a) 1. ClSO2NCO, CH2Cl2, À 788 !À 608, 1 h; 2.H2O, r.t. ! 608, 4 h; 94%. b) tBuOK, THF, 08, 2.5 h; 80%. c) 4n
aq. NaOH, EtOH, 608, overnight. d) 1. 08, CO2; 2. NaHCO3, TsCl, acetone, r.t., 6 h. e) 1. tBuPh2SiCl (TBDPS-
Cl), 1H-imidazole, cat. DMAP, dry DMF, 558, overnight; 2.H2O, 608, 2 h. f) CH2N2, Et2O, r.t., 0.5 h; 10b: 54%;
25: ca. 25%. g) NaHCO3, H2O/acetone 1:1, r.t., overnight.

Helvetica Chimica Acta Vol. 86 (2003)
239
1
high 1,3-syn selectivity. The H-NMR studies (300 MHz) of the purified product 22
showed a diastereoisomer ratio > 19 :1 in favor of the desired (3R,5R)-configured
cyclic carbamate.
To preserve the ethyl ester function of 22, the cleavage of the carbamate ring was
first attempted under anhydrous biphasic conditions with carbonate (K2CO3, Na2CO3,
Cs2CO3) and hydroxide (KOH, NaOH) bases in various dry organic solvents (THF,
DMF, MeCN, and CH2Cl2), but this did not meet with success. Unlike the descriptions
of Ishizuka and Kunieda [16], even the mild cleavage procedure via N-Boc activation of
the carbamate ring did not produce the desired results. The only conditions capable of
splitting the 1,3-oxazin-2-one into a free 1,3-amino alcohol required strong aqueous
bases but were not compatible with the conservation of the ethyl ester function, so that
the concomitant hydrolysis to the highly polar amino acid 23 could not be avoided.
Thus, oxazinone 22 was first heated overnight at 608 with an excess of 4n aqueous
NaOH in EtOH, then the mixture was saturated with dry-ice, followed by the addition
of NaHCO3 and a 4.5-fold excess of TsCl in acetone. After acidic workup, the crude
reaction mixture (composed of the N-tosylated (3R,5R)-3-amino-5-hydroxydecanoic
acid 24 and the chiral lactone 25) was subjected to bis-silylation with 5.0 equiv. of both
tBuPh2SiCl (TBDPS-Cl) and 1H-imidazole and catalytic amounts of N,N-dimethylpyr-
idin-4-amine (DMAP) in dry DMF at 558 overnight. Mild hydrolysis of the undesired
silyl ester and subsequent treatment with diazomethane in Et2O gave the final N-
tosylated, O-silylated ester 10b in 54% overall yield starting from 22. Up to 25% of the
starting material 22 were lost in the formation of the rather stable 6-membered lactone
25, which was isolated together with the desired linear moiety 10b at the end of the
reaction sequence. With NaHCO3 in aqueous acetone, it was possible to cleave the
lactone ring without racemization and to recover a small quantity of the chiral
(tosylamino)hydroxy acid 24 re-usable in a new reaction cycle.
With the chiral synthon 10b in hands, we could apply the ring-construction strategy
optimized in our synthesis of (R,R)-hopromine (2) [1] to build up the corresponding
diastereoisomerically pure N-tosylated 4-substituted hexahydro-1,5-diazocin-2(1H)-
one 7b. The insertion of the missing C3-N fragment (Scheme 5) was achieved by
alkylating the TsNH group of 10b with tert-butyl (3-iodopropyl)carbamate (26; readily
available from 3-aminopropan-1-ol after Boc-protection to 27 followed by iodination
with I2, 1H-imidazole, and PPh3 in CH2Cl2), after heterogeneous deprotonation by
cesium carbonate in dry DMF at 558. Subsequent removal of the Boc protection group
from the resulting N-alkylated tosylamino ester 28 by means of a several-fold excess of
CF3COOH in toluene gave the linear ring precursor 29 in 93% yield. Fortunately, the
presence of the bulky O-silyl protection group at the C7 side chain of 29 did not have
any negative influence on the directing metal effects of Sb(OEt)3 in the following Sb-
mediated cyclization: refluxing 29 with 1.2 equiv. of Sb(OEt)3 under high-dilution
conditions overnight in dry benzene yielded the eight-membered lactam 7b in an
excellent 95% yield. The exclusive formation of the monomeric azalactam system 7b
was confirmed by an ESI-MS analysis.
Together with 7a, we had now at our disposal of the necessary chiral building blocks
to assemble the bis-8-membered azalactam structure of hoprominol (3). The bridging
of the two structural elements 7a and 7b by a C4 chain was attempted iteratively [6][17]
(Scheme 5). In a first step, 7a was mono-alkylated with 1,4-dibromobutane to the

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 5. Synthesis of the N-Tosylated 4-Substituted Hexahydro-1,5-diazocin-2(1H)-one 7b and Attempted
Iterative Coupling with 7a to the Hoprominol Precursor 6
O
O
b)
TBDPSO
OMe
TBDPSO
OMe
H
H
N
NHBoc
N
NH2
Ts
Ts
28
29
c)
a)
10b
O
H
NH
TsN
TBDPSO
7b
O
NTs
H
e)
N
O
H11C5
C5H11
N
H
TsN
TBDPSO
6
NTs
C5H11
NTs
d)
N
HN
C5H11
Br
H
H
O
O
7a
TBDPS = tBuPh2Si
30
a) I(CH2)3NHBoc (26; from HO(CH2)3NHBoc (27)), Cs2CO3, DMF, r.t., overnight; 73%. b) CF3COOH,
toluene, 508, overnight; 93%. c) Sb(OEt)3, dry benzene, 3-ä mol. sieves, reflux, overnight; 95%. d) Br(CH2)4Br,
powdered KOH, dry DMSO, 08 ! r.t., overnight; 71%. e) 1. Powdered KOH, dry DMSO, 08 ! r.t., 4 h; 2. cat.
KOH, r.t., overnight; 8%.
bromo derivative 30 under the action of powdered KOH in dry DMSO at room
temperature overnight. Several trials to subsequently attach 30 to 7b analogously to our
slightly modified KOH/DMSO-coupling method [1], i.e., by adding a mixture of both
compounds to a frozen suspension of 2.0 equiv. of KOH in dry DMSO at 08 and slowly
defreezing the solid reaction mixture overnight, were only moderately successful: apart
from mostly unreacted educts, the desired bis-eight-membered structure 6 was isolated
in low yield. The identification of the coupling product 6 was achieved by IR- and
1H-NMR spectroscopy (600 MHz) and through the fragmentation pattern obtained by
an ESI-MS analysis.

Helvetica Chimica Acta Vol. 86 (2003)
241
We are, however, confident that, by changing the order of the iterative coupling
sequence, i.e., by first mono-alkylating the azalactam 7b with a large excess of the cheap
1,4-dibromobutane and then attaching the second building block 7a to the resulting
bromo derivative, it is possible to achieve the assembly of the bicyclic scaffold in good
yield, and to get sufficiently great amounts of the chiral N-tosylated, O-silylated
hoprominol precursor 6 to successfully terminate the total synthesis of (R,R,R)-
hoprominol (3) by a simple exchange of the protection groups.
Conclusions. The diastereoisomerically pure (R,R,R)-compound 6, an N-tosyl-
and O-silyl-protected derivative of the naturally occurring spermine alkaloid (À)-
hoprominol (3), was prepared by convergent synthesis from the two chiral 4-alkyl-
substituted hexahydro-1,5-diazocin-2(1H)-ones 7a and 7b, respectively (see also [1]).
The optical purity of the target compound 6 was assured by the use of the commercially
available chiral-pool materials (‡)-l-aspartic acid (8) and (À)-(S)-malic acid (9) as
(S)-configured starting materials for the syntheses of the basic chiral b-amino fatty acid
moieties 10a and 10b. The diastereoselective preparation of the difunctionalized C10
synthon 10b from 9 via the key step of an intramolecular 1,3-syn-selective cyclo-
carbamation is described in detail. The build up of the corresponding eight-membered
azalactam 7b, based on the Sb(OEt)3-assisted cyclization of the linear amino ester 29,
was successfully achieved by means of the ring-construction strategy optimized for the
syntheses of (R,R)-hopromine (2), thus establishing the general applicability of the
earlier developed set of reactions. With the synthesis of 7b, we completed the list of the
four basic chiral lactam systems into which the members of the Homalium family (Fig.)
can be decomposed retro-synthetically. By coupling 7b with the pentyl-substituted
azalactam 7a to the fully protected, bis-eight-membered product 6, we were able to
disclose an asymmetric entry to (R,R,R)-hoprominol (3), since the remaining steps of
the total synthesis, i.e., the electrolytic detosylation of the secondary amines, the
deprotection of the OH function, and finally the reductive methylation of the free
amino groups should be feasible without substantial problems.
We thank the analytical departments of our institute for all measurements and gratefully acknowledge the
financial support of the Swiss National Science Foundation.
Experimental Part
General. See [1].
(À)-(4R)-Hexahydro-4-pentyl-5-tosyl-1,5-diazocin-2(1H)-one (7a). For the preparation of 7a from (‡)-l-
aspartic acid (8), see [1].
(À)-(3S)-3-(Acetyloxy)-3,4-dihydrofuran-2,5-dione (18). (À)-(S)-Malic acid (9, 17.8g, 0.13 mol) was
treated according to [12]. After evaporation, the viscous residue was crystallized from CH2Cl2, washed with
21
Et2O (2Â), and dried in vacuo: 18 (20.7 g, 99%). Small colorless plates. M.p. 54 568. ‰aŠ ˆ À25.9 (c ˆ 5.0,
D
21
D
CHCl3) ([12]): ‰aŠ ˆ À26 (c ˆ 5.11, CHCl3)). 1H-NMR: 5.52 (dd, J ˆ 9.8, 5.8, 1 H); 3.41 (dd, J ˆ 18.7, 9.6, 1 H);
3.05 (dd, J ˆ 18.9, 5.8, 1 H); 2.19 (s, 3 H). 13C-NMR: 169.7, 167.9, 166.7 (3 s); 67.8( d); 35.0 (t); 20.2 (q).
(À)-(4S)-4,5-Dihydro-4-hydroxyfuran-2(3H)-one (16). The soln. of 18 (20.7 g, 0.13 mol) in MeOH (40 ml)
was stirred at r.t. overnight. Evaporation yielded the half-ester 19 as a pale yellow oil (24.9 g, 0.13 mol, quant.),
t
which was immediately taken up in BuOH/MeOH 5 :1 (120 ml). This soln. was added dropwise over 1 h to a
refluxing suspension of NaBH4 (20.1 g, ca. 96% purity, 0.52 mol, 4.0 equiv.) in BuOH (250 ml). Boiling was
t
continued for additional 2 h, then the mixture was cooled to 08 and quenched by the slow addition of HCl/
MeOH previously prepared by adding AcCl (48ml) to MeOH (300 ml) at 0 8. The acidic mixture was allowed to

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Helvetica Chimica Acta Vol. 86 (2003)
warm to r.t. over 1 h and was then evaporated. The solid residue was taken up in AcOEt, the insoluble salts
eliminated by filtration, and the org. filtrate neutralized by washing several times with sat. aq. Na2CO3 soln.
21
D
Evaporation and purification of the oily residue by CC (AcOEt) gave 16. Colorless oil (10.2 g, 76%). ‰aŠ
ˆ
21
D
À81.6 (c ˆ 1.95, EtOH) ([12]: ‰aŠ ˆ À81.0 (c ˆ 1.97, EtOH)). IR: 3640 3100m, 3600w, 3020m, 2960w, 2930w,
2900w, 1775s, 1465w, 1405m, 1370m, 1325m, 1300 1220w, 1240m, 1180s, 1170s, 1085s, 1050s, 1025m, 1000s, 970m,
1
890w, 8 65w, 8 40w, 68 5w, 615w. H-NMR: 4.71 4.67 (m, 1 H); 4.42 (dd, J ˆ 10.3, 4.5, 1 H); 4.29 (dm, J ˆ 10.3,
1 H); 2.81 (br. s, 1 H); 2.75 (dd, J ˆ 17.9, 6.0, 1 H); 2.52 (dm, J ˆ 17.9, 1 H). 13C-NMR: 176.2 (s); 75.9 (t); 67.4
‡
(d); 37.7 (t). CI-MS: 120 ([M ‡ NH4] ).
Ethyl (À)-(3S)-3-Hydroxy-4-iodobutanoate (17). To a soln. of 16 (5.26 g, 51.6 mmol) in abs. EtOH (9 ml,
0.15 mol, 3.0 equiv.) and activated molecular sieves (3 ä; 5 g) in dry CH2Cl2 (215 ml) at r.t., Me3SiI (10.5 ml,
77.3 mmol, 1.5 equiv.) was slowly added within 45 min. After stirring for one night at r.t., the solvent was
evaporated and the oily brown residue dissolved in Et2O. The soln. was twice washed with 5% aq. Na2S2O3 soln.,
dried (MgSO4), and evaporated, the residual oil subjected to CC (AcOEt/hexane 1 :3): 17 (11.9 g, 89%). Pale
21
21
yellow oil. ‰aŠ ˆ À9.9 (c ˆ 3.1, EtOH) ([11b]: ‰aŠ ˆ À10.7 (c ˆ 3.0, EtOH)). IR: 3630 3200w, 3020w, 3000m,
D
D
2980m, 2940w, 2900w, 1725s, 1475w, 1465w, 1445w, 1405m, 1375m, 1350-1230m, 1180s, 1170s, 1125m, 1095m,
1075m, 1035m, 1020m, 98 0w, 950w, 8 8 w5, 8 60w, 8 40w, 640w, 620w. 1H-NMR: 4.19 (q, J ˆ 7.1, 2 H); 4.04 3.96
(m, 1 H); 3.38 3.26 ( m, 2 H); 3.15 (br. s, 1 H); 2.67 (dd, J ˆ 16.5, 4.4, 1 H); 2.59 (dd, J ˆ 16.5, 7.8, 1 H); 1.28
‡
(t, J ˆ 7.1, 3 H ) . 13C-NMR: 171.6 (s); 67.4 (d); 60.9, 40.6 (2 t); 14.0 (q); 11.8( t). CI-MS: 276 (100, [M ‡ NH4] ),
‡
‡
‡
259 (10, [M ‡ H] ), 241 (17, [M À H2O ‡ H] ), 148(16, [ M À HI ‡ NH4] ).
Ethyl (À)-(2S)-Oxirane-2-acetate (15). A soln. of 17 (4.48g, 17.4 mmol) in dry MeCN (10 ml) was added
dropwise to a suspension of Ag2O (4.83 g, 20.8 mmol, 1.2 equiv.) in MeCN (40 ml). After stirring for 4 h at r.t.,
the solvent was evaporated, the residue taken up in AcOEt, the mixture filtered over Celite¾, and the filtrate
washed with 5% aq. Na2S2O3 soln (2Â). The collected aq. layers were extracted with AcOEt (3Â) and the
combined org. layers washed with brine, dried (MgSO4), and evaporated. The residue was subjected to CC
21
(AcOEt/hexane 1:3): 15 (1.84 g, 81.5%). Colorless oil. ‰aŠ ˆ À23.5 (c ˆ 3.8, MeOH, e.e. ca. 93%) ([11b]:
D
21
‰aŠ ˆ À25.3 (c ˆ 3.7, MeOH)). IR: 3620 3200w, 3530w, 3025w, 3015m, 3000s, 2980s, 2930m, 2910w, 2880w,
D
1730s, 1480w, 1465w, 1445w, 1420w, 1410m, 1370m, 1325m, 1300m, 1265s, 1240w, 1180s, 1165m, 1130m, 1095m,
1075w, 1050w, 1025s, 1020m, 98 0m, 955w, 940w, 905w, 8 70w, 8 40m, 615w. 1H-NMR: 4.18( q, J ˆ 7.1, 2 H); 3.32
3.26 (m, 1 H); 2.82 (dd, J ˆ 4.9, 4.0, 1 H); 2.57 2.54 (m, 3 H); 1.28( t, J ˆ 7.1, 3 H ) . 13C-NMR: 170.1 (s); 60.5 (t);
‡
‡
47.7 (d); 46.3, 37.8(2 t); 13.9 (q). EI-MS: 85 (100, [M À C2H5O] ), 72 (66, [M À C3H6O] ), 57 (15, [M À
‡
C3H5O2] ).
Ethyl (À)-(3R)-3-Hydroxyoctanoate (13). At À 658, 1.6m BuLi in hexane (19.5 ml, 31.1 mmol, 2.2 equiv.)
was added slowly to a suspension of CuBr¥ Me2S (3.20 g, 15.6 mmol, 1.1 equiv.) in dry Et2O/THF 5 :3 (80 ml).
The dark brown suspension was stirred at À 658 !À 408 for ca. 25 min until all the CuI salts were dissolved.
Then the homogeneous mixture was recooled to À 658 before a soln. of 15 (1.84 g, 14.2 mmol, 1.0 equiv.) in dry
Et2O/THF 1 :1 (40 ml) was added dropwise over 30 min. The mixture was stirred for 3.5 h at a temp. below
À 358 and subsequently poured on sat. aq. NH4Cl/25% aq. NH3 soln. 1:1 (120 ml). The biphasic mixture was
vigorously stirred for 30 min at r.t. until a clear colorless org. phase was obtained. The deep blue aq. phase was
extracted with Et2O (3Â) and the combined org. layer washed with brine, dried (MgSO4), and evaporated.
Purification of the oily residue (2.12 g) by distillation under vacuum gave 13 (1.62 g, 61%). Colorless oil. B.p.
21
D
21
D
89 948/9 mbar. ‰aŠ ˆ À2.45 (c ˆ 2.0, MeOH, e.e. ca. 98%) ([11b]: ‰aŠ ˆ À2.5 (c ˆ 1.9, MeOH, e.e. > 99%)).
IR: 3640 3200w, 3020w, 3000m, 2980m, 2960s, 2930s, 2870m, 2860m, 1720s, 1660w, 1480w, 1465w, 1455w, 1445w,
1405w, 1375m, 1325w, 1305m, 1280m, 1240w, 1180s, 1170m, 1130 1060w, 1095m, 1040w, 1025m, 955w, 940w,
615w. 1H-NMR: 4.17 (q, J ˆ 7.1, 2 H); 4.21 3.97 (m, 1 H); 2.90 (br. s, 1 H); 2.50 (dd, J ˆ 16.4, 3.3, 1 H); 2.45
(dd, J ˆ 16.4, 8.8, 1 H); 1.57 1.24 (m, 8H); 1.27 ( t, J ˆ 7.1, 3 H); 0.89 (t, J ˆ 6.7, 3 H). 13C-NMR: 172.9 (s); 67.9
‡
‡
(d); 60.5, 41.2, 36.4, 31.6, 25.0, 22.4 (6 t); 14.0, 13.9 (2 q). CI-MS: 206 (100, [M ‡ NH4] ), 189 (11, [M ‡ H] ), 171
‡
(7, [M À H2O ‡ H] ).
Diastereoisomer Mixture Ethyl (3R)-3-[(Tetrahydro-2H-pyran-2-yl)oxy]octanoate (20). To a mixture of
TsOH ¥ H2O (13.4 mg, 0.07 mmol, 1 mol-%) and 13 (1.32 g, 7.03 mmol) in CH2Cl2 (13 ml) was added dropwise
over 15 min a soln. of 3,4-dihydro-2H-pyran (0.83 ml, 9.14 mmol, 1.3 equiv.) in CH2Cl2 (15 ml). After stirring
the pale blue mixture for 3 h at r.t., the solvent was evaporated and the oily residue purified by CC (AcOEt/
hexane 1:4): 20 (1.83 g, 96%). Colorless oil. IR: 3620 3100w, 3000m, 2950m, 2940s, 2860m, 1725s, 1660w,
1480w, 1465m, 1455m, 1440m, 1400w, 1375m, 1350w, 1340w, 1320w, 1300m, 1285m, 1275m, 1260m, 1240w, 1195w,
1185m, 1175m, 1160m, 1140 1095m, 1075m, 1035m, 1025s, 990m, 945w, 905w, 8 70w, 8 10w, 705w, 660w, 615w.
1H-NMR: 4.71 4.66 (m, 2 H); 4.14 (q, J ˆ 7.1, 2 H); 4.13 (q, J ˆ 7.1, 2 H); 4.04 (quint.-like m, 2 H); 3.93 3.82
(m, 2 H); 3.55 3.42 (m, 2 H); 2.67 (dd, J ˆ 15.0, 6.9, 1 H); 2.54 2.40 (m, 3 H); 1.87 1.20 (m, 28H); 1.26

Helvetica Chimica Acta Vol. 86 (2003)
243
(t, J ˆ 7.1, 3 H); 1.25 (t, J ˆ 7.1, 3 H); 0.89 (t, J ˆ 6.7, 6 H); ratio of diastereoisomers ca. 1:3. 13C-NMR: 171.7,
170.9 (2 s); 98.3 (br., 2 d); 74.3, 74.1 (2 d); 62.6, 62.4 (2 t); 60.2 (br.), 41.0, 39.7, 35.5, 34.0, 31.7, 30.9, 25.3, 24.9,
24.6, 22.4, 19.7, 19.6 (13 t); 14.0 (2 q); 13.9 (2 q).
Diastereoisomer Mixture (3R)-3-[(Tetrahydro-2H-pyran-2-yl)oxy]octanal (21). A soln. of 20 (1.72 g,
6.32 mmol) in dry THF (40 ml) was added dropwise over 20 min to a suspension of LiAlH4 (371 mg, ca. 97%
purity, 9.48mmol, 1.5 equiv.) in dry THF (50 ml) at r.t. The mixture was then warmed to 55 8 and stirred for 2.5 h
before it was cooled to 08 and carefully poured onto an ice-cold sat. aq. K,Na-tartrate soln. (70 ml). The
resulting biphasic mixture was vigorously stirred until a neat phase separation was obtained. The aq. layer was
extracted with Et2O (3Â) and the combined org. layer washed with sat. aq. NH4Cl soln., dried (MgSO4), and
evaporated. The colorless residue was taken up in CH2Cl2 (40 ml) and added rapidly at r.t. to a suspension of
PDC (4.75 g, 12.6 mmol, 2.0 equiv.) in CH2Cl2 (60 ml). After stirring for 4 h under reflux, the mixture was
¾
evaporated and the residue filtered over Celite to discard the insoluble metal salts. Evaporation of the org.
filtrate and purification of the oily residue by CC (AcOEt/hexane 1:4) gave 21 (1.10 g, 76%). Colorless oil. IR:
3620 2400w, 3000m, 2940s, 2860m, 1720s, 1465w, 1455m, 1440m, 1410w, 1380m, 1355m, 1345w, 1325w, 1300m,
1285m, 1275m, 1260m, 1240w, 1195w, 1185m, 1175m, 1160m, 1140 1110m, 1075s, 1055w, 1035m, 1025s, 990m,
945w, 905w, 8 70w, 8 10w, 705w, 660w, 615w. 1H-NMR: 9.82 9.79 (m, 2 H); 4.71 4.68( m, 1 H); 4.67 4.64
(m, 1 H); 4.14 (quint.-like m, 2 H); 3.95 3.79 (m, 2 H); 3.54 3.42 (m, 2 H); 2.73 2.44 (m, 3 H); 2.05 (m, 1 H);
1.87 1.22 (m, 28H); 0.89 ( t, J ˆ 6.8, 6 H). 13C-NMR: 202.0, 201.5 (2 s); 98.7, 97.7 (2 d); 72.9, 72.2 (2 d); 62.9, 62.7
(2 t); 49.2, 48.0, 35.6, 34.5, 31.6, 30.9, 25.3, 25.0, 24.7, 22.4, 19.9, 19.6 (12 t); 13.8(2 q).
Ethyl (À)-(2E,5R)-5-Hydroxydec-2-enoate (14). Ethyl(diethoxyphosphinyl)acetate (1.16 ml, 5.78mmol,
1.2 equiv.) and DBU (0.72 ml, 4.82 mmol, 1.0 equiv.) were subsequently dissolved in a suspension of LiCl
(245 mg, 5.78mmol, 1.2 equiv.; dried in vacuo prior to use) in dry MeCN (60 ml). The pale yellow mixture was
stirred at r.t. for 10 min before a soln. of 21 (1.10 g, 4.82 mmol) in dry MeCN (40 ml) was added dropwise. After
stirring for ca. 1 h at r.t., the end of the reaction was signaled by the formation of a white precipitate. The solvent
was evaporated, the residue taken up in Et2O, and the soln. washed first with H2O followed by sat. aq. NH4Cl
soln. The collected aq. washing phases were extracted with AcOEt (3Â) and the combined org. layers dried
(MgSO4) and evaporated. The pale yellow oily residue (THP-protected ester) was dissolved in MeOH (20 ml)
and treated with TsOH ¥ H2O (91.7 mg, 0.48mmol, 10 mol-%) for 1 h at r.t. After this, the deprotection was
completed, the solvent evaporated, and the residue purified by CC (AcOEt/hexane 1:4): 14 (637 mg, 62%).
21
21
Colorless oil. ‰aŠ ˆ À4.9 (c ˆ 0.95, MeOH), ‰aŠ ˆ À4.3 (c ˆ 0.95, CHCl3). IR: 3640 3100w, 3610w, 3000w,
D
D
2960s, 2930s, 2875m, 2860m, 1710s, 1655m, 1480w, 1465w, 1445w, 1395w, 1370m, 1320m, 1280m, 1260w, 1175w,
1160m, 1140-1080m, 1040m, 98 5w, 615w. 1H-NMR: 6.98( td, J ˆ 15.6, 7.5, 1 H); 5.90 (dt, J ˆ 15.6, 1.5, 1 H); 4.18
(q, J ˆ 7.1, 2 H); 3.78 3.71 ( m, 1 H); 2.50 2.26 (m, 2 H); 1.71 (br. s, 1 H); 1.53 1.37 (m, 2 H); 1.36 1.25
(m, 6 H); 1.29 (t, J ˆ 7.1, 3 H); 0.89 (t, J ˆ 6.7, 3 H). 13C-NMR: 166.2 (s); 145.1, 123.8(2 d); 70.5 (d); 60.2, 40.1,
‡
37.0, 31.6, 25.1, 22.5 (6 t); 14.1, 13.9 (2 q). CI-MS: 232 ([M ‡ NH4] ).
Ethyl (‡)-(2E,5R)-5-(Carbamoyloxy)dec-2-enoate (11). To a soln. of 14 (630 mg, 2.94 mmol) in dry CH2Cl2
(25 ml) at À 788 was added dropwise by syringe a soln. of chlorosulfonyl isocyanate (0.42 ml, ca. 97% purity,
4.71 mmol, 1.6 equiv.) in CH2Cl2 (5 ml). After stirring for 1 h at À 788 !À 608, the mixture was quenched in the
cold with H2O (20 ml) and warmed to r.t. within 10 min. The biphasic mixture was heated to 608 and vigorously
stirred for 4 h to remove CH2Cl2 and to hydrolyze the chlorosulfonyl group. The aq. soln. was saturated at r.t.
with NaCl and extracted with AcOEt. The combined org. layers were washed with sat. aq. NaHCO3 soln., dried
(MgSO4), and evaporated. Purification of the oily residue by CC (AcOEt/hexane 1 :2) gave 11 (711 mg, 94%).
21
D
Colorless amorphous solid. M.p. 35.0 36.58. ‰aŠ ˆ ‡24.8( c ˆ 0.95, CHCl3). IR: 3550m, 3500w, 3430m, 3350w,
3260w, 3180w, 3020w, 3000m, 2980m, 2960s, 2930s, 2870m, 2860m, 1710vs, 1655m, 1585m, 1480w, 1465w, 1445w,
1435w, 1385s, 1370s, 1325s, 1275s, 1240w, 1175s, 1140 1090m, 1045s, 98 0w, 8 65w, 8 35w, 615w. 1H-NMR: 6.91
(td, J ˆ 15.6, 7.4, 1 H); 5.87 (dt, J ˆ 15.6, 1.4, 1 H); 4.83 (quint.-like m, 1 H); 4.72 (br. s, 2 H); 4.19 (q, J ˆ 7.1,
2 H); 2.47 (oct.-like m, 2 H); 1.59 1.50 (m, 2 H); 1.36 1.23 (m, 6 H); 1.29 (t, J ˆ 7.1, 3 H); 0.88 (t, J ˆ 6.7, 3 H).
13C-NMR: 166.1, 156.4 (2 s); 143.7, 123.9 (2 d); 73.2 (d); 60.2, 36.7, 33.6, 31.4, 24.8, 22.4 (6 t); 14.1, 13.8(2 q). CI-
‡
‡
MS: 275 (100, [M ‡ NH4] ), 258(7, [ M ‡ H] ).
Ethyl (À)-(4R,6R)-3,4,5,6-Tetrahydro-2-oxo-6-pentyl-2H-1,3-oxazine-4-acetate (22). To a soln. of 11
t
(200 mg, 0.78mmol) in dry THF (7.8ml) at 0 8 was added slowly precooled 0.1m BuOK in dry THF (1.56 ml,
0.16 mmol, 0.2 equiv.). The pale yellow mixture was stirred for 2.5 h at 08 and quenched in the cold with sat. aq.
NH4Cl soln. The aq. layer was extracted with AcOEt (3Â), the combined org. phase dried (MgSO4), and
evaporated, and the residue purified by CC (AcOEt/hexane 1 :1): 22 (160 mg, 80%). Colorless crystalline solid.
21
D
M.p. 88.0 91.58. ‰aŠ ˆ À10.9 (c ˆ 1.0, CHCl3). IR: 3620 3100w, 3420m, 3020w, 3000w, 2960m, 2930m, 2870w,
2860w, 1730s, 1700s, 1465w, 1450m, 1430w, 1410w, 1380w, 1350w, 1325w, 1300w, 1275w, 1260w, 1240w, 1180m,

244
Helvetica Chimica Acta Vol. 86 (2003)
1
1160 1130w, 1100m, 1075w, 1025w, 995w, 900w, 8 65w, 615w. H-NMR: 5.88 (br. s, 1 H); 4.28 4.20 ( m, 1 H);
4.17 (q, J ˆ 7.1, 2 H); 3.91 3.82 (m, 1 H); 2.56 (dd, J ˆ 16.6, 4.6, 1 H); 2.45 (dd, J ˆ 16.5, 8.7, 1 H); 2.02
(ddm, J ˆ 13.6, 4.7, 1 H); 1.76 1.63 (m, 1 H); 1.61 1.28( m, 8H); 1.27 ( t, J ˆ 7.1, 3 H); 0.89 (t, J ˆ 6.7, 3 H).
13C-NMR: 170.5, 154.1 (2 s); 76.5 (d); 61.0 (t); 47.2 br. (s); 40.5, 34.8, 33.1, 31.4, 24.2, 22.3 (6 t); 14.1, 13.9 (2 q).
‡
‡
CI-MS: 275 (11, [M ‡ NH4] ), 258(100, [ M ‡ H] ).
Methyl (‡)-(3R,5R)-5-{[(tert-Butyl)diphenylsilyl]oxy}-3-(tosylamino)decanoate (10b). A soln. of 22
(185 mg, 0.72 mmol) and 4n aq. NaOH (2.5 ml) in EtOH (7.5 ml) was stirred overnight at 608. The mixture
was then cooled to 08, and small pieces of solid CO2 were added until the precipitation of Na2CO3 ceased. After
the suspension had warmed to r.t., NaHCO3 (332 mg, 3.96 mmol, 5.5 equiv.) was added, stirring was continued
for 15 min, and finally a soln. of TsCl (617 mg, 3.24 mmol, 4.5 equiv.) in acetone (5 ml) was added dropwise.
After stirring for 6 h at r.t., the mixture was acidified at 08 to pH 2 by careful addition of conc. aq. HCl soln. The
aq. layer was extracted with CH2Cl2 (2 Â 15 ml) and AcOEt (2 Â 15 ml) and the combined org. phase dried
(MgSO4) and evaporated. The oily residue (composed of (5-hydroxy-3-(tosylamino)decanoic acid 24 and the
chiral lactone 25), 1H-imidazole (245 mg, 3.60 mmol, 5.0 equiv.), and DMAP (17 mg, 0.14 mmol, 0.2 equiv.)
t
were dissolved in dry DMF (7 ml), and the resulting mixture was warmed to 558 before a soln. of BuPh2SiCl
(0.92 ml, 3.60 mmol, 5.0 equiv.) in DMF (1 ml) was added dropwise. After one night at 558, H2O (10 ml) was
added, and the biphasic mixture was stirred for 2 h at 608 to hydrolyze the undesired silyl ester function. The
mixture was then diluted with Et2O, the aq. layer extracted with Et2O (3Â) and the combined org. layer washed
with a sat. aq. NH4Cl soln., dried (MgSO4), and evaporated. The oily residue was again taken up in Et2O (10 ml)
and esterified at r.t. by dropwise addition of ca. 0.3m CH2N2 in Et2O. Stirring was continued for 30 min at r.t., the
reaction quenched with AcOH, and the org. soln. washed with a sat. aq. NaHCO3 soln., dried (MgSO4), and
evaporated. Purification of the residue by CC (AcOEt/hexane 1 :3 ! 1:0) gave 10b (237 mg, 54%). Colorless
21
D
oil. ‰aŠ ˆ ‡12.1 (c ˆ 1.5, CHCl3). IR: 3600 3100w, 3350w, 3070w, 3010w, 2960s, 2930s, 2870w, 2860m, 1730s,
1600w, 1590w, 1490w, 1460m, 1440w, 1430s, 1415w, 1390w, 1375m, 1360w, 1340m, 1305w, 1290w, 1195m, 1175m,
1160s, 1110s, 1105s, 1095s, 1075m, 1050w, 1005w, 995w, 955w, 8 90w, 8 65w, 8 20w, 8 10m, 700w, 695w, 660m, 615w.
1H-NMR: 7.69 7.59 (m, 6 H); 7.46 7.31 (m, 6 H); 7.21 (d, J ˆ 8.0, 2 H); 4.62 (d, J ˆ 9.0, 1 H); 3.54 (s, 3 H);
3.49 3.45 (m, 2 H); 2.40 (s, 3 H); 2.33 2.30 (m, 2 H); 1.59 1.52 (m, 2 H); 1.22 1.05 (m, 4 H); 1.03 0.95
(m, 4 H); 1.01 (s, 9 H); 0.79 (t, J ˆ 7.1, 3 H ) . 13C-NMR: 171.5, 143.1, 137.6 (3 s); 135.8, 135.7 (2 d); 132.7 (s);
129.7, 129.4, 127.6, 127.5, 127.0 (5 d); 70.2 (d); 52.1 (q); 47.5 (d); 41.0, 38.6, 35.8, 31.5 (4 t); 26.9 (q); 24.1, 22.4 (2 t);
‡
21.3 (q); 19.1 (s); 13.8( q). ESI-MS: 632 ([M ‡ Na] ).
Methyl (3R,5R)-3-{{{3-[(tert-Butoxy)carbonyl]amino}propyl}tosyl}amino-5-{[(tert-butyl)diphenyl-
silyl]oxy}decanoate (28). A soln. of 10b (95 mg, 0.16 mmol) in dry DMF (2.5 ml) was treated with Cs2CO3
(56 mg, 0.17 mmol, 1.1 equiv.; dried in vacuo prior to use) at r.t. for 0.5 h before the solid iodide 26 (67 mg,
0.23 mmol, 1.5 equiv.) was added in one portion. The pale yellow suspension was vigorously stirred at r.t.
overnight and then evaporated. The residue was taken up in AcOEt and washed with 5% aq. Na2S2O3 soln. and
H2O. The collected aq. washing phases were extracted with AcOEt (2Â) and the combined org. layers re-
washed with brine, dried (MgSO4), and evaporated. The residual oil was purified by CC (AcOEt/hexane 1 :3 !
1:1): pure 28 (87 mg, 73%). Colorless oil. IR: 3600 3100w, 3450w, 3010w, 3000m, 2980m, 2960s, 2930s, 2880w,
2860m, 1725s, 1710s, 1600w, 1505m, 1470w, 1460w, 1430w, 1390w, 1365m, 1340w, 1315w, 1305w, 1270m, 1250m,
1180m, 1175m, 1160s, 1110s, 1090m, 1075m, 1050 920w, 8 65w, 8 20w, 700m, 695w, 660w, 615w. 1H-NMR: 7.68
7.61 (m, 6 H); 7.44 7.34 (m, 6 H); 7.21 (d, J ˆ 8.1, 2 H); 4.63 (br. s, 1 H); 4.19 (quint.-like m, 1 H); 3.59 (s, 3 H);
3.51 (quint.-like m, 1 H); 3.01 2.90 (m, 4 H); 2.48( dd, J ˆ 15.6, 7.9, 1 H); 2.40 (s, 3 H); 2.30 (dd, J ˆ 15.6, 6.7,
1 H); 1.71 1.54 (m, 5 H); 1.45 (s, 9 H); 1.27 1.0 (m, 7 H); 1.04 (s, 9 H); 0.81 (t, J ˆ 7.1, 3 H ) . 13C-NMR: 171.2,
155.9, 143.1, 137.5 (4 s); 135.8( d); 134.1, 133.8(2 s); 129.6, 129.5, 129.4, 127.5, 127.4, 127.3 (6 d); 78.9 (s); 70.2,
52.8(2 d); 51.5 (q); 42.4, 39.7, 38.4, 37.5, 35.7, 31.6, 30.6 (7 t); 28.3, 26.9 (2 q); 23.6, 22.4 (2 t); 21.3 (q); 19.2 (s);
‡
13.8( q). ESI-MS: 789 ([M ‡ Na] ).
Methyl (À)-(3R,5R)-3-{[(3-Aminopropyl)tosyl]amino}-5-{[(tert-butyl)diphenylsilyl]oxy}decanoate (29).
A soln. of 28 (87 mg, 0.11 mmol) and CF3COOH (0.17 ml, 2.27 mmol, 20.0 equiv.) in toluene (5 ml) was heated
to 508 and stirred overnight. The mixture was then diluted with CH2Cl2 and alkalinized at r.t. by dropwise
addition of 4n aq. NaOH. After stirring the biphasic mixture for 30 min, the aq. layer was extracted with CH2Cl2
(3Â), the combined org. layer washed with brine, dried (MgSO4), and evaporated, and the crude product
21
D
purified by CC (CH2Cl2/MeOH/25% aq. NH3 soln. 90 :10 :0.7): 29 (70 mg, 93%). Colorless oil. ‰aŠ ˆ À7.0 (c ˆ
1.2, CHCl3). 1H-NMR: 7.68 7.61 ( m, 6 H); 7.44 7.33 (m, 6 H); 7.19 (d, J ˆ 8.0, 2 H); 4.17 (quint.-like m, 1 H);
3.60 (s, 3 H); 3.57 (quint.-like m, 1 H); 3.10 2.88 (m, 2 H); 2.54 (t, J ˆ 6.7, 2 H); 2.49 (dd, J ˆ 15.6, 7.4, 1 H); 2.39
(s, 3 H); 2.33 (dd, J ˆ 15.6, 6.8, 1 H); 1.79 1.48 (m, 7 H); 1.26 0.98( m, 7 H); 1.04 (s, 9 H); 0.81 (t, J ˆ 7.1, 3 H ) .
13C-NMR: 171.5, 142.9, 137.8(3 s); 135.8( d); 134.1, 133.8(2 s); 129.6, 129.4, 127.5, 127.4 (4 d); 70.2, 52.7 (2 d);

Helvetica Chimica Acta Vol. 86 (2003)
245
51.5 (q); 43.0, 39.7, 39.2, 38.6, 35.7, 33.9, 31.6 (7 t); 26.9 (q); 23.6, 22.4 (2 t); 21.5 (q); 19.2 (s); 13.8( q). ESI-MS:
‡
689 ([M ‡ Na] ).
(À)-(4R)-4-{[(tert-Butyl)diphenylsilyl]oxy}heptyl}hexahydro-5-tosyl-1,5-diazocin(1H)-2-one (7b). In a dry
flask (N2 inlet and pressure-equalized addition funnel (half-filled with 4-ä molecular sieves (beads) and
functioning as Soxhlet extractor) surmounted by a reflux condenser)), a soln. of 29 (70 mg, 0.11 mmol) in dry
benzene (25 ml) under N2 was brought to reflux. After 2 h, refluxing was briefly interrupted, and Sb(OEt)3
(21.4 ml, 0.13 mmol, 1.2 equiv.) was rapidly added. The mixture was refluxed overnight, then cooled to r.t., and
quenched with sat. aq. NH4Cl soln. Stirring was continued for 15 min before the biphasic mixture was filtered
¾
over Celite to discard the inorganic salts. The clear aq. layer was then extracted with AcOEt (3Â), the
combined org. phase washed with brine, dried (MgSO4), and evaporated, and the residue purified by CC
21
D
(CH2Cl2/MeOH 19 :1): 7b (64 mg, 95%). Pale yellow oil. ‰aŠ ˆ À50.9 (c ˆ 1.5, CHCl3). IR: 3600 3100w,
3400w, 3050w, 2990w, 2960s, 2930s, 2860m, 1720w, 1680w, 1660s, 1640m, 1600w, 1465m, 1425w, 1390w, 1370w,
1335m, 1305w, 1290w, 1260w, 1200-1000w, 1175m, 1160s, 1110s, 1090m, 1075m, 990w, 940w, 910w, 8 75w, 8 30w,
1
810w, 700w, 660w, 615w. H-NMR2): 7.72 (d, J ˆ 8.4, 2 H); 7.70 7.65 (m, 4 H); 7.44 7.35 (m, 6 H); 7.24 (d, J ˆ
8.3, 2 H); 5.74 (q-like m, 1 H); 4.59 (sext.-like m, 1 H); 3.83 3.74 (m, 1 H); 3.54 3.10 (m, 3 H); 2.88 2.58
(m, 2 H); 2.42 (s, 3 H); 2.27 2.05 (m, 2 H); 1.79 1.57 (m, 2 H); 1.50 0.82 (m, 9 H); 1.09 (s, 9 H); 0.76 (t, J ˆ
7.1, 3 H ) . 13C-NMR: 173.5, 143.2, 137.4 (3 s); 135.9 (d); 134.5, 133.8(2 s); 129.6, 129.5, 127.6, 127.4, 127.3 (5 d);
70.3, 52.5 (2 d); 39.7 (br.), 37.9, 36.9, 32.2, 31.5, 29.6 (6 t); 27.0 (q); 23.7, 22.3 (2 t); 21.4 (q); 19.3 (s); 13.8( q). ESI-
‡
MS: 657 ([M ‡ Na] ).
(4R)-4-{(2R)-2-{[(tert-Butyl)diphenylsilyl]oxy}heptyl}hexahydro-1-{4-[(4R)-octahydro-2-oxo-4-pentyl-5-
tosyl-1,5-diazocin-1-yl]butyl}-5-tosyl-1,5-diazocin-2(1H)-one (6). A suspension of powdered KOH (6 mg,
0.11 mmol, 2.0 equiv.) in dry DMSO (1 ml) was stirred for 10 min at r.t. and then cooled to 08. (À)-(4R)-1-(4-
Bromobutyl)hexahydro-4-pentyl-5-tosyl-1,5-diazocin-2(1H)-one (30; 24 mg, 49.3 mmol, 1.0 equiv.) [1] and 7b
(30 mg, 47.3 mmol, 0.96 equiv.) were dissolved in dry DMSO (1 ml) and canulated slowly at 08 under N2 into the
frozen KOH suspension. The mixture was warmed to r.t. under vigorous stirring within 4 h before a
supplementary (cat.) amount of powdered KOH was added. After stirring for one night at r.t., H2O was added,
the aq. phase extracted with Et2O (3 Â 5 ml) and the combined org. layer washed with brine, dried (MgSO4),
and evaporated. Separation by CC (CH2Cl2/MeOH 40 :1 ! 15 :1) permitted partial recycling of the unreacted
educts 30 and 7b and the isolation of 6 (4 mg). IR: 3660w, 3600 3100w, 3000m, 2960s, 2930s, 2860m, 1625s,
1600m, 1465m, 1450w, 1430m, 1400w, 1380w, 1335s, 1305m, 1290w, 1260w, 1240w, 1185w, 1160s, 1110m, 1090s,
1
1075m, 1015w, 990 930w, 8 95w, 8 60w, 8 30w, 8 15m, 700m, 690m, 650w, 615w, 605w. H-NMR (280 K)3): 7.77
7.70 (m, 8H); 7.45 7.34 ( m, 6 H); 7.31 7.24 (m, 4 H); 4.03 (br. s, 1 H); 3.83 3.70 (m, 3 H); 3.68 3.61
(m, 2 H); 3.52 (t-like m, 1 H); 3.34 3.12 (m, 2 H); 3.11 2.92 (m, 2 H); 2.82 (br. s, 1 H); 2.76 2.66 (m, 1 H);
2.60 (d-like m, 1 H); 2.47 2.37 (m, 2 H); 2.41 (s, 6 H); 2.23 2.08( m, 2 H); 1.79 1.60 (m, 7 H); 1.59 1.40
(m, 4 H); 1.30 1.13 (m, 8H); 1.09 0.92 ( m, 8 H); 1.07 (s, 9 H); 0.87 (t, J ˆ 7.1, 3 H); 0.75 (t, J ˆ 6.8, 3 H). ESI-
t
‡
t
‡
MS: 825 (54, [M À BuSiPh2 ‡ Na] ), 803 (100, [M À BuSiPh2 ‡ H] ).
tert-Butyl (3-Hydroxypropyl)carbamate (27). A soln. of 3-aminopropan-1-ol (3.0 g, 40 mmol) in dry
CH2Cl2 (50 ml) was treated with Et3N (5.6 ml, 40 mmol, 1.0 equiv.) at r.t. for 0.5 h before a soln. of Boc2O (9.6 g,
44 mmol, 1.1 equiv.) in CH2Cl2 (50 ml) was added slowly. During the dropwise addition of the Boc2O soln.,
heating and thickening of the mixture was observed. The resulting colorless mixture was stirred under reflux
overnight and quenched with a sat. aq. NH4Cl soln. The aq. layer was extracted with CH2Cl2 (2Â) and the
combined org. phase washed with brine, dried (MgSO4), and evaporated: crude 27 (6.9 g, 99%). Colorless oil,
pure enough (by 1H-NMR) to be used in the next step without further purification. 1H-NMR: 5.25 (br. s, 1 H);
3.84 (dt, J ˆ 11.6, 5.8, 2 H); 3.71 (br. s, OH); 3.45 (dt, J ˆ 12.5, 6.2, 2 H); 1.87 (m, 2 H); 1.63 (s, 9 H). 13C-NMR:
156.9, 85.1 (2 s); 59.2, 36.9, 32.6 (3 t); 28.2 (3 q).
1
2
)
)
In the H-NMR spectrum of 7b recorded at r.t., no fine structures were detectable except for the O-silyl-
and N-tosyl protection groups and the terminal Me group of the alkyl side chain. This explains why, in the
description of the spectrum, the protons are mostly gathered in groups over larger ppm ranges.
Similarly to the 1H-NMR spectrum of 7b, the only fine signals detectable in the 300-MHz 1H-NMR
spectrum of 6 at r.t. were those of the O-silyl- and the N-tosyl protection groups and of the terminal Me
groups of the two side chains at both ring systems. A better refinement of the spectrum was obtained with
a long-term measurement at ‡ 78 with a Bruker DRX-600. This, together with the ESI-MS analysis,
allowed the unambiguous identification of 6.
3

246
Helvetica Chimica Acta Vol. 86 (2003)
tert-Butyl (3-Iodopropyl)carbamate (26). I2 (2.6 g, 10.3 mmol, 1.2 equiv.) was added portionwise to a soln.
of 1H-imidazole (0.7 g, 10.3 mmol, 1.2 equiv.) and PPh3 (2.69 g, 10.3 mmol, 1.2 equiv.) in CH2Cl2 (50 ml) at 08.
The resulting dark yellow suspension was warmed to r.t. before a soln. of 27 (1.5 g, 8.6 mmol) in CH2Cl2 (10 ml)
was added. The mixture was stirred at r.t. for 3.5 h, filtered over Celite, and washed with 5% aq. Na2S2O3 soln
(2Â). The combined washing phases were extracted with CH2Cl2 and the org. layers dried (MgSO4) and
evaporated. The residual yellow oil was subjected to CC (AcOEt/hexane 1:1): 26 (1.86 g, 84%). Amorphous,
pale yellow solid. M.p. 37 408. IR: 3457m, 3020s, 2980m, 2936w, 1710s, 1506s, 1455w, 1390m, 1370s, 1250s, 1230s,
1170s, 1070w, 1040w, 970w, 8 65w, 790s, 745 720s, 670s, 617w. 1H-NMR: 4.65 (br. s, 1 H); 3.20 (m, 4 H); 1.99
(m, 2 H); 1.44 (s, 9 H). 13C-NMR: 155.8, 79.3 (2 s); 41.0, 33.4 (2 t); 28.3 (3 q); 2.98( t). CI-MS: 571 (15, [2 M ‡
‡
‡
‡
‡
H] ), 471 (34, [2 M À Boc ‡ H] ), 461 (6, [2 M À I ‡ NH4] ), 387 (6, [2 M À I À C4H8] ), 303 (100, [M ‡ NH4]),
‡
‡
‡
‡
286 (30, [M ‡ H] ), 247 (41, [M À C4H8 ‡ NH4] ), 186 (28, [M À Boc ‡ H] ), 176 (6, [M À I ‡ NH4] ), 119 (57).
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Received June 13, 2002