Selective access to e - And Z -ΔIle-containing peptides via a stereospecific E2 dehydration and an O → N acyl transfer

Article abstract of DOI:10.1021/ol5018933

A concise synthesis of peptides that contain E- or Z-dehydroisoleucine (ΔIle) residues is reported. The key reaction is an unusual anti dehydration of β-tert-hydroxy amino acid derivatives that is mediated by the Martin sulfurane. A subsequent tandem Staudinger reduction-O → N acyl transfer process forges an amide bond to the ΔIle residue with minimal E/Z alkene isomerization. Density functional calculations attribute the stereospecific dehydration to a highly asynchronous E2 anti process.

Full text of DOI:10.1021/ol5018933

Letter
pubs.acs.org/OrgLett
Selective Access to E- and Z‑ΔIle-Containing Peptides via a
Stereospecific E2 Dehydration and an O → N Acyl Transfer
Zhiwei Ma, Jintao Jiang, Shi Luo, Yu Cai, Joseph M. Cardon, Benjamin M. Kay, Daniel H. Ess,*
and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States
S
* Supporting Information
ABSTRACT: A concise synthesis of peptides that contain E- or Z-
dehydroisoleucine (ΔIle) residues is reported. The key reaction is an
unusual anti dehydration of β-tert-hydroxy amino acid derivatives that is
mediated by the Martin sulfurane. A subsequent tandem Staudinger
reduction−O → N acyl transfer process forges an amide bond to the
ΔIle residue with minimal E/Z alkene isomerization. Density functional calculations attribute the stereospecific dehydration to a
highly asynchronous E2 anti process.
α,β-Dehydroisoleucine (ΔIle) is present in several bioactive
natural products including phomopsin A and yaku’amide A
(Figure 1).1 E-ΔIle is more common than its Z-isomer, with
Scheme 1. Syntheses of ΔIle-Containing Peptides
Figure 1. Representative natural products that contain ΔIle.
yaku’amides A and B1a representing the only natural products
isolated to date that contain the latter residue. Bulky
dehydroamino acids such as ΔIle are valued for their rigidifying
effect on peptides2,3 and their increased stability to proteases
relative to standard amino acids.4 Accordingly, new and efficient
methods that facilitate their stereoselective incorporation into
peptides are in demand.
order to prevent generation of an azlactone that readily
undergoes alkene isomerization.6,7 Herein, we report the
incorporation of E- and Z-ΔIle into peptides without recourse
to amide protection. Our strategy features an O → N acyl transfer
reaction8 and relies on an unusual anti dehydration of tertiary
alcohols that is mediated by the Martin sulfurane.9,10
Recently, we found that OsO4-catalyzed base-free amino-
hydroxylations11 can be conducted on trisubstituted alkenes with
complete regioselectivity, affording rapid access to derivatives of
β-tert-hydroxy amino acids.12 In the context of this study, we
generated a ΔVal-containing peptide via dehydration of β-
OHVal. In an effort to extend this aminohydroxylation−
As part of synthetic efforts targeting the phomopsins, the
Wandless5 and Joullie6
́
groups developed stereospecific dehy-
drations of β-hydroxyisoleucine (β-OHIle) derivatives for
constructing E-ΔIle (Scheme 1). In the course of preparing
yaku’amide A, Inoue et al. devised a different strategy for
accessing E- and Z-ΔIle featuring a Cu-catalyzed coupling
reaction.7 Unfortunately, in each case peptide coupling of the C-
terminal ΔIle requires protection of the neighboring amide in
Received: June 30, 2014
Published: July 16, 2014
© 2014 American Chemical Society
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Letter
dehydration strategy to the construction of ΔIle derivatives, we
examined the aminohydroxylation of E-enoate 13 (Scheme 2).
demonstrating the impact of subtle structural differences on the
reactivity of these compounds. We next attempted to perform
the aminohydroxylation on a substrate possessing an activated
carboxylate group that could be employed directly in a
subsequent amidation. Although the phenyl ester21 analogous
to 17 was a viable aminohydroxylation substrate, problems with
the deprotection and coupling steps caused us to abandon this
approach.
Scheme 2. Synthesis and anti Dehydration of 15 and 19
Attempted dehydrations of tripeptides with a β-hydroxy amino
acid as the central residue did not proceed, demonstrating the
necessity of performing the dehydration prior to amidation. At
this stage, we were drawn to O → N acyl transfer chemistry8 as a
means of precluding alkene isomerization without resorting to
protection of the neighboring backbone amide. We envisioned
that β-azidoethyl esters could be stereoselectively dehydrated
and then converted into amides via a tandem reduction/
rearrangement process. The requisite substrates were con-
structed via saponification of ester 15 followed by alkylation with
iodides 21a and 21b (Scheme 3).22 Alkylative esterification was
Scheme 3. Stereoselective Synthesis of Z-ΔIle-Containing
a
Peptides 24a and 24b
This alkene reacted sluggishly when CbzHN−OC(O)p-ClPh11
was employed as the nitrogen source reagent, and copious
quantities of benzyl carbamate (CbzNH2) were obtained.
Inspired by the work of Donohoe et al. on tethered amino-
hydroxylations,13 we reasoned that a less basic leaving group on
the carbamate would improve the reaction. Indeed, CbzHN−
OMs gave significantly better results, as racemic β-OHIle
derivative 14 was produced in good yield (70%) along with
smaller amounts of CbzNH2 byproduct. While this work was in
progress, the virtues of sulfonyloxycarbamates as reagents for
base-free aminohydroxylations were noted by McLeod et al.14
Hydrogenolysis of 14 and coupling of the resulting free amine
to Cbz-Gly afforded dipeptide 15. Since dehydrations of tertiary
alcohols with the Martin sulfurane are reported to proceed via
E1-like mechanisms,9,15 we were not expecting this reagent to
dehydrate 15 stereoselectively. We were therefore surprised to
find that exposure of 15 to the Martin sulfurane furnished Z-
ΔIle-containing dipeptide 16 as the product of clean anti
dehydration. No minor isomers were visible by 1H NMR. While
anti-selective or E2-like dehydrations of tertiary alcohols
promoted by this reagent are not unprecedented,16 they are
much less common than E1-like dehydrations of these substrates.
In our hands, application of the Wandless protocol to 15
delivered 16 with varying levels of selectivity (4−8:1 dr), so we
continued our studies with the Martin sulfurane as our reagent of
choice.17 Importantly, we were able to establish the stereospecific
nature of this process by applying the four-step sequence
developed with E-enoate 13 to Z-enoate 17 (Scheme 2). The
dehydration of dipeptide 19 produced E-ΔIle-containing peptide
20 as a single detectable isomer.
a
Asterisks on adjacent atoms indicate the portrayal of relative
b
stereochemistry. The conversion of 23b into 24b was conducted
with piperidine instead of morpholine as the base.
necessary to avoid nonselective dehydration that would occur
under typical conditions (i.e., DCC), and iodides 21a and 21b
were selected to serve as surrogates for the simplest (Gly) and
bulkiest (Val) amino acids that are coupled to the C-termini of
ΔIle residues in yaku’amide A. Esters 22a and 22b were
produced in good yields, with the latter generated as an
inconsequential mixture of diastereomers due to the racemic
nature of 15.
Pleasingly, the esters underwent stereoconvergent anti
dehydration when exposed to the Martin sulfurane, furnishing
Z-ΔIle derivatives 23a and 23b as single isomers. Dehydration of
22a was clean at 0 °C, whereas a small amount of E-isomer was
obtained when the bulkier 22b was dehydrated at 0 °C (ca. 7:1
dr). Fortunately, only the desired Z-23b was observed when the
reaction was maintained at −20 °C. Staudinger reduction of
azides 23a and 23b was facile, and addition of an amine base to
the mixture upon completion of the reduction triggered O → N
acyl transfer, producing amides 24a and 24b in good yields.
Minor amounts of alkene isomerization occurred during this
process (≥10:1 dr), but to our knowledge these are the best
results to date for amidations of ΔIle derivatives in the absence of
backbone amide protecting groups. This anti dehydration−O →
N acyl transfer strategy worked equally well for the production of
E-ΔIle-containing peptides (Scheme 4). Dehydrations of esters
25a and 25b were conducted at the same temperatures as the
corresponding reactions in the Z-series, and isomerically pure
Since standard peptide couplings would scramble the alkene
stereochemistry in the absence of amide protection, we
considered other strategies (e.g., Staudinger ligations,18 thio-
acid−based couplings,19 and B(OCH2CF3)320) for elaborating
16. In preparation for evaluating these methods, we hydrolyzed
the ethyl ester of 16. Surprisingly, saponification was sluggish and
accompanied by alkene isomerization (ca. 2:1 dr). Presumably,
the hindered nature of the ester moiety allows enolization via γ-
deprotonation to compete with saponification, thereby enabling
isomerization. In contrast, Shangguan and Joullie
́
reported the
isomerization-free saponification of a related ΔIle-derived ester,6
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Letter
(CF3)2CHO− anion. Without this hydrogen bond the
carbocation is endergonic by >50 kcal/mol. These thermody-
namics provide strong evidence against an E1 dehydration
mechanism.
Scheme 4. Stereoselective Synthesis of E-ΔIle-Containing
a
Peptides 27a and 27b
We then searched for possible E2 and E1cb transition states
from 32. TS1-anti (Figure 2) is the lowest-energy transition
a
Asterisks on adjacent atoms indicate the portrayal of relative
b
stereochemistry. The conversion of 26b into 27b was conducted
in DMF−H2O instead of THF−H2O.
alkenes were obtained. The reduction and rearrangement of
esters 26a and 26b proceeded without incident, delivering the
targeted amides in excellent yields with minimal E-to-Z
isomerization (≥10:1 dr).
The high stereoselectivity facilitated by the Martin sulfurane
was unexpected since earlier reports have proposed that tertiary
alcohols may undergo elimination via an E1-like mechanism.9,15
However, at least one study suggests the feasibility of an E2-type
dehydration.16 This prompted us to employ density functional
calculations (Gaussian 09)23 to examine E1, E2, and E1cb
pathways for our anti dehydration using alcohol 28 (Scheme 5,
Figure 2. M06-2X anti and syn E2 transition states (distances reported in
Å; phenyl groups partially obscured for clarity).
state, with ΔG‡ = 13.9 kcal/mol. Inspection of TS1-anti indicates
that it is either a highly asynchronous E2 transition state or an
E1cb transition state. The nascent partial O1−H bond (1.26 Å)
and the breaking C1−H bond (1.34 Å) are both highly advanced,
while the C2−O bond (1.53 Å) is only stretched by 0.03 Å. While
normal-mode vibrational analysis for TS1-anti did not show
significant motion in the C2−O bond, IRC calculations suggest
that TS1-anti connects to alkene 30 with no intermediate. We
were unable to locate an E1cb transition state, and mapping of the
entire potential energy landscape showed only TS1-anti and no
local minimum for a carbanion intermediate. This suggests that
TS1-anti is best interpreted as a highly asynchronous E2
transition state. A similar transition state was found by Itoh and
Yamataka for the elimination reactions of 2-aryl-3-chloro-2-
propanols.27 We also considered that TS1-anti might be a
merged transition state for E2 and E1cb pathways that could
dynamically branch to alkene 30 and a carbanion.28 We have
discounted this possibility for two reasons. First, attempts to
optimize a carbanion intermediate resulted in the formation of
30 and ejection of the OSPh2 leaving group. Second, Itoh and
Yamataka have shown that if the IRC follows an asynchronous E2
pathway, then all dynamics trajectories show only E2 products
and no reaction pathway branching.
The observed stereoselectivity is likely the result of an anti
transition state that is lower in energy than any of the possible syn
transition states. Figure 2 shows the lowest-energy syn transition
state that was located (TS1-syn). It is not completely eclipsed
and exhibits a moderate twist with a H−C1−C2−O2 dihedral
angle of ∼46°. The ΔG‡ for TS1-syn is 16.6 kcal/mol, which is
2.7 kcal/mol higher in free energy than TS1-anti and
qualitatively in accordance with the high stereoselectivity
reported in Scheme 2 for the dehydration of 15.
In summary, we have developed a concise and efficient route to
E- and Z-ΔIle-containing peptides featuring an anti-selective
dehydration of β-OHIle derivatives and a tandem Staudinger
reduction/O → N acyl transfer. The former reaction is a rare
example of a Martin sulfurane mediated tertiary alcohol
dehydration that proceeds by a concerted asynchronous E2
mechanism. The latter process furnishes E- and Z-ΔIle-derived
amides without recourse to backbone amide protection. It is
Scheme 5. M06-2X/6-31+G(d,p) [CHCl3, SMD Solvent]
Energies for Dehydration (kcal/mol)
a model of substrate 15) and sulfurane 29 (a slightly simplified
version of the Martin sulfurane). M06-2X/6-31+G(d,p) theory24
was selected since it provides accurate E2 transition state
barriers.25 Geometry optimizations and normal-mode frequency
analysis were carried out in CHCl3 using the SMD implicit
solvent model.26
The reaction of 28 with sulfurane 29 creates an equivalent of
(CF3)2CHOH and intermediate 31, which is endergonic by 4.4
kcal/mol. Subsequent loss of the alkoxide (CF3)2CHO−
generates the −OSPh2 leaving group. Complete dissociation of
(CF3)2CHO− requires 22.5 kcal/mol of free energy, so it is
possible that this anion does not actually leave the solvation
sphere of 31. Indeed, structure 32 contains a hydrogen bond
between the alkoxide and the amide. Intermediate 32, the key
species from which the E1, E2, and E1cb pathways diverge, is
endergonic by 9.2 kcal/mol. The E1 pathway, which involves loss
of OSPh2 to form carbocation 33, requires 26.6 kcal/mol of free
energy. This cation retains its hydrogen bond to the
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Spampinato, S.; Civera, M.; Juaristi, E.; Escudero, M. Eur. J. Med. Chem.
2013, 66, 258.
anticipated that oxidation of the primary alcohols present in 24
and 27 will enable elongation of the peptide chains. The
dehydration substrates are rapidly prepared via regioselective
aminohydroxylation of trisubstituted alkenes. The stereo-
convergent nature of the dehydration (i.e., the two diastereomers
of 22b and 25b are converted into single alkene products) allows
the use of a racemic aminohydroxylation. Density functional
calculations indicate that the excellent stereoselectivity of the
dehydration can be attributed to a highly asynchronous E2 anti
pathway in which deprotonation is significantly more advanced
at the transition state than C−O bond cleavage. This pathway is
considerably lower in energy than all others that were examined
(i.e., E2 syn, E1). Although no E1cb transition state was located, it
is likely that the electron-withdrawing carboxylate group of the
substrates is at least partially responsible for stabilizing the E2
anti transition state. This suggests that tertiary alcohols with
vicinal electron-withdrawing groups might be good substrates for
anti-selective dehydrations mediated by the Martin sulfurane.
Due to the importance of ΔIle1 and related bulky dehydroamino
acids,2−4 we envision many future applications of this strategy.
(3) For a review, see: Bonauer, C.; Walenzyk, T.; Konig, B. Synthesis
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ASSOCIATED CONTENT
■
S
* Supporting Information
(11) Harris, L.; Mee, S. P. H.; Furneaux, R. H.; Gainsford, G. J.;
Luxenburger, A. J. Org. Chem. 2011, 76, 358.
(12) Ma, Z.; Naylor, B. C.; Loertscher, B. M.; Hafen, D. D.; Li, J. M.;
Castle, S. L. J. Org. Chem. 2012, 77, 1208.
(13) Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.;
Rossignol, E. Org. Lett. 2007, 9, 1725.
Experimental procedures, characterization data, and NMR
spectra for all new compounds, as well as descriptions of
computational methods. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Masuri; Willis, A. C.; McLeod, M. D. J. Org. Chem. 2012, 77, 8480.
(15) (a) Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008,
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7184.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: dhe@chem.byu.edu.
*E-mail: scastle@chem.byu.edu.
(17) In our earlier studies, low yields of ΔVal-containing products were
obtained via the Cu(OTf)2−EDC protocol. Accordingly, this method
was not explored for the dehydration of 15.
Notes
The authors declare no competing financial interest.
(18) (a) Soellner, M. B.; Tam, A.; Raines, R. T. J. Org. Chem. 2006, 71,
9824. (b) Kosal, A. D.; Wilson, E. E.; Ashfeld, B. L. Chem.Eur. J. 2012,
18, 14444.
(19) (a) Crich, D.; Sana, K.; Guo, S. Org. Lett. 2007, 9, 4423. (b) Chen,
W.; Shao, J.; Hu, M.; Yu, W.; Giulianotti, M. A.; Houghten, R. A.; Yu, Y.
Chem. Sci. 2013, 4, 970.
(20) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013,
78, 4512.
(21) Fang, G.-M.; Cui, H.-K.; Zheng, J.-S.; Liu, L. ChemBioChem 2010,
11, 1061.
ACKNOWLEDGMENTS
■
We thank Brigham Young University (Graduate Studies and
Bradshaw Fellowships to Z.M., Cancer Research Center
Fellowships to J.J. and Y.C., Undergraduate Research Awards
to S.L. and J.M.C., CHIRP Award to S.L.C.) for support. We also
thank Prof. Jeremy May (University of Houston) for helpful
discussions.
(22) Details of the synthesis of 21a and 21b are found in the
Supporting Information.
(23) Frisch, M. J., et al. Gaussian 09, revision B.01; Gaussian, Inc.:
Wallingford, CT, 2009.
(24) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
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