Imine additions of internal alkynes for the synthesis of trisubstituted (E)-alkene and cyclopropane peptide isosteres

Article abstract of DOI:10.1002/adsc.200505171

Divergent multi-component reactions (DMCR) involving C-C bond formations can provide large increases in structural diversity and allow the rapid assembly of complex products from readily available starting materials. Cascade hydrozirconation-Zr/Zn transmetalation-imine addition of alkynes represents a versatile methodology for the synthesis of (E)-alkene and cyclopropane dipeptide isosteres. Appropriate substitutions at the sp²-carbon of (E)-alkene peptide isosteres allow a range of Pd-catalyzed cross-coupling reactions, which can be used for the fine-tuning of the conformational and electronic properties of the parent peptide bond mimic. C-C bond formation by microwave-accelerated Stille coupling of stannylalkenes represents a fast, convergent synthetic approach toward trisubstituted (E)-alkene dipeptide isosteres.

Full text of DOI:10.1002/adsc.200505171

FULL PAPERS
DOI: 10.1002/adsc.200505171
Imine Additions of Internal Alkynes for the Synthesis of
Trisubstituted (E)-Alkene and Cyclopropane Peptide Isosteres
Peter Wipf,* Jingbo Xiao, Steven J. Geib
Department of Chemistry and Center for Chemical Methodologies &Library Development, University of Pittsburgh,
219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, USA
Fax: (þ1)-412-624-0787, e-mail: pwipf@pitt.edu
Received: April 22, 2005; Accepted: July 25, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Divergent multi-component reactions cross-coupling reactions, which can be used for the
À
(DMCR) involving C C bond formations can provide fine-tuning of the conformational and electronic
large increases in structural diversity and allow the properties of the parent peptide bond mimic. C C
À
rapid assembly of complex products from readily bond formation by microwave-accelerated Stille cou-
available starting materials. Cascade hydrozircona- pling of stannylalkenes represents a fast, convergent
tion-Zr/Zn transmetalation-imine addition of alkynes synthetic approach toward trisubstituted (E)-alkene
represents a versatile methodology for the synthesis dipeptide isosteres.
of (E)-alkene and cyclopropane dipeptide isosteres.
Appropriate substitutions at the sp2-carbon of (E)-al- Keywords: (E)-alkene; C C bond formation; cyclo-
À
kene peptide isosteres allow a range of Pd-catalyzed propanes; palladium; peptide isosteres; zirconocenes
Introduction
peptide bond and the aC(iþ1) –aC(iþ2) distance (Fig-
ure 1).[7,9]
While the past success of peptide mimicry in pharma-
In order to generate a closer correlation between the
ceutical R&D has been mixed,[1] the recent worldwide conformational and electrostatic properties of peptide
surge in marketed peptides as well as peptides in clinical bonds and the corresponding alkene isosteres, we have
testing bodes well for the future of this field. Most cur- begun a systematic study of trisubstituted (E)-alkene
¼
rent peptidic drugs such as insulin, oxytocin, and cyclo- peptide isosteres (y[XC CH], TEADIs) where X¼ar-
sporin are of natural origin,[2] but synthetically produced yl, alkyl, Me, H, F, and CF3.[7b,10,11] However, alkenes
structures such as fuzeon (enfuvirtide) and integrilin can suffer from potential isomerization, oxidation and
(eptifibatide) are also taking hold.[3] The broad applica- general chemical lability.[12] Accordingly, we are also in-
tion of peptides as drugs is still limited since they are rap- vestigating novel cyclopropane dipeptide isosteres
idly metabolized in vivo, exhibit poor oral bioavailabil- (y[RCp], CPDIs),[11] which are expected to display in-
ity, and are not easily transported across cellular and nu- creased metabolic stability compared to the correspond-
clear membranes.[4] Many of these shortcomings can be ing TEADIs.[13] Furthermore, we have developed an ap-
attributed to the polar amide bonds which comprise the proach to backbone-extended a,b-cyclopropyl-g-amino
peptide backbone.[5] The design of isosteric replace- acids,[14] which were inspired by the natural occurrence
ments of the amide bond offers an attractive strategy and conformational properties of vinylogous amino
to overcome these limitations.[6] In particular, the re- acids.[15]
placement of the scissile peptide bond with non-hydro-
The divergent multi-component cascade reaction
lyzable analogues is an important design motif in medic- (DMCR)[16] of alkenylzirconocenes 1 allows a conven-
inal and bioorganic chemistry due to enhanced stability ient access to allylic amines,[17,18] homoallylic amines,[19]
against enzymatic degradation. The rigid (E)-alkene C-cyclopropylalkylamines,[17,18] and C,C-dicyclopropyl-
peptide isostere design, based on the concept of amide alkylamines by stereoselective formation of multiple
[20]
À
w-angle planarity, has proven to yield useful, conforma- C C bonds (Figure 2).
tionally pre-organized structural mimetics of hydrolyti-
We now report an extension of this methodology using
cally labile amide bonds.[7,8] The main rationale for this internal alkynes as readily available precursors of in situ
strategy is the accurate mimicry of the geometry of the prepared alkenylzirconocenes for the convergent syn-
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Figure 1. The structural and electronic features of peptide bonds served as inspiration for the design of trisubstituted (E)-al-
kene peptide isosteres (TEADIs) and cyclopropane dipeptide isosteres (y[Cp], CPDIs), which are related to backbone-ex-
tended vinylogous amino acids and a,b-cyclopropyl-g-amino acids.
Figure 2. Examples for synthetic scaffolds that are available by addition of alkenylzirconocenes to imines and carbonyl com-
pounds.
thesis of TEADIs and CPDIs, and the use of Pd-cata- Results and Discussion[22]
lyzed cross-couplings for a variation of the X substituent
on TEADIs.[21]
Treatment of the (S)-(þ)-Roche ester derived dibro-
moalkene 2[11] with n-BuLi, and quenching of the reac-
tion mixture with methyl iodide, trimethylchlorosilane
or tributyltin chloride afforded the key internal alkynes
3a–c in high yields (Scheme 1).
1st Generation Approach to Trisubstituted (E)-Alkene
Dipeptide Isosteres (TEADIs)
Methylated alkyne 3a and silylated alkyne 3b were hy-
Scheme 1. Synthesis of chiral internal alkynes.
drozirconated with Cp2ZrHCl,[23] transmetalated to
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Scheme 2. Synthesis of methyl- and TMS-substituted TEA-
DIs.
Scheme 3. Introduction of the fluoro- and iodoalkene moiet-
ies by electrophilic halogenation of stannylated alkenes.
Me2Zn and added to (diphenylphosphinylimino)methyl-
arenes to provide the corresponding allylic amides,
which were converted to the desired TEADIs 4 and 5 us-
ing standard protocols (Scheme 2).[11,24] Naphthylamine with the protocol developed by Tius et al. (XeF2/
was selected as a coupling component due to the relative AgOTf/DMAP) to afford the vinyl fluoride 8 in 50%
ease of crystallization of the resulting amides. The as- yield.[27] Alkene 8 served as the substrate for the syn-
signment of the configuration of the diastereomers thesis of fluorine-substituted TEADIs, which have
was based on chemical degradation and further secured been used as mimics of the dipolar properties of amide
by X-ray structural analyses of 5a and 5b (Figure 3).
groups and as potential hydrogen bond acceptors.[28,29]
The microwave-accelerated Stille coupling[30] of
stannyl intermediate 6a proved to be a versatile method
for installment of substituents on the alkene sp2-carbon
(Table 1). Under monomode microwave irradiation
2nd Generation Approach to TEADIs
We initially planned to access the halogen-substituted conditions, the reaction time was shortened from 24 h
TEADIs as common intermediates generated from the to less than 1 h and the scope was extended to sterically
corresponding silylated alkenes in order to establish a hindered substrates like 2,6-dimethyliodobenzene. Both
convergent approach toward TEADIs bearing different p-electron-rich and -deficient heterocycles such as thio-
functional groups on the conformation-controlling[10] phene, pyrazole, pyridine, and pyrazine could be cou-
double bond. Interestingly, we were unable to convert pled in high yields. This methodology thus enabled us
the trimethylsilyl group into the corresponding vinyl to pursue a convergent approach for the attachment of
halides using a variety of halodesilylation methods.[25] a broad selection of aromatic groups to the alkene moi-
The unusual stability of the TMS-alkene to electrophilic ety of TEADIs.[31]
attack is most likely due to the steric shielding effect of
Alternatively, Negishi coupling[32] of vinyl iodide 7
the bulky substituents flanking the double bond and the with phenylzinc bromide can also be used to install aro-
relatively rigid conformation due to A1,3- and A1,2-strain matic groups on the double bond (Scheme 4). More-
on this system.
over, this coupling variant provides a way to introduce
The difficulties of the TMS-halogen exchange could aliphatic groups like methyl or ethyl.[33] For example,
be circumvented by the selection of stannylated alkyne phenyl-substituted TEADIs 11 and 12 were obtained
3c as a substrate. The 1,1-heterobimetallic species[26] de- from 9a after separation by chromatography on SiO2
rived from hydrozirconation/transmetalation of stanny- (Scheme 4). The configuration of these coupling prod-
lalkyne 3c readily added to the electron-poor aldimine, ucts was assigned by X-ray structural analysis of 11,
and no regioisomeric addition products were detected which was shown to have the anti-[(Liþ1Liþ2)]-configu-
(Scheme 3). This reaction represents the first example ration (Figure 3).
of a vinylstannylzinc addition to an aldimine.
Matching the extraordinary electrostatic and hydro-
À
À
The higher reactivity of the C Sn bond vs. a C Si gen-bonding properties of the amide bond represents
À
bond and the longer C Sn bond distance both worked the most challenging parameter for isostere design and
in concert to facilitate the halogen exchange reaction. effective peptidomimicry. Our recent study of gramici-
In contrast to the TMS substrates, stannyl intermediate din S analogues showed that the trifluoromethyl-substi-
6a rapidly succumbed to NIS to give vinyl iodide 7 in tuted (E)-alkene was a superior mimetic of the electro-
63% yield. Furthermore, fluorination of 6a was possible static effects of the carbonyl group vs. its methyl-substi-
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Table 1. Microwave-accelerated Stille couplings.
Entry
1
RI
Product
Yield [%]
63%
9a
2
3
4
5
9b
9c
9d
9e
64%
79%
77%
51%
Scheme 5. Synthesis of trifluoromethyl-substituted TEADIs
from iodide 14.
tuted counterpart.[7b,34] However, when we subjected io-
dide 7 to coupling conditions with nucleophilic trifluor-
omethyl groups,[35] the reaction suffered from unexpect-
ed low yield and partial conversion because of compet-
ing TBDPS-deprotection and other side reactions. Grat-
ifyingly, when 7 was converted to the corresponding
amide 14, the coupling with FSO2CF2CO2Me[36] in the
presence of copper(I) thiophenecarboxylate (CuTc) in
DMFafforded the corresponding CF3-substituted TEA-
DIs 15 and 16, which were separated by chromatography
on SiO2 (Scheme 5).
6
7
8
9f
82%
58%
61%
9g
9h
9
9i
9j
72%
95%
10
Methyl-Substituted Cyclopropane Dipeptide Isosteres
(CPDIs)
One of the highlights of the coupling of organozircono-
cenes and imines is its ready combination with Sim-
mons–Smith[37] chemistry for the preparation of cyclo-
propanated derivatives. CPDI analogues of TEADIs
can be obtained by closely related DMCR processes
(Scheme 6). A 3:2 syn,syn:syn,anti mixture of N-phos-
phinoylaminocyclopropanes 17 was obtained in 60%
yield from 3a. Simultaneous N- and O-deprotection fol-
lowed by selective N-reprotection with CbzCl afforded a
separable mixture of alcohols 18 and 19. After oxidation
to the carboxylic acid, carbodiimide mediated cou-
pling[38] with amines provided CPDIs 20 and 21.[39] Inter-
estingly, upon scale-up of the preparation of 19 and 20 to
the multi-gram level, the chlorocyclopropane by-prod-
uct 22 was isolated in ca. 2% yield as a single diastereo-
mer. While the mechanism of the stereoselective chlori-
nation of the cyclopropane is not completely obvious, a
radical process during the sodium chlorite oxidation
step is likely involved.
Scheme 4. Negishi cross-coupling for the synthesis of phenyl-
substituted TEADIs.
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Synthesis of Trisubstituted (E)-Alkene and Cyclopropane Peptide Isosteres
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and a more compact backbone-side chain packing, facil-
itating the formation of the intramolecular hydrogen
bond. In proteins, type V’ b-turns occur much less fre-
quently than type II’, and they are often not hydrogen-
bonded.[42] However, for both types, the D(iþ1)L(iþ2)-con-
figuration at the amino acid a-carbons is preferred,
which is the configuration present in both 5a and 5b.
In contrast, the L(iþ1)L(iþ2)-configuration present in 11,
21, and 22 would be expected to stabilize turn types I
and III, but maybe due to crystal packing forces two an-
gles (f2 and y3 for 11, and y2 and y3 for 21 and 22) differ
by more than 408 from type I (Figure 4). Therefore, the
latter reverse turns should be classified as type IV b-
turns. The introduction of the chlorine substituent on
the cyclopropane ring has almost no effect on the turn
conformation (21 vs. 22). In addition, the distances be-
tween aC(iþ1) and aC(iþ2) were found to be very similar
to the parent amide (3.8 Š) for both the trisubstituted
(E)-alkene isosteres (5a, 3.904 Š; 5b, 4.034 Š; 11,
3.908 Š) and the cyclopropane isosteres (21, 3.909 Š;
22, 3.881 Š). Significantly, all isosteres thus represent re-
alistic replacements for the amide linkage in peptides.
Conclusion
We have developed a new and convergent protocol for
the efficient synthesis of trisubstituted (E)-alkene di-
¼
peptide isosteres (y[(E)-C(X) CH], TEADIs). A
Scheme 6. Synthesis of methyl-substituted CPDIs.
broad variation of the conformation-determining al-
kene X-substituent was accomplished that allows the
preparation of methyl-, trifluoromethyl-, trimethylsil-
yl-, stannyl-, iodo-, fluoro-, aryl-, and heteroaryl-func-
tionalized alkenes. Novel trisubstituted cyclopropane
dipeptide isosteres (y[RCp], CPDIs) were obtained by
DMCR methodology. d-Amino acid scaffolds with
(E)-alkene or cyclopropane core elements can be used
as building blocks for bioorganic and supramolecular
chemistry as well as for structure-activity studies of bio-
logically active peptide sequences in medicinal chemis-
try.[43]
Solid State Structural Analyses of Selected TEADIs
and CPDIs
The single crystal X-ray structural analysis plays a very
important role in peptide secondary structure determi-
nation, even though sometimes solution structures dif-
fer from those in the solid state.[6b,40] In order to evaluate
the potential of these dipeptide isosteres as b-turn pro-
moters[10] as well as obtain unambiguous assignments
of diastereomers, X-ray structures of 5a, 5b, 11, 21 and
22 were procured (Figures 3 and 4). By comparison to
typical b-turns,[41] the conformation of isostere 5b can
be assigned as a type II’ b-turn (the four core dihedral
angles are f2 ¼65.88, y2 ¼ À121.18, f3 ¼ À101.58, and
y3 ¼4.28) with a characteristic ten-membered hydrogen
bonding interaction and a bond length of 2.52 Š. Nor-
mally, the length of a typical b-turn hydrogen bond
measures around 2.3 Š. Due to the bulk of the TMS sub-
stituent, the conformation-anchoring allylic strain inter-
action is particularly severe for isostere 5b. It was also in-
teresting to note that the conformations of the other iso-
steres varied quite broadly. Isostere 5a could be classi-
fied as a type V’ b-turn, a less common relative of the
type II’ b-turn with a variable y3 dihedral angle. The
larger steric bulk of the TMS vs. the methyl group ac-
Experimental Section
General Remarks
All moisture-sensitive reactions were performed using syringe-
septum cap techniques under an N2 atmosphere and all glass-
ware was dried in an oven at 1508C for 2 h prior to use. THF
was distilled over sodium/benzophenone ketyl; CH2Cl2, tol-
uene and Et3N were distilled from CaH2. Me2Zn (2.0 M solu-
tion in toluene) was purchased from Aldrich Company. Reac-
tions were monitored by TLC analysis (EM Science pre-coated
silica gel 60 F254 plates, 250 mm layer thickness) and visualiza-
tion was accomplished with a 254 nm UV light and by staining
counts for a narrower tolerance of the y3 dihedral angle with Vaughnꢁs reagent [4.8 g (NH4)6Mo7O24 ·4 H2O, 0.2 g
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Peter Wipf et al.
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Figure 4. X-ray structures of CPDIs 21 and 22.
Ce(SO4)2 ·4 H2O in 10 mL concentrated H2SO4 and 90 mL
H2O). Flash chromatography on SiO2 was used to purify the
crude reaction mixtures. An Emrys Optimizer microwave reac-
tor from Personal Chemistry (Biotage) was used for micro-
wave reactions.
N-[5-(tert-Butyldiphenylsilanyloxy)-2-tributyltinyl-
(4R)-methyl-(1SR)-(methyl-4-formylbenzoic)pent-
(2Z)-enyl]-P,P-diphenylphosphinamide (6a); Typical
Protocol for Imine Addition
A suspension of 5.05 g (19.6 mmol) of Cp2ZrHCl in 50.0 mL of
CH2Cl2 was treated at room temperature with 6.00 g
(9.81 mmol) of 3c. After 15 min, CH2Cl2 was removed on the
rotatory evaporator and 50.0 mL of toluene were added. The
reaction mixture was cooled to À788C and treated over a pe-
Figure 3. X-ray structures of TEADIs 5a, 5b, and 11.
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Synthesis of Trisubstituted (E)-Alkene and Cyclopropane Peptide Isosteres
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riod of 30 min with 4.91 mL (9.82 mmol) of Me2Zn (2.0 M sol-
ution in toluene). The mixture was stirred at À788C for 30 min,
warmed to room temperature over a period of 5 min and treat-
ed in one portion with 2.38 g (6.55 mmol) of methyl 4-[(diphe-
nylphosphinylimino)methyl]benzoate. The mixture was stir-
red at room temperature overnight, quenched with saturated
NH4Cl, diluted with EtOAc, filtered through Celite, and wash-
ed with H2O and brine. The organic layer was dried (MgSO4),
concentrated under vacuum, and purified by chromatography
on deactivated SiO2 (1:1, hexanes/EtOAc containing 1%
Et3N) to afford 6a as a yellow, oily ~ 2:1 mixture of diastereom-
ers; yield: 4.18 g (65%); IR (neat). n¼3380, 3314, 3186, 3071,
2956, 2929, 2856, 1724, 1609, 1463, 1438, 1428, 1279, 1192,
0.95 (d, 1.5H, J¼6.7 Hz); 13C NMR (75 MHz, CDCl3): d¼
166.9, 166.8, 146.8 (2C), 141.5, 141.4, 137.9, 137.3, 135.5 (2C),
135.4, 134.1, 133.6 (2C), 133.5, 133.4, 133.1, 132.6, 132.7,
132.5, 132.4, 132.3 (2C), 131.9, 131.8 (2C), 129.7, 129.6, 129.5,
129.4, 129.1, 128.9, 128.8, 128.5, 128.4, 128.3 (2C), 128.1, 127.6
(2C), 127.5, 127.3, 127.2 (2C), 68.5, 68.3, 61.3, 60.8, 51.9, 35.9,
26.8 (2C), 19.2 (2C), 17.4, 17.3; EI-MS: m/z¼763 (Mþ, 0.44),
706 (38), 416 (5), 398 (18), 364 (25), 259 (8), 218 (17), 201
(100), 183 (17), 135 (37), 91 (14), 77 (28); HR-MS (EI): m/z
calcd. for C44H41NO4PSi (MÀC4H9): 706.2543; found:
706.2509.
;
1111, 1078, 1020, 824, 741, 726, 702 cmÀ1 1H NMR
Supporting Information
(300 MHz, CDCl3): d¼7.98–7.79 (m, 6H), 7.72–7.66 (m,
4H), 7.43 (d, 2H, J¼9.0 Hz), 7.47–7.28 (m, 12H), 6.21 [d,
0.35H, J¼9.9 Hz, dd (117Sn 7.5%, 119Sn 8.6%), 3JH-Sn ¼118 Hz,
3JH-H ¼9.9 Hz], 6.08 [d, 0.65 H, J¼10.0 Hz, dd (117Sn 7.5%,
Comprehensive experimental protocols and spectroscopic
data for all new compounds.
3
3
119Sn 8.6%), JH-Sn ¼119 Hz, JH-H ¼10.0 Hz), 4.97–4.86 (m,
1H), 3.91 (s, 3H), 3.71–3.51 (m, 2H), 3.15 (dd, 0.65H, J¼
10.6, 6.7 Hz), 3.02 (dd, 0.35H, J¼10.5, 6.6 Hz), 2.50–2.40 (m,
1H), 1.26–1.13 (m, 15H), 1.10 (s, 4H), 1.08 (s, 5H), 0.77 (t,
9H, J¼7.0 Hz), 0.70–0.60 (m, 6H); 13C NMR (75 MHz,
CDCl3): d¼174.8, 166.7, 148.2, 148.0, 144.7, 144.6, 144.4,
144.0, 143.9, 143.2, 135.5, 133.8 (2C), 133.5, 133.4, 133.3,
132.7, 132.6, 132.5, 132.1 (2C), 131.7, 131.5 (2C), 131.4, 130.9,
130.8, 129.6, 129.5, 128.8, 128.7, 128.4, 128.2, 128.0 (2C),
127.6, 127.5, 68.6, 68.3, 62.3, 61.4, 51.8, 42.0, 29.0, 28.8 (2C),
28.6, 27.5, 27.1, 26.8, 26.7, 19.2 (2C), 18.0 (2C), 13.9, 13.6,
13.4, 10.8, 10.6; EI-MS: m/z¼976 (Mþ, 0.52), 947 (0.44), 920
(87), 630 (30), 552 (6), 450 (24), 336 (100), 201 (57), 135 (39).
Acknowledgements
This work was supported by the NIH-NIGMS CMLD program
(P50-GM067082). J. X. gratefully acknowledges the Andrew W.
Mellon Foundation for a predoctoral fellowship.
References and Notes
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N-[5-(tert-Butyldiphenylsilanyloxy)-2-phenyl-(4R)-
methyl-(1SR)-(methyl-4-formylbenzoic)pent-(2E)-
enyl]-P,P-diphenylphosphinamide (9a); Typical
Protocol for Microwave-Accelerated Stille Coupling
In a 10-mL microwave tube, 16.4 mg (387 mmol) of LiCl was
flame fused under vacuum. After cooling to room temperature,
7.45 mg (6.44 mmol) of Pd(PPh3)4 and 25.4 mg (257 mmol) of
CuCl were added. The mixture was degassed 3 times under vac-
uum with an argon purge. A solution of 47.0 mg (48.1 mmol) of
6a and 13.1 mg (64.2 mmol) of iodobenzene in DMSO
(2.00 mL) was added with stirring. The resulting black mixture
was degassed by a freeze-thaw process and heated under mi-
crowave irradiation at 608C for 40 min. The brown solution
was quenched with H2O, and extracted with EtOAc. The com-
bined organic layers were dried (MgSO4), concentrated under
vacuum, and purified by chromatography on SiO2 (1:1, hex-
anes/EtOAc) to afford 9a as a colorless, solid ~ 1:1 mixture
of diastereomers; yield: 23.0 mg (63%); mp 72–748C (ether);
IR (neat): n¼3184, 3054, 2958, 2930, 2858, 1723, 1610, 1437,
1280, 1192, 1111, 1020, 917, 824, 743, 725, 701 cmÀ1; 1H NMR
(300 MHz, CDCl3): d¼7.92–7.86 (m, 2H), 7.84–7.76 (m,
4H), 7.67–7.63 (m, 2H), 7.59–7.59 (m, 2H), 7.48–7.32 (m,
14H), 7.23–7.17 (m, 3H), 6.84 (dd, 1H, J¼7.7, 1.9 Hz), 6.78
(dd, 1H, J¼7.7, 1.7 Hz), 5.63 (d, 0.5H, J¼10.1 Hz), 5.51 (d,
0.5H, J¼10.0 Hz), 5.07 (t, 0.5H, J¼10.7 Hz), 5.04 (t, 0.5H,
J¼10.7 Hz), 3.91 (s, 1.5H), 3.90 (s, 1.5H), 3.58–3.43 (m, 2H),
3.28–3.21 (m, 1H), 2.49–2.44 (m, 0.5H), 2.39–2.33 (m,
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1612
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Synthesis of Trisubstituted (E)-Alkene and Cyclopropane Peptide Isosteres
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