The carbenoid approach to peptide synthesis

Article abstract of DOI:10.1002/1521-3765(20000616)6:12<2160::AID-CHEM2160>3.0.CO;2-Y

A different approach to the synthesis of dipeptides is described based on the formation of the NHCHR¹CONH-CHR-CO bond by carbenoid N-H insertion, rather than the formation of the peptide bond itself. Thus decomposition of triethyl diazophosphon

Full text of DOI:10.1002/1521-3765(20000616)6:12<2160::AID-CHEM2160>3.0.CO;2-Y

FULL PAPER
The Carbenoid Approach to Peptide Synthesis
Richard T. Buck,[a] Paul A. Clarke,[a] Diane M. Coe,[b] Martin J. Drysdale,[b] Leigh Ferris,[c]
David Haigh,[d] Christopher J. Moody,*[a] Neil D. Pearson,[d] and Elizabeth Swann[a]
Abstract: A different approach to the
synthesis of dipeptides is described
based on the formation of the
phosphonates 9. Subsequent Wads-
worth ± Emmons reaction of 9 with al-
dehydes in the presence of DBU gives
dehydro dipeptides 10. The reaction has
been extended to a simple two-step
procedure, without the isolation of the
intermediate phosphonate, for conver-
sion of a range of amino acid amides 11
into dehydro dipeptides 12 and to an N-
methylamide 11h, and for conversion of
a dipeptide to tripeptide (13 ! 14). Di-
rect conversion, by using methyl diazo-
phenylacetate, of amino acid amides to
phenylglycine-containing dipeptides 19
proceeds in good chemical yield, but
with poor diastereoselectivity.
1
2
À
NHCHR CONH CHR CO bond by
À
carbenoid N H insertion, rather than
the formation of the peptide bond itself.
Thus decomposition of triethyl diazo-
phosphonoacetate catalysed by rhod-
ium(ii) acetate in the presence of N-pro-
tected amino acid amides 8 gives the
Keywords: amino acids ´ carbenoids
´ insertions ´ peptides ´ rhodium
Introduction
Peptides and proteins play a central role in all living
organisms, and hence the synthesis of such compounds has
emerged as a subject in its own right.[1] In fact, peptide
synthesis is so highly developed that chemists rarely, if ever,
consider any approach other than the formation of the amide
bond (Scheme 1, disconnection 1). We now report a new
approach to peptide synthesis that involves the formation of
Scheme 1. Alternative disconnections for dipeptides.
À
À
the CONH CHRCO bond by a metal-carbene N H insertion
reaction (Scheme 1, disconnection 2), and its application in
synthesis.
anilinoacetophenone and a-piperidinoacetophenone in 33%
and 80% yield, respectively.[2] Further copper-mediated
À
The N H insertion reactions of metallocarbenoids have
À
intermolecular N H carbenoid insertion reactions followed,
been known for some time. Early work by Yates involved the
copper/bronze-catalysed decomposition of diazoacetophe-
none in the presence of aniline or piperidine to give a-
but it was the 1974 report by Paulissen and co-workers, that
À
rhodium(ii) acetate was an effective catalyst for N H
insertion reactions of carbenoids, which stimulated much of
the subsequent work in this area.[3] In particular, following the
original report from the Merck group in 1978,[4] the intra-
[a] Prof. C. J. Moody, R. T. Buck, Dr. P. A. Clarke, Dr. E. Swann
School of Chemistry, University of Exeter
Stocker Road, Exeter, Devon EX4 4QD (UK)
Fax : (‡44)1392-263434
À
molecular rhodium-carbenoid insertion into a b-lactam N H
bond has become a standard synthetic route to a range of
bicyclic b-lactams.[5]
E-mail: c.j.moody@exeter.ac.uk
We have recently described the application of carbenoid
[b] Dr. D. M. Coe, Dr. M. J. Drysdale
À
N H insertion reactions in the preparation of a-amino acids,
GlaxoWellcome, Medicines Research Centre
Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY (UK)
a-aminophosphonates and phosphonoglycines (Scheme 2),[6, 7]
and therefore were attracted by the possibility of using such
[c] L. Ferris
Department of Chemistry, Loughborough University
Loughborough, Leicestershire LE11 3TU (UK)
À
N H insertions in a synthesis of dipeptides which, unusually,
does not rely on formation of the peptide bond itself.
[d] Dr. D. Haigh, Dr. N. D. Pearson
Two approaches that start from readily available N-
protected amino acid amides 1 were considered (Scheme 3,
Pg ˆ protecting group). The first was the use of diazoesters,
which would lead directly to dipeptides 2 (Scheme 3, path a).
Department of Medicinal Chemistry
SmithKline Beecham Pharmaceuticals
New Frontiers Science Park (North), Coldharbour Road
The Pinnacles, Harlow, Essex CM19 5AW (UK)
2160
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Chem. Eur. J. 2000, 6, No. 12

2160±2167
À
Scheme 2. Rhodium carbenoid N H insertion reactions in the synthesis of
amino acid and aminophosphonate derivatives.
À
Scheme 4. Carbenoid insertions into the N H bond of primary amides.
3,3,3-trifluoropropionate catalysed by rhodium(ii) acetate
(Scheme 4).[10] We now report the details of our new approach
to peptide synthesis,[11] concentrating on the preparation of
dehydro dipeptides 4 (Scheme 3b).
Results and Discussion
A range of N-protected a-amino acid amides was prepared
from the corresponding acids by using standard techniques;
the subsequent insertion reactions were initially carried out
on amino acids with simple alkyl side chains to prevent
À
competing carbenoid reactions. The key N H insertion
reaction was carried out by treating a mixture of the
N-protected amino acid amide 8 and triethyl diazophospho-
noacetate with a catalytic amount of rhodium(ii) acetate in
toluene, and resulted in the formation of the phosphonates 9.
Initial reactions were carried out in toluene under reflux, and
gave the phosphonates 9 in good yield (Table 1). However, at
these temperatures decomposition of the diazophosphonate
Scheme 3. Possible approaches to dipeptides using rhodium carbenoid
À
N H insertion reactions.
The second involves diazophosphonoacetate as the carbenoid
precursor, to give the phosphonates 3, Wadsworth ± Emmons
reaction of which leads to the dehydro dipeptide 4 (Scheme 3,
path b). Stereoselective hydrogenation of dehydro dipeptide 4
would, of course, provide an alternative route to the dipeptide
2 (R2 ˆ CH2R3).
À
appears to compete with N H insertion, and although the
product phosphonates 9 gave satisfactory spectroscopic data
À
they could never be obtained analytically pure. The N H
insertion reaction was completely regioselective in that no
À
À
Our initial work on the N H insertion reactions of amino
products resulting from insertion into the carbamate N H
À
acid amides employed methyl 2-diazo-3-oxobutanoate as the
bond or C H bonds were observed. Although related
À
carbenoid precursor. This resulted in a regioselective N H
phosphonates have been prepared by the synthesis of
the corresponding a-aminophosphonate, H2NCH(CO2R)-
PO(OR1)2, followed by standard peptide coupling[12, 13] this
new method has the advantage of simplicity.
insertion reaction to give the dipeptides 5, which were
subsequently dehydrated to the oxazoles 6 (Scheme 4).[8, 9]
In addition to our own work in the area, there is another
reported example of this approach that resulted in the
synthesis of the dipeptide Z-Phe-b,b,b-trifluoroAla-OMe 7
by reaction of N-Z-phenylalaninamide with methyl 2-diazo-
To complete the synthesis of dehydro dipeptides, the
phosphonates 9 were subjected to the Wadsworth ± Emmons
reaction with aldehydes. Although various protocols have
Chem. Eur. J. 2000, 6, No. 12
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C. J. Moody et al.
FULL PAPER
Table 1. Formation of phosphonates 9 from amides 8.
Table 2. Formation of dehydrodipeptides 10 from phosphonates 9.
.
Phos-
phonate
Pg
Z
R1
H
R2
Dehydro-dipeptide
Yield
[%]
Starting
amino acid
Amide
Pg
R
R1
Phosphonate
Yield
[%][a]
9a
9b
9e
9e
9e
Ph
Ph
Z-Gly-DPhe-OEt
10a 82
10b 88
10c 88
10d 80
Gly
Ala
Ala
Val
Leu
Pro
8a
8b
8c
8d
8e
8 f
Z
Boc
Z
Boc
Boc
Z
H
H
H
H
H
H
9a
9b
9c
9d
9e
9 f
81
88
80
80
82
80
Boc Me
Boc iBu Ph
Boc iBu iPr
Boc iBu Ar[a] Boc-Leu-DTrp(Boc)-OEt 10e 79
Boc-Ala-DPhe-OEt
Boc-Leu-DPhe-OEt
Boc-Leu-DLeu-OEt
Me
Me
iPr
iBu
À
[a] Arˆ N-Boc-indol-3-yl.
À
(CH2)3
[a] The phosphonates 9 could not be obtained analytically pure; yield refers
to material that is homogeneous by TLC and that gave satisfactory
spectroscopic data.
rhodium carbenoid on the aromatic rings of Phe, Tyr or Trp
was observed. However, in the case of Trp, indole-N-
protection was necessary to achieve a high yield in the
Wadsworth ± Emmons reaction. Use of N-Boc-methionin-
been developed for the synthesis of dehydro amino acid
derivatives by using the Wadsworth ± Emmons reaction, we
used the Schmidt method with 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as base.[14] This is highly Z selective, and gave the
corresponding Z-dehydro dipeptides 10 in good yield
(Table 2) with benzaldehyde, isobutyraldehyde, or N-Boc-
indole-3-carboxaldehyde as the carbonyl component.
À
amide failed to give any N H insertion product; the reaction
mixture immediately turned purple, presumably due to
catalyst poisoning.
The reaction sequence could be extended to include N-
methyl amides such as 11h, which gave the dehydro dipeptide
12h of an N-methyl amino acid (Scheme 5). Finally, in order
À
to demonstrate the selectivity of the carbenoid N H insertion
reaction, the dipeptide amide Boc-Ala-Leu-NH2 (13) was
There is no need to purify the phosphonates before carrying
À
out the subsequent olefination reaction. If the N H insertion
treated with trimethyl diazophosphonoacetate to give an
N H insertion product, which was immediately subjected to
Wadsworth ± Emmons reaction with benzaldehyde to give the
tripeptide Boc-Ala-Leu-DPhe-OMe (14) in 50% yield over
the two steps (Scheme 5).
The carbenoid approach to dipeptides was applied to the
synthesis of the dehydro dipeptide fragment of Mm-2 15
(Ar1 ˆ 3,4-dihydroxyphenyl), a blood pigment of the tunicate
Molgula manhattensis.[16] Although this compound has been
synthesized previously,[16] the projected disconnection
(Scheme 6) to the protected dehydro dipeptide 16 (Ar2 ˆ
3,4-dibenzyloxyphenyl) differs from the published strategy.
The phosphonate 17, prepared from N-Boc-leucinamide (8e)
reaction with trimethyl diazophosphonoacetate is carried out
over a longer period of time at a lower temperature
(dichloromethane, reflux), a cleaner reaction mixture ensues.
À
À
After a brief aqueous work-up, the N H insertion product can
be used directly in the Wadsworth ± Emmons reaction. In this
way, a range of amides 11 derived from Leu, Phe, Ser, Tyr and
Trp were converted into dehydro dipeptides 12 by using
benzaldehyde, isobutyraldehyde, N-Boc-indole-3-carboxalde-
hyde, acetaldehyde or acetone as the carbonyl component
(Table 3). In the case of Ser and Tyr, the side chain OH groups
had to be protected; without this O-protection the insertion
reaction was more complex, presumably as a result of
[15]
À
competing O H insertion.
No competing attack of the
Table 3. Formation of dehydro dipeptides 12 from amides 11.
Starting
Amide
Pg
R1
R2
R3
Dehydrodipeptide
Yield [%]
amino acid
Leu
Leu
Phe
Ser
Ser
Tyr
Trp
11a
11b
11c
11d
11d
11e
11 f
Z
Ac
iBu
iBu
CH2Ph
CH2OTBS[a]
CH2OTBS
CH2-C6H4-OTBS
CH2Ar[b]
Ph
Ph
H
H
H
H
Me
H
H
Z-Leu-DPhe-OMe
Ac-Leu-DPhe-OMe
Boc-Phe-DLeu-OMe
Boc-Ser(TBS)-DTrp(Boc)-OMe
Boc-Ser(TBS)-DVal-OMe
Boc-Tyr(TBS)-DLeu-OMe
Boc-Trp(Boc)-DAbu-OMe[c]
12a
12b
12c
12d
12e
12 f
12g
65
37
60
77
30
61
86
Boc
Boc
Boc
Boc
Boc
iPr
Ar[b]
Me
iPr
Me
[a] TBS ˆ tert-butyldimethylsilyl. [b] Arˆ N-Boc-indol-3-yl. [c] Abu ˆ 2-aminobutanoic acid.
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Chem. Eur. J. 2000, 6, No. 12

Peptide Synthesis
2160±2167
diastereoselectivity of the inser-
tion reaction for the formation
of 19a and 19b as 24% and
20% de, respectively. Hence,
this preliminary study shows
that, perhaps not surprisingly,
the existing stereocentre in the
amino acid amide 8 causes little
asymmetric induction in the
insertion reaction. This clearly
raises the question of the use of
À
chiral catalysts in the N H in-
sertion reaction. We and others
have explored a wide range of
chiral copper- and rhodium-
based catalysts for carbenoid
transformations, and although
to date there is only the report-
ed example of an intramolecu-
À
Scheme 5. N H Insertion/Wadsworth ± Emmons reaction sequence.
À
lar N H insertion reaction with
a chiral catalyst,[17] we are pursuing the use of such catalysts to
À
increase the stereoselectivity of the N H insertion reactions
that lead directly to dipeptides (Scheme 3a and Scheme 7).
Scheme 7. Synthesis of Boc-Ala-Phg-OMe and Boc-Val-Phg-OMe dipep-
tides.
À
In summary, we have shown that carbenoid N H insertion
reactions can be applied in a different approach to peptides
that does not involve the formation of the peptide bond itself;
whilst the method is unlikely to supplant traditional peptide
chemistry, we believe that it may find use in the synthesis of
peptide sequences that incorporate non-coded amino acids
such as N-methyl and dehydro derivatives.[18]
Scheme 6. Synthesis of the dehydro dipeptide fragment 16 of Mm-2.
and trimethyl phosphonoacetate in exactly the same way as its
triethyl analogue 9e, reacted readily with 3,4-dibenzyloxy-
benzaldehyde to give the required dipeptide 18 (Ar2 ˆ 3,4-
dibenzyloxyphenyl) as a single Z diastereomer. Hydrolysis of
ester 18 gave the required acid 16 in 95% yield (Scheme 6).
Having established the carbenoid-based route to dehydro
dipeptides (Scheme 3b), we briefly investigated the alterna-
tive route to dipeptides (Scheme 3a). Thus, N-Boc-Ala-NH2
(8b) and the valine-derived analogue 8d were treated with
methyl 2-diazophenylacetate in the presence of rhodium(ii)
Experimental Section
Commercially available reagents were used throughout without further
purification; solvents were dried by standard procedures. Light petroleum
refers to the fraction with b.p. 40 ± 608C and ether refers to diethyl ether.
Reactions were routinely carried out under
a nitrogen atmosphere.
Analytical thin-layer chromatography was carried out by using alumi-
nium-backed plates coated with Merck Kieselgel 60 GF254. Plates were
visualized under UV light (at 254 and/or 360 nm). Flash chromatography
was carried out using Merck Kieselgel 60 H silica or Matrex silica 60.
Fully characterized compounds were chromatographically homogeneous.
IR spectra were recorded in the range 4000 ± 600 cmÀ1 using a Nicolet
Magna FT-550 spectrometer. 1H and 13C NMR spectra were recorded using
Bruker 250, 300 and 400 MHz instruments (1H frequencies, corresponding
13C frequencies are 63, 75 and 100 MHz). High- and low-resolution mass
spectra were recorded on a Kratos HV3 instrument, or at the EPSRC Mass
Spectrometry Service (Swansea). Rotations were recorded on an Optical
Activity PolAAR 2001 polarimeter.
À
acetate. The N H insertion reaction proceeded chemoselec-
tively and gave the expected dipeptidesÐN-Boc-alanyl-
phenylglycine methyl ester 19a and its valine analogue
19bÐin 55% and 66% yield, respectively (Scheme 7). The
dipeptides 19 were formed as mixtures of diastereomers as
evidenced by the presence of two sets of signals in their
1H NMR spectra. By integration of the methyl ester singlets in
the 1H NMR spectra it was possible to determine the
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C. J. Moody et al.
FULL PAPER
N-Protected amino acid amides: These were prepared by published
methods for the racemization-free conversion of N-protected amino acids
into the corresponding amides.[19±21]
65.0 (d, J ˆ 6.7 Hz, CH2OP), 63.0, 54.5, 51.9 (d, J ˆ 133.6 Hz, CHP), 42.6,
29.5, 26.0, 24.2, 23.1, 17.5 (d, J ˆ 5.1 Hz, MeCH2OP), 15.3, 14.7; 31P NMR
‡
(101.3 MHz, CDCl3): d ˆ 16.9; MS (EI): m/z (%): 453 (100) [M‡H] , 397
‡
(42), 353 (10), 131 (47), 86 (49); (found: 453.2366 [M‡H] ; C19H38N2O8P
À
N H insertion reactions of N-protected amino acid amides: A solution of
calcd 453.2366).
triethyl diazophosphonoacetate (1.4 mmol) and the N-protected amino
acid amide 8 (1.4 mmol) in dry toluene (5 mL) was treated with rhodium(ii)
acetate (2 mol%). The mixture was heated under reflux for 2 h and
evaporated, and the residue chromatographed on silica gel (ethyl acetate/
ether) to give the insertion product.
Ethyl 2-[(S)-2-(1-benzyloxycarbonylpyrrolidin-2-yl)carbonyl]amino-2-(di-
ethoxyphosphoryl)acetate (9 f): Compound 9 f was prepared in 80% yield
from Z-Pro-NH2 8 f[24] as a colourless waxy solid (80%). [a]2D3 À57.2 (c ˆ 1
in CHCl3); IR (CHCl3): nÄ ˆ 2981, 1735, 1697, 1677, 1241, 1177, 1029 cmÀ1
;
1H NMR (400 MHz, CDCl3): d ˆ 7.37 ± 7.30 (m, 5H; ArH), 5.17 ± 5.16 (m,
2H; PhCH2), 5.11 (dd, J ˆ 21.2 Hz, 8.8 Hz, 1H; CHP), 4.27 ± 4.11 (m, 6H;
OCH2Me), 3.54 (brs, 1H; NH), 3.47 (brs, 1H; NCH), 2.21 (m, 1H; CH),
1.98 ± 1.90 (m, 2H; CH), 1.58 ± 1.56 (m, 3H; CH), 1.38 ± 1.28 (m, 9H;
CH2Me); 13C NMR (100 MHz, CDCl3): d ˆ 171.5, 166.4, 155.8, 136.4, 128.4,
127.9, 127.7, 67.1, 63.7 (d, J ˆ 6.7 Hz, CH2OP), 60.4, 50.7 (d, J ˆ 145.6 Hz,
CHP), 46.9, 31.1, 28.7, 24.4, 16.3 (d, J ˆ 6.7 Hz, MeCH2OP), 13.9; 31P NMR
Ethyl
2-[(benzyloxycarbonylamino)acetyl]amino-2-(diethoxyphosphor-
yl)acetate (9a): This compound was prepared in 81% yield from Z-Gly-
NH2 8a[22] as a waxy solid. IR (CHCl3): nÄ ˆ 2983, 1739, 1698, 1694, 1265,
1047 cmÀ1; 1H NMR (250 MHz, CDCl3): d ˆ 7.37 ± 7.34 (m, 5H; ArH), 6.82
(br, 1H; NHCH), 5.41 (s, 1H; NH), 5.14 (s, 2H; PhCH2), 5.13 (dd, J ˆ
21.8 Hz, 9.0 Hz, 1H; CHP), 4.11 ± 4.10 (m, 6H; OCH2), 3.97 (d, J ˆ 5.7 Hz,
2H; NHCH2), 1.39 ± 1.29 (m, 9H; CH2Me); 13C NMR (100 MHz, CDCl3):
d ˆ 169.3, 166.4, 156.5, 136.3, 128.3, 127.9, 127.8, 66.7, 63.8 (d, J ˆ 6.8 Hz,
CH2OP), 63.7 (d, J ˆ 6.8 Hz, CH2OP), 62.1, 50.5 (d, J ˆ 141.6 Hz, CHP),
44.0, 16.2 (d, J ˆ 6.7 Hz, MeCH2OP), 13.9; 31P NMR (101.3 MHz, CDCl3):
‡
(101.3 MHz, CDCl3): d ˆ 16.95; MS (EI) m/z (%): 470 (4) [M] , 335 (8), 231
‡
(6), 204 (10), 160 (32), 91 (100), 70 (12), 44 (11); (found: 470.1827 [M] ;
C21H31N2O8P calcd 470.1825).
‡
General procedure for Wadsworth ± Emmons reactions: A solution of the
appropriate triethyl aminophosphonoacetate 9 (0.66 mmol) and DBU
(0.1 mL, 0.66 mmol) in anhydrous dichloromethane was treated with the
appropriate aldehyde (1.3 mmol). The reaction mixture was stirred over-
night and evaporated, and the residue was purified by chromatography on
silica gel (ether/light petroleum) to give the dehydrodipeptide 10.
d ˆ 17.1; MS (EI): m/z (%): 430 (1) [M] , 127 (10), 107 (28), 91 (59), 44
‡
(100); (found: 430.1505 [M] ; C18H27N2O8P calcd 430.1528).
Ethyl 2-[(S)-(2-tert-butoxycarbonylamino)propanoyl]amino-2-(diethoxy-
phosphoryl)acetate (9b): Compound 9b was prepared in 88% yield from
Boc-Ala-NH2 8b[21] as a yellow waxy solid. [a]D23 À13.9 (c ˆ 1 in CHCl3); IR
(CHCl3): nÄ ˆ 2980, 1732, 1694, 1674, 1250, 1167, 1024 cmÀ1
;
1H NMR
Z-Gly-DPhe-OEt (10a): Dipeptide 10a was prepared in 82% yield from 9a
and benzaldehyde as a yellow oil. IR (CHCl3): nÄ ˆ 1710, 1685, 1643,
(400 MHz, CDCl3): d ˆ 6.91 (brs, 1H; NH), 5.22 (brs, 1H; CHP), 4.17 ±
4.03 (m, 7H; CH, OCH2), 1.33 (s, 9H; Boc), 1.27 ± 1.13 (m, 12H; CH2Me
and CHMe); NH not observed; 13C NMR (100 MHz, CDCl3): d ˆ 173.8,
164.6, 153.6, 78.1, 67.4, 61.8 (d, J ˆ 7.0 Hz, CH2OP), 61.7 (d, J ˆ 7.0 Hz,
CH2OP), 53.5, 50.5 (d, J ˆ 140.6 Hz, CHP), 26.3, 16.6 (d, J ˆ 6.0 Hz,
MeCH2OP), 14.3, 12.1; 31P NMR (101.3 MHz, CDCl3): d ˆ 16.9; MS (EI):
1
1262 cmÀ1; H NMR (250 MHz, CDCl3): d ˆ 7.90 (s, 1H; CH C), 7.36 ± 7.16
ˆ
(m, 11H; ArH, NH), 5.75 (s, 1H; NH), 4.97 (s, 2H; PhCH2), 4.12 (q, J ˆ
7.0 Hz, 2H; OCH2), 3.85 (s, 2H; CH2), 1.20 (t, J ˆ 7.0 Hz, 3 H ; CH2Me);
13C NMR (63 MHz, CDCl3): d ˆ 168.4, 165.0, 156.9, 136.2, 133.0, 129.9,
129.7, 128.6, 128.3, 127.9, 127.7, 125.9, 124.0, 67.2, 61.8, 44.8, 14.2; MS (EI):
‡
m/z (%): 411 (18) [M‡H] , 327 (8), 301 (10), 266 (13), 224 (89), 197 (15),
‡
‡
m/z (%): 383 (82) [M‡H] , 292 (51), 275 (39), 249 (100), 191 (21), 108 (19);
152 (18), 88 (22), 57 (93), 44 (100); (found: 410.1827 [M] ; C16H31N2O8P
‡
(found: 383.1610 [M‡H] ; C21H23N2O5 calcd 383.1607).
calcd 410.1818).
Boc-Ala-DPhe-OEt (10b): Dipeptide 10b was prepared in 88% yield from
Ethyl 2-[(S)-(2-benzyloxycarbonylamino)propanoyl]amino-2-(diethoxy-
phosphoryl)acetate (9c): Compound 9c was prepared in 80% yield from
Z-Ala-NH2 8c[21] as a waxy solid. [a]D23 À11.0 (c ˆ 1 in CHCl3); IR (CHCl3):
9b and benzaldehyde as a yellow oil. [a]2D5 À21.7 (c ˆ 1 in CHCl3); IR
(CHCl3): nÄ ˆ 2981, 1715, 1690, 1645, 1265 cmÀ1
;
1H NMR (250 MHz,
ˆ
nÄ ˆ 2982, 1741, 1682, 1674, 1252, 1047 cmÀ1
;
1H NMR (400 MHz, CDCl3):
CDCl3): d ˆ 8.04 (s, 1H; CH C), 7.41 ± 7.38 (m, 2H; ArH), 7.29 ± 7.21 (m,
4H; ArH, NH), 5.31 (s, 1H; NH), 4.31 (m, 1H; NHCH), 4.14 (q, J ˆ 7.3 Hz,
2H; OCH2), 1.32 (s, 9H; Boc), 1.22 (t, J ˆ 7.3 Hz, 3 H ; CH2Me), 1.14 (d, J ˆ
7.0 Hz, 3H; CHMe); 13C NMR (63 MHz, CDCl3): d ˆ 171.9, 165.1, 155.7,
132.9, 132.6, 129.8, 129.4, 128.8, 124.3, 80.1, 61.7, 50.3, 28.3, 18.2, 14.2; MS
d ˆ 7.36 (s, 5H; ArH), 6.90 (brs, 1H; NH), 5.30 (s, 1H; NH), 5.15 (dd, J ˆ
21.2 Hz, 8.7 Hz, 1H; CHP), 5.12 (s, 2H; PhCH2), 4.19 ± 4.08 (m, 7H;
NHCH, OCH2), 1.41 (d, J ˆ 7.0 Hz, 3H; CHMe), 1.37 ± 1.23 (m, 9H;
CH2Me); 13C NMR (100 MHz, CDCl3): d ˆ 172.8, 166.3, 155.7, 136.3, 128.2,
127.8, 127.7, 66.5, 63.6 (d, J ˆ 6.8 Hz, CH2OP), 63.5, 50.9 (d, J ˆ 139.2 Hz,
CHP), 49.3, 18.6, 16.1 (d, J ˆ 6.8 Hz, MeCH2OP), 13.8; 31P NMR
‡
(EI): m/z (%): (100) [M‡H] , 307 (55), 263 (27); (found: 363.1920
‡
[M‡H] ; C19H27N2O5 calcd 369.1920).
‡
(101.3 MHz, CDCl3): d ˆ 16.8; MS (EI): m/z (%): 444 (6) [M] , 266 (9),
Boc-Leu-DPhe-OEt (10c): Dipeptide 10c was prepared in 88% yield from
‡
9e and benzaldehyde as a yellow oil. [a]2D5 À18.8 (c ˆ 1 in CHCl3); IR
224 (49), 197 (10), 155 (12), 91 (100); (found: 444.1665 [M] ; C19H29N2O8P
(CHCl3): nÄ ˆ 2960, 1735, 1709, 1677, 1265 cmÀ1
;
1H NMR (250 MHz,
calcd 444.1661).
ˆ
CDCl3): d ˆ 7.66 (s, 1H; CH C), 7.50 ± 7.48 (m, 2H; ArH), 7.40 ± 7.31 (m,
4H; ArH, NH), 4.84 (s, 1H; NH), 4.29 (q, J ˆ 7.0 Hz, 2H; OCH2), 4.23 (brs,
1H; NHCH), 1.79 ± 1.72 (m, 2H; CH2CHMe2), 1.55 (m, 1H; CHMe2), 1.47
(s, 9H; Boc), 1.34 (t, J ˆ 7.0 Hz, 3H; CH2Me), 0.99 ± 0.94 (m, 6H; CHMe2);
13C NMR (63 MHz, CDCl3): d ˆ 171.7, 165.1, 155.9, 133.7, 132.6, 129.9,
129.4, 128.6, 124.4, 80.2, 61.7, 53.3, 40.9, 28.4, 24.7, 22.9, 22.1, 14.3; MS (EI):
Ethyl 2-[(S)-2-tert-butoxycarbonylamino-3-methylbutanoyl]amino-2-(di-
ethoxyphosphoryl)acetate (9d): Compound 9d was prepared in 80% yield
from Boc-Val-NH2 8d[23] as a colourless solid. [a]D23 À9.2 (c ˆ 1 in CHCl3);
IR (CHCl3): nÄ ˆ 1712, 1673, 1670, 1249, 1169, 1023 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d ˆ 6.75 (brs, 1H; NH), 5.22 (dd, J ˆ 21.1 Hz, 8.6 Hz,
1H; CHP), 5.05 (brs, 1H; NH), 4.28 ± 4.09 (m, 6H; OCH2), 3.95 (brs, 1H;
NHCH), 2.04 (sept, J ˆ 6.7 Hz, 1H; CHMe2), 1.44 (s, 9H; Boc), 1.35 ± 1.23
(m, 9H; CH2Me), 1.00 ± 0.92 (m, 6H; CHMe2); 13C NMR (100 MHz,
CDCl3): d ˆ 173.7, 165.1, 154.6, 77.1, 67.3, 61.7 (d, J ˆ 6.8 Hz, CH2OP), 61.6
(d, J ˆ 6.8 Hz, CH2OP), 53.5, 50.5 (d, J ˆ 140.9 Hz, CHP), 38.4, 26.4, 22.9,
16.6 (d, J ˆ 6.7 Hz, MeCH2OP), 14.2, 12.1; 31P NMR (101.3 MHz, CDCl3):
‡
m/z (%): 405 (69) [M‡H] , 349 (85), 305 (100), 259 (15), 191 (30), 131 (15),
‡
86 (55); (found: 405.2389 [M‡H] ; C22H33N2O5 calcd 405.2389).
Boc-Leu-DLeu-OEt (10d): Dipeptide 10d was prepared in 80% yield from
9e and isobutyraldehyde as a yellow oil. [a]2D5 À18.3 (c ˆ 0.5 in CHCl3); IR
(CHCl3): nÄ ˆ 2976, 1725, 1685, 1645, 1245 cmÀ1
;
1H NMR (250 MHz,
‡
ˆ
d ˆ 17.0; MS (EI): m/z (%): 438 (18) [M] , 327 (8), 301 (10), 266 (13), 224
CDCl3): d ˆ 7.34 (s, 1H; NH), 6.50 (d, J ˆ 10.5 Hz, 1H; CH C), 4.85 (s, 1H;
NH), 4.21 (q, J ˆ 7.3 Hz, 2H; OCH2), 4.18 (s, 1H; NHCH), 2.59 (m, 1H;
CHMe2), 1.79 ± 1.74 (m, 3H; CHMe2, CH2CHMe2), 1.46 (s, 9H; Boc), 1.29
(t, J ˆ 7.3 Hz, 3H; CH2Me), 1.06 ± 1.03 (m, 6H; CHMe2), 0.99 ± 0.95 (m, 6H;
CHMe2); 13C NMR (63 MHz, CDCl3): d ˆ 171.6, 164.6, 155.8, 145.1, 123.4,
80.1, 61.1, 53.1, 52.9, 40.8, 28.1, 27.7, 24.6, 22.8, 21.9, 21.8, 14.0; MS (EI): m/z
‡
(89), 197 (15), 152 (18), 88 (22), 57 (93), 44 (100); (found: 438.2129 [M] ;
C18H35N2O8P calcd 438.2131).
Ethyl 2-[(S)-2-tert-butoxycarbonylamino-4-methylpentanoyl]amino-2-(di-
ethoxyphosphoryl)acetate (9e): Compound 9e was prepared in 82% yield
from Boc-Leu-NH2 8e[20] as a yellow oil. [a]D23 À18.7 (c ˆ 1 in CHCl3); IR
‡
(%): 371 (100) [M‡H] , 315 (85), 297 (70), 271 (61), 225 (12), 157 (13), 86
(CHCl3): nÄ ˆ 2980, 1749, 1717, 1683, 1253, 1167, 1027 cmÀ1
;
1H NMR
‡
(52); (found: 371.2546 [M‡H] ; C19H35N2O5 calcd 371.2546).
(400 MHz, CDCl3): d ˆ 6.48 (brs, 1H; NH), 6.05 (brs, 1H; NH), 5.15 (dd,
J ˆ 22.1 Hz, 10.4 Hz, 1H; CHP), 4.27 ± 4.14 (m, 7H; NHCH, OCH2), 1.64 ±
1.61 (m, 2H; CH2CHMe2), 1.51 ± 1.49 (m, 1H; CHMe), 1.35 (s, 9H; Boc),
1.34 ± 1.29 (m, 9H; CH2Me), 0.96 ± 0.93 (m, 6H; CHMe2); 13C NMR
(100 MHz, CDCl3): d ˆ 173.9, 167.9, 157.1, 81.2, 65.1 (d, J ˆ 7.4 Hz, CH2OP),
Boc-Leu-DTrp(Boc)-OEt (10e): Dipeptide 10e was prepared in 79% yield
from 9e and N-tert-butoxycarbonylindole-3-carboxaldehyde as a yellow oil.
[a]2D5 À11.3 (c ˆ 0.5 in CHCl3); IR (CHCl3): nÄ ˆ 2991, 1725, 1695, 1665,
1235 cmÀ1; 1H NMR (250 MHz, CDCl3): d ˆ 8.12 (d, J ˆ 7.6 Hz, 1H; indole
2164
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0612-2164 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 12

Peptide Synthesis
2160±2167
7-H), 7.81(s, 1H; NH), 7.79 (s, 1H; indole 2-H), 7.70 (d, J ˆ 8.7 Hz, 1H;
(CHCl3): nÄ ˆ 3410, 2982, 2954, 2931, 2859, 1719, 1695, 1644, 1483, 1371,
indole 4-H), 7.35 ± 7.22 (m, 3H; indole 5/6-H, CH C), 4.81 (s, 1H; NH), 4.32
1255, 1154, 1088, 1020, 839 cmÀ1
;
1H NMR (400 MHz, CDCl3): d ˆ 8.41
ˆ
(q, J ˆ 7.0 Hz, 2H; OCH2), 4.26 (m, 1H; NHCH), 1.76 (m, 2H;
CH2CHMe2), 1.68 (m, 1H; CHMe2), 1.64 (s, 9H; Boc), 1.32 (s, 9H; Boc),
1.37 (t, J ˆ 7.0 Hz, 3H; CH2Me), 0.97 (m, 6H; CHMe2); 13C NMR
(100 MHz, CDCl3): d ˆ 171.4, 165.0, 155.9, 149.3, 134.8, 129.6, 127.9,
125.0, 123.7, 123.4, 123.1, 119.0, 115.3, 114.1, 84.5, 80.2, 61.6, 53.4, 40.7,
(brs, 1H; NH), 8.14 (d, J ˆ 8.0 Hz, 1H; indole 7-H), 7.88 (s, 1H; indole
ˆ
2-H), 7.71 (s, 1H; CH C), 7.68 (d, J ˆ 7.3 Hz, 1H; indole 4-H), 7.38 ± 7.26
(m, 2H; indole 5-H, 6-H), 4.47 (brs, 1H; NH), 4.31 (m, 1H; NHCH), 4.12
(dd, J ˆ 4.4 Hz, 9.9 Hz, 1H; CHHOSi), 3.86 (s, 3H; OMe), 3.79 (dd, J ˆ
7.7 Hz, 9.9 Hz, 1H; CHHOSi), 1.68 (s, 9H; Boc), 1.45 (s, 9H; Boc), 0.85 (s,
9H; tBuSi), 0.13 (s, 3H; MeSi), 0.095 (s, 3H; MeSi); 13C NMR (100 MHz,
CDCl3): d ˆ 169.1, 165.1, 155.6, 149.1, 134.9, 129.4, 127.7, 125.0, 124.0, 123.2,
122.9, 118.9, 115.3, 113.9, 84.5, 80.1, 62.8, 55.8, 52.5, 28.3, 28.2, 25.8, 18.0,
‡
28.3, 28.2, 24.8, 23.2, 21.8, 14.3; MS (EI): m/z (%): 544 (49) [M‡H] , 488
(19), 444 (100), 388 (15), 344 (22), 231 (10), 131 (31), 86 (54); (found:
‡
544.3023 [M‡H] ; C29H41N3O7 calcd 544.3023).
‡
À5.4, À5.6; MS (FAB): m/z (%): 618 (30) [M‡H] , 518 (55), 216 (77), 174
À
General procedure for the N H insertionÐWadsworth ± Emmons reaction
‡
(100); (found: 618.3193 [M‡H] ; C31H48N3O8Si calcd 618.3211).
sequence:
A
solution of trimethyl diazophosphonoacetate (125 mg,
Boc-Ser(TBS)-DVal-OMe (12e): Peptide 12e was prepared in 30% overall
yield starting from Boc-Ser(TBS)-NH2 11d and acetone. [a]2D8 ‡13.9 (c ˆ
1.04 in CHCl3); IR (CHCl3): nÄ ˆ 3421, 2945, 2852, 1710, 1680, 1485, 1367,
0.6 mmol) in dichloromethane (2.5 mL) was added over 10 min, under
nitrogen, to a stirred solution of N-protected amino acid amide 11
(0.43 mmol) and rhodium(ii) acetate (23 mg, 10 mol% with respect to the
diazo compound) in dichloromethane (3 mL), which was heated at reflux.
After 24 h the mixture was cooled to room temperature and diluted with
ethyl acetate. The solution was washed in turn with water, saturated sodium
bicarbonate solution and brine. The organic layer was then dried with
magnesium sulfate and evaporated to yield the crude insertion product. A
solution of DBU (140 mg, 1 mmol) in dichloromethane (1 mL) was then
added to a stirred solution of the crude insertion product (ca. 0.43 mmol) in
dichloromethane (0.5 mL), under nitrogen. After 10 min, a solution of
aldehyde or ketone (0.78 mmol) in dichloromethane (0.5 mL) was added to
the reaction mixture. The reaction was followed by TLC (ethyl acetate),
and when complete the mixture was diluted with ethyl acetate. The solution
was washed in turn with water, saturated sodium bicarbonate solution and
brine. The organic layer was dried with magnesium sulfate and evaporated
to yield the crude product, which was purified by flash column chromatog-
raphy (mixtures of ethyl acetate/hexane).
1
1163, 1081, 937, 841 cmÀ1; H NMR (400 MHz, CDCl3): d ˆ 7.73 (brs, 1H;
NH), 5.37 (brs, 1H; NH), 4.19 (brs, 1H; NHCH), 4.04 (dd, J ˆ 4.0 Hz,
9.8 Hz, 1H; CHHOSi), 3.70 (s, 3H; OMe), 3.69 (m, 1H; CHHOSi), 2.15 (s,
ˆ
ˆ
3H; CMe), 1.81 (s, 3H; CMe), 1.44 (s, 9H; Boc), 0.88 (s, 9H; tBuSi), 0.09
(s, 3H; MeSi), 0.08 (s, 3H; MeSi); 13C NMR (100 MHz, CDCl3): d ˆ 169.2,
164, 155.5, 146.1, 120.6, 80.1, 63.1, 55.5, 51.7, 28.3, 25.8, 22.5, 21.2, 18.1, À5.5,
‡
À5.6; MS (FAB): m/z (%): 431 (42) [M‡H] , 375 (54), 331 (63), 174 (64);
‡
(found: 430.2506 [M] ; C20H38N2O6Si calcd 430.2499).
Boc-Tyr(TBS)-DLeu-OMe (12 f): Peptide 12 f was prepared in 61% overall
yield starting from Boc-Tyr(TBS)-NH2 11e and isobutyraldehyde. [a]D28
À8.4 (c ˆ 2.76 in CHCl3); IR (CHCl3): nÄ ˆ 3677, 3411, 3027, 2965, 2929,
2858, 1716, 1700, 1608, 1516, 1475, 1419, 1260, 1209, 1014, 927, 794, 737,
661 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 7.21 (brs, 1H; NH), 7.10 (d, J ˆ
8.5 Hz, 2H; ArH), 6.76 (d, J ˆ 8.5 Hz, 2H; ArH), 6.72 (d, J ˆ 10.4 Hz, 1H;
ˆ
CH C), 5.01 (brs, 1H; NH), 4.39 (br, X of ABX system, 1H; NHCH), 3.73
(s, 3H; OMe), 3.11 ± 2.99 (AB of ABX, J ˆ 14.0 Hz, 6.9 Hz, 7.0 Hz, 2H;
Z-Leu-DPhe-OMe (12a): Peptide 12a was prepared in 65% overall yield
starting from Z-Leu-NH2 11a[24] and benzaldehyde. [a]2D8 À13.4 (c ˆ 2.36 in
CH2Ar), 2.45 (m, 1H; CHMe2), 1.42 (s, 9H; Boc), 1.01 (d, J ˆ 6.5 Hz, 3H;
ˆ
ˆ
CHCHMeMe), 0.99 (d, J ˆ 6.5 Hz, 3H; CHCHMeMe), 0.97 (s, 9H;
tBuSi), 0.18 (s, 6H; MeSi); 13C NMR (100 MHz, CDCl3): d ˆ 170.3, 164.9,
155.5, 154.7, 145.8, 130.3, 129.1, 122.8, 120.2, 80.2, 56.1, 52.3, 37.1, 28.2, 27.8,
CHCl3); IR (CHCl3): nÄ ˆ 3430, 2959, 1717, 1645, 1505, 1438, 1266, 1106,
1
1045, 909 cmÀ1; H NMR (400 MHz, CDCl3): d ˆ 7.62 (s, 1H; CH C), 7.48 ±
ˆ
7.42 (m, 3H; ArH and NH), 7.36 ± 7.29 (m, 8H; ArH), 5.14 (brs, 3H; PhCH2
and NH), 4.32 (brd, J ˆ 5.1 Hz, 1H; NHCH), 3.80 (s, 3H; OMe), 1.78 ± 1.70
(m, 2H; CH2CHMe2), 1.55 (m, 1H; CHMe2), 0.96 (m, J ˆ 6.4 Hz, 6H;
CHMe2); 13C NMR (100 MHz, CDCl3): d ˆ 170.6, 165.4, 156.4, 136.0, 133.6,
132.8, 129.7, 129.5, 128.6, 128.4, 128.3, 128.1, 123.4, 67.3, 53.8, 52.6, 40.6, 24.7,
‡
25.6, 21.6, 18.2, À4.5; MS (CI): m/z (%): 521 (65) [M‡H] , 465 (20), 250
(25), 223 (28), 146 (55), 144 (100), 132 (32), 86 (42), 72 (58); (found:
‡
521.3056 [M‡H] ; C27H45N2O6Si calcd 521.3047).
Boc-Trp(Boc)-DAbu-OMe (12g): Peptide 12g was prepared in 86%
overall yield starting from Boc-Trp(Boc)-NH2 11 f and acetaldehyde;
[a]2D8 À7.4 (c ˆ 3.70 in CHCl3); IR (CHCl3): nÄ ˆ 3684, 3418, 3018, 2984, 1723,
1690, 1602, 1505, 1438, 1453, 1370, 1212, 1159, 1088, 1018, 928, 909, 749,
‡
22.8, 21.9; MS (EI): m/z (%): 424 (1) [M] , 316 (63), 228 (82), 203 (60), 177
(40), 131 (52), 117 (100), 91 (85); (found: 424.2568 [M] ; C24H28N2O5 calcd
‡
424.1998).
669 cmÀ1
;
1H NMR (400 MHz, CDCl3): d ˆ 8.13 (brd, J ˆ 8.2 Hz, 1H;
Ac-Leu-DPhe-OMe (12b): Peptide 12b was prepared in 37% overall yield
starting from Ac-Leu-NH2 11b[25] and benzaldehyde. [a]2D8 À25.7 (c ˆ 0.54
in CHCl3); IR (CHCl3): nÄ ˆ 2959, 2361, 1718, 1700, 1666, 1601, 1506, 1437,
1370, 1266, 1202, 929 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 8.37 (brs, 1H;
indole 7-H), 7.61 (d, J ˆ 7.7 Hz, 1H; indole 4-H), 7.48 (s, 1H; indole 2-H),
7.40 (s, 1H; NH), 7.35 ± 7.20 (m, 2H; indole 5-H, 6-H), 6.77 (q, J ˆ 7.2 Hz,
ˆ
1H; CH C), 5.18 (brs, 1H; NH), 4.59 (brd, J ˆ 5.0 Hz, 1H; NHCH), 3.69
(s, 3H; OMe), 3.26 (dd, J ˆ 6.9 Hz, 14.8 Hz, 1H; CHHindole), 3.19 (dd, J ˆ
ˆ
CH C), 7.44 (d, J ˆ 5.6 Hz, 2H; ArH), 7.34 ± 7.27 (m, 3H; ArH), 6.56 (d,
ˆ
6.3 Hz, 14.8 Hz, 1H; CHHindole), 1.67 (d, J ˆ 7.2 Hz, 3 H ; CMe), 1.65 (s,
J ˆ 8.0 Hz, 1H; NH), 4.73 (dd, J ˆ 8.2 Hz, 14.2 Hz, 1H; NHCH), 3.80 (m,
1H; NH), 3.76 (s, 3H; OMe), 1.85 (s, 3H; Ac), 1.78 ± 1.65 (m, 2H;
CH2CHMe2), 1.53 (m, 1H; CHMe2), 0.93 (m, 6H; CHMe2); 13C NMR
(100 MHz, CDCl3): d ˆ 171.5, 170.7, 165.3, 133.4, 133.2, 129.8, 129.5, 128.5,
9H; Boc), 1.42 (s, 9H; Boc); 13C NMR (100 MHz, CDCl3): d ˆ 169.7, 164.5,
155.5, 149.5, 135.6, 134.4, 130.3, 125.8, 124.6, 124.4, 122.7, 119.0, 115.3, 83.6,
‡
80.4, 54.7, 52.2, 28.2, 28.1, 27.8, 14.5; MS (FAB): m/z (%): 502 (20) [M‡H] ,
390 (14), 284 (20), 203 (30), 170 (25), 159 (32), 130 (100), 116 (41); (found:
‡
124.3, 52.5, 51.7, 40.7, 24.7, 22.8, 22.7, 22.4; MS (EI): m/z (%): 332 (4) [M] ,
‡
502.2554 [M‡H] ; C26H36N3O7 calcd 502.2553).
301 (9), 271 (22), 191 (25), 177 (100), 117 (63), 91 (41); (found: 332.1730
‡
Z-Leu-DMeLeu-OMe (12h): Peptide 12h was prepared in 46% overall
yield (as a mixture of amide bond rotamers and double bond isomers)
starting from Z-Leu-NHMe 11g[26] and isobutyraldehyde; IR (CHCl3): nÄ ˆ
3684, 3400, 3018, 2960, 2871, 1731, 1704, 1658, 1525, 1438, 1309, 1217, 1092,
1027, 928, 749, 668 cmÀ1; 1H NMR (400 MHz, CDCl3) (all signals reported;
mixture of isomers/rotamers): d ˆ 7.35 ± 7.25 (m, 20H; ArH), 6.64 (brs, 1H;
NH), 6.54 (brs, 1H; NH), 6.35 (brd, J ˆ 4.2 Hz, 1H; NH), 6.29 (brd, J ˆ
[M] ; C18H24N2O4 calcd 332.1736).
Boc-Phe-DLeu-OMe (12c): Peptide 12c was prepared in 60% overall yield
starting from Boc-Phe-NH2 11c[21] and isobutyraldehyde. [a]2D8 À16.2 (c ˆ
2.00 in CHCl3); IR (CHCl3): nÄ ˆ 3421, 2968, 1716, 1698, 1495, 1438, 1368,
1255, 1160, 1029, 929 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 7.45 (brs, 1H;
ˆ
NH), 7.29 ± 7.19 (m, 5H; ArH), 6.47 (d, J ˆ 10.4 Hz, 1H; CH C), 5.18 (d,
J ˆ 8.2 Hz, 1H; NH), 4.48 (m, 1H; NHCH), 3.70 (s, 3H; OMe), 3.15 (dd,
J ˆ 6.7 Hz, 13.9 Hz, 1H; PhCHH), 3.05 (dd, J ˆ 7.2 Hz, 13.9 Hz, 1H;
PhCHH), 2.40 (m, 1H; CHMe2), 1.38 (s, 9H; Boc), 0.98 (d, J ˆ 6.6 Hz, 3H;
ˆ
4.8 Hz, 1H; NH), 6.25 (d, J ˆ 10.0 Hz, 1H; CH C), 6.21 (d, J ˆ 11.5 Hz,
ˆ
ˆ
1H; CH C), 5.71 (d, J ˆ 10.4 Hz, 1H; CH C), 5.59 (d, J ˆ 10.5 Hz, 1H;
ˆ
CH C), 5.25 ± 5.08 (m, 8H; PhCH2), 4.26 ± 4.05 (m, 4H; NHCH), 3.71 (s,
CHCHMeMe), 0.96 (d, J ˆ 6.7 Hz, 3H; CHCHMeMe); 13C NMR
(100 MHz, CDCl3): d ˆ 170.4, 164.9, 155.6, 145.9, 136.6, 129.4, 128.6,
122.9, 80.2, 55.9, 52.2, 38.0, 28.2, 27.7, 21.6, 21.5; MS (EI): m/z (%): 391 (1)
ˆ
ˆ
3H; OMe), 3.66 (s, 3H; OMe), 3.63 (s, 3H; OMe), 3.59 (s, 3H; OMe),
2.70 ± 2.68 (m, 6H; NMe), 2.63 ± 2.61 (m, 6H; NMe), 1.70 ± 1.49 (m, 16H;
CH2CHMe2), 1.06 ± 0.78 (m, 48H; CHMe2); 13C NMR (100 MHz, CDCl3):
d ˆ 174.9, 174.8, 174.7, 163.4, 163.1, 162.8, 162.5, 149.9, 149.4, 148.7, 148.3,
139.5, 137.4, 137.3, 137.2, 136.7, 136.6, 136.4, 136.3, 136.2, 136.5, 128.5, 128.4,
128.3, 128.1, 127.9, 127.7, 127.5, 127.3, 70.9, 70.8, 70.1, 69.9, 57.6, 57.5, 57.4,
52.1, 51.7, 43.7, 43.6, 43.5, 27.9, 26.2, 25.8, 25.7, 25.6, 25.5, 24.7, 24.6, 23.6, 23.6,
‡
[M] , 335 (32), 303 (32), 241 (31), 164 (62), 142 (73), 120 (96), 91 (38), 57
(100); (found: 391.2246 [M] ; C21H31N2O5 calcd 391.2238).
‡
Boc-Ser(TBS)-DTrp(Boc)-OMe (12d): Peptide 12d was prepared in 77%
overall yield starting from Boc-Ser(TBS)-NH2 11d and N-tert-butoxycar-
bonylindole-3-carboxaldehyde; [a]2D8 ‡3.9 (c ˆ 4.04 in CHCl3); IR
‡
23.5, 23.4, 22.5, 21.8, 21.7, 21.6, 21.5; MS (EI): m/z (%): 404 (1) [M] , 347
Chem. Eur. J. 2000, 6, No. 12
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0612-2165 $ 17.50+.50/0
2165

C. J. Moody et al.
FULL PAPER
‡
(100), 171 (74), 114 (74), 91 (73), 57 (61); (found: 404.2328 [M] ;
53.4, 40.8, 28.3, 24.7, 23.2, 21.6; the signals for 2 ArCH and 3 quaternary C
C22H32N2O5 calcd 404.2311).
atoms were not observed as discrete non-overlapped signals; MS (FAB):
‡
‡
‡
m/z (%): 612 (43) [M‡H‡Na] , 611 (100) [M‡Na] , 589 (19) [M‡H] ,
Boc-Ala-Leu-DPhe-OMe (14): Peptide 14 was prepared in 50% overall
yield starting from Boc-Ala-Leu-NH2 (13)[27] and benzaldehyde. [a]2D5
À44.1 (c ˆ 2.00 in CHCl3); IR (CHCl3): nÄ ˆ 3421, 3303, 2955, 1705, 1490,
1424, 1357, 1270, 1152, 927 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 8.15 (brs,
‡
588 (34) [M] , 512 (36), 511 (92), 376 (27), 284 (39), 107 (76); (found:
‡
611.2741 [M‡Na] ; C34H40N2O7 ´ Na calcd 611.2733); elemental analysis
calcd (%) for C34H40N2O7 ´ 1.5H2O: C 66.3, H 7.0, N 4.5; found C 66.6, H 6.6,
N 4.5.
ˆ
1H; NH), 7.48 ± 7.43 (brd, J ˆ 6.7 Hz, 2H; ArH), 7.37 (s, 1H; CH C), 7.32 ±
Boc-Ala-Phg-OMe (19a): Boc-Ala-NH2 8b (58.8 mg, 0.31 mmol) followed
by rhodium(ii) acetate (2 mol%) was added to a stirred solution of methyl
2-(diazo)phenylethanoate (50 mg, 0.28 mmol) in dry dichloromethane
(4 mL) under a nitrogen atmosphere. After stirring for 1 h, the solvent
was removed under reduced pressure to yield a green oil. This crude
product was then subjected to flash silica-gel chromatography with light
petroleum and ethyl acetate (7:3) as eluant to yield an inseparable
diastereomeric mixture (24% de by NMR) of the 19a as a colourless oil
(52 mg, 55%). IR (film): nÄ ˆ 3423, 3321, 3055, 2979, 1744, 1710, 1677, 1538,
1505, 1456, 1067, 742 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 7.36 (brs, 1H;
NH), 7.34 (m, 5H; ArH), 5.55 (m, 1H; NHCH), 5.05 (m, 1H; NH), 4.24 (m,
1H; NHCH), 3.71 and 3.70 (s, 3H; OMe; ratio 62:38), 1.43 (s, 9H; Boc),
1.35 (d, J ˆ 4.4 Hz, 3H; CHMe); 13C NMR (100 MHz, CDCl3): d ˆ 172.1,
171.1, 155.6, 136.3, 128.9, 128.5, 127.2, 80.2, 56.4, 52.7, 49.9, 28.3, 17.9; MS
7.26 (m, 3H; ArH), 6.91 (brd, J ˆ 6.0 Hz, 1H; NH), 5.15 (brd, J ˆ 4.6 Hz,
1H; NH), 4.61 (ddd, J ˆ 5.6 Hz, 8.9 Hz, 14.2 Hz, 1H; NHCH), 4.17 (br, 1H;
NHCH), 3.78 (s, 3H; OMe), 1.81 ± 1.54 (m, 3H; CH2CHMe2), 1.38 (s, 9H;
Boc), 1.31 (d, J ˆ 7.0 Hz, 3H; CHMe), 0.92 (m, 6H; CHMe2); 13C NMR
(100 MHz, CDCl3): d ˆ 173.1, 170.9, 165.4, 155.7, 133.6, 133.4, 129.9, 129.5,
128.5, 124.2, 80.4, 52.5, 51.9, 50.3, 40.2, 28.2, 24.7, 22.9, 21.9, 17.9; MS (FAB):
‡
m/z (%): 462 (75) [M‡H] , 406 (12), 285 (20), 229 (100), 201 (44), 178 (31);
‡
(found: 461.2531 [M] ; C24H35N3O6 calcd 461.2526).
Methyl 2-[(S)-2-tert-butoxycarbonylamino-4-methylpentanoylamino]-2-
(dimethoxyphosphoryl)acetate (17): Trimethyl diazophosphonoacetate
(0.88 g, 4.2 mmol) in toluene (5 mL) was added dropwise over a period
of 10 min to a stirred solution of amide 8e (0.89 g, 3.9 mmol) and
rhodium(ii) acetate (0.17 g, 0.039 mmol) in boiling toluene (50 mL). The
reaction was monitored by TLC and had gone to completion within 1 h.
The solvent was evaporated and the residue purified by column chroma-
tography (1:1 ethyl acetate/light petroleum elution) to yield a colourless oil
(0.89 g, 56%) (ref. [13] foam). [a]2D5 À28.6 (c ˆ 1.16 in CHCl3); IR (film):
‡
(EI): m/z (%): 336 (42) [M] , 281 (77), 237 (42), 221 (29), 203 (26), 144 (71),
132 (30), 121 (55), 106 (100), 88 (76), 77 (37), 57 (95); (found: 336.1684
‡
[M] ; C17H24N2O5 calcd 336.1685).
nÄ ˆ 3440, 3306, 3063, 2955, 1755, 1694 cmÀ1; H NMR (300 MHz, CDCl3):
1
Boc-Val-Phg-OMe (19b): Boc-Val-NH2 8e (67.5 mg, 0.31 mmol) followed
by rhodium(ii) acetate (2 mol%) was added to a stirred solution of methyl
2-(diazo)phenylethanoate (50 mg, 0.28 mmol) in dry chloroform (4 mL)
under a nitrogen atmosphere. After stirring for 1 h the solvent was removed
under reduced pressure to yield a green oil. This crude product was then
subjected to flash silica-gel chromatography with light petroleum and ethyl
acetate (4:1) as eluant to yield an inseparable diastereomeric mixture (20%
de by NMR) of the 19b as a colourless oil (67 mg, 66%). IR (film): nÄ ˆ
d ˆ 7.09 (m, 1H; NH), 5.19 (m, 1H; CHP), 4.96 (m, 1H; NHCH), 4.20 (brs,
1H; NH), 3.78 (m, 9H; OMe), 1.66 (m, 2H; CH2CHMe2), 1.47 (m, 1H;
CHMe2), 1.43 (s, 9H; Boc), 0.93 (m, 6H; CHMe2); 13C NMR (100 MHz,
CDCl3): d ˆ 172.4, 166.8, 155.5, 80.2, 54.6, 54.2 (d, J ˆ 6.0 Hz, MeOP), 54.1
(d, J ˆ 5.5 Hz, MeOP), 53.3, 52.3, 50.0 (d, J ˆ 146.7 Hz, CHP), 40.9, 28.2,
‡
24.7, 22.9, 21.8; MS (EI): m/z (%): 410 (2) [M] , 367 (4), 337 (8), 182 (43),
130 (45), 86 (100).
3423, 3321, 3055, 2979, 1744, 1711, 1677, 1537, 1506, 1456, 1017, 738 cmÀ1
;
Methyl 3-(3,4-dibenzyloxyphenyl)-2-[(S)-2-tert-butoxycarbonylamino-4-
methylpentanoylamino]propenoate (18): DBU (1.06 g, 7.0 mmol) was
added to a solution of phosphonate 17 (1.37 g, 3.3 mmol) in dichloro-
methane (14 mL), and the mixture was stirred at room temperature for
10 min. 3,4-Dibenzyloxybenzaldehyde (1.17 g, 3.7 mmol) was added in one
portion, and the reaction was stirred for 2 h. The solvent was evaporated,
and the residue purified by column chromatography (ethyl acetate elution)
and recrystallized (ethyl acetate/light petroleum) to yield the 18 as
colourless crystals (1.51 g, 75%). M.p. 65 ± 678C; [a]2D5 ‡6.3 (c ˆ 0.95 in
1H NMR (400 MHz, CDCl3): d ˆ 7.33 (m, 5H; ArH), 7.03 (brs, 1H; NH),
5.55 (m, 1H; NHCH), 5.06 (brs, 1H; NH), 3.98 (m, 1H; NHCH), 3.72 and
3.71 (s, 3H; OMe; ratio 60:40), 2.15 (m, 1H; CHMe2), 1.42 (s, 9H; Boc),
0.90 (d, J ˆ 6.8 Hz, 3H; CHMe), 0.86 (d, J ˆ 6.8 Hz, 3H; CHMe); 13C NMR
(100 MHz, CDCl3): d ˆ 171.1, 171.0, 155.8, 136.3, 128.9, 128.4, 127.2, 80.0,
‡
59.7, 56.5, 52.7, 30.9, 28.3, 19.2, 17.7; MS (CI): m/z (%): 365 (65) [M‡H] ,
309 (46), 265 (58), 172 (9), 116 (25), 106 (37), 91 (11), 72 (100), 57 (80);
‡
(found: 365.2070 [M‡H] ; C19H29N2O5 calcd 365.2076).
CHCl3); IR (CHCl3): nÄ ˆ 3292, 2955, 2874, 1728, 1681 cmÀ1
;
1H NMR
ˆ
(300 MHz, CDCl3): d ˆ 7.72 (s, 1H; NH), 7.47 ± 7.28 (m, ArH, 11H; CH C),
7.16 ± 7.12 (m, 2H; ArH), 6.89 (d, J ˆ 8.3 Hz, 1H; ArH), 5.16 (s, 2H;
PhCH2), 5.14 (s, 2H; PhCH2), 4.92 (brd, J ˆ 7.1 Hz, 1H; NH), 4.28 (brs,
1H; NHCH), 3.80 (s, 3H; OMe), 1.77 ± 1.74 (m, 2H; CH2CHMe2), 1.51 (m,
1H; CHMe2), 1.43 (s, 9H; Boc), 0.95 (m, 6H; CHMe2); 13C NMR
(100 MHz, CDCl3): d ˆ 171.5, 165.7, 155.8, 150.4, 148.6, 137.1, 136.9, 133.3,
128.5, 128.4, 127.9, 127.8, 127.4, 127.3, 126.9, 124.3, 122.1, 116.8, 114.2, 80.3,
71.4, 70.9, 53.5, 52.5, 40.7, 28.3, 24.7, 23.0, 21.9; MS (EI): m/z (%): 603 (27)
Acknowledgements
We are grateful to Loughborough University, the University of Exeter and
the Leverhulme Trust for support of this work, to SmithKline Beecham
(SB) for a CASE Award (to L.F.), to SB and GlaxoWellcome for support
under the DTI Link Programme in Asymmetric Synthesis (studentship to
R.T.B.) and to the EPSRC Mass Spectrometry Service at Swansea for high-
resolution mass spectra.
‡
‡
[M‡H] , 602 (6) [M] , 548 (14), 547 (33), 503 (52), 131 (52), 108 (94), 106
‡
(58), 86 (100); (found: 603.3070 [M‡H] ; C35H43N2O7 calcd 603.3070);
elemental analysis calcd (%) for C35H43N2O7: C 69.7, H 7.0, N 4.7; found C
69.7, H 7.0, N 4.8.
3-(3,4-Dibenzyloxyphenyl)-2-[(S)-2-tert-butoxycarbonylamino-4-methyl-
pentanoylamino]propenoic acid (16): A solution of lithium hydroxide
(0.22 g, 9.2 mmol) in water (25 mL) was added to a stirred solution of ester
18 (1.1g, 1.84 mmol) in THF (75 mL). The mixture was stirred for 4 h, and
then acidified with 3m hydrochloric acid. Ammonium chloride solution was
added,and the acid was extracted into ethyl acetate. The organic layer was
dried (Na2SO4) and concentrated. The crude material was purified by
column chromatography (ethyl acetate elution) and recrystallized (ethyl
acetate/light petroleum) to yield the 16 as a colourless crystalline solid
(1.03 g, 95%). M.p. 124 ± 1268C; [a]2D5 À30.5 (c ˆ 1.09 in CHCl3); IR
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(CH2Cl2): nÄ ˆ 3407, 3270, 3059, 2993, 2960, 1690, 1518 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 8.95 (brs, 1H; CO2H), 7.94 (s, 1H; NH), 7.50 ± 7.27
ˆ
(m, ArH, 11H; CH C), 7.14 ± 7.12 (m, 2H; ArH), 6.87 (d, J ˆ 8.3 Hz, 1H;
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136.9, 128.4, 128.3, 127.7, 127.5, 127.2, 124.4, 116.7, 114.0, 80.2, 71.3, 70.8,
2166
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0947-6539/00/0612-2166 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 12

Peptide Synthesis
2160±2167
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Received: October 26, 1999 [F2105]
Chem. Eur. J. 2000, 6, No. 12
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0947-6539/00/0612-2167 $ 17.50+.50/0
2167