Enantioselective Synthesis of Metathesis-Derived Ureapeptoid Macrocycles

Article abstract of DOI:10.1055/s-2004-815425

Ring-closing metathesis (RCM) was used for the preparation of the first member of a new class of ureapeptoid-containing macrocycles. Key to the approach was the enantioselective synthesis of functionalized carbamoyl alkenylglycine equivalents using (-)-B-allyldiisopinocampheylborane [(-)-d-Ipc₂Ball]-mediated asymmetric allylation.

Full text of DOI:10.1055/s-2004-815425

LETTER
469
Enantioselective Synthesis of Metathesis-Derived Ureapeptoid Macrocycles
Enantioselective
U
i
reape
p
a
toid Macro
n
cycles g-Zhu Wang, Terrence R. Burke Jr *
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NCI-Frederick,
Frederick, MD 21702-1201, USA
Fax +1(301)8466033; E-mail: tburke@helix.nih.gov
Received 1 December 2003
taining allyl-variant 7 required for ureapeptoid formation,
Abstract: Ring-closing metathesis (RCM) was used for the prepa-
would spontaneously decompose in the free acid form.
ration of the first member of a new class of ureapeptoid-containing
For this reason, the carbamate 8 was chosen as a synthetic
alternative, since it would be chemically stable. Addition-
macrocycles. Key to the approach was the enantioselective syn-
thesis of functionalized carbamoyl alkenylglycine equivalents us-
ing (–)-B-allyldiisopinocampheylborane [(–)-d-Ipc2Ball]-mediated ally, phenylcarbamates have already been shown to be
sufficiently activated for direct use in amino-coupling.10
asymmetric allylation.
Key words: asymmetric synthesis, macrocycles, metathesis, ring
closure, stereoselective
Synthesis of 8 was approached from (4-formylphenyl)me-
thylphosphonic acid diethyl ester (11, Scheme 1). Com-
pound 11 was prepared by reduction of commercially
available 4-(bromomethyl)benzonitrile (9) with DIBAL-
H to give 4-(bromomethyl)benzaldehyde (10)11 in nearly
quantitative yield. This was then heated with triethylphos-
phite and vacuum distilled to yield 11 (90% yield).12
Based on the procedure of Ellman,13 (S)-(–)-tert-
butanesulfinylamide14 was then condensed with 11 in the
presence of Ti(OEt)4 to provide sulfinylimine 12 that con-
tained functionality necessary for stereochemically-con-
trolled introduction of the benzylic allyl group.15 Due to
the potential instability of the phosphonate functionality
in 12 toward strong base or organometallic reagents, con-
version to 13 was first attempted unsuccessfully using al-
lylboration.16 The failure of this approach, accompanied
by a significant recovery of a starting 12, indicated the
low reactivity of the imine group. Subsequently, 1,2-addi-
tion to 12 using allylic metal reagents (Mg and Zn) pro-
vided the desired 13, but in lower yields (ca 50% yield)
than had been reported using other functionalized im-
ines.17
Replacement of amino acid a-methylenes of peptides (1)
with nitrogen species provides peptidyl ureas and ure-
apeptoid-type peptidomimetics (2) that can exhibit altered
physiological properties (Figure 1).1–5 Likewise, macro-
cyclization through ring-closing olefin metathesis (RCM)
of alkenylglycine residues has proven useful for induction
of turn geometries (3).6,7 Although application of RCM
ring-closure to ureapeptoids would result in hybrid mac-
rocycles (4) that could potentially exhibit novel proper-
ties, such urea-containing macrocycles have not yet been
reported. In order to develop synthetic methodology for
the RCM-dependent preparation of ureapeptoid macrocy-
cles, target 5 was selected as a turn-constrained tetrapep-
tide mimetic similar to a previously reported Grb2 SH2
domain-binding antagonist.8,9 Key to the preparation of 5
was the synthesis of a functionalized carbamoyl alkenylg-
lycine equivalent analogous to the vinylic ring-juncture
mimetic 6 used in the previous work.8 However, unlike 6,
which is stable in its free acid form, the a-nitrogen-con-
Figure 1 Structures of analogues discussed in the text.
SYNLETT 2004, No. 3, pp 0469–0472
1
8.
0
2.
2
0
0
4
Advanced online publication: 26.01.2004
DOI: 10.1055/s-2004-815425; Art ID: S10703ST
© Georg Thieme Verlag Stuttgart · New York

470
X.-Z. Wang, T. R. Burke Jr.
LETTER
With the critical ring-closing residue 8 in hand, assembly
of the open-chain ureapeptoid 18 was undertaken prior to
final RCM macrocyclization (Scheme 3). This was
achieved by heating 8 with amine-containing 178 (DMSO,
110 °C)27 to yield 18 in 78% yield.28 Subsequent macro-
cyclization of 18 was initially attempted using the first
generation Grubbs catalyst [(PCy3)2Cl2Ru=CHPh].29
Disappointingly, no evidence of product was observed,
even after changing solvent from CH2Cl2 to the higher
boiling toluene and examining a variety of enhancers,
including CuCl and Ti(i-OPr)4.30–33 Conformational de-
pendence of RCM reactions is known34 and failure to
achieve ring closure may have been due to the lack of ap-
propriate conformational restriction in the acyclic 18.35–37
Greater success was found using the second generation
N-heterocyclic carbene-containing RCM catalyst,
{[(PCy3)(Im(Mes)2]Ru=CHPh}, 20 (0.1 molar
equiv)],38–40 which provided ring-closed products E-19
and Z-19 in an approximate 1:1 ratio. These could be
separated by careful silica gel flash chromatography us-
ing Et3N as a ruthenium scavenger.41–43 The synthesis
was completed by bromotrimethylsilane (TMSBr)-medi-
ated cleavage of ethylphosphonate protection followed
by HPLC purification to yield the desired final products
E-544 and Z-5.45
Scheme 1 Reagents and conditions: (i) a) DIBAL-H, toluene, 0 °C;
b) 2 N HCl (98% yield); (ii) (EtO)3P, 130 °C (90% yield); (iii) (S)-
(–)-tert-butanesulfinylamide, Ti(EtO)4, THF, reflux (94% yield);
(iv) allylmagnesium bromide, THF–Et2O (1:4), 0 °C (50% yield).
Difficulty encountered in the conversion of 12 to 13 lead
to the synthesis of phenylcarbamate 8 by a different route
involving asymmetric allylation of aldehyde 11 using (–)-
B-allyldiisopinocampheylborane [(–)-d-Ipc2BAll]. This
provided homoallylic alcohol (S)-14 (Scheme 2).18,19 It
was then necessary to transform (S)-14 to azide 15 with
inversion of stereochemistry. Generally, this could be ap-
proached either by nucleophilic displacement of the cor-
responding sulfonate using azide anion20 or by a
Mitsunobu reaction.21,22 However these procedures failed
to give adequate yields in the present circumstances, pri-
marily due to elimination side-reactions caused by the
high reactivity of the homoallylic position. Alternatively,
application of the Thompson procedure, which uses ex-
cess 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
diphenyl phosphorazidate [(PhO)2P(O)N3],23 gave 15 in
good yield without elimination by-product.24 Finally,
triphenylphosphine (PPh3)-mediated reduction of 15 gave
amine 16,25 which was reacted with phenyl chloroformate
in the presence of Et3N at –78 °C to give the desired func-
tionalized carbamate 8 in 80% overall yield from 11.26
Scheme 2 Reagents and conditions: (i) (–)-d-IPC2BAllyl, –78 °C
(98% yield); (ii) (PhO)2P(O)N3, DBU, toluene (94% yield); (iii) PPh3,
THF–H2O, reflux (92% yield); (iv) Et3N, ClCOOPh, –78 °C (95%
yield).
Scheme 3 Reagents and conditions: (i) DMSO, 110 °C (78% yield);
(ii) catalyst 20, CH2Cl2, reflux (71% yield); (iii) TMSBr, Et3N,
CH3CN.
Synlett 2004, No. 3, 469–472 © Thieme Stuttgart · New York

LETTER
Enantioselective Ureapeptoid Macrocycles
471
(19) Compound 14: [a]D = –36.9 (c 1.02 CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.21 (m, 4 H), 5.71 (ddt, J = 7.0, 10.2,
17.2 Hz, 1 H), 5.02 (m, 2 H), 4.65 (t, J = 6.4 Hz, 1 H), 3.92
(m, 4 H), 3.05 (d, J = 21.7 Hz, 2 H), 2.73 (br s, 1 H, OH),
2.42 (t, J = 7.4 Hz, 2 H), 1.16 (t, J = 7.0 Hz, 6 H). IR (neat):
3376, 2980, 1228, 1021, 962 cm–1. FABMS: m/z = 299
[MH+]. Anal. Calcd for C15H23O4P·0.2H2O: C, 59.67; H,
7.81. Found: C, 59.69; H, 7.83.
(20) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(21) Mitsunobu, O. Synthesis 1981, 1.
(22) Luo, Y.; Blaskovich, M. A.; Lajoie, G. A. J. Org. Chem.
1999, 64, 6106.
In conclusion, reported herein is the utilization of ring-
closing metathesis for the preparation of the first member
of a new class of ureapeptoid-containing macrocycles.
Important aspects of the work include the enantioselective
synthesis of functionalized alkenyl amines and their con-
version to phenylcarbamates that serve as chemically sta-
ble pre-activated substrates for coupling to peptide amino-
termini. Although a ‘proof-of-principle’ application of
ureapeptoid ring closure was provided using a specific ex-
ample modeled on a previously reported signal transduc-
tion-related peptide, the approach may be of general
utility in the construction of novel new classes of bend-
constrained peptidomimetics.
(23) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.;
Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58,
5886.
(24) Compound 15: [a]D = +65.9 (c 1.22 CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.31 (m, 2 H), 7.23 (m, 2 H), 5.70 (ddt, J
= 6.9, 10.4, 17.2 Hz, 1 H), 5.07 (m, 2 H), 4.45 (t, J = 7.2 Hz,
1 H), 3.97 (m, 4 H), 3.13 (d, J = 21.7 Hz, 2 H), 2.51 (m, 2 H),
1.20 (t, J = 7.0 Hz, 6 H). IR (neat): 2095 (N3), 1246, 1022,
958 cm–1. FABMS: m/z = 324 [MH+].
Acknowledgment
Appreciation is expressed to Dr. James Kelley of the LMC for mass
spectral analysis.
(25) Compound 16: [a]D = +14.8 (c 1.19 CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.23 (m, 4 H), 5.67 (m, 1 H), 5.04 (m, 2
H), 3.95 (m, 5 H, 2 × OCH2 + CHN), 3.07 (d, J = 21.7 Hz, 2
H), 2.38 (m, 1 H), 1.18 (t, J = 7.0 Hz, 6 H). IR (neat): 3368,
3291, 2978, 1731, 1632, 1051 cm–1. FABMS: m/z = 298
[MH+]. Anal. Calcd for C15H24NO3P: C, 60.59; H, 8.14; N,
4.71. Found: C, 60.14; H, 8.11; N, 4.69.
(26) Compound 8: [a]D = +69.5 (c 0.53, CHCl3); mp 56–57 °C.
1H NMR (400 MHz, CDCl3): d = 7.27 (m, 6 H), 7.12 (m, 1
H), 7.05 (m, 2 H), 5.70 (m, 2 H), 5.05 (m, 2 H), 4.78 (dt, J =
7.0 Hz, 7.2 Hz, 1 H), 3.97 (m, 4 H), 3.10 (d, J = 21.7 Hz, 2
H), 2.55 (m, 2 H), 1.19 (t, J = 7.4 Hz, 6 H). IR (neat): 3240,
1737, 1200 cm–1. FABMS: m/z = 418 [MH+]. Anal Calcd for
C22H28NO5P: C, 63.30; H, 6.76; N, 3.36. Found: C, 63.15; H,
6.55; N, 3.49.
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7.42 (d, J = 7.9 Hz, 2 H), 3.99 (m, 4 H), 3.19 (d, J = 22.4 Hz,
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(28) Compound 18: mp 69–71 °C. 1H NMR (400 MHz, MeOH-
d): d = 8.08 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1 H),
7.78 (d, J = 8.4 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.48 (t,
J = 7.6 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 8.8
Hz, 1 H), 6.93 (m, 2 H), 6.79 (m, 2 H), 5.88 (ddt, J = 6.8 Hz,
10.2 Hz, 17.0 Hz, 1 H), 5.62 (ddt, J = 6.8 Hz, 10.2 Hz, 17.2
Hz, 1 H), 5.06 (m, 4 H), 4.56 ( dd, J = 4.9 Hz, 6.9 Hz, 1 H),
4.51 (t, J = 7.0 Hz, 1 H), 4.0 (m, 4 H), 3.22 (dd, J = 8.0 Hz,
13.1 Hz, 1 H), 3.10–3.02 (m, 3 H), 2.93 (dd, J = 7.2 Hz, 13.9
Hz, 1 H), 2.67 (m, 2 H), 2.34 (m, 3 H), 2.16 (m, 3 H), 1.98
(m, 1 H), 1.88(m, 1 H), 1.79 (m, 1 H), 1.66 (m, 4 H), 1.57
(m, 1 H), 1.43 (m, 1 H), 1.32 (m, 1 H), 1.28 (t, J = 7.0 Hz,
6 H). FABMS; m/z = 788 [MH+]. Anal Calcd for
C43H58N5O7P·0.5H2O: C, 64.65; H, 7.31; N, 8.77. Found: C,
64.80; H, 7.42; N, 8.75.
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(15) Compound 12: 1H NMR (400 MHz, CDCl3): d = 8.57 (s, 1
H), 7.80 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 4.03
(m, 4 H), 3.20 (d, J = 22.3 Hz, 2 H), 1.25 (m, 15 H). IR
(neat): 2980, 1598, 1247, 1021 cm–1. FABMS: m/z = 360
[MH+]. Anal. Calcd for C16H26NO4PS: C, 53.47; H, 7.29; N,
3.90. Found: C, 53.21; H, 7.58; N, 3.78.
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Synlett 2004, No. 3, 469–472 © Thieme Stuttgart · New York

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X.-Z. Wang, T. R. Burke Jr.
LETTER
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J = 8.0 Hz, 2 H), 5.68 [q(apparent), J = 8.5 Hz, 16.7 Hz, 1
H], 5.12 (ddd, J = 4.3 Hz, 10 Hz, 16.7 Hz, 1 H), 4.51 (m, 1
H), 4.37 (dd, J = 4.3 Hz, 10.7 Hz, 1 H), 3.45 (m, 1 H), 3.36
(dd, J = 5.3 Hz, 13.9 Hz, 1 H), 3.11 (d, J = 21.5 Hz, 2 H),
2.98 (m, 2 H), 2.80 (m, 3 H), 2.60 (m, 1 H), 2.50 (m, 1 H),
2.12 (m, 1 H), 1.98 (m, 1 H), 1.70 (m, 3 H), 1.53 (m, 4 H),
1.47 (m, 1 H), 1.35 (m, 1 H), 1.19 (m, 1 H).
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(44) Compound E-5: mp 182–184 °C (dec.). 1H NMR (400 MHz,
MeOH-d): d = 8.08 (m, 1 H), 7.83 (m, 1 H), 7.70 (dd, J = 2.3
Hz, 7.0 Hz, 1 H), 7.44 (m, 4 H), 7.32 (m, 2 H), 7.11 (d,
(45) Compound Z-5: mp 214–216 °C. 1H NMR (400 MHz,
MeOH-d): d = 7.96 (d, J = 8.6 Hz, 1 H), 7.74 (d, J = 7.2 Hz,
1 H), 7.60 ( d, J = 7.6 Hz, 1 H), 7.41 (m, 1 H), 7.37 (m, 1 H),
7.28 (m, 2 H), 7.19 (m, 2 H), 7.12 (m, 2 H), 5.60 (m, 1 H),
5.14 (m, 1 H), 4.82 (m, 1 H), 4.61 (m, 1 H), 3.74 (d, J = 12.8
Hz, 1 H), 3.31 (d, J = 12.8 Hz, 1 H), 3.05 (m, 1 H), 2.99 (d,
J = 21.7 Hz, 2 H), 2.86 (dd, J = 6.6 Hz, 15.6 Hz, 1 H), 2.74
(m, 2 H), 2.17 (m, 3 H), 1.94 (m, 3 H), 1.74 (m, 2 H), 1.53
(m, 4 H), 1.40 (m, 1 H), 1.20 (m, 3 H).
Synlett 2004, No. 3, 469–472 © Thieme Stuttgart · New York