A straightforward approach to MMP-2 and MMP-9 inhibitors based on chelate claisen rearrangements

Article abstract of DOI:10.1002/ejoc.201101318

The chelate Claisen rearrangement is a versatile tool for the stereoselective synthesis of β-substituted γ,δ-unsaturated amino acids, which can be converted into β-substitutedaspartates by oxidative cleavage. These are ideal precursors for the synthesis o

Full text of DOI:10.1002/ejoc.201101318

FULL PAPER
DOI: 10.1002/ejoc.201101318
A Straightforward Approach to MMP-2 and MMP-9 Inhibitors Based on
Chelate Claisen Rearrangements
Jens L. Burkhart,[a] Björn Diehl,[b] Manfred J. Schmitt,[b] and Uli Kazmaier*[a]
Keywords: Amino acids / Rearrangement / Hydroxamic acids / Metalloenzymes / Inhibitors
The chelate Claisen rearrangement is a versatile tool for the
stereoselective synthesis of β-substituted γ,δ-unsaturated
amino acids, which can be converted into β-substituted
aspartates by oxidative cleavage. These are ideal precursors
for the synthesis of hydroxamate-type MMP inhibitors.
tivity of the inhibitors. Small substituents are preferred for
MMP-1 activity, whereas MMP-2 and MMP-9 with a large
binding pocket at this position can be addressed with long
R1 side-chains.
Introduction
Metastasis, the invasion of tumour cells into distant or-
gans, is often a deadly consequence of tumour growth. It
requires the degradation of extracellular matrices by pro-
teolytic enzymes.[1] In addition to serine and cysteine prote-
ases, the matrix metalloproteases (MMPs) in particular play
a dominant role.[2] Therefore MMPs are interesting targets
for the development of antitumour drugs.[3] This large
group of calcium-dependent zinc-containing endopeptid-
ases can be divided into subclasses, for example, collagen-
ases, gelatinases, stromelysines, matrilysines and membrane-
type MMPs, depending on their preferred substrates and
function. MMP-2 and -9 in particular play a central role in
tumour growth and metastasis, whereas other MMPs are
involved in arthritis, arteriosclerosis or cardiovascular dis-
eases. In the cellular system, MMPs are regulated by hor-
Figure 1. SAR of right-hand side MMP inhibitors.
The introduction of polar side-chains at position Rα
mones and growth factors and are strictly controlled by en- often increases the activity, mainly by increasing the solubil-
dogenous MMP inhibitors (MMPIs) and tissue inhibitors ity of the inhibitors. The substituent R2 is rather flexible.
of MMPs (TIMPs).[4] The overexpression of MMPs causes Aromatic side-chains are preferred for in vitro activity,
an imbalance in the cell, which leads to a variety of patho- whereas sterically demanding groups are beneficial for bio-
logical disorders.[5] Therefore the development of efficient availability by suppressing hydrolysis of the adjacent amide
selective inhibitors is essential for the treatment of a wide bond. This side-chain can also be connected to substituent
range of diseases.[6]
With respect to cancer treatment, a wide range of inhibi- backbone, whereas reverse amide bonds reduce activity.
tors have been developed during recent decades, most of Two typical examples of inhibitors are shown in Fig-
Rα and R3. N-Methylations are tolerated on the amide
them belonging to the group of so-called right-hand-side ure 2. Whereas batimastat (A) is a highly potent broadband
inhibitors with a hydroxamate functionality as the zinc- inhibitor,[8] compound B with a larger R1 side-chain inter-
binding motif. Figure 1 gives an overview of the structure– acts selectively with the cancer-relevant MMP-2 and -9,
activity relationship (SAR) of this type of inhibitor.[7] The whereas MMP-1 and -3 are much less affected.[1,9] The
R1 substituent mainly determines the activity and the selec- slightly lower activity of B relative to A might be the result
of the missing Rα substituent.
For some time our group has been involved in the syn-
thesis of unusual amino acids and pharmaceutically impor-
tant peptides.[10] The key intermediates in our synthetic pro-
tocols are chelated amino acid ester enolates. These are ex-
cellent nucleophiles in a wide range of reactions, for exam-
ple, Michael additions[11] and transition-metal-catalysed
allylic alkylations.[12] If allylic esters are used, the chelated
[a] Institute for Organic Chemistry, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
Fax: +49-681-302-2409
E-mail: u.kazmaier@mx.uni-saarland.de
[b] Department of Molecular and Cell Biology, Saarland
University,
P. O. Box 151150, 66041 Saarbrücken, Germany
Fax: +49-681-302-4710
E-mail: mjs@microbiol.uni-sb.de
Eur. J. Org. Chem. 2012, 567–575
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J. L. Burkhart, B. Diehl, M. J. Schmitt, U. Kazmaier
FULL PAPER
Figure 2. MMP inhibition of selected hydroxamate-type inhibitors.
Scheme 1. Retrosynthesis of 1.
enolates can undergo Claisen rearrangement to give γ,δ-un-
saturated amino acids.[13] This approach is not limited to
amino acids, but can also be applied to the modification of
peptides.[14] Herein, we describe an application of the che-
late enolate Claisen rearrangement for the synthesis of
MMP inhibitors 1 (Figure 3).
Steglich conditions (DCC, DMAP)[17] provided allyl ester 5
in excellent yield. Subjecting this ester to the typical reac-
tion conditions of the chelate Claisen rearrangement
(3 equiv. LDA, 1.2 equiv. ZnCl2) and allowing the reaction
mixture to warm overnight to room temperature provided
the γ,δ-unsaturated amino acid, which was directly con-
verted into the corresponding methyl ester 6a.[18]
Figure 3. Potential MMP inhibitors 1.
Results and Discussion
Our retrosynthetic plan is shown in Scheme 1. The hy-
droxamate functionality should be generated in the last step
from a suitable α-amino acid ester I after coupling of the
phenylalanine amide with the β-carboxylic acid. This func-
tionality should be accessible by oxidative cleavage of the
γ,δ-unsaturated acid II, which is available by chelate Claisen
rearrangement of chiral allylic ester III.
Our synthesis started with the preparation of the re-
quired chiral allylic alcohol (Scheme 2). Starting from 4-
phenylbutyraldehyde, easily accessible from commercial 4-
phenylbutanol or butyric acid, the α,β-unsaturated ketone
2 was obtained from a Wittig reaction with excellent E
selectivity (determined by NMR). Subsequent Luche re-
duction[15] provided the corresponding allylic alcohol 3 in Scheme 2. Synthesis of γ,δ-unsatutrated amino acid ester 6a; ds =
diastereoselectivity.
almost quantitative yield in a few minutes. This allyl alcohol
is a perfect substrate for enzymatic kinetic resolution using
Novozym 435®.[16] The reaction stopped after 50% conver-
In accord with Scheme 3, ester 6a was subjected to oxi-
sion giving rise to both enantiomers of the allylic alcohol 3 dative cleavage with NaIO4/RuCl3. This reaction has
with Ͼ99% ee. For our synthesis we required the R-config- worked well with related substrates without a phenyl
ured alcohol (R)-3, which was obtained from the acetate ring,[19] but in this case the yield was limited to 60%. Proba-
(R)-4 by saponification. Coupling with Boc-glycine under bly the phenyl ring is also attacked during the long reaction.
568
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MMP Inhibitors by Chelate Claisen Rearrangement
Reducing the reaction time led to no improvement, in this resulted in a very clean reaction (spot to spot on TLC).
case the required carboxylic acid 7a was accompanied by However, the required carboxylic acid was not formed, but
the corresponding aldehyde and diol.
the succinimide 9.[20] Evidently, under the basic conditions,
deprotonation of the amide occurred followed by nucleo-
philic attack on the methyl ester. Attempts to open the suc-
cinimide by using O-protected hydroxylamine to give the
required O-protected hydroxamate were unsuccessful.
Therefore we decided to change our protocol slightly by
replacing the methyl ester 6a with benzyl ester 6b. This ester
was obtained in 93% yield by a similar approach to that
described in Scheme 2 simply by alkylating the crude carb-
oxylic acid with benzyl bromide (instead of methyl iodide).
Attempts to cleave the ester 6b directly to give the required
carboxylic acid by using the RuCl3/NaIO4 protocol also
failed with this substrate.
Therefore we switched to a two-step protocol starting
with ozonolysis to give the corresponding aldehyde fol-
lowed by oxidation. The ozonolysis of 6b proceeded with-
out any problems and with PPh3 as reducing agent the ex-
pected aldehyde was obtained in 88% yield after flash
chromatography. Interestingly, around 20% epimerization
at the β-position of the amino acid ester was observed dur-
Scheme 3. Formation of succinimide 9.
Carboxylic acid 7a was subsequently coupled to the ing chromatography (as determined by NMR). The subse-
methylamide of (S)-phenylalanine to give dipeptide 8a. At quent oxidation with sodium chlorite gave the required as-
this point, in principle, the methyl ester only has to be con- partate derivative 7b in quantitative yield and without fur-
verted into the corresponding hydroxamate to finalize the ther epimerization.[21] Therefore we decided not to perform
synthesis. But this operation was far from trivial. The at- the purification step and to oxidize the crude aldehyde di-
tempt to saponify the methyl ester with LiOH (or NaOH) rectly. And indeed, under these conditions the acid 7b was
Scheme 4. Syntheses of MMP inhibitors 1.
Eur. J. Org. Chem. 2012, 567–575
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J. L. Burkhart, B. Diehl, M. J. Schmitt, U. Kazmaier
FULL PAPER
obtained in enantiomerically pure form in good yield tuted aspartates, which can be used as building blocks for
(Scheme 4). Subsequent peptide coupling with (S)-Phe- the synthesis of hydroxamate-based MMP inhibitors. The
NHMe according to the previous protocol gave rise to the new derivatives 1 showed inhibition of MMP-2 and -9, pro-
dipeptide 8b in good yield. Note that the free amine should teases involved in tumour growth and metastasis, in the low
be used in the coupling step and not the corresponding hy- or sub μm range. The major handicap of the new inhibitors
drochloride. In the presence of excess base (to liberate the is their low solubility in most solvents and probably also
amine) the desired peptide 8b was not obtained but the cy- under physiological conditions.
clization product 9.
Benzyl ester 8b was subjected to catalytic hydrogenation
providing the required N-protected peptide acid 10 in high
yield. The next step, the coupling with the O-protected hy-
droxylamine, was critical because we had to activate the
acid without the previously mentioned cyclization taking
place. We decided to activate the acid by the mixed anhy-
dride method, with the free O-benzylhydroxylamine (not
Experimental Section
General: All reactions were carried out in oven-dried glassware
(70 °C) under nitrogen. Dried solvents were distilled before use:
THF was distilled from LiAlH4 and dry DMF was purchased from
Sigma–Aldrich. The products were purified by flash chromatog-
raphy on silica gel columns (Macherey–Nagel 60, 0.063–0.2 mm).
the hydrochloride) and exactly 1 equiv. of NEt3 to remove
the HCl formed. Under these conditions the desired pro-
tected hydroxamate 11a was obtained in high yield without
the formation of imide 9. Unfortunately, this compound is
nearly insoluble in most solvents. Therefore we had to per-
form the final hydrogenation in DMF as solvent. Because
of the poor solubility it was nearly impossible to monitor
the reaction. After hydrogenation for 1 d the free hydrox-
amate 1a was obtained in good yield. This compound was
investigated as an inhibitor of the cancer-relevant MMP-2
and -9 (Table 1). Although the activity was not in the low
nm range as with the standard inhibitor Batimastat, IC50
values in the sub μm range were not disappointing for our
first inhibitor molecule with a simple Boc-protecting group.
This protecting group was chosen because it can easily be
removed, allowing the introduction of a wide range of other
substituents at the α position. To increase the polarity and
solubility in polar solvents we decided to convert 11a into
the glycolic acid derivative 11b. TBTU [2-(1H-benzotriazol-
1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate] was
used as the coupling reagent, allowing the removal of the
byproducts by diluting the DMF solution with CH2Cl2 be-
cause 11b is insoluble in CH2Cl2 and can be filtered off
easily. The final hydrogenation in DMF gave 1b.
Mixtures of ethyl acetate and hexanes were generally used as el-
uents. Analytical TLC was performed on precoated silica gel plates
(Macherey–Nagel, Polygram® SIL G/UV254). Visualization was
accomplished with UV light, KMnO4, or ninhydrin solution. The
enantiomeric and diastereomeric ratios were determined by HPLC
using
a chiral column (Trentec, Reprosil 100 Chiral-NR,
250ϫ4.6 mm) or by GC (Chirasil–Dex-CB). Optical rotations were
measured with a Perkin–Elmer PE 341 polarimeter. 1H and 13C
NMR spectra were recorded with a Bruker AC-400 [400 (1H) and
100 MHz (13C)] spectrometer in CDCl3, MeOD, or [D6]DMSO.
Chemical shifts are reported in ppm (δ) with respect to TMS and
CHCl3 was used as the internal standard. Mass spectra were re-
corded with a Finnigan MAT 95 spectrometer by using the CI or
EI technique. Elemental analyses were performed at Saarland Uni-
versity.
(E)-7-Phenylhept-3-en-2-one (2):[22] A solution of 1-(triphenylphos-
phoranylidene)-2-propanone (10.4 g, 32.5 mmol) and 4-phenyl-
butyraldehyde (4.68 g, 31.6 mmol) in THF (150 mL) was heated at
reflux for 24 h. The reaction mixture was concentrated and diluted
with hexanes. The precipitate was filtered off and the filtrate was
concentrated again. After purification by flash chromatography
(hexanes/ethyl acetate, 9:1) unsaturated ketone
2
(4.95 g,
26.3 mmol, 81%, Ͼ95% E) was obtained as a colourless oil. TLC:
1
Rf = 0.19 (hexanes/ethyl acetate, 9:1). H NMR (CDCl3): δ = 1.82
3
3
(tt, J6,5 = 7.6, J6,7 = 7.5 Hz, 2 H, 6-H), 2.23–2.29 (m, 5 H, 7-H,
11-H), 2.66 (t, 3J5,6 = 7.6 Hz, 2 H, 5-H), 6.08 (dt, 3J9,8 = 16.0, 4J9,7
3
4
= 1.5 Hz, 1 H, 9-H), 6.80 (dt, J8,9 = 16.0, J8,7 = 6.9 Hz, 1 H, 8-
H), 7.16–7.21 (m, 3 H, 1-H, 3-H), 7.29 (m, 2 H, 2-H) ppm. 13C
NMR (CDCl3): δ = 26.9 (q, C-11), 29.7 (t, C-6), 31.9 (t, C-7), 35.3
(t, C-5), 126.0 (d, C-1), 128.4 (d, C-2, C-3), 131.5 (d, C-9), 141.6
(s, C-4), 147.9 (d, C-8), 198.6 (s, C-10) ppm. No signals of the Z
isomer were detected by NMR spectroscopy.
Table 1. IC50 values of MMP inhibitors 1.
MMP
IC50 [μm]
1c
1a
1b
1d
MMP-2
MMP-9
0.39
0.15
24.7
11.5
19,6
6.2
16.8
6.2
(E)-7-Phenylhept-3-en-2-ol (3): Sodium borohydride (0.92 g,
24.4 mmol) was added over 5 min to a solution of 2 (4.59 g,
24.4 mmol) and CeCl3·7H2O (9.09 g, 24.4 mmol) in MeOH
(60 mL). After stirring for an additional 5 min at room tempera-
ture, the reaction mixture was quenched with 1 m aqueous KHSO4
and extracted thrice with diethyl ether. The organic layer was
washed with brine and concentrated. After purification by flash
chromatography (hexanes/ethyl acetate, 8:2) racemic alcohol 3
(4.58 g, 24.1 mmol, 99%) was obtained as a colourless oil. TLC: Rf
= 0.21 (hexanes/ethyl acetate 8:2). HPLC (Reprosil, hexanes/
After removal of the solvent, the crude product was sus-
pended in MeOH and filtered to provide 1b in pure form.
Interestingly, although 1b seems to be more soluble, the
IC50 values were significantly worse that those of com-
pound 1a. Therefore we also replaced the Boc group by
other less polar acyl groups, namely the acetyl (1c) and ben-
zoyl (1d) groups. These derivatives showed comparable ac-
tivity in the μm range.
iPrOH, 98:2, 1 mL/min): (S)-3: tR = 9.64 min, (R)-3: tR
10.11 min. H NMR (CDCl3): δ = 1.26 (d, J11,10 = 6.3 Hz, 3 H,
=
Conclusions
1
3
3
3
We have shown that the chelate enolate Claisen re-
11-H), 1.41 (br. s, 1 H, OH), 1.72 (tt, J6,5 = 7.7, J6,7 = 7.6 Hz, 2
arrangement is a powerful tool for the synthesis of β-substi- H, 6-H), 2.07 (m, 2 H, 7-H), 2.62 (t, 3J5,6 = 7.7 Hz, 2 H, 5-H), 4.26
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MMP Inhibitors by Chelate Claisen Rearrangement
3
3
4
(m, 1 H, 10-H), 5.53 (ddt, J9,8 = 15.4, J9,10 = 6.5, J9,7 = 1.2 Hz, = 20.4 (q, C-13), 21.4 (q, C-11), 30.6 (t, C-6), 31.6 (t, C-7), 35.3 (t,
1 H, 9-H), 5.65 (dt, 3J8,9 = 15.4, 3J8,7 = 6.6 Hz, 1 H, 8-H), 7.16–7.20
C-5), 71.1 (d, C-10), 125.7 (d, C-1), 128.3, 128.4 (2 d, C-2, C-3),
(m, 3 H, 1-H, 3-H), 7.28 (m, 2 H, 2-H) ppm. 13C NMR (CDCl3): δ 130.0 (d, C-9), 132.8 (d, C-8), 142.3 (s, C-4), 170.3 (s, C-12) ppm.
= 23.4 (q, C-11), 30.8 (t, C-6), 31.6 (t, C-7), 35.3 (t, C-5), 68.9 (d,
HRMS (CI): calcd. for C13H16 [M – C2H4O2]+ 172.1252; found
C-10), 125.7 (d, C-1), 128.3, 128.4 (2 d, C-2, C-3), 130.5 (d, C-8), 172.1255. C15H20O2 (232.32): calcd. C 77.55, H 8.68; found C
134.6 (d, C-9), 142.3 (s, C-4) ppm. HRMS (CI): calcd. for C13H18O 77.08, H 8.57.
[M]+ 190.1358; found 190.1363.
(2R,E)-7-Phenylhept-3-en-2-yl 2-(tert-Butoxycarbonylamino)acetate
(2S,E)-7-Phenylhept-3-en-2-ol [(S)-3]: Novozym 435® (207 mg) was (5): A solution of Boc-protected glycine (1.58 g, 9.00 mmol) in di-
added to a solution of racemic 3 (3.85 g, 20.2 mmol) in vinyl acetate
(18.7 mL, 202 mmol). The reaction mixture was shaken at room
temperature for 18 h. The enzyme was filtered off and washed with
diethyl ether. The combined filtrates were concentrated and the res-
idue was purified by flash chromatography (hexanes/ethyl acetate,
ethyl ether (40 mL) was added to a solution of alcohol (R)-3
(1.55 g, 8.20 mmol) in diethyl ether (40 mL) followed by solid
DMAP (105 mg, 0.86 mmol). The solution was cooled to 0 °C and
a solution of DCC (1.88 g, 9.10 mmol) in diethyl ether (20 mL) was
added. The solution was warmed to room temperature overnight
9:1) to give acetate (R)-4 (2.38 g, 10.3 mmol, 50%, Ͼ99% ee) and and the precipitate was filtered off. The filtrate was washed with
alcohol (S)-3 (1.69 g, 8.90 mmol, 45%, Ͼ99% ee), both as colour-
less oils. TLC: Rf = 0.32 (hexanes/ethyl acetate, 7:3). HPLC (Re-
prosil, hexanes/iPrOH, 98:2, 1 mL/min): (S)-3: tR = 9.64 min;
[α]2D0 = –9.2 (c = 1.1, CHCl3, Ͼ99% ee). 1H NMR (CDCl3): δ =
1 m KHSO4 (twice), water, saturated NaHCO3, brine, dried with
Na2SO4 and concentrated. The crude product was purified by flash
chromatography (hexanes/ethyl acetate, 8:2) to yield ester 5 (2.83 g,
8.15 mmol, 99%, Ͼ99% ee) as a colourless oil. TLC: Rf = 0.31
(hexanes/ethyl acetate, 8:2); [α]2D0 = +39.2 (c = 0.8, CHCl3, Ͼ99%
1.26 (d, 3J11,10 = 6.3 Hz, 3 H, 11-H), 1.41 (br. s, 1 H, OH), 1.72 (tt,
3
3J6,5 = 7.7, J6,7 = 7.6 Hz, 2 H, 6-H), 2.07 (m, 2 H, 7-H), 2.62 (t, ee). HPLC (Reprosil, hexanes/iPrOH, 98:2, 1 mL/min): (R)-5: tR
=
3
1
3J5,6 = 7.7 Hz, 2 H, 5-H), 4.26 (m, 1 H, 10-H), 5.53 (ddt, J9,8
=
26.52 min, (S)-5: tR = 40.20 min. H NMR (CDCl3): δ = 1.31 (d,
3
4
3
3
15.4, J9,10 = 6.5, J9,7 = 1.2 Hz, 1 H, 9-H), 5.65 (dt, J8,9 = 15.4,
3J11,10 = 6.4 Hz, 3 H, 11-H), 1.45 (s, 3 H, 16-H), 1.71 (tt, J6,5
7.7, J6,7 = 7.5 Hz, 2 H, 6-H), 2.07 (m, 2 H, 7-H), 2.61 (t, J5,6
=
=
3J8,7 = 6.6 Hz, 1 H, 8-H), 7.16–7.20 (m, 3 H, 1-H, 3-H), 7.29 (m,
3
3
2 H, 2-H) ppm. 13C NMR (CDCl3): δ = 23.4 (q, C-11), 30.8 (t, C- 7.7 Hz, 2 H, 5-H), 3.88 (m, 2 H, 13-H), 4.99 (br. s, 1 H, NH), 5.38
3
3
4
6), 31.6 (t, C-7), 35.3 (t, C-5), 68.9 (d, C-10), 125.7 (d, C-1), 128.3,
128.4 (2 d, C-2, C-3), 130.5 (d, C-8), 134.6 (d, C-9), 142.3 (s, C-
4) ppm. HRMS (CI): calcd. for C13H18O [M]+ 190.1358; found
190.1363.
(m, 1 H, 10-H), 5.46 (ddt, J9,8 = 15.2, J9,10 = 6.9, J9,7 = 1.4 Hz,
1 H, 9-H), 5.73 (dt, 3J8,9 = 15.2, 3J8,7 = 6.8 Hz, 1 H, 8-H), 7.15–7.19
(m, 3 H, 1-H, 3-H), 7.27 (m, 2 H, 2-H) ppm. 13C NMR (CDCl3): δ
= 20.3 (q, C-11), 28.3 (q, C-16), 30.5 (t, C-6), 31.6 (t, C-7), 35.3 (t,
C-8), 42.7 (t, C-13), 72.5 (d, C-10), 79.9 (s, C-15), 125.7 (d, C-1),
128.3, 128.4 (2 d, C-2, C-3), 129.4 (d, C-9), 133.5 (d, C-8), 142.2
(s, C-4), 155.6 (s, C-14), 169.6 (s, C-12) ppm. HRMS (CI): calcd.
for C20H30NO4 [M + H]+ 348.2175; found 348.2192. C20H29NO4
(347.45): calcd. C 69.14, H 8.41, N 4.03; found C 68.95, H 8.30, N
4.09.
(2R,E)-7-Phenylhept-3-en-2-ol [(R)-3]: A 1 m sodium hydroxide
solution (12.0 mL, 12.0 mmol) was added to a solution of acetate
(R)-4 (2.28 g, 9.80 mol) in methanol (50 mL) at 0 °C. After 30 min
the cooling bath was removed and the solution was warmed to
room temperature overnight. The reaction mixture was quenched
with 1 m KHSO4 solution and extracted with diethyl ether. The
combined organic layers were washed with saturated NaHCO3,
dried with Na2SO4 and concentrated in vacuo. After purification
by flash chromatography (hexanes/ethyl acetate, 7:3) alcohol (R)-3
(1.77 g, 9.30 mmol, 95%, Ͼ99% ee) was obtained as a colourless
oil. TLC: Rf = 0.32 (hexanes/ethyl acetate, 7:3). HPLC (Reprosil,
Methyl (2R,3S,E)-2-(tert-Butoxycarbonylamino)-3-(3-phenylpropyl)-
hex-4-enoate (6a): nBuLi (1.6 m in hexanes, 12.0 mL, 19.2 mmol)
was added dropwise to a solution of diisopropylamine (3.40 mL,
24.1 mmol) in dry THF (24 mL) at –30 °C. The clear solution was
warmed to room temperature and then cooled to –78 °C (base solu-
tion). In another Schlenk tube, ester 5 (2.70 g, 7.80 mmol) was
added to a solution of ZnCl2 (1.28 g, 9.40 mmol) in dry THF
(45 mL). This solution was also cooled to –78 °C (substrate solu-
tion). The base solution was then slowly added to the substrate
solution over 20 min and the resulting solution was warmed to
room temperature overnight (20 h). The reaction mixture was di-
hexanes/iPrOH, 98:1, 1 mL/min): (R)-3: tR = 10.11 min; [α]2D0
=
1
+8.5 (c = 1.2, CHCl3, Ͼ99% ee). H NMR (CDCl3): δ = 1.26 (d,
3
3J11,10 = 6.3 Hz, 3 H, 11-H), 1.41 (br. s, 1 H, OH), 1.72 (tt, J6,5
=
=
3
3
7.7, J6,7 = 7.6 Hz, 2 H, 6-H), 2.07 (m, 2 H, 7-H), 2.62 (t, J5,6
3
7.7 Hz, 2 H, 5-H), 4.26 (m, 1 H, 10-H), 5.53 (ddt, J9,8 = 15.4,
3J9,10 = 6.5, J9,7 = 1.2 Hz, 1 H, 9-H), 5.65 (dt, J8,9 = 15.4, J8,7
4
3
3
= 6.6 Hz, 1 H, 8-H), 7.16–7.20 (m, 3 H, 1-H, 3-H), 7.29 (m, 2 H, luted with diethyl ether and hydrolysed with 1 m KHSO4. The
2-H) ppm. 13C NMR (CDCl3): δ = 23.4 (q, C-11), 30.8 (t, C-6), phases were separated and the aqueous layer was extracted with
31.6 (t, C-7), 35.3 (t, C-5), 68.9 (d, C-10), 125.7 (d, C-1), 128.3,
128.4 (2 d, C-2, C-3), 130.5 (d, C-8), 134.6 (d, C-9), 142.3 (s, C-
4) ppm. HRMS (CI): calcd. for C13H18O [M]+ 190.1358; found
190.1363.
diethyl ether. The combined organic layers were washed with brine,
dried with Na2SO4 and concentrated in vacuo.
The crude acid was dissolved in dry DMF (30 mL) and cooled to
0 °C. K2CO3 (1.35 g, 9.80 mmol) was added followed by methyl
iodide (1.45 mL, 23.3 mmol). The reaction mixture was warmed to
room temperature over 20 h, quenched with water and extracted
with ethyl acetate. The combined organic layers were washed with
water (three times), 5% Na2SO3 and brine, dried with Na2SO4 and
(2R,E)-7-Phenylhept-3-en-2-yl Acetate [(R)-4]: The acetate (R)-4
was obtained together with (S)-3 in the enzymatic kinetic resolution
of racemic 3. TLC: Rf = 0.36 (hexanes/ethyl acetate, 9:1); [α]2D0
=
+52.1 (c = 1.2, CHCl3, Ͼ99% ee). GC (Chirasil–Dex-CB, 1. 80 °C,
3 min; 2. 4 °C/min; 3. 220 °C, 20 min): (S)-4: tR = 35.78 min, (R)- concentrated. The crude product was purified by flash chromatog-
1
4: tR = 36.17 min. H NMR (CDCl3): δ = 1.29 (d, 3J11,10 = 6.4 Hz,
raphy (hexanes/ethyl acetate, 8:2) to yield ester 6a (2.16 g,
5.98 mmol, 77%, 97% ee, Ͼ95% ds) as a colourless oil. TLC: Rf =
0.40 (hexanes/ethyl acetate, 8:2); [α]2D0 = –14.8 (c = 1.2, CHCl3, 97%
3
3
3 H, 11-H), 1.71 (tt, J6,5 = 7.7, J6,7 = 7.6 Hz, 2 H, 6-H), 2.03–
2.10 (m, 5 H, 7-H, 13-H), 2.61 (t, J5,6 = 7.7 Hz, 2 H, 5-H), 5.32
3
3
3
4
(m, 1 H, 10-H), 5.47 (ddt, J9,8 = 15.4, J9,10 = 6.8, J9,7 = 1.4 Hz, ee, Ͼ95% ds). HPLC (Reprosil, hexanes/iPrOH, 98:2, 1 mL/min):
1 H, 9-H), 5.71 (dt, 3J8,9 = 15.4, 3J8,7 = 6.8 Hz, 1 H, 8-H), 7.16–7.20
(2R,3S)-6a: tR = 11.39 min; (2S,3R)-6a: tR = 12.66 min. H NMR
1
(m, 3 H, 1-H, 3-H), 7.28 (m, 2 H, 2-H) ppm. 13C NMR (CDCl3): δ (CDCl3): δ = 1.33 (m, 1 H, 8-Ha), 1.43 (s, 9 H, 6-H), 1.47–1.56 (m,
Eur. J. Org. Chem. 2012, 567–575
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
571

J. L. Burkhart, B. Diehl, M. J. Schmitt, U. Kazmaier
2 H, 8-Hb, 9-Ha), 1.64 (m, 1 H, 9-Hb), 1.67 (dd, 3J17,16 = 6.4, 4J17,15 and ozone was bubbled through the reaction mixture until a blue
FULL PAPER
= 1.6 Hz, 3 H, 17-H), 2.30 (m, 1 H, 7-H), 2.59 (m, 2 H, 10-H),
3.68 (s, 3 H, 1-H), 4.23 (dd, J3,NH = 8.4, J3,7 = 6.0 Hz, 1 H, 3-
colour persisted. After purging the excess of ozone with nitrogen,
triphenylphosphane (2.15 g, 8.20 mmol) was added and the solu-
3
3
3
2
H), 4.98 (d, JNH,3 = 8.7 Hz, 1 H, NH), 5.12 (ddq, J15,16 = 15.2, tion was warmed to room temperature. Concentration in vacuo
4
3
3J15,7 = 9.6, J15,17 = 1.6 Hz, 1 H, 15-H), 5.50 (dq, J16,15 = 15.2,
gave the crude aldehyde as a colourless oil. The aldehyde was dis-
solved in tert-butyl alcohol (170 mL) before 2-methyl-2-butene
3J16,17 = 6.4 Hz, 1 H, 16-H), 7.14–7.19 (m, 3 H, 12-H, 14-H), 7.27
(m, 2 H, 13-H) ppm. 13C NMR (CDCl3): δ = 17.9 (q, C-17), 28.3 (17.6 mL, 164 mmol) was added followed by a solution of NaClO2
(q, C-6), 29.1 (t, C-9), 30.8 (t, C-8), 35.7 (t, C-10), 46.3 (d, C-7),
(80%, 9.27 g, 82.0 mmol) and NaH2PO4·2H2O (8.95 g, 57.4 mmol)
51.8 (q, C-1), 57.0 (d, C-3), 79.8 (s, C-5), 125.7 (d, C-14), 128.3, in water (60 mL). The yellow emulsion was stirred for 16 h at room
128.4 (2 d, C-12, C-13), 129.0 (d, C-16), 129.5 (d, C-15), 142.3 (s, temperature. The tert-butyl alcohol was removed in vacuo, the resi-
C-11), 155.3 (s, C-4), 172.4 (s, C-2) ppm. HRMS (CI): calcd. for
C21H32NO4 [M + H]+ 362.2331; found 362.2296. C21H31NO4
(361.48): calcd. C 69.78, H 8.64, N 3.87; found C 69.87, H 8.40, N
4.18.
due was acidified with 1 m HCl (pH = 1) and extracted 3ϫ with
diethyl ether (50 mL each). The combined organic layers were dried
with Na2SO4 and concentrated. The crude product was purified by
flash chromatography (hexanes/ethyl acetate/acetic acid, 70:29:1) to
yield acid 7b (3.34 g, 7.60 mmol, 93% over two steps) as a colour-
less resin. TLC: Rf = 0.28 (hexanes/ethyl acetate/acetic acid,
70:29:1); [α]2D0 = –4.1 (c = 1.1, CHCl3). 1H NMR (CDCl3): δ = 1.32
(s, 9 H, 10-H), 1.54 (m, 1 H, 12-Ha), 1.61 (m, 1 H, 13-Ha), 1.72
Benzyl (2R,3S,E)-2-(tert-Butoxycarbonylamino)-3-(3-phenylpropyl)-
hex-4-enoate (6b): In accord with the synthesis of 6a, diisopropyl-
amine (1.5 mL, 10.6 mmol), nBuLi (1.6 m in hexanes, 5.60 mL,
8.96 mmol), ester 5 (1.25 g, 3.60 mmol) and ZnCl2 (605 mg,
4.40 mmol) were allowed to react. After workup, the crude acid
was dissolved in dry DMF (20 mL) and cooled to 0 °C. Then
Cs2CO3 (1.24 g, 3.80 mmol) was added followed by benzyl bromide
(0.63 mL, 4.32 mmol). The reaction mixture was warmed to room
temperature over 20 h, quenched with water and extracted with
ethyl acetate. The combined organic layers were washed with water
(three times), 5% Na2SO3 and brine, dried with Na2SO4 and con-
centrated in vacuo. The crude product was purified by flash
chromatography (hexanes/ethyl acetate, 9:1) to yield benzyl ester 6b
(1.46 g, 3.30 mmol, 93%, 98% ee, Ͼ95% ds) as a colourless oil.
TLC: Rf = 0.23 (hexanes/ethyl acetate, 9:1); [α]2D0 = +11.5 (c = 1.1,
CHCl3, 98% ee, Ͼ95% ds). HPLC (Reprosil, hexanes/iPrOH, 98:2,
1 mL/min): (2R,3S)-6b: tR = 17.17 min; (2S,3R)-6b: tR = 18.78 min.
1H NMR (CDCl3): δ = 1.26 (m, 1 H, 12-Ha), 1.43 (s, 9 H, 10-H),
1.45–1.53 (m, 2 H, 12-Hb, 13-Ha), 1.62 (m, 1 H, 13-Hb), 1.61 (dd,
3J21,20 = 6.4, 4J21,19 = 1.5 Hz, 3 H, 21-H), 2.31 (m, 1 H, 11-H), 2.51
3
(m, 1 H, 13-Hb), 1.82 (m, 1 H, 12-Hb), 2.55 (t, J14,13 = 7.6 Hz, 2
2
H, 14-H), 2.89 (m, 1 H, 11-H), 4.68 (m, 1 H, 7-H), 5.13 (d, J5a,5b
2
= 12.2 Hz, 1 H, 5-Ha), 5.19 (d, J5b,5a = 12.2 Hz, 1 H, 5-Hb), 5.33
3
(d, JNH,7 = 8.2 Hz, 1 H, NH), 7.11 (m, 2 H, 16-H), 7.19 (m, 1 H,
18-H), 7.26 (m, 2 H, 17-H), 7.30–7.37 (m, 5 H, 1-H, 2-H, 3-H),
8.50 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3): δ = 27.5 (t, C-12),
28.1 (q, C-10), 29.1 (t, C-13), 35.5 (t, C-14), 47.9 (d, C-11), 54.3 (d,
C-7), 67.4 (t, C-5), 80.3 (s, C-9), 125.7 (d, C-18), 128.2, 128.3, 128.4,
128.5 (5 d, C-1, C-2, C-3, C-16, C-17), 135.0 (s, C-4), 141.6 (s, C-
15), 155.2 (s, C-8), 170.4 (s, C-6), 177.8 (s, C-19) ppm. HRMS (CI):
calcd. for C25H32NO6 [M + H]+ 442.2229; found 442.2231.
C
25H31NO6 (441.52): calcd. C 68.01, H 7.08, N 3.17; found C
67.58, H 7.07, N 3.30.
N-Methyl-(R)-2-[(R)-2-(methyloxy)-1-(tert-butoxycarbonylamino)-
2-oxoethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (8a): NEt3
(0.21 mL, 1.53 mmol) was added to a solution of crude acid 7a
(397 mg, 1.09 mmol), (S)-Phe-NHMe (232 mg, 1.30 mmol) and
TBTU (357 mg, 1.11 mmol) in dry dichloromethane (10 mL) at
0 °C. The reaction mixture was warmed to room temperature over
18 h. The resulting suspension was diluted with dichloromethane
and washed with water (twice), 1 m KHSO4, saturated NaHCO3,
water and brine, dried with Na2SO4 and concentrated in vacuo.
The crude product was purified by flash chromatography (dichloro-
methane/methanol, 98:2) to yield peptide 8a (436 mg, 0.83 mmol,
76%, Ͼ95% ds) as a white solid; m.p. 189–190 °C. TLC: Rf = 0.51
(dichloromethane/methanol, 95:5); [α]2D0 = –21.6 (c = 0.9, CHCl3,
Ͼ95% ds). 1H NMR (CDCl3): δ = 1.42 (s, 9 H, 6-H), 1.47–1.66
3
3
(m, 2 H, 14-H), 4.28 (dd, J7,11 = 8.9, J7,NH = 8.8 Hz, 1 H, 7-H),
3
4.99 (d, JNH,7 = 8.8 Hz,1 H, NH), 5.05–5.10 (m, 2 H, 5-Ha, 19-
3
3
H), 5.17 (d, J5b,5a = 12.3 Hz, 1 H, 5-Hb), 5.46 (dq, J20,19 = 15.2,
3J20,21 = 6.4 Hz, 1 H, 20-H), 7.11 (d, J16,17 = 7.0 Hz, 2 H, 16-H),
3
7.16 (m, 1 H, 18-H), 7.25 (m, 2 H, 17-H), 7.33–7.38 (m, 5 H, 1-H,
2-H, 3-H) ppm. 13C NMR (CDCl3): δ = 17.9 (q, C-21), 28.3 (q, C-
10), 29.1 (t, C-13), 30.8 (t, C-12), 35.7 (t, C-14), 46.4 (d, C-11), 57.1
(d, C-7), 66.7 (t, C-5), 79.8 (s, C-9), 125.7 (d, C-18), 128.3, 128.3,
128.4, 128.5 (5 d, C-1, C-2, C-3, C-16, C-17), 129.0 (s, C-20), 129.5
(d, C-19), 135.5 (s, C-4), 142.3 (s, C-15), 155.3 (s, C-8), 171.7 (s, C-
6) ppm. HRMS (CI): calcd. for C27H36NO4 [M + H]+ 438.2644;
found 438.2597. C27H35NO4 (437.58): calcd. C 74.11, H 8.06, N
3.20; found C 74.00, H 8.05, N 3.58.
3
(m, 4 H, 8-H, 9-H), 2.55 (t, J10,9 = 7.0 Hz, 2 H, 10-H), 2.65 (br.
3
s, 1 H, 7-H), 2.68 (d, J18,NH = 4.8 Hz, 3 H, 18-H), 3.07 (m, 2 H,
19-H), 3.67 (s, 3 H, 1-H), 4.48 (br. s, 1 H, 3-H), 4.57 (m, 1 H, 16-
H), 5.34 (d, 3JNH,3 = 7.4 Hz, 1 H, NH), 6.02 (br. s, 1 H, NH), 6.29
(R)-2-[(R)-1-(tert-Butoxycarbonylamino)-2-methoxy-2-oxoethyl]-
5-phenylpentanoic Acid (7a): CCl4 (5 mL) and water (7.5 mL) were
added to a solution of 6a (461 mg, 1.28 mmol) in acetonitrile
(5 mL) followed by RuCl3·H2O (35–40%, 18.8 mg, 0.03 mmol) and
sodium periodate (1.13 g, 5.28 mmol). The reaction mixture was
stirred vigorously for 20 h at room temperature, diluted with water
and extracted with dichloromethane. The combined organic layers
were dried with Na2SO4 and concentrated in vacuo. The residue
was filtered through silica gel (hexanes/ethyl acetate, 1:1). After
evaporating the solvent, the crude acid 7a (274 mg, 0.75 mmol,
60%) was obtained as an orange resin. This acid was used in the
next step without further purification.
3
(d, JNH,16 = 5.6 Hz, 1 H, NH), 7.10–7.12 (m, 2 H, Ar-H), 7.15–
7.20 (m, 3 H, Ar-H), 7.21–7.30 (m, 5 H, Ar-H) ppm. 13C NMR
(CDCl3): δ = 26.1 (q, C-18), 28.1 (t, C-9), 28.2 (q, C-6), 28.8 (t, C-
8), 35.5 (t, C-10), 38.0 (t, C-19), 49.5 (d, C-7), 52.5 (s, C-1), 54.7
(d, C-16), 54.8 (d, C-3), 80.4 (s, C-5), 125.9, 127.0 (2 d, C-14, C-
23), 128.3, 128.7, 129.1 (4 d, C-12, C-13, C-21, C-22), 136.7 (s, C-
20), 141.5 (s, C-11), 155.4 (s, C-4), 171.0, 171.5, 171.9 (3 s, C-2, C-
15, C-17) ppm. No signals of the S,S,S diastereomer were detected
by NMR spectroscopy. HRMS (CI): calcd. for C29H40N3O6 [M +
H]+ 526.2917; found 526.2971. C29H39N3O6 (525.65): calcd. C
66.27, H 7.48, N 7.99; found C 66.00, H 7.45, N 7.93.
(R)-2-[(R)-2-(Benzyloxy)-1-(tert-butoxycarbonylamino)-2-oxo-
ethyl]-5-phenylpentanoic Acid (7b): A solution of olefin 6b (3.59 g,
8.20 mmol) in dry dichloromethane (80 mL) was cooled to –78 °C
N-Methyl-(R)-2-[(R)-2-(benzyloxy)-1-(tert-butoxycarbonylamino)-
2-oxoethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (8b): NEt3
(0.25 mL, 1.81 mmol) was added to a solution of acid 7b (800 mg,
572
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 567–575

MMP Inhibitors by Chelate Claisen Rearrangement
1.81 mmol), (S)-Phe-NHMe (387 mg, 2.17 mmol) and TBTU
(581 mg, 1.81 mmol) in dry dichloromethane (20 mL) at 0 °C. The
reaction mixture was warmed to room temperature over 18 h. The
resulting suspension was diluted with dichloromethane and washed
with water (twice), 1 m KHSO4, saturated NaHCO3, water and
brine, dried with Na2SO4 and concentrated. The crude product was
MeOH). 1H NMR (MeOD): δ = 1.39–1.49 (m, 11 H, 5-H, 8-H),
1.56 (m, 2 H, 7-H), 2.50 (t, J9,8 = 7.4 Hz, 2 H, 9-H), 2.61 (s, 3 H,
3
2
3
22-H), 2.72 (m, 1 H, 6-H), 2.98 (dd, J16a,16b = 13.7, J16a,15
=
2
3
7.7 Hz, 1 H, 16-Ha), 3.12 (dd, J16b,16a = 13.7, J16b,15 = 7.3 Hz, 1
3
3
H, 16-Hb), 4.35 (d, J2,6 = 8.4 Hz, 1 H, 2-H), 4.50 (dd, J15,16a
=
3J15,16b = 7.5 Hz, 1 H, 15-H), 7.10–7.12 (m, 3 H, 11-H, 13-H), 7.16
purified by flash chromatography (dichloromethane/methanol, (m, 1 H, 20-H), 7.20–7.27 (m, 6 H, 12-H, 18-H, 19-H) ppm. 13C
98:2) to yield peptide 8b (900 mg, 1.50 mmol, 81%, Ͼ95% ds) as a
white solid; m.p. 189–192 °C. TLC: Rf = 0.27 (dichloromethane/
methanol, 98:2); [α]2D0 = –8.4 (c = 1.0, CHCl3, Ͼ95% ds). 1H NMR
(CDCl3): δ = 1.40 (s, 9 H, 10-H), 1.43–1.49 (m, 3 H, 12-Ha, 13-H),
NMR (MeOD): δ = 26.3 (q, C-22), 28.8 (q, C-5), 29.7, 29.8 (2 t,
C-7, C-8), 36.7 (t, C-9), 38.7 (t, C-16), 49.6 (d, C-6), 56.4 (d, C-2),
56.6 (d, C-15), 80.7 (s, C-4), 126.8 (d, C-13), 127.8 (d, C-20), 129.3,
129.5, 130.2 (4 d, C-11, C-12, C-18, C-19), 138.7 (s, C-17), 143.4
1.60 (m, 1 H, 12-Hb), 2.45 (t, 3J14,13 = 7.1 Hz, 2 H, 14-H), 2.65 (m, (s, C-10), 157.9 (s, C-3), 173.4 (s, C-22), 174.6 (s, C-14), 175.1 (s,
3
3 H, 11-H), 2.68 (d, J22,NH = 4.8 Hz, 3 H, 22-H), 3.03 (m, 2 H, C-1) ppm. HRMS (CI): calcd. for C28H36N3O5 [M – OH]+
2
23-H), 4.48 (br. s, 1 H, 7-H), 4.52 (m, 1 H, 20-H), 5.11 (d, J5a,5b 494.2655; found 494.2643. C28H37N3O6 (511.61): calcd. C 65.73, H
2
= 12.2 Hz, 1 H, 5-Ha), 5.17 (d, J5b,5a = 12.2 Hz, 1 H, 5-Hb), 5.37 7.29, N 8.21; found C 65.63, H 7.36, N 7.59.
3
(d, JNH,7 = 7.2 Hz, 1 H, NH), 5.92 (br. s, 1 H, NH), 6.14 (d,
N-Methyl-(R)-2-[(R)-2-(benzyloxyamino)-1-(tert-butoxycarbonyl-
amino)-2-oxoethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (11a):
N-Methylmorpholine (56 μL, 0.53 mmol) and isobutyl chloro-
formate (71 μL, 0.53 mmol) were added to a solution of acid 10
(267 mg, 0.52 mmol) in dry THF (25 mL) at –20 °C. After 20 min,
O-benzylhydroxylamine (172 mg, 1.38 mmol) was added dropwise
and the reaction mixture was warmed to room temperature (18 h).
3
3JNH,20 = 7.2 Hz, 1 H, NH), 7.06 (d, J16,17 = 7.0 Hz, 2 H, 16-H),
7.12–7.23 (m, 3 H, 18-H, 25-H), 7.25–7.30 (m, 5 H, 17-H, 26-H,
27-H), 7.32–7.37 (m, 5 H, 1-H, 2-H, 3-H) ppm. 13C NMR (CDCl3):
δ = 26.1 (q, C-22), 28.0 (t, C-12), 28.2 (q, C-10), 28.9 (t, C-13),
35.5 (t, C-14), 38.0 (t, C-23), 49.3 (d, C-11), 54.7 (d, C-20), 54.8 (d,
C-7), 67.5 (t, C-5), 80.4 (s, C-9), 125.9 (d, C-18), 127.0 (d, C-27),
128.3, 128.3, 128.5, 128.5, 128.6, 128.7, 129.1 (7 d, C-1, C-2, C-3,
The solvent was removed in vacuo and the residue was washed with
C-16, C-17, C-25, C-26), 135.1 (s, C-4), 136.7 (s, C-24), 141.5 (s, C-
dichloromethane and diethyl ether to yield 11a (290 mg,
0.47 mmol, 90%) as a white solid; m.p. 216–218 °C. TLC: Rf = 0.27
15), 155.4 (s, C-8), 170.9 (2 s, C-19, C-21), 171.8 (s, C-6) ppm. No
signals of the S,S,S diastereomer were detected by NMR spec-
(dichloromethane/methanol, 98:2); [α]2D0 = +3.6 (c = 1.0, DMF).
troscopy. HRMS (CI): calcd. for C35H44N3O6 [M + H]+ 602.3231;
1H NMR ([D6]DMSO): δ = 1.30–1.43 (m, 13 H, 13-H, 10-H, 12-
found 602.3241. C35H43N3O6 (601.74): calcd. C 69.86, H 7.20, N
H), 2.42 (m, 2 H, 14-H), 2.52–2.61 (m, 4 H, 11-H, 22-H), 2.85 (dd,
6.98; found C 69.89, H 7.21, N 6.96.
2
3
3J23a,23b = 7.6, J23a,20 = 6.0 Hz, 1 H, 23-Ha), 2.95 (dd, J23b,23a
=
=
2
3
3
tert-Butyl (3R,4R)-1-[(S)-1-(Methylamino)-1-oxo-3-phenylpropan-2- 7.6, J23b,20 = 6.0 Hz, 1 H, 23-Hb), 4.11 (dd, J7,11 = 9.0, J7,NH
yl]-2,5-dioxo-4-(3-phenylpropyl)pyrrolidin-3-ylcarbamate (9): A
LiOH solution (1 m, 0.19 mL, 0.19 mmol) was added dropwise to 1 H, 5-Ha), 4.70 (d, J5b,5a = 10.6 Hz, 1 H, 5-Hb), 6.88 (d, JNH,7
a solution of peptide 8a (94.0 mg, 0.18 mmol) in THF (5 mL) at = 9.0 Hz, 1 H, NH), 7.08–7.25 (m, 10 H, 16-H, 17-H, 18-H, 25-H,
2
9.0 Hz, 1 H, 7-H), 4.39 (m, 1 H, 20-H), 4.62 (d, J5a,5b = 10.6 Hz,
2
3
0 °C. After stirring for 2 h at this temperature, the reaction mixture
was quenched with 1 m KHSO4 (5 mL) and extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
with Na2SO4 and concentrated in vacuo. After purification by flash
chromatography (hexanes/ethyl acetate, 1:1) imide 9 (70.1 mg,
0.14 mmol, 78 %) was obtained as a colourless solid; m.p. 174–
175 °C. TLC: Rf = 0.29 (hexanes/ethyl acetate, 1:1). 1H NMR
(CDCl3): δ = 1.12–1.31 (m, 3 H, 9-H, 8-Ha), 1.41–1.49 (m, 10 H,
1-H, 8-Hb), 2.46 (t, 3J10,9 = 7.0 Hz, 2 H, 10-H), 2.76–2.80 (m, 4 H,
26-H, 27-H), 7.34–7.36 (m, 5 H, 1-H, 2-H, 3-H), 7.85 (br. s, 1 H,
NH), 8.12 (d, 3JNH,20 = 7.9 Hz, 1 H, NH), 11.10 (s, 1 H, NH) ppm.
13C NMR ([D6]DMSO): δ = 25.5 (q, C-22), 27.9 (t, C-12), 28.1 (t,
C-13), 28.2 (q, C-10), 35.2 (t, C-14), 37.3 (t, C-23), 47.5 (d, C-11),
53.4 (d, C-7), 54.3 (d, C-20), 76.9 (t, C-5), 78.3 (s, C-9), 125.6 (d,
C-18), 126.2 (d, C-27), 128.1, 128.2, 128.2, 128.3 (5 d, C-1, C-16,
C-17, C-25, C-26), 128.8, 129.0 (2 d, C-2, C-3), 135.8 (s, C-4), 137.9
(s, C-24), 142.1 (s, C-15), 155.2 (s, C-8), 167.7 (s, C-6), 171.3, 171.8
(2 s, C-19, C-21) ppm. HRMS (CI): calcd. for C28H36N3O5 [M –
C7H8NO]+ 494.2655; found 494.2660. C35H44N4O6 (616.74): calcd.
C 68.16, H 7.19, N 9.08; found C 67.61, H 7.17, N 8.94.
3
3
7-H, 17-H), 3.20 (dd, J4,NH = 7.0, J4,7 = 4.9 Hz, 1 H, 4-H), 3.40
2
3
(dd, J18a,18b = 14.2, J18a,15 = 12.6 Hz, 1 H, 18-Ha), 3.66 (dd,
2J18b,18a = 14.2, J18b,15 = 5.0 Hz, 1 H, 18-Hb), 5.03 (dd, J15,18a
=
3
3
N-Methyl-(R)-2-[(R)-2-(benzyloxyamino)-1-(2-hydroxyacetyl-
amino)-2-oxoethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (11b):
HCl in dioxane (4 m, 300 μL, 1.20 mmol) was added to 11a (41 mg,
66 μmol) at room temperature and the reaction mixture was stirred
for 30 min before it was concentrated in vacuo. The residue was
dissolved in dry DMF (2 mL) and glycolic acid (7 mg, 92 μmol)
and TBTU (28 mg, 87 μmol) were added. After cooling to 0 °C,
NEt3 (26 μL, 180 μmol) was added and the reaction mixture was
warmed to room temperature overnight. The solvent was removed
in vacuo and the residue was washed with dichloromethane to yield
11b (15 mg, 26 μmol, 40%) as a white solid; m.p. 215–218 °C (dec.);
[α]2D0 = +2.1 (c = 0.5, DMF). 1H NMR ([D6]DMSO): δ = 1.29–
1.52 (m, 4 H, 11-H, 12-H), 2.41 (m, 2 H, 13-H), 2.60 (m, 3 H, 26-
H), 2.64 (m, 1 H, 10-H), 2.85 (dd, 2J20a,20b = 13.2, 3J20a,19 = 7.8 Hz,
3
3
12.6, J15,18b = 5.0 Hz, 1 H, 15-H), 5.44 (d, JNH,4 = 6.6 Hz, 1 H,
NH), 6.95–7.13 (m, 8 H, Ar-H, NH), 7.19–7.31 (m, 3 H, Ar-
H) ppm. 13C NMR (CDCl3): δ = 26.4 (q, C-17), 27.3 (t, C-9), 28.2
(q, C-1), 28.7 (t, C-8), 33.3 (t, C-18), 35.5 (t, C-10), 46.4 (d, C-7),
54.9 (d, C-4), 55.4 (d, C-15), 82.0 (s, C-2), 126.1, 126.7, (2 d, C-14,
C-22), 128.4, 128.8, (2 d, C-12, C-13, C-20, C-21), 137.2 (s, C-19),
141.2 (s, C-11), 155.9 (s, C-3), 168.1, 174.5, 176.1 (3 s, C-5, C-6, C-
16) ppm. HRMS (CI): calcd. for C28H36N3O5 [M + H]+ 494.2655;
found 494.2650.
(2R,3R)-2-(tert-Butoxycarbonylamino)-3-[(S)-1-(methylamino)-1-
oxo-3-phenylpropan-2-ylcarbamoyl]-6-phenylhexanoic Acid (10): A
solution of peptide 8b (208 mg, 0.35 mmol) in dry THF (5 mL) was
hydrogenated with Pd/C (10%, 23 mg) until TLC showed comple-
tion of the reaction. The Pd/C was filtered off and the filtrate was
concentrated in vacuo. The crude product was purified by flash
chromatography (ethyl acetate/acetic acid, 99:1) to yield acid 10
(160 mg, 0.31 mmol, 90%) as a white solid; m.p. 171–173 °C. TLC:
Rf = 0.35 (ethyl acetate/acetic acid, 99:1); [α]2D0 = +3.1 (c = 0.7,
2
3
1 H, 20-Ha), 2.97 (dd, J20b,20a = 13.3, J20b,19 = 6.2 Hz, 1 H, 20-
3
Hb), 3.83 (d, J9,OH = 4.6 Hz, 2 H, 9-H), 4.42–4.49 (m, 2 H, 7-H,
19-H), 4.66 (d, J5a,5b = 10.6 Hz, 1 H, 5-Ha), 4.71 (d, J5b,5a
2
2
=
10.6 Hz, 1 H, 5-Hb), 5.54 (br. s, 1 H, OH), 7.10–7.26 (m, 10 H, 15-
H, 16-H, 17-H, 22-H, 23-H, 24-H), 7.32–7.40 (m, 5 H, 1-H, 2-H,
Eur. J. Org. Chem. 2012, 567–575
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
573

J. L. Burkhart, B. Diehl, M. J. Schmitt, U. Kazmaier
FULL PAPER
3
3-H), 7.62 (d, JNH,7 = 8.6 Hz, 1 H, NH), 7.83 (br. s, 1 H, NH),
(8 d, C-1, C-2, C-3, C-11, C-18, C-19, C-27, C-28), 133.9 (s, C-9),
135.7 (s, C-4), 137.9 (s, C-26), 141.9 (s, C-17), 166.4 (s, C-8), 167.4
3
8.14 (d, JNH,19 = 7.5 Hz, 1 H, NH), 11.22 (br. s, 1 H, NH) ppm.
13C NMR ([D6]DMSO): δ = 25.4 (q, C-26), 27.4 (t, C-11), 28.1 (t, (s, C-6), 171.3, 171.9 (2 s, C-21, C-23) ppm. HRMS (CI): calcd. for
C-12), 35.0 (t, C-13), 37.3 (t, C-20), 47.6 (d, C-10), 51.2 (d, C-7),
54.1 (d, C-19), 61.1 (t, C-9), 76.8 (t, C-5), 125.5 (d, C-17), 126.1 (d,
C-24), 128.0, 128.1, 128.2, 128.3 (5 d, C-1, C-15, C-16, C-22, C-
23), 128.8, 128.9 (2 d, C-2, C-3), 135.6 (s, C-4), 137.8 (s, C-21),
141.9 (s, C-14), 166.9 (s, C-6), 171.0, 171.3, 171.5 (3 s, C-8, C-18,
C-25) ppm. HRMS (CI): calcd. for C25H30N3O5 [M – C7H8NO]+
452.2186; found 452.2185.
C29H32N3O3 [M – C8H9NO]+ 470.2444; found 470.2451.
N-Methyl-(R)-2-[(R)-2-(hydroxyamino)-1-(tert-butoxycarbonyl-
amino)-2-oxoethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (1a):
A solution of 11a (150 mg, 0.24 mmol) in dry DMF (2 mL) was
hydrogenated with Pd/C (10%, 25 mg) until TLC showed comple-
tion of the reaction. The Pd/C was filtered off and the filtrate was
concentrated in vacuo. The crude product was washed with meth-
anol and diethyl ether to yield hydroxamic acid 1a (105 mg,
0.20 mmol, 90%) as a white solid; m.p. 245–247 °C; [α]2D0 = –5.8 (c
N-Methyl-(R)-2-[(R)-2-(benzyloxyamino)-1-(acetylamino)-2-oxo-
ethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (11c): HCl
in dioxane (4 m, 1.0 mL, 4.0 mmol) was added to 11a (97 mg,
0.16 mmol) at room temperature and the reaction mixture was
stirred for 30 min before it was concentrated in vacuo. The
residue was stirred in dry DMF (3 mL) at 0 °C and NEt3 (53 μL,
0.38 mmol) was added followed by acetyl chloride (13 μL,
0.18 mmol). The reaction mixture was stirred overnight at room
temperature. The solvent was removed in vacuo and the residue
was washed with dichloromethane to yield 11c (44 mg, 79 μmol,
50%) as a white solid; m.p. 234–235 °C; [α]2D0 = +24.2 (c = 0.8,
1
= 0.5, DMF). H NMR ([D6]DMSO): δ = 1.21–1.52 (m, 13 H, 5-
H, 7-H, 8-H), 2.40 (m, 2 H, 9-H), 2.52–2.60 (m, 4 H, 6-H, 22-H),
2
3
2.86 (dd, J16a,16b = 13.6, J16a,15 = 7.9 Hz, 1 H, 16-Ha), 2.99 (dd,
3
3
2J16b,16a = 13.7, J16b,15 = 6.2 Hz, 1 H, 16-Hb), 4.14 (dd, J2,6
=
=
3J2,NH = 8.6 Hz, 1 H, 2-H), 4.37 (m, 1 H, 15-H), 6.76 (d, JNH,2
3
8.8 Hz, 1 H, NH), 7.08–7.20 (m, 10 H, 11-H, 12-H, 13-H, 18-H,
3
19-H, 20-H), 7.83 (br. s, 1 H, NH), 8.06 (d, JNH,15 = 7.8 Hz, 1 H,
NH), 8.82 (br. s, 1 H, OH), 10.46 (br. s, 1 H, NH) ppm. 13C NMR
([D6]DMSO): δ = 25.4 (q, C-22), 27.7 (t, C-7), 28.1 (qt, C-5, C-8),
35.1 (t, C-9), 37.1 (t, C-16), 47.7 (d, C-6), 53.3 (d, C-2), 54.2 (d, C-
15), 78.1 (s, C-4), 125.5 (d, C-13), 126.1 (d, C-20), 128.0, 128.1,
128.9 (4 d, C-11, C-12, C-18, C-19), 137.9 (s, C-17), 142.0 (s, C-
10), 155.0 (s, C-3), 167.4 (s, C-1), 171.1 (s, C-14), 171.6 (s, C-
21) ppm. HRMS (CI): calcd. for C28H39N4O5 [M – O + H]+
511.2876; found 511.2871.
1
DMSO). H NMR ([D6]DMSO): δ = 1.23–1.27 (m, 4 H, 11-H, 12-
H), 1.82 (s, 3 H, 9-H), 2.34–2.56 (m, 5 H, 13-H, 21-H), 2.60 (m, 1
2
3
H, 10-H), 2.84 (dd, J22a,22b = 13.7, J22a,19 = 7.8 Hz, 1 H, 22-Ha),
2
3
2.92 (dd, J22b,22a = 13.4, J22b,19 = 6.1 Hz, 1 H, 22-Hb), 4.26–4.47
2
(m, 2 H, 7-H, 19-H), 4.64 (d, J5a,5b = 10.6 Hz, 1 H, 5-Ha), 4.69
2
(d, J5b,5a = 10.6 Hz, 1 H, 5-Hb), 7.08–7.25 (m, 10 H, 15-H, 16-H,
17-H, 24-H, 25-H, 26-H), 7.35 (br. s, 5 H, 1-H, 2-H, 3-H), 7.80 (q,
3JNH,21 = 4.0 Hz, 1 H, NH), 8.01 (d, JNH,7 = 8.9 Hz, 1 H, NH),
3
N-Methyl-(R)-2-[(R)-2-(hydroxyamino)-1-(2-hydroxyacetylamino)-
2-oxoethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (1b): A solu-
tion of 11b (51 mg, 89 μmol) in dry DMF (3 mL) was hydrogenated
with Pd/C (10%, 10 mg) until completion of the reaction. The Pd/
C was filtered off and the filtrate was concentrated in vacuo. The
crude product was triturated with methanol to yield hydroxamic
acid 1b (36 mg, 74 μmol, 84%) as a white solid; m.p. 175–180 °C
(dec.); [α]2D0 = –5.8 (c = 0.6, DMF). 1H NMR ([D6]DMSO): δ =
1.24–1.53 (m, 4 H, 6-H, 7-H), 2.39 (m, 2 H, 8-H), 2.51 (m, 3 H,
3
8.13 (d, JNH,19 = 7.7 Hz, 1 H, NH), 11.10 (s, 1 H, NH) ppm. 13C
NMR ([D6]DMSO): δ = 22.4 (q, C-9), 25.4 (q, C-21), 27.8 (t, C-
11), 28.1 (t, C-12), 35.0 (t, C-13), 37.3 (t, C-22), 47.3 (d, C-10), 51.4
(d, C-7), 54.1 (d, C-19), 76.7 (t, C-5), 125.5 (d, C-17), 126.1 (d, C-
26), 128.0, 128.1, 128.2, 128.7, 128.9 (7 d, C-1, C-2, C-3, C-15, C-
16, C-24, C-25), 125.7 (s, C-4), 137.8 (s, C-23), 142.0 (s, C-14),
167.4 (s, C-6), 169.2 (s, C-8), 171.1, 171.6 (2 s, C-18, C-20) ppm.
HRMS (CI): calcd. for C24H30N3O3 [M – C8H8NO2]+ 408.2287;
found 408.2270.
2
3
21-H), 2.63 (m, 1 H, 5-H), 2.87 (dd, J15a,15b = 13.2, J15a,14
=
2
3
7.3 Hz, 1 H, 15-Ha), 3.00 (dd, J15b,15a = 13.4, J15b,14 = 5.8 Hz, 1
H, 15-Hb), 3.82 (d, J4,OH = 5.2 Hz, 1 H, 4-H), 4.40 (m, 1 H, 14-
H), 4.40 (dd, J2,5 = J2,NH = 8.3 Hz, 1 H, 2-H), 5.50 (t, JOH,4
N-Methyl-(R)-2-[(R)-2-(benzyloxyamino)-1-(benzoylamino)-2-oxo-
ethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (11d): HCl
in dioxane (4 m, 2.0 mL, 8.0 mmol) was added to 11a (150 mg,
0.24 mmol) at room temperature and the reaction mixture was
stirred for 30 min before it was concentrated in vacuo. The
residue was stirred in dry DMF (4 mL) at 0 °C and NEt3 (82 μL,
0.59 mmol) was added followed by benzoyl chloride (33 μL,
0.28 mmol). The reaction mixture was stirred overnight at room
temperature. The solvent was removed in vacuo and the residue
was washed with dichloromethane to yield 11d (82 mg, 0.13 mmol,
54%) as a white solid; m.p. 241–242 °C; [α]2D0 = +14.8 (c = 1.1,
DMSO). 1H NMR ([D6]DMSO): δ = 1.30 (m, 2 H, 15-H), 1.47 (m,
3
3
3
3
=
5.3 Hz, 1 H, OH), 7.09–7.26 (m, 10 H, 10-H, 11-H, 12-H, 17-H,
3
18-H, 19-H), 7.61 (d, JNH,2 = 8.9 Hz), 7.84 (br. s, 1 H, NH), 6.08
3
(d, JNH,14 = 7.7 Hz, 1 H, NH), 8.91 (br. s, 1 H, OH), 10.60 (br. s,
1 H, NH) ppm. 13C NMR ([D6]DMSO): δ = 25.5 (q, C-21), 27.5
(t, C-6), 28.3 (t, C-7), 35.1 (t, C-8), 37.2 (t, C-15), 47.8 (d, C-5),
51.3 (d, C-2), 54.2 (d, C-14), 61.2 (t, C-4), 125.5 (d, C-12), 126.1
(d, C-19), 128.0, 128.1, 128.9 (4 d, C-10, C-11, C-17, C-18), 138.0
(s, C-16), 142.0 (s, C-9), 166.7 (s, C-1), 171.0, 171.1, 171.3 (3 s, C-
3, C-13, C-20) ppm. HRMS (CI): calcd. for C25H32N4O6
[M + H]+ 485.2400; found 485.2432.
3
2 H, 14-H), 2.40 (m, 2 H, 16-H), 2.54 (d, J24,NH = 4.4 Hz, 3 H,
24-H), 2.82 (m, 1 H, 13-H), 2.88 (dd, J25a,25b = 13.8, J25,22
2
3
=
N-Methyl-(R)-2-[(R)-2-(hydroxyamino)-1-(acetylamino)-2-oxoethyl]-
8.4 Hz, 1 H, 25-Ha), 2.88 (dd, J25a,25b = 13.8, J25b,22 = 8.4 Hz, 1 5-phenylpentanoyl-(S)-phenylalanineamide (1c): A solution of 11c
2
3
H, 25-Ha), 3.01 (dd, 2J25b,25a = 13.7, 3J25a,22 = 5.8 Hz, 1 H, 25-Hb),
(35 mg, 63 μmol) in dry DMF (14 mL) was hydrogenated with Pd/
4.42 (m, 1 H, 22-H), 4.65–4.72 (m, 3 H, 5-H, 7-H), 7.05–7.19 (m, C (10%, 8 mg). After completion of the reaction the Pd/C was fil-
10 H, 18-H, 19-H, 20-H, 27-H, 28-H, 29-H), 7.31–7.38 (m, 5 H, 1- tered off and the filtrate was concentrated in vacuo. The crude
H, 2-H, 3-H), 7.46 (m, 2 H, 11-H), 7.54 (m, 1 H, 12-H), 7.82 (d,
product was triturated with methanol to yield hydroxamic acid 1c
3
3J10,11 = 7.3 Hz, 1 H, 10-H), 7.88 (q, JNH,24 = 4.5 Hz, 1 H, NH), (26 mg, 55 μmol, 88%) as a white solid; m.p. 208–210 °C (dec.);
8.22 (d, JNH,22 = 7.8 Hz, 1 H, NH), 8.46 (d, 3JNH,7 = 8.5 Hz, 1 H, [α]2D0 = +12.8 (c = 0.6, DMSO). H NMR ([D6]DMSO): δ = 1.28
3
1
NH), 11.14 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO): δ = 25.5 (m, 2 H, 7-H), 1.40 (m, 2 H, 6-H), 1.82 (s, 3 H, 4-H), 2.37 (m, 1
3
(q, C-24), 27.8 (t, C-15), 28.1 (t, C-14), 35.0 (t, C-16), 37.1 (t, C- H, 8-Ha), 2.44 (m, 1 H, 8-Hb), 2.51 (d, J21,NH = 5.0 Hz, 3 H, 21-
25), 47.0 (d, C-13), 52.4 (d, C-7), 54.3 (d, C-22), 76.8 (t, C-5), 125.5
(d, C-20), 126.1 (d, C-29), 127.5 (d, C-10), 128.1, 128.2, 128.8, 128.9
3
H), 2.60 (m, 1 H, 5-H), 2.85 (dd, 2J15a,15b = 13.7, J15a,14 = 7.9 Hz,
2
3
1 H, 15-Ha), 2.98 (dd, J15b,15a = 13.7, J15b,14 = 6.2 Hz, 1 H, 15-
574
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 567–575

MMP Inhibitors by Chelate Claisen Rearrangement
3
3
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a) R. E. Babine, S. L. Bender, Chem. Rev. 1997, 97, 1359–1472;
b) J. F. Fisher, S. Mobashery, Cancer Metastasis Rev. 2006, 25,
115–136; c) Q. X. A. Sang, Y. H. Jin, R. G. Newcomer, S. C.
Monroe, X. X. Fang, R. Hurst, S. Lee, Q. Cao, M. T. A.
Schwartz, Curr. Top. Med. Chem. 2006, 6, 289–316; d) S. P.
Gupta, Chem. Rev. 2007, 107, 3042–3087.
Hb), 4.37 (m, 1 H, 14-H), 4.49 (dd, J2,5 = J2,NH = 9.1 Hz, 1 H,
2-H), 7.08–7.25 (m, 10-H, 11-H, 12-H, 17-H, 18-H, 19-H), 7.82 (q,
3JNH,21 = 4.5 Hz, 1 H, NH), 8.00 (d, JNH,2 = 9.2 Hz, 1 H, NH),
3
3
8.12 (d, JNH,14 = 7.7 Hz, 1 H, NH), 8.82 (s, 1 H, OH), 10.51 (s, 1
H, NH) ppm. 13C NMR ([D6]DMSO): δ = 22.4 (q, C-4), 25.4 (q,
C-21), 27.8 (t, C-7), 28.1 (t, C-6), 35.0 (t, C-8), 37.1 (t, C-15), 47.6
(d, C-5), 51.3 (d, C-2), 54.2 (d, C-14), 125.4 (d, C-12), 126.0 (d, C-
19), 128.0, 128.1, 128.9 (4 d, C-10, C-11, C-17, C-18), 137.9 (s, C-
16), 142.0 (s, C-9), 167.1 (s, C-1), 169.1 (s, C-3), 171.1 (s, C-20),
171.6 (s, C-13) ppm. HRMS (CI): calcd. for C25H30N3O4 [M –
NHOH]+ 436.2237; found 436.2235.
[7]
[8]
M. Whittaker, C. D. Floyd, P. Brown, A. J. Gearing, Chem.
Rev. 1999, 99, 2735–2776.
a) B. Davies, P. D. Brown, N. East, M. J. Crimmin, F. R. Balk-
will, Cancer Res. 1993, 53, 2087–2091; b) E. C. Kohn, L. A.
Liotta, Cancer Res. 1995, 55, 1856–1862.
A. Miller, M. Askew, R. P. Beckett, C. L. Bellamy, E. A. Bone,
R. E. Coates, A. H. Davidson, A. H. Drummond, P. Huxley,
F. M. Martin, L. Saroglou, A. J. Thompson, S. E. van Dijk, M.
Whittaker, Bioorg. Med. Chem. Lett. 1997, 7, 193–197.
a) U. Kazmaier, S. Maier, F. L. Zumpe, Synlett 2000, 1523–
1535; b) J. Deska, U. Kazmaier, Curr. Org. Chem. 2008, 12,
355–385.
a) M. Pohlman, U. Kazmaier, Org. Lett. 2003, 5, 2631–2633;
b) B. Mendler, U. Kazmaier, Org. Lett. 2005, 7, 1715–1718; c)
B. Mendler, U. Kazmaier, V. Huch, M. Veith, Org. Lett. 2005,
7, 2643–2646; d) C. Schmidt, U. Kazmaier, Org. Biomol. Chem.
2008, 6, 4643–4648.
a) U. Kazmaier, Curr. Org. Chem. 2003, 7, 317–328; b) U. Kaz-
maier, T. Lindner, Angew. Chem. 2005, 117, 3368–3371; Angew.
Chem. Int. Ed. 2005, 44, 3303–3306; c) U. Kazmaier, J. Deska,
A. Watzke, Angew. Chem. 2006, 118, 4973–4976; Angew. Chem.
Int. Ed. 2006, 45, 4855–4858; d) J. Deska, U. Kazmaier, Angew.
Chem. 2007, 119, 4654–4657; Angew. Chem. Int. Ed. 2007, 46,
4570–4573; e) U. Kazmaier, M. Pohlman, Synlett 2004, 623–
626.
a) U. Kazmaier, A. Krebs, Angew. Chem. 1995, 107, 2213–2214;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2012–2013; b) U. Kaz-
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Maier, Tetrahedron 1996, 52, 941–954; d) A. Krebs, U. Kazma-
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bigs Ann./Recueil 1997, 285–295.
a) U. Kazmaier, J. Org. Chem. 1994, 59, 6667–6670; b) U. Kaz-
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[9]
N-Methyl-(R)-2-[(R)-2-(hydroxyamino)-1-(benzoylamino)-2-oxo-
ethyl]-5-phenylpentanoyl-(S)-phenylalanineamide (1d): A solution of
11d (39 mg, 63 μmol) in dry DMF (14 mL) was hydrogenated with
Pd/C (10%, 8 mg), the Pd/C was filtered off and the filtrate was
concentrated in vacuo. The crude product was triturated with
methanol to yield hydroxamic acid 1d (25 mg, 47 μmol, 75%) as a
white solid; m.p. 225–228 °C (dec.); [α]2D0 = +7.9 (c = 0.9, DMSO).
1H NMR ([D6]DMSO): δ = 1.29 (m, 2 H, 7-H), 1.48 (m, 2 H, 6-
H), 2.40 (m, 2 H, 8-H), 2.53 (d, 3J21,NH = 3.7 Hz, 3 H, 21-H), 2.78
[10]
[11]
2
(m, 1 H, 5-H), 2.89 (m, 1 H, 15-Ha), 2.98 (dd, J15b,15a = 13.6,
3
[12]
3J15b,14 = 5.3 Hz, 1 H, 15-Hb), 4.40 (m, 1 H, 14-H), 4.73 (dd, J2,5
= 3J2,NH = 8.7 Hz, 1 H, 2-H), 7.05–7.20 (m, 10-H, 11-H, 12-H, 17-
H, 18-H, 19-H), 7.46 (m, 2 H, 23-H), 7.54 (m, 1 H, 24-H), 7.82 (d,
3J22,23 = 7.2 Hz, 1 H, 22-H), 7.91 (q, JNH,21 = 3.1 Hz, 1 H, NH),
3
8.21 (d, JNH,14 = 7.7 Hz, 1 H, NH), 8.41 (d, 3JNH,2 = 8.4 Hz, 1 H,
3
NH), 8.87 (s, 1 H, OH), 10.57 (s, 1 H, NH) ppm. 13C NMR
([D6]DMSO): δ = 25.5 (q, C-21), 27.9 (t, C-7), 28.1 (t, C-6), 35.0
(t, C-8), 37.0 (t, C-15), 47.3 (d, C-5), 52.3 (d, C-2), 54.3 (d, C-14),
125.4 (d, C-12), 126.1 (d, C-19), 127.5 (d, C-22), 128.0, 128.1, 128.9
(5 d, C-10, C-11, C-17, C-18, C-23), 131.3 (d, C-24), 131.3 (s, C-
4), 138.1 (s, C-16), 141.9 (s, C-9), 166.3 (s, C-1), 167.2 (s, C-3),
171.2, 171.8 (2 s, C-13, C-20) ppm. HRMS (CI): calcd. for
C30H32N3O4 [M – NHOH]+ 498.2393; found 498.2366.
[13]
[14]
Acknowledgments
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Received: September 9, 2011
Published Online: November 22, 2011
Eur. J. Org. Chem. 2012, 567–575
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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