Practical approaches to the matrix metalloproteinase inhibitor Trocade (Ro 32-3555) and to the TNF-α converting enzyme inhibitor Ro 32-7315

Article abstract of DOI:10.1016/S0040-4020(01)00720-7

Stereoselective methods were found to efficiently prepare 2- and 3-substituted succinates with anti configuration. In the synthesis of Trocade 1, the hydantoinmethyl residue was introduced by alkylation of the non-chelated potassium enolate 19 with the br

Full text of DOI:10.1016/S0040-4020(01)00720-7

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 7675±7683
Practical approaches to the matrix metalloproteinase inhibitor
Trocadew ꢀRo 32-3555) and to the TNF-a converting enzyme
inhibitor Ro 32-7315q
Hans Hilpertp
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Non-Clinical DevelopmentÐProcess Research, Grenzacherstr. 124,
CH-4070 Basel, Switzerland
Received 23 April 2001; revised 9 July 2001; accepted 10 July 2001
AbstractÐStereoselective methods were found to ef®ciently prepare 2- and 3-substituted succinates with anti con®guration. In the synthesis
of Trocadew 1, the hydantoinmethyl residue was introduced by alkylation of the non-chelated potassium enolate 19 with the bromomethyl
hydantoin 9 to give a 92:8 mixture favouring the 2,3-anti con®gurated succinate 18. The preparation of TNF-a converting enzyme /TACE)
inhibitor 2 was accomplished by a highly stereoselective protonation of the dialkylated enolate 23 using CF3CONH2 affording a 98:2 mixture
in favour of the 2,3-anti con®gurated succinate 24. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Hydroxamic acid derivatives have been reported as
potent inhibitors of matrix metalloproteinases /MMPs)
and for the recently characterized TNF-a converting
enzyme /TACE), both enzymes are involved in
degrading all components of the extracellular matrix.1
This process has been implicated in rheumatoid and
osteoarthritis, a chronic in¯ammatory disease leading to
the loss of normal joint function. For the clinical evaluation
of the MMP inhibitor 1 /Trocadew, Ro 32-3555)2 and the
TACE inhibitor 2 /Ro 32-7315)3 stereoselective syntheses
were required. Herein we report on ef®cient and practical
methods to speci®cally prepare anti con®gurated
succinates /Fig. 1).
2.1. Synthesis of Trocadew
1
The synthesis of hydroxamic acid 1 employed the new and
readily available homoallyl nosylate 6 /Scheme 1) prepared
by the enantioselective glyoxylate ene reaction4 of benzyl
glyoxylate /3)5 and methylenecyclopentane /4). The
enantioselectivity of this reaction proved to be highly sensi-
tive to the water content of the molecular sieve6,7 required
for the preparation of the catalyst /1.5 mol%) generated in
situ from /i-PrO)2TiBr2 and /R)-1,10-binaphthol. Thus, high
water contents of 6±10% resulted in ee of 95±98% whereas
activated, dry molecular sieves containing 3% or less of
water reduced the ee to 20±30%.
Figure 1. anti Con®gurated succinates as inhibitors of MMPs and TACE.
q Part of these results were previously communicated: Hilpert, H., VIII Ischia Advanced School of Organic Chemistry, September 26, 1998, Ischia, Italy.
Keywords: anti-in¯ammatory compounds; chelation; ene reactions; enolates; hydroxamic acids and derivatives.
Tel.: 141-61-688-7264; fax: 141-61-688-6459; e-mail: hans.hilpert@roche.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00720-7

7676
H. Hilpert / Tetrahedron 57 -2001) 7675±7683
0
Ê
Scheme 1. Reagents and conditions: /a) /i) /R)-1,1 -binaphthol, powdered molecular sieves 4 A /containing 8% H2O), /i-PrO)2TiBr2, CH2Cl2, 228C, 1.3 h;
/ii) 4, 3/toluene, 228C, 16 h; /b) 5, o-nitrobenzenesulfonyl chloride, NEt3, toluene, 2158C, 22 h; /c) /i) benzyl tert-butyl malonate, NaH, DMF, 228C, 30 min;
/ii) 6, 228C, 28 h; /d) 8, paraformaldehyde, HBr/AcOH, 808C, 4.5 h; /e) 7, NaH, DMF, 228C, 9, DMF, 08C, 4 h; /f) /i) 10, Pd/C /5%), i-PrOH, 228C, 24 h; /g) /i)
N-methylmorpholine, i-PrOAc, 908C, 4 h; /ii) /1)-pseudoephedrine; /h) /i) 11a, partitioning between AcOEt and 1N HCl; /ii) 11b, piperidine, N-hydroxy-2-
pyridone, N,N0-dicyclohexylcarbodiimide, AcOEt, 228C, 20 h; /iii) HBr/AcOH, 08C, 3 h; /i) /i) 12, N-hydroxy-2-pyridone, 2-morpholinoethyl isocyanide,
CH2Cl2, 228C, 19 h; /ii) TMSO±NH2, 08C, 7 h; /iii) NaHCO3/H2O.
Activation of crude 5 was achieved by formation of the
tri¯ate, p- and o-nosylate with the advantage of the latter
to crystallize readily from acetone/H2O 3:1 at 408C leading
to 6 in high yield /88%) and high enantiomeric purity
/eeˆ.99.9%). Alkylation of 6 was accomplished with the
mixed benzyl tert-butyl malonate furnishing a 1:1 mixture
of the epimers of 7, which upon treatment with the bromo-
methyl hydantoin 9 led to the triester 10 in quantitative
yield. Compound 9 was expediently prepared from
trimethyl hydantoin 88 in high yield /88%) employing para-
formaldehyde/HBr.9 Hydrogenation and hydrogenolysis of
10 followed by decarboxylation of the intermediate di-acid
preferably in the presence of 1 equiv. of N-methyl-
morpholine and i-PrOAc gave a 5:1 mixture of the anti-/
syn-succinates 11 which was ef®ciently separated via the
/1)-pseudoephedrine or the ethanolamine salt affording
pure anti-11a in 68% yield over the two steps. The relative
and absolute con®guration of anti-11 was unambiguously
established by an X-ray analysis10 of the corresponding /1)-
pseudoephedrine salt 11a /Fig. 2).
Introduction of the two amide residues in 1 was readily
achieved via the corresponding active esters prepared in
situ from N-hydroxy-2-pyridone11 and DCC furnishing
anti-12 after cleavage of the tert-butyl group or, in the
ultimate step, 2-morpholinoethyl isocyanide12 a potent
dehydrating agent giving 2-morpholinoethyl formamide,
readily removed by an acidic extraction. Formation of the
Figure 2. Stereoview of the /1)-pseudoephedrine salt anti-11a.

H. Hilpert / Tetrahedron 57 -2001) 7675±7683
7677
Scheme 2. Reagents and conditions: /a) /i) 14, n-BuLi, THF, 2458C; /ii) 13, 2458, 1 h; /iii) LDA, 2458C, 1.5 h; /iv) tert-butyl bromoacetate, 2458C, 4 h;
/b) 15, i-PrOH, then NaOH/H2O, H2O2, 08C, 10 min, 228C, 1 h; /c) 16, piperidine, N-hydroxy-2-pyridone, i-PrOAc, 08C, then N,N0-dicyclohexylcarbodiimide,
08C, 1 h, 228C, 16 h; /d) KN/TMS)2, THF, 2608C, then 17 in THF, 2608C, 30 min, then 9 in THF, 2608C, 1.5 h; /e) HBr/AcOH, 08C, 1.5 h.
hydroxamic acid residue was best accomplished with
O-TMS protected hydroxylamine thus avoiding O-acylation
followed by hydrolysis during work-up to furnish the pure
and crystalline hydroxamic acid 1 in 82% yield and a
high stereoisomeric purity /de and ee.99.5%) after
crystallization.
2.2. Synthesis of the TACE inhibitor 2
The key step in the synthesis of the TACE inhibitor 2
/Scheme 3) comprises of the stereoselective alkylation of
the succinic acid 2014 with cinnamyl bromide followed by a
deprotonation/protonation sequence to give anti-24. A
related alkylation of 20 using allyl bromide at 2788C
described by Crimmin et al.14 afforded a 94:6 mixture in
favour of the corresponding syn isomer followed by a
repeated epimerisation involving deprotonation with LDA
and protonation with methanol at 2788C then providing
preferentially the anti-isomer in a ratio of 83:17. In search
of a signi®cantly higher selectivity, we investigated the
protonation of the enolate 23 at 280±2908C testing three
categories of protic reagents, namely O±H /Scheme 3, entry
1±5), C±H /entry 6) and N±H acidic compounds /entry
7±12). Alkylation of 20 with cinnamyl bromide gave as
expected, a 93:7 mixture favouring the syn-isomer. After
an additional deprotonation with LDA and protonation
with CF3CONH2 /entry 12), a remarkably high selectivity
of 98:2 in favour of anti-24 /85% yield after isolation) was
observed. These selectivities can be rationalized by a
chelation effect of the enolate 21 which is alkylated on the
sterically less hindered side leading to syn-22. A second
deprotonation of 22 to the chelated enolate 23 and protona-
tion again from the sterically less hindered side accounts for
anti-24. The general tendency of N±H acidic compounds
towards highest selectivities is rationalized by protonation
of the enolate 23 occurring at the softer carbanion center
which is closer to the adjacent stereo center.
In search of a shorter and even more ef®cient route to 1, the
alkylation of the piperidine amide 17 /Scheme 2), prepared
from the homochiral succinic acid 16,13 was investigated.
Attempts to alkylate the precursors, i.e. the enolates of 15 or
16 with 9 under various conditions resulted in mixtures of
multiple products or were lacking selectivity, respectively.
However, the reaction of the amide 17 with 9 proceeded
with a surprisingly high degree of selectivity leading either
to the syn- or to the anti-succinate 18 depending on the
counter ion of the base used. Thus, lithium bases such as
LDA furnished preferentially syn-18 whereas potassium
bases like KN/TMS)2 provided anti-18 with reasonable
degrees of selectivity /Scheme 2, entry 1 and 3). These
results are consistent with the assumption of a lithium
enolate chelating with the adjacent carbonyl amide group
thereby controlling the alkylation from the sterically less
hindered side leading to the syn isomer as proposed earlier
by Crimmin et al.14 Alternatively, a potassium enolate is
assumed to favour the non-chelated, thermodynamically
more stable conformation 19 consequently affording anti
alkylation. Running the reaction at a higher temperature,
e.g. 2408C /entry 5) in¯uenced the result signi®cantly
affording a 99:1 ratio of anti-/syn-18 but at a reduced
yield of about 40%. This ratio and yield is a result of a
concomitant b-elimination preferentially of the syn isomer
to give the hydantoin 8 and the corresponding acrylate. At
the optimal temperature of 2608C /entry 4), a 92:8 mixture
of anti-/syn-18 was obtained which was deprotected and
crystallized furnishing isomerically pure anti-12 in 59%
yield over the two steps.
Formation of the hydrazide anti-25 was accomplished in
74% yield employing i-butyl hydrazine´H2SO4 /27, Scheme
4) conveniently prepared by a one-pot procedure starting
with the Schiff base formation of tert-butyl carbazate
and i-butylaldehyde, followed by hydrogenation of the
hydrazone and cleavage of the BOC protecting group

7678
H. Hilpert / Tetrahedron 57 -2001) 7675±7683
Scheme 3. Reagents and conditions: /a) /i) 20, LDA, THF, 2208C, 1 h, then cinnamyl bromide, 2208C, 40 min, 228C, 2 h, then LDA, 2208C, 30 min, then
CF3CONH2/THF, 2908C, 1 h; /ii) tert-BuNH2/i-PrOAc, 08C, 3 h; /b) 24a /i) partitioning between i-PrOAc and 1N HCl; /ii) 24b, N-hydroxy-2-pyridone, N,N0-
dicyclohexylcarbodiimide, i-PrOAc, 08C, 4 h, then N-ethylmorpholine, 27, 228C, 17 h, 458C, 8 h; /c) /i) 25, CH3SO2Cl, NEt3, CH2Cl2, 08C, 30 min; /ii) HBr/
AcOH, 2158C, 1.5 h; /d) 26, N-hydroxy-2-pyridone, N,N0-dicyclohexylcarbodiimide, THF, 228C, 22 h, then NH2-OH´H2O, 228C, 4 h.
Trocadew 1 and the TACE inhibitor 2 in overall yields of
36 and 31 /including the preparation of 20) and avoiding
chromatographic puri®cations, which were applied on a
multi ton and multi kilogram scale.
Scheme 4. Reagents and conditions: /i) tert-butyl carbazate, i-butylalde-
4. Experimental
hyde, i-PrOH, 08C, 2 h; /ii) H2, Pt/C /5%), i-PrOH, 308C, 42 h; /iii) H2SO4,
508C, 5 h.
4.1. General
Melting points: Tottoli or BuÈchi 535, uncorrected. IR
spectra: Nicolet, FT-IR 20 SXB. H NMR spectra: Bruker
using sulfuric acid to give 27 in 88% overall yield. Mesyl-
ation of anti-25 followed by in situ deprotection provided
1
AC 250, internal standard TMS, J values in Hz. MS spectra:
the acid 26 /96%) ready to introduce the hydroxamic acid
Finnigan MAT SSQ 7000, EI at 70 eV. HPLC: Agilent
residue, accomplished with unprotected hydroxylamine
1100. GLC: Perkin±Elmer AutoSystem. Monitoring of the
hydrate. This reaction proved to be highly solvent depen-
reactions and quality control of the products by TLC /silica
dent leading in dichloromethane to an approximately 1:1
gel) or by HPLC /RP-18, CH3CN/buffered water of
mixture of N- and O-acylated products. However, in THF
various ratios). HPLC columns: Chiralpak AS and Chiracel
OJ: Daicel Chemical, LTD; Symmetrye C18: Waters,
a 94:6 mixture favouring the desired N-acylated compound
2 was obtained. A ®nal crystallization from ethanol/water
provided the pure hydroxamic acid 2 in 78% yield with a de
and ee of .99.5%.
Lichrospher 100, RP-18: Merck. Benzyl glyoxylate:
Hoechst France; Powdered molecular sieves: Aldrich
/containing ca. 8% of water); Diisopropoxytitanium
dibromide prepared according to Ref. 4; benzyl tert-butyl
3. Summary
malonate: Lancaster; Pd/C /5%) and Pt/C /5%, type F 101
R/D): Degussa; N-hydroxy-2-pyridone, 2-morpholinoethyl
isocyanide, TMSO±NH2 and LDA in THF/heptane: Fluka;
KN/TMS)2: Callery.
Two methods of general interest were found to synthesize
anti con®gurated 2- and 3-alkylated succinates. The ®rst one
involves the alkylation of the potassium enolate 19 particu-
larly suited for base sensitive products such as 18 that
cannot be enolized without concomitant b-elimination.
The second method proceeds via a syn alkylation to 22
followed by a highly stereoselective protonation of the
dialkylated enolate 23 providing anti-24. Two linear six
step syntheses were developed to ef®ciently prepare
4.1.1. ꢀR)-3-Cyclopent-1-enyl-2-ꢀ2-nitro-phenylsulfonyl-
oxy)-propionic acid benzyl ester ꢀ6). To a solution of
/R)-/1)-1,10-bi-2-naphthol /0.453 g, 1.58 mmol) in
dichloromethane /40 ml) was subsequently added at 228C
Ê
powdered molecular sieves /4 A, 7.93 g) and a solution
of diisopropoxytitanium dibromide in toluene /20%,

H. Hilpert / Tetrahedron 57 -2001) 7675±7683
7679
1.49 mmol). The suspension was stirred at 228C for 1.3 h
and subsequently treated with methylene±cyclopentane /4,
8.22 g, 100 mmol) and with a solution of benzyl glyoxylate
/3, 19.83 g, 82.8% pure, 100 mmol) in toluene /46 ml) over
40 min keeping the temperature at 228C. Prior to the addi-
tion of the solution, the benzyl glyoxylate /3) should be
depolymerized by heating the solution to re¯ux temperature
for 5 h followed by rapid cooling. The brown suspension
was stirred at 228C for 16 h, ®ltered, the residue was washed
with dichloromethane /100 ml) and the combined ®ltrates
were evaporated. The residue containing crude 5 /eeˆ98%,
HPLC, Chiralpak AS, n-hexane/EtOH 98:2) was dissolved
in toluene /185 ml) and treated at 228C with o-nitrobenzene-
sulfonyl chloride /18.69 g, 84.3 mmol) in one portion. The
orange solution was cooled to 2158C, treated with NEt3
/14.22 g, 140.5 mmol) over 30 min and stirring was con-
tinued at 210±2158C for 3 h. The suspension was treated
again with o-nitrobenzenesulfonyl chloride /3.11 g,
14.0 mmol) and NEt3 /3.55 g, 35.1 mmol), stirring was
continued for 3 h and this operation was repeated again to
drive the reaction to completion. The suspension was stirred
at 2208C for 16 h, warmed to 08C, treated with water
/31 ml), the mixture was stirred for 15 min and ®ltered.
The residue containing the crude nosylate 6 was washed
with toluene /2£50 ml) and with water /2£50 ml) and wet
6 was dissolved in acetone /265 ml) at 408C. The solution
was diluted with water /81 ml) over 20 min, the suspension
was cooled to 228C over 2 h and ®ltered. The residue was
washed with a solution of acetone/water /2:1, 2£30 ml) and
dried at 228C/9 mbar overnight to give the pure title
4.1.3.
1-ꢀBromomethyl)-3,4,4-trimethyl-2,5-imidazo-
lidinedione ꢀ9). A suspension of 3,4,4-trimethyl-2,5-imi-
dazolidinedione8 /8, 21.3 g, 150 mmol) and para-
formaldehyde /5.86 g, 195 mmol) in HBr/AcOH /33%,
34 ml, 195 mmol) was heated to 808C for 2 h, the yellow
solution was treated again with HBr/AcOH /33%, 7.9 ml,
45 mmol) and stirring was continued at 808C for 2.5 h after
which time the reaction was complete. The solution was
cooled to 08C, diluted with dichloromethane /100 ml) and
ice-cold water /100 ml) keeping the temperature at 08C. The
organic layer was washed with water /2£100 ml), dried and
evaporated. The residual oil was dissolved in tert-butyl
methyl ether /20 ml), the solution was rapidly diluted with
n-hexane /100 ml), the suspension was cooled to 08C and
stirring was continued for 20 min. The suspension was
®ltered, the residue washed with n-hexane /3£40 ml) and
dried at 228C/12 mbar overnight to give the pure title
compound 9 /30.89 g, 88% yield) as white crystals, mp
1
86±888C. IR /KBr): 1779 m and 1733 s /CvO). H NMR
/250 MHz, CDCl3): 5.30 /s, 2H), 2.92 /s, 3H), 1.41 /s, 6H).
MS /EI): 155/100 [M2Br]1. C7H11N2BrO2 requires: C
35.77%, H 4.72%, N 11.92%, Br 33.99%; found: C
36.03%, H 4.79%, N 12.02%, Br 33.62%.
4.1.4. 1:1 Mixture of ꢀ2R,3R)- and ꢀ2S,3R)-2-tert-butoxy-
carbonyl-3-cyclopent-1-enylmethyl-2-ꢀ3,4,4-trimethyl-
2,5-dioxo-imidazolidin-1-ylmethyl)-succinic acid di-
benzyl ester ꢀ10). To a suspension of NaH /3.15 g, 55±
65% pure, 78.8 mmol, pre-washed with n-hexane) in
dimethylformamide /30 ml) was added at 228C, a solution
of the crude triester 7 /34.95 g, 87.4% pure, 63.8 mmol) in
dimethylformamide /60 ml) over 50 min and stirring was
continued for 30 min after which gas evolution ceased.
The solution obtained was added at 08C to a freshly prepared
solution of the bromomethyl hydantoin 9 /20.20 g,
85.93 mmol) in dimethylformamide /30 ml) over 15 min
and stirring was continued at 08C for 4 h. The suspension
was diluted at 0±108C with cyclohexane /300 ml) and with
water /300 ml) and the organic layer was washed with
aqueous NaOH /0.1N, 150 ml), with aqueous HCl /0.1N,
150 ml) and with water /2£150 ml). The organic layer
was dried and evaporated to give the crude title compound
10 /47.33 g, 84.5% pure, 99% yield) as a pale yellow oil
which was further processed without puri®cation.
compound
6 /26.68 g, 62% yield) as pale yellow
crystals, mp 123±1258C. eeˆ.99.9% /HPLC, Chiracel
OJ, n-hexane/EtOH 40:60). Caution: neat 6 can decompose
vigorously above 808C. IR /KBr): 1736 s /CvO). 1H NMR
/250 MHz, CDCl3): 8.10 /d, Jˆ6.9 Hz, 1H), 7.77±7.60 /m,
3H), 7.35±7.25 /m, 5H), 5.45 /s, br. 1H), 5.28 /dd, Jˆ5.4,
7.0 Hz, 1H), 5.11 /s, 2H), 2.90±2.60 /m, 2H), 2.27±2.10 /m,
4H), 1.85±1.65 /m, 2H). MS /EI): 413/1 [M2H2O]1,
186/10, 137/85, 91/100. C21H21NO7S requires: C 58.46%,
H 4.91%, N 3.25%, S 7.43%; found: C 58.41%, H 4.88%, N
3.15%, S 7.33%.
4.1.2. 1:1 Mixture of ꢀ2R,3R)- and ꢀ2S,3R)-2-tert-butoxy-
carbonyl-3-cyclopent-1-enylmethyl-succinic acid di-
benzyl ester ꢀ7). To a suspension of NaH /3.17 g,
55±65% pure, 79.2 mmol, pre-washed with n-hexane) in
dimethylformamide /30 ml) was added at 228C, a solution
of benzyl tert-butyl malonate /18.02 g, 72.0 mmol) in
dimethylformamide /30 ml) over 30 min /gas evolution
ceased) which was followed by the portionwise addition
of the nosylate 6 /31.06 g, 72.0 mmol) over 35 min and
stirring was continued at 228C for 6 h. The mixture was
treated again with 6 /6.21 g, 14.4 mmol) and stirring
was continued for 22 h after which time the conversion
was complete. The red solution was cooled to 108C,
diluted with n-hexane /100 ml) and water /200 ml) and
stirring was continued at 108C for 1 h. The mixture was
®ltered /the residue contained 4.18 g of recovered and
pure 6), the organic layer of the ®ltrate was washed with
water /2£100 ml), dried and evaporated to give the
crude title compound 7 /35.15 g, 87.4% pure, 89% yield)
as a yellow oil which was further processed without
puri®cation.
4.1.5. 4-tert-Butyl-2ꢀR)-ꢀcyclopentylmethyl)-3ꢀR)-[ꢀ3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]succinate
ꢀ1)-pseudoephedrine salt ꢀanti-11a). A vigorously stirred
suspension of the crude triester 10 /47.33 g, 84.5% pure,
63.2 mmol) and Pd/C /5%, 9.47 g) in i-PrOH /475 ml)
was hydrogenated at 25±308C for 24 h after which hydrogen
up-take ceased. The suspension was ®ltered, the residue was
washed with i-PrOH /2£50 ml) and the combined ®ltrates
were evaporated at 258C/12 mbar. To remove traces of
residual i-PrOH, the residue was dissolved in i-PrOAc
/200 ml) and evaporated again. The residue was treated
with i-PrOAc /465 ml) and with N-methylmorpholine
/7.25 g, 71.7 mmol) and the mixture was heated to re¯ux
temperature for 4 h after which gas evolution ceased. The
solution containing a 83:17-mixture of anti-/syn-11 was
treated at re¯ux temperature with /1)-pseudoephedrine
/11.83 g, 71.6 mmol), the solution was slowly cooled to
228C over 1 h and stirring was continued for 4 h. The

7680
H. Hilpert / Tetrahedron 57 -2001) 7675±7683
suspension was ®ltered and the residue was washed with
cold /08C) i-PrOAc /2£100 ml) to give the pure title
compound anti-11a /24.73 g, 68% yield) as white crystals,
mp 169±1708C. IR /KBr): 3433 m and 3234 m /NH, OH),
97.4% pure, 97.4 mmol) and 2-morpholinoethyl isocyanide
/15.42 g, 110 mmol) and stirring was continued for 19 h
after which time formation of the intermediate pyridone
active ester was complete. The solution was treated at 08C
with TMSO±NH2 /11.57 g, 97.3% pure, 107 mmol) and
stirring was continued at 08C for 7 h. The solution was
washed with sat. aqueous NaHCO3 /440 ml) and with
water /3£440 ml), the aqueous layers were extracted with
dichloromethane /420 ml), the combined organic layers
were diluted with acetic acid /0.6 g, stabilizes the product)
and the solution was evaporated at 228C/400 mbar to a
weight of 120 g. The solution was diluted with tert-butyl
methyl ether /440 ml) and evaporated at 228C/240 mbar to a
weight of 260 g. The residue was diluted with tert-butyl
methyl ether /145 ml) and with water /4.2 ml) and stirring
was continued at 228C for 16 h. The suspension was diluted
with n-hexane /220 ml), stirring was continued for 30 min,
the suspension was ®ltered, the residue was washed with
n-hexane/tert-butyl methyl ether /35:15, 260 ml) and dried
to give the pure title compound 1 /35.25 g, 96% pure, 79%
yield) as white crystals, mp 108±1148C /gas evolution). A
second crop yielded an additional 1.50 g /3% yield) of 1.
deˆ.99.5% /HPLC, Symmetrye C18); eeˆ.99.5%
/HPLC, Chiralpack AD, n-hexane/i-PrOH 3:1). IR /nujol):
3570 w and 3302 m /OH, NH), 1765m and 1715 s /CvO).).
1H NMR /250 MHz, CDCl3): 10.4 /s, very br., 1±2H), 3.80±
3.35 /m, 6H), 3.26 /m, 1H), 3.15 /m, 1H), 2.86 /s, 3H),
1.80±1.30 /m, 15H), 1.37 /s, 3H), 1.35 /s, 3H), 1.15 /m,
2H). MS /EI): 436/15 [M]1, 404/100. C22H36N4O5 /contain-
ing 0.6 mol% of H2O) requires: C 59.07%, H 8.38%, N
12.52%; found: C 59.27%, H 8.33%, N 12.68%.
1
1771 s and 1714 s /CvO). H NMR /250 MHz, CDCl3):
8.54 /s, br., 3H), 7.45±7.20 /m, 5H), 4.67 /d, Jˆ9.5 Hz, 1H),
3.93 /dd, Jˆ11.0, 13.0 Hz, 1H), 3.56 /dd, Jˆ13.0, 4.0 Hz,
1H), 3.20 /m, 1H), 2.90 /m, 1H), 2.82 /s, 3H), 2.71 /s, 3H),
2.55 /m, 1H), 1.90±1.10 /m, 11H), 1.41 /s, 9H), 1.33 /s, 3H),
1.32 /s, 3H), 1.08 /d, Jˆ6.6 Hz, 3H). MS /neg. ion spray):
409 [M2H]2. C31H49N3O7 requires: C 64.67%, H 8.58%, N
7.30%; found: C 64.44%, H 8.44%, N 7.39%.
4.1.6. 1-[2ꢀR)-[1ꢀR)-Carboxy-2-ꢀ3,4,4-trimethyl-2,5-dioxo-
1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piper-
idine ꢀanti-12). anti-11a /38.92 g, 67.6 mmol) was par-
titioned between EtOAc /150 ml) and aqueous HCl /1N,
100 ml), the organic layer was washed with water
/2£150 ml) and the aqueous layers were back extracted
with EtOAc /100 ml). The combined organic layers were
dried over MgSO4, the suspension was ®ltered and the
®ltrate was evaporated to a weight of 163 g. The solution
containing the free acid anti-11b was treated at 228C with
N-hydroxy-2-pyridone /3.00 g, 27.0 mmol), the solution
was cooled to 08C and treated subsequently with piperidine
/6.04 g, 70.9 mmol) and with a solution of N,N0-dicyclo-
hexylcarbodiimide /15.34 g, 74.35 mmol) in EtOAc
/45 ml). The suspension was stirred at 08C for 2 h and at
228C for 20 h, the yellow mixture was cooled to 08C, ®ltered
and the residue was washed with cold /08C) EtOAc
/2£15 ml). The combined ®ltrates were treated at 08C
with HBr/AcOH /33%, 47.5 ml, 271 mmol) and stirring
was continued at 08C for 3 h. The suspension was treated
at 0±108C with aqueous NaOH /2N, 325 ml) until the pH
was adjusted to 5 and the suspension was ®ltered. The
aqueous layer of the ®ltrate was extracted with EtOAc
/2£200 ml), the organic layers were washed with brine
/2£200 ml) and the combined organic layers were dried
and evaporated at 308C/12 mbar. To remove traces of acetic
acid disturbing the forthcoming crystallization, the residue
was diluted with toluene /150 ml) and the solvent was
evaporated at 308C/12 mbar. This procedure was repeated
twice. The residue was dissolved in EtOAc /60 ml) and the
solution was diluted at 228C with n-hexane /60 ml). After
the crystallization sets in, the suspension was further diluted
with n-hexane /180 ml), the suspension was cooled to 08C
and stirring was continued for 16 h. The suspension was
®ltered, the residue was washed with n-hexane /2£20 ml)
and dried to give the pure title compound anti-12 /23.30 g,
82% yield) as pale yellow crystals, mp 116±1178C. IR
/KBr): 2600 w, br. /COOH), 1768 m and 1713 s /CvO).
1H NMR /250 MHz, CDCl3): 11.3 /s, br., 1H), 4.03 /dd,
Jˆ4.4, 14.3 Hz, 1H), 3.80±3.35 /m, 5H), 3.10 /m, 2H),
2.89 /s, 3H), 1.85±1.45 /m, 15H), 1.38 /s, 6H), 1.26 /m,
1H), 1.10 /m, 1H). MS /pos. ion spray): 422/100
[M1H]1. C22H35N3O5 requires: C 62.69%, H 8.37%, N
9.97%; found: C 62.47%, H 8.51%, N 9.68%.
4.1.8. ꢀR)-3-Cyclopentylmethyl-4-oxo-4-piperidin-1-yl-
butyric acid tert-butyl ester ꢀ17). A suspension of
the acid 1613 /eeˆ99.6%, 34.48 g, 134.5 mmol) and
N-hydroxy-2-pyridone /5.98 g, 53.8 mmol) in i-PrOAc
/170 ml) was subsequently treated at 08C with piperidine
/12.03 g, 141.2 mmol) and with a solution of N,N0-dicyclo-
hexylcarbodiimide /30.53 g, 148.0 mmol) in i-PrOAc
/90 ml) and stirring was continued at 08C for 1 h and at
228C for 16 h. Excess of N,N0-dicyclohexylcarbodiimide
was destroyed by the addition of an aqueous solution of
acetic acid /10%, 82 g) and the mixture was stirred for
4 h. The suspension was cooled to 08C, ®ltered and the
residue washed with i-PrOAc /3£40 ml). The organic
layer was washed with aqueous Na2CO3 /10%, 200 ml)
and water /3£200 ml), the aqueous layers were extracted
with i-PrOAc /200 ml), the combined organic layers were
dried and evaporated to give the pure title compound 17
/43.89 g, 98.9% pure, 100% yield) as a pale yellow liquid
which solidi®ed on storing at 228C, mp 38.0±40.58C.
eeˆ99.6% /HPLC, Chiralpack AD, n-hexane/EtOH 95:5).
1
IR /neat): 1729 s and 1641 s /CvO). H NMR /250 MHz,
CDCl3): 3.65±3.45 /m, 4H), 3.15 /m, 1H), 2.68 /dd, Jˆ8.6,
16.3 Hz, 1H), 2.31 /dd, Jˆ5.3, 16.3 Hz, 1H), 1.85±1.30 /m,
15H), 1.42 /s, 9H), 1.10 /m, 2H). MS /EI): 324/2 [M1H]1,
185/100.
4.1.7. 1-[3-Cyclopentyl-2ꢀR)-[1ꢀR)-ꢀhydroxycarbamoyl)-
2-ꢀ3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]pro-
pionyl]piperidine ꢀ1). A suspension of N-hydroxy-2-pyri-
done /12.22 g, 110 mmol) in dichloromethane /420 ml) was
subsequently treated at 228C with the acid anti-12 /42.15 g,
4.1.9. anti-12 from 17. To a solution of KN/TMS)2 /20.2%
in THF, 153.6 g, 154 mmol) in THF /155 ml) was added at
2608C a solution of the amide 17 /35.96 g, 98.9% pure,
110 mmol) in THF /180 ml) over 50 min and stirring was
continued for 30 min. The yellow solution was treated at

H. Hilpert / Tetrahedron 57 -2001) 7675±7683
7681
2608C using a syringe pump with a solution of the bromo-
methyl hydantoin 9 /28.44 g, 121 mmol) in THF /140 ml)
over 1 h keeping the inner temperature strictly at 2608C and
stirring was continued at 2608C for 1.5 h. The reaction was
quenched at 250±2608C with brine /20%, 200 ml) over
30 min, the cooling bath was removed and a further portion
of brine /20%, 350 ml) was added. The organic layer was
washed with brine /20%, 550 ml, containing hydrochloric
acid, 25%, 90 ml) and with brine /20%, 2£550 ml), dried
and evaporated. The residue containing crude anti-18/syn-
18 /92:8) was dissolved in AcOH /52 ml), treated at 08C
with HBr/AcOH /33%, 47 ml, 268 mmol) and stirring was
continued at 08C for 1.5 h. The mixture was diluted at 08C
with dichloromethane /250 ml) and water /250 ml), the
organic layer was washed with ice-cold water /4£250 ml),
the aqueous layers were extracted with dichloromethane
/250 ml) and the combined organic layers were dried
and evaporated. The residue was dissolved in tert-butyl
methyl ether /100 ml), the solution was diluted at 228C
with n-hexane /10 ml) until it became cloudy, crystalliza-
tion was awaited and the suspension was further diluted with
n-hexane /75 ml) over 1 h and stirring was continued at
228C for 1.5 h and at 108C for 30 min. The suspension
was ®ltered, the residue washed with cold /108C) tert-
butyl methyl ether/n-hexane /1:1, 3£60 ml) and dried to
give the pure title compound anti-12 /27.36 g, 59% yield)
/s, br., 3H), 7.35±7.15 /m, 5H), 6.36 /d, Jˆ15.8 Hz, 1H),
6.09 /dt, Jˆ15.8, 6.5 Hz, 1H), 2.70±2.35 /m, 4H), 1.75±
1.55 /m, 2H), 1.38 /s, 9H), 1.33 /s, 9H), 1.11 /m, 1H),
0.90 /d, Jˆ6.4 Hz, 3H), 0.87 /d, Jˆ6.4 Hz, 3H). MS /EI):
290/45 [M2C4H8]1, 174/100. C25H41NO4 /containing
0.2 mol% of i-PrOAc) requires: C 70.97%, H 9.85%, N
3.18%; found: C 70.97%, H 9.87%, N 3.37%.
4.1.11. i-Butylhydrazine´H2SO4 ꢀ27). A solution of tert-
butyl carbazate /100 g, 0.757 mol) in i-PrOH /1000 ml)
was treated at 08C with i-butylaldehyde /54.6 g,
0.757 mol) over 30 min and stirring was continued at 08C
for 2 h and at 228C for 2 h. To the yellow solution contain-
ing the intermediate Schiff base was added a suspension of
Pt/C /5%, type F 101 R/D, 9.0 g) in i-PrOH /60 ml) and the
vigorously stirred mixture was hydrogenated at 308C/1 bar
H2 for 42 h after which time hydrogen up-take ceased. The
suspension was ®ltered and the ®ltrate was evaporated to a
volume of ca. 720 ml. The pale yellow solution was treated
at 08C with sulfuric acid /65.7 ml) over 20 min and stirring
was continued at 508C for 5 h after which time gas evolution
ceased. The suspension was diluted at 228C with tert-butyl
methyl ether /580 ml), cooled to 2158C and stirring was
continued for 1 h. The suspension was ®ltered, the residue
was washed with cold /2108C) tert-butyl methyl ether/
i-PrOH /4:1, 3£250 ml) and dried to give the pure title
compound 27 /124.09 g, 88% yield) as white crystals, mp
1
as a white solid, mp 110±1128C. IR, H NMR and MS are
identical with anti-12 from Section 4.1.6.
1
145±1478C /dec.). H NMR /250 MHz, CD3OD): 2.88 /d,
Jˆ7.1 Hz, 2H), 1.98 /hept., Jˆ6.0 Hz, 1H), 1.01 /d,
Jˆ6.0 Hz, 6H). MS /EI): 88/15 [M]1, 45/100.
C4H14N2O4S requires: C 25.80%, H 7.58%, N 15.04%, S
17.22%; found: C 25.91%, H 7.61%, N 15.06%, S 17.18%.
4.1.10. 4-tert-Butyl ꢀE)-2ꢀR)-isobutyl-3ꢀS)-ꢀ3-phenyl-
allyl)succinate tert-butylamine salt ꢀanti-24a). A solution
of the acid 2014 /34.70 g, 150 mmol) in THF /140 ml) was
treated at 2208C with a solution of LDA in THF/heptane
/2.0 M, 150 ml, 300 mmol) over 40 min and stirring was
continued at 2208C for 1 h. The orange solution was treated
with a solution of cinnamyl bromide /31.67 g, 98% pure,
157.5 mmol) in THF /50 ml) over 40 min, the yellow solu-
tion was allowed to warm to 228C over 1 h and stirring was
continued for 2 h. The solution containing a mixture of anti-
24/syn-24 /7:93, GLC, DB17 capillary column, 50%
phenyl±50% methyl-polysiloxane, derivatized with N,O-
bis-/trimethylsilyl)-tri¯uoroacetamide) was cooled to
2208C and treated with a solution of LDA in THF/heptane
/2.0 M, 79 ml, 158 mmol) over 15 min and stirring was
continued at 2208C for 30 min. The brown solution was
cooled to 2908C and treated with a solution of CF3CONH2
/20.35 g, 180 mmol) in THF /20 ml) and stirring was
continued at 2908C for 1 h. The yellow solution containing
a mixture of anti-24/syn-24 /98:2) was allowed to warm to
08C, water /300 ml) was added and the organic solvents
were distilled off. The pH of the aqueous solution was
adjusted at 08C to 3 by adding hydrochloric acid /36%,
27 ml), the mixture was diluted with i-PrOAc /270 ml),
the organic layer was washed with water /3£150 ml) and
the aqueous layers were extracted with i-PrOAc /270 ml).
The combined organic layers were dried and treated at 228C
with tert-butylamine /10.97 g, 150 mmol) over 2 min. The
suspension obtained was stirred at 228C for 1 h and at 08C
for 3 h, ®ltered, the residue was washed with cold /08C)
i-PrOAc /50 ml) and dried to give the pure title compound
anti-24a /53.50 g, 85% yield) as a pale yellow solid, mp
155±1578. deˆ96%, /HPLC, Symmetrye C18). IR
4.1.12. ꢀE)-2ꢀR)-[1ꢀS)-ꢀtert-Butoxycarbonyl)-4-phenyl-3-
butenyl]-20-isobutyl-4-methylvalerohydrazide ꢀanti-25).
A stirred suspension of the tert-butylamine salt anti-24a
/41.96 g, 100 mmol) in i-PrOAc /400 ml) and water
/400 ml) was treated at 08C with hydrochloric acid /25%,
13.7 ml) until the pH reached a value of 2±3. The organic
layer was washed with water /2£200 ml), dried and evapo-
rated to a volume of 200 ml. The solution containing 24b
was treated with N-hydroxy-2-pyridone /12.22 g,
110 mmol), the suspension was cooled to 08C and treated
with a solution of N,N0-dicyclohexylcarbodiimide /22.70 g,
110 mmol) in i-PrOAc /25 ml) over 30 min and stirring was
continued at 08C for 4 h. The pale yellow suspension was
subsequently treated at 08C with 4-ethyl morpholine
/40.31 g, 350 mmol) and i-butylhydrazine H2SO4 /27,
19.55 g, 105 mmol) and the suspension was stirred at
228C for 17 h and at 458C for 7.5 h. The suspension was
treated at 08C with a solution of acetic acid /6.01 g,
100 mmol) in water /60 ml) and stirring was continued at
228C for 1.5 h. The suspension was cooled to 08C, diluted
with aqueous NaHCO3 /5%, 75 ml), ®ltered and the residue
was washed with i-PrOAc /3£45 ml). The combined
organic layers were washed with aqueous NaHCO3 /5%,
75 ml), with hydrochloric acid /1N, 2£75 ml), with brine
/20%, 2£75 ml) and with water /100 ml). The aqueous
layers were extracted with i-PrOAc /100 ml), the combined
organic layers were dried and evaporated. The residue was
diluted with n-hexane /200 ml) and evaporated again. The
pale yellow solid was treated with n-hexane /60 ml),
the suspension was stirred at 228C for 5 h and ®ltered.
1
/nujol): 1718 s /CvO). H NMR /250 MHz, CDCl3): 7.74

7682
H. Hilpert / Tetrahedron 57 -2001) 7675±7683
The residue was washed with n-hexane /20 ml) and dried to
give the pure title compound anti-25 /30.72 g, 74% yield)
as white crystals, mp 109±1118C. deˆ97% /HPLC,
/Symmetrye C18). IR /nujol): 3224 m /NH), 1728 s,
with water /3£110 ml), the aqueous layers were extracted
with i-PrOAc /200 ml), the combined organic layers were
dried and evaporated. The residue was treated with
dichloromethane /440 ml), the suspension was stirred at
228C for 2.5 h, ®ltered and the residue was washed with
dichloromethane /2£150 ml) and dried. The residue
/17.56 g) was dissolved in EtOH /176 ml), the solution
was diluted at 228C with water /198 ml) over 20 min and
stirring was continued until crystallization sets in. The
suspension was diluted with water /154 ml) over 45 min
and stirring was continued for 3.5 h. The suspension was
®ltered, the residue washed with EtOH/water /1:2, 2£35 ml)
and dried to give the pure title compound 2 /15.97 g, 78%
yield) as a white solid, mp 200±2058C /dec.). deˆ.99.5%
/HPLC, Symmetrye C18); eeˆ.99.5% /HPLC, Chiralpak
AD, n-hexane/i-PrOH 7:3). IR /nujol): 3237 m /NH, OH),
1
1718 s and 1628 s /CvO). H NMR /250 MHz, CDCl3):
7.8 /s, very br., 1H), 7.30±7.15 /m, 5H), 6.38 /d, Jˆ15.8 Hz,
1H), 6.10 /dt, Jˆ15.8, 7.6 Hz, 1H), 5.6 /s, very br., 1H),
2.75±2.60 /m, 3H), 2.45±2.30 /m, 3H), 1.80 /m, 2H), 1.50
/m, 1H), 1.40 /s, 9H), 1.11 /m, 1H), 0.95 /d, Jˆ6.7 Hz, 6H),
0.89 /d, Jˆ6.5 Hz, 6H). MS /pos. ion spray): 417/70
[M1H]1, 361/100. C25H40N2O3 requires: C 72.08%, H
9.68%, N 6.72%; found: C 71.59%, H 9.66%, N 6.74%.
4.1.13. ꢀE)-2ꢀR)-ꢀ1ꢀS)-Carboxy-4-phenyl-3-butenyl)-20-
isobutyl-20-ꢀmethanesulfonyl)-4-methylvalerohydrazide
ꢀ26). To a solution of anti-25 /57.20 g, 137.3 mmol) in
dichloromethane /450 ml) was subsequently added at 08C
methansulfonyl chloride /17.30 g, 151.0 mmol) and
triethylamine /18.06 g, 178.5 mmol) and stirring was
continued at 08C for 30 min. The pale yellow solution was
treated at 2158C with HBr/AcOH /33%, 96.5 ml,
550 mmol) over 30 min and stirring was continued at
2158C for 1.5 h. The reaction mixture was diluted with
water /600 ml), the organic layer was washed with water
/2£600 ml), the aqueous layers were extracted with
dichloromethane /200 ml) and the combined organic layers
were dried and evaporated to a weight of 200 g. The stirred
solution was diluted at 228C with n-hexane /750 ml) over
5 min, from the suspension obtained 200 ml of solvent were
distilled off, a further portion of n-hexane /200 ml) was
added and stirring was continued for 2 h. The suspension
was ®ltered and the residue was washed with n-hexane
/200 ml) and dried to give the pure title compound 26
/57.60 g, 96% yield) as white crystals. IR /nujol): 3254 m
/NH), 1697 s and 1672 s /CvO), 1347 s and 1158 s /SO2).
1H NMR /250 MHz, d6-DMSO): 12.4 /s, br. 1H), 10.50 /s,
1H), 7.40±7.15 /m, 5H), 6.37 /d, Jˆ15.9 Hz, 1H), 6.20 /dt,
Jˆ15.9, 7.1 Hz, 1H), 3.30±3.00 /m, 5H), 2.60±2.25 /m,
3H), 1.85±1.20 /m 4H), 1.03 /m, 1H), 0.98±0.80 /m,
12H). MS /pos. ion spray): 461/100 [M1Na]1, 439
[M1H]1. C22H34N2O5S /containing 0.8% of dichloro-
methane) requires: C 59.88%, H 7.77%, N 6.34%, S
7.25%; found: C 59.58%, H 7.87%, N 6.19%, S 7.18%.
1
1709 m and 1650 s /CvO), 1347 s and 1151 s /SO2). H
NMR /250 MHz, d6-DMSO): 10.58 /s, 1H), 10.45 /s, 1H),
8.87 /s, 1H), 7.35±7.15 /m, 5H), 6.30 /d, Jˆ15.8 Hz, 1H),
6.09 /dt, Jˆ15.8, 6.9 Hz, 1H), 3.30±2.95 /m, 5H), 2.65±
2.15 /m, 4H), 1.85±1.15 /m, 3H), 0.98 /m, 1H), 0.95±0.75
/m, 12H). MS /neg. ion spray): 452/100 [M2H]2.
C22H35N3O5S requires: C 58.26%, H 7.78%, N 9.26%, S
7.07%; found: C 57.95%, H 7.88%, N 9.35%, S 7.16%.
Acknowledgements
The author thanks Jean±Pierre Gaertner and Maya Zur¯uh
È
for their skilful technical assistance, Florian Stabler for
the improvement of the isolation procedure of 1, our
colleagues from the analytical service labs and Michael
Hennig for the X-ray analysis. The reading of the manu-
script by Martin Karpf and Ulrich Widmer is gratefully
acknowledged.
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