Synthesis and Conformational Studies of Peptidomimetics Containing Furanoid Sugar Amino Acids and a Sugar Diacid

J . Org. Chem. 2000, 65, 6441-6457

6441

Syn th esis a n d Con for m a tion a l Stu d ies of P ep tid om im etics

Con ta in in g F u r a n oid Su ga r Am in o Acid s a n d a Su ga r Dia cid

T. K. Chakraborty,*^,†S. Ghosh,^†S. J ayaprakash,^†J . A. R. P. Sharma,^†V. Ravikanth,^†

P. V. Diwan,^†R. Nagaraj,^‡and A. C. Kunwar*^,†

Indian Institute of Chemical Technology and Centre for Cellular and Molecular Biology,

Hyderabad 500 007, India

chakraborty@iict.ap.nic.in

Received March 21, 2000

Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce

interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid

structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such

molecules, 6-amino-2,5-anhydro-6-deoxy-^D-gluconic acid (3, Gaa) and its mannonic (4, Maa), idonic

(5, Iaa), and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthesized. The synthesis followed a

novel reaction path in which an intramolecular 5-exo S_N2 opening of the hexose-derived terminal

aziridine ring in 2 by the γ-benzyloxy oxygen with concomitant debenzylation occurred during

pyridinium dichromate oxidation of the primary δ-hydroxyl group to carboxyl function, leading to

the formation of furanoid sugar amino acid frameworks in a single step. Incorporation of these

furanoid sugar amino acids into Leu-enkephalin replacing its Gly-Gly portion gave analogues 8-11.

Detailed structural analysis of these molecules by circular dichroism (CD) and various NMR

techniques in combination with constrained molecular dynamics (MD) simulations revealed that

two of these analogues, 8a and 10a , have folded conformations composed of an unusual

nine-membered pseudo â-turn-like structure with a strong intramolecular H-bond between LeuNH

f sugarC3-OH. This, in turn, brings the two aromatic rings of Tyr and Phe in close proximity, a

prerequisite for biological activities of opioid peptides. The analgesic activities of 8a ,b determined

by mouse hot-plate and tail-clip methods were similar to that of Leu-enkephalin methyl ester. The

syn disposition of the â-hydroxycarboxyl motif on the sugar rings appears to be the driving force to

nucleate the observed turn structures in some of these molecules (8 and 10). Repetition of the

motif on both sides of a furanose ring resulted in a novel molecular design of sugar diacid, 2,5-

anhydro-^D-idaric acid (7, Idac). Bidirectional elongation of the diacid moieties of 7 with identical

peptide strands led to the formation of a C₂-symmetric reverse-turn mimetic 12 which displayed a

very ordered structure consisting of identical intramolecular H-bonds at two ends between LeuNH

f sugar-OH, the same as in 8 and 10.

In tr od u ction

as amino acids, sugars, and nucleosides, are amalgam-

ated to produce nature-like, and yet unnatural, de novo

structural entities with multifunctional groups anchored

on a single ensemble.³One such hybrid design is repre-

sented by a class of compounds called sugar amino acids

(Saa).⁴These are carbohydrate molecules bearing both

amino and carboxyl functional groups on the regular

Despite an exponential growth in the number of reports

on the development of constrained non-peptide scaffolds

as peptidomimetics,¹very few peptide-based drugs have

been developed,²necessitating an overhaul in the existing

design principles. Newer concepts are emerging where

the fundamental building blocks used by nature, such

(3) (a) Gademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew.

Chem., Int. Ed. 1999, 38, 1223-1226. (b) Rouhi, A. M. Chem. Eng.

News 1999, 77(30), 39-47. (c) Nielsen, P. E. Acc. Chem. Res. 1999,

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2552. (j) Wendeborn, S.; Wolf, R. M.; De Mesmaeker, A. Tetrahedron

Lett. 1995, 36, 6879-6882. (k) Wessel, H. P.; Mitchell, C. M.; Lobato,

C. M.; Schmid, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2712-2713.

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Vale, W.; Freidinger, R. M.; Cascieri, M. A.; Strader, C. D. J . Am. Chem.

Soc. 1993, 115, 12550-12568.

^†Indian Institute of Chemical Technology.

^‡Centre for Cellular and Molecular Biology.

(1) (a) Hruby, V. J .; Li, G.; Haskell-Luevano, C.; Shenderovich, M.

Biopolymers 1997, 43, 219-248. (b) Hanessian, S.; McNaughton-Smith,

G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854.

(c) Voyer, N. Top. Curr. Chem. 1996, 184, 1-37. (d) Gante, J . Angew.

Chem., Intl. Ed. Engl. 1994, 33, 1699-1720. (e) Olson, G. L.; Bolin, D.

R.; Bonner, M. P.; Bos, M.; Cook, C. M.; Fry, D. C.; Graves, D. J .;

Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V. K.;

Sarabu, R.; Sepinwall, J .; Vincent, G. P.; Voss, M. E. J . Med. Chem.

1993, 36, 3039-3049. (e) Giannis, A.; Kolter, T. Angew. Chem., Int.

Ed. Engl. 1993, 32, 1244-1267. (f) Peptide Secondary Structure

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49(17)]; Kahn, M., Guest Ed.; Pergamon Press: Oxford. (g) Rizo, J .;

Gierasch, L. M. Annu. Rev. Biochem. 1992, 61, 387-418. (h) Hir-

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Schmidt, G. Top. Curr. Chem. 1986, 136, 109-160.

(2) See ref 1 for leading references. Also see: Peptides and Pepti-

domimetics that Adopt Folded Structures; Symposia-in-Print, No. 15,

[Bioorg. Med. Chem. 1999, 7(1)]; Kelly, J . W., Guest Ed.; Pergamon:

Oxford, U.K.

Published on Web 09/06/2000

6442 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

sugar framework. The rigid furan or pyran rings of these

molecules make them ideal candidates as non-peptide

scaffolds in peptidomimetics where they can be easily

incorporated by using their carboxyl and amino termini.

Sugar amino acids exist in nature in the form of neuramin-

ic and muramic acids as cell wall components⁵and also

in some natural products.⁶In recent years they have been

used as novel monomeric entities in the developments

of sequenceamers and foldamers^3g,i,4c-h,kand as dipeptide

isosteres in peptidomimetics.^4a,i-j,mThe diversity of sugar

molecules can be exploited to create a combinatorial

library of sugar amino acid based molecular frameworks

predisposed to fold into architecturally beautiful, ordered

structures which may also have interesting properties.

The protected/unprotected hydroxyl groups of sugar rings

can also influence the hydrophobic/hydrophilic nature of

such molecular assemblies.

Recently, we have communicated the synthesis of

furanoid sugar amino acids 1 from the hexose-derived

substrate 2, involving an unusual intramolecular 5-exo

opening of the terminal aziridine ring of 2 by the

γ-benzyloxy oxygen with concomitant debenzylation dur-

ing pyridinium dichromate (PDC) oxidation of the pri-

mary δ-hydroxyl group.⁴ⁱComplete stereocontrol was

achieved in this electrophile-activated S_N2 opening of the

aziridine ring under remarkably mild conditions. The

method was followed to synthesize 6-amino-2,5-anhydro-

6-deoxy-^D-gluconic acid (3, Gaa) and its mannonic con-

gener (4, Maa).⁷

The rigid frameworks of these furanoid sugar amino

acids prompted us to use them as dipeptide isosteres in

peptidomimetic studies. These molecules with con-

strained backbone angles, ω_iand æ_i+1, were expected to

induce folded conformations in linear peptides. To verify

this, it was decided to incorporate them into Leu-

enkephalin, chosen as a representative example of a short

peptide, replacing its Gly-Gly spacer segment that is

known to be flexible and amenable to different conforma-

tions depending on the binding environment.⁸Structure-

(4) (a) Schrey, A.; Osterkamp, F.; Straudi, A.; Rickert, C.; Wagner,

H.; Koert, U.; Herrschaft, B.; Harms, K. Eur. J . Org. Chem. 1999,

2977-2990. (b) Lee, R. E.; Smith, M. D.; Pickering, L.; Fleet, G. W. J .

Tetrahedron Lett. 1999, 40, 8689-8692. (c) Watterson, M. P.; Pickering,

L.; Smith, M. D.; Hudson, S. J .; Marsh, P. R.; Mordaunt, J . E.; Watkin,

D. J .; Newman, C. J .; Fleet, G. W. J . Tetrahedron Asymmetry 1999,

10, 1855-1859. (d) Claridge, T. D. W.; Long, D. D.; Hungerford, N. L.;

Aplin, R. T.; Smith, M. D.; Marquess, D. G.; Fleet, G. W. J . Tetrahedron

Lett. 1999, 40, 2199-2202. (e) Long, D. D.; Hungerford, N. L.; Smith,

M. D.; Brittain, D. E. A.; Marquess, D. G.; Claridge, T. D. W.; Fleet,

G. W. J . Tetrahedron Lett. 1999, 40, 2195-2198. (f) Smith, M. D.; Long,

D. D.; Mart´ın, A.; Marquess, D. G.; Claridge, T. D. W.; Fleet, G. W. J .

Tetrahedron Lett. 1999, 40, 2191-2194. (g) Smith, M. D.; Claridge, T.

D. W.; Tranter, G. E.; Sansom, M. S. P.; Fleet, G. W. J . Chem. Commun.

1998, 2041-2042. (h) Smith, M. D.; Long, D. D.; Marquess, D. G.;

Claridge, T. D. W.; Fleet, G. W. J . Chem. Commun. 1998, 2039-3040.

(i) Chakraborty, T. K.; J ayaprakash, S.; Diwan, P. V.; Nagaraj, R.;

J ampani, S. R. B.; Kunwar, A. C. J . Am. Chem. Soc. 1998, 120, 12962-

12963. (j) Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann, M.;

Kessler, H. J . Am. Chem. Soc. 1996, 118, 10156-10167. (k) McDevitt,

J . P.; Lansbury, P. T., J r. J . Am. Chem. Soc. 1996, 118, 3818-3828.

(l) Poitout, L.; Le Merrer, Y.; Depezay, J .-C. Tetrahedron Lett. 1995,

36, 6887-6890. (m) Graf von Roedern, E.; Kessler, H. Angew. Chem.,

Intl. Ed. Engl. 1994, 33, 687-689. (n) Fuchs, E.-F.; Lehmann, J . Chem.

Ber. 1975, 108, 2254-2260.

activity relationship studies have revealed that in en-

kephalins the C-terminal “address” segment stabilizes

specific bioactive conformations of the N-terminal “mes-

sage” segment, Tyr-Gly-Gly-Phe, in which the two phar-

macophoric residues, Tyr and Phe, come close to each

other.^8a,9This happens when enkephalins interact with

lipid bilayer membranes in which opioid receptors are

located, and it is this membrane-bound conformation that

is suggested to be essential for biological activity.¹⁰Many

potent δ-receptor-selective opioid antagonists, based on

the N-terminal message domain of the enkephalins,

contain at least two aromatic residues in close proximity

having approximate parallel orientation of the aromatic

rings.¹¹

(8) (a) Aldrich, J . V. In Burger’s Medicinal Chemistry and Drug

Discovery; Wolff, M. E., Ed.; J ohn Wiley & Sons: New York, 1996; Vol.

3, pp 321-441 and the references therein. (b) Smith, G. D.; Griffin, J .

F. Science 1978, 199, 1214-1216.

(9) Toth, G.; Russel, K. C.; Landis, G.; Kramer, T. H.; Fang, L.;

Knapp, R.; Davis, P.; Burks, T. F.; Yamamura, H.; Hruby, V. J . J . Med.

Chem. 1992, 35, 2384-2391.

(10) (a) Kimura, A.; Takamoto, K.; Fujiwara, H. J . Am. Chem. Soc.

1998, 120, 9656-9661 and the references therein. (b) Graham, W. H.;

Carter, E. S., II; Hicks, R. P. Biopolymers 1992, 32, 1755-1764 and

the references therein.

(11) Bryant, S. D.; Salvadori, S.; Cooper, P. S.; Lazarus, L. H. Trends

Pharmacol. Sci. 1998, 19, 42-46.

(5) Baschang, G. Tetrahedron 1989, 45, 6331-6360.

(6) (a) Ghosh, A. K.; Wang, Y. J . Org. Chem. 1998, 63, 6735-6738

and the references therein. (b) Waltho, J . P.; Williams, D. H.; Selva,

E.; Ferrari, P. J . Chem. Soc., Perkin Trans. 1 1987, 2103-2107. (c)

Lichtenthaler, F. W.; Morino, T.; Menzel, H. M. Tetrahedron Lett. 1975,

665-668. (d) Isono, K.; Asahi, K.; Suzuki, S. J . Am. Chem. Soc. 1969,

91, 7490-7505. (e) Fox, J . J .; Kuwada, Y.; Watanabe, K. A. Tetrahedron

Lett. 1968, 6029-6032.

(7) For the first synthesis of furanoid sugar amino acids, see

ref 4l.

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6443

To determine whether furanoid sugar amino acids can

bring the aromatic pharmacophoric residues into close

proximity or not, these templates were inserted into Leu-

enkephalin in its Gly-Gly segment giving peptidomimetic

analogues 8 and 9. One of these analogues, Boc-Tyr-Gaa-

Phe-Leu-OMe (8a ) showed a nine-membered â-turn-like

ring structure involving H-bonding between LeuNH f

sugarC3-OH determined by CD and detailed structural

studies by NMR.⁴ⁱThis structure has a very strong

resemblance to the conformation of the natural peptide

bound to the cell surface δ-receptor. The analgesic

activities of 8a ,b were found to be similar to that of Leu-

enkephalin by mouse hot-plate and tail-clip tests. The

Maa-containing analogues showed less activity.

acids. The hexose-derived aziridinyl compound 2 was

chosen as an ideally functionalized intermediate where

oxidation of the primary C1-hydroxyl group and the

aziridine ring opening by C2-oxygen would lead to the

formation of carboxyl and amino termini, respectively,

anchored on the resulting tetrahydrofuran framework.

It was also conceived that a double inversion at C5

position, first during the aziridine ring formation and

second during its opening, would ensure the synthesis

of any sugar amino acid using its corresponding hexose

as the starting material, e.g., glucose for Gaa (3), man-

nose for Maa (4), etc.

The actual synthesis is depicted in Scheme 1. The

starting material for Gaa (3) was methyl 6-deoxy-6-azido-

2,3,4-tri-O-benzyl-R-^D-glucopyranoside (13) which was

prepared from methyl R-^D-glucopyranoside in five simple

steps according to the reported procedure.¹³Acid hydroly-

sis of the methyl pyranoside 13 was followed by opening

of the ring by borohydride reduction to furnish the

intermediate diol 15 in 72% yield. Treatment of 15 with

triphenylphosphine in refluxing toluene led to the forma-

tion of the aziridinyl compound 16, which was protected

in situ with Boc₂O to give the target intermediate 17 in

85% yield. The aziridine formation followed an S_N2

mechanism executing the first inversion at C5 position.

In this paper, we present the details of the above-

mentioned syntheses as well as structural and biological

studies. This paper also includes the synthesis of two new

furanoid sugar amino acids, 6-amino-2,5-anhydro-6-deoxy-

D-idonic acid (5, Iaa) and its 3,4-dideoxy congener 6

(ddIaa) and their incorporation in Leu-enkephalin giving

peptidomimetics 10a and 11a . Structural studies re-

vealed that the Iaa-containing peptidomimetic 10a ex-

hibited similar, but somewhat less prominent, turn

structure as it was seen in 8a , whereas dideoxy sugar

amino acid 7 did not induce any significant turn in 11a .

Compounds 10a and 11a showed reduced analgesic

activities. Careful investigations of the 3-D structures of

these enkephalin analogues 8-11 eventually led to the

identification of a cis-â-hydroxycarboxyl moiety anchored

on a five-membered ring as the essential structural motif

whose presence in some of these analogues was respon-

sible for their folded conformations. Designing a logical

structural exploitation of this motif, a novel C₂-symmetric

reverse-turn molecular scaffold of a sugar diacid, 2,5-

anhydro-^D-idaric acid (7, Idac), was synthesized for the

first time. Attachment of identical peptide strands to the

carboxyl groups of 7 resulted in the formation of a C₂-

symmetric reverse-turn mimetic 12. The two cis-â-

hydroxycarboxyl moieties appropriately anchored on two

sides of the scaffold were expected to nucleate identical

â-turn-like structures at both ends involving intramo-

lecular H-bonding, as observed earlier, between amideNH

f sugar-OH. The conformational studies of the peptido-

mimetics 8-12 were carried out by circular dichroism

(CD) spectra and various NMR techniques in combination

with distance geometry calculations that was subse-

quently used in constrained molecular dynamic (MD)

simulations to derive energy-minimized structures. The

aim of our present study is to project furanoid sugar

amino acids and sugar diacids as novel class of rigid

structural templates capable of instilling defined second-

ary structures in small linear peptides.

Sch em e 1. Syn th esis of Meth yl

N-Boc-6-a m in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-

6-d eoxy-D-glu con a te (20)

Resu lts

Syn th eses of Su ga r Am in o Acid s. On the basis of

the known susceptibility of linear molecules having S_N2

active sites to undergo spontaneous ring-closure, induced

by heteroatom at the γ-position to produce thermody-

namically favorable five-membered cyclic product,¹²we

envisaged that a terminal aziridine ring could be opened

regio- and stereoselectively by a γ-hydroxy group, to build

the tetrahydrofuran ring of our targeted sugar amino

The stage was now set to try out the crucial cyclization

step. Our initial plan was to oxidize first the primary

hydroxyl group, followed by deprotection of benzyl groups

by hydrogenation before the cycloetherification could be

carried out. Accordingly, the Boc-protected aziridinyl

intermediate 17 was treated with an excess of PDC (5

(12) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-

619. (b) Dehmlow, H.; Mulzer, J .; Seilz, C.; Strecker, A. R.; Kohlmann,

A. Tetrahedron Lett. 1992, 33, 3607-3610.

(13) (a) Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. J . Org.

Chem. 1996, 61, 1894-1897. (b) Liptak, A.; J odal, I.; Nanasi, P.

Carbohydr. Res. 1975, 44, 1-11.

6444 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

Sch em e 3. Syn th esis of Meth yl

molar equivalents) in DMF as solvent, leading to the

formation of two products, 18 and 19. After workup, the

crude mixture was treated with diazomethane in ether.

Chromatographic purification at this stage gave two

compounds, unchanged 19, as shown by TLC, and 20,

presumably the ester of 18, in ca. 1:2 ratio, with a

N-Boc-6-a m in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-

6-d eoxy-D-id on a te (38)

1

combined yield of about 75%. The H NMR spectrum of

major product 20 in CDCl₃showed, besides other peaks,

one signal at δ 5.3 characteristic of a Boc-protected-NH

and the loss of one benzyl group. Careful analysis of all

the spectroscopic data for the minor product established

its structure as 19. Treatment of 19 with anhydrous K₂-

CO₃in MeOH converted it to 20, increasing its overall

yield to 72% from 17. It is noteworthy that the crucial

cyclization reaction took place concomitantly during the

oxidation step under remarkably mild conditions involv-

ing the intramolecular 5-exo S_N2 opening of the aziridine

ring by γ-oxygen as planned previously with simulta-

neous loss of its benzyl protective group. Smooth trans-

formation of the linear molecule 17 into the cyclic sugar

amino acid 18 in one step under mild oxidative conditions

is the essence of our methodology.

Similar oxidative rearrangement of 21 (Scheme 2),

prepared from ^D-mannose following the same route as

outlined for 17, furnished the expected mannonate 23 as

the only product in 78% yield. In this case, the “2,5-trans”

geometry in the furanoid framework prevented the

formation of “19-type” bicyclic product.

Sch em e 2. Syn th esis of Meth yl

N-Boc-6-a m in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-

6-d eoxy-D-m a n n on a te (23)

Because of the high cost of ^D-idose, an alternate route

was followed for the synthesis of Iaa, i.e., 6-amino-2,5-

anhydro-6-deoxy-^D-idonic acid (5) where D-mannitol was

used as the starting material. Scheme 3 outlines the

synthesis. Monotosylation of 1,3:4,6-di-O-benzylidene-^D-

mannitol (24) gave 25 which was followed by Swern

oxidation of the remaining hydroxyl group leading to a

keto intermediate 26. Excellent diastereoselectivity was

achieved in the reduction of 26 by sodium borohydride

to get the ^D-glucitol derivative 27 as the major product

in ca. 6:1 ratio. The mixture itself was subjected to a base-

catalyzed intramolecular ring-closure reaction in which

only the ^D-glucitol derivative 27 underwent cycloetheri-

fication with S_N2 type inversion at the tosylate center

giving the desired ^D-iditol framework 28, in 45% overall

yield in four steps starting from 24. The minor ^D-

mannitol derivative failed to cyclize due to structural

constraints, making it easier to purify 28 by chromatog-

raphy. Removal of the benzylidene protections by hydro-

genation gave quantitative yield of the known¹⁴tetrol 29,

the spectroscopic data of which were in all aspects

identical with reported values. Routine functional group

manipulations transformed 29 into the 2,5-anhydro-3,4-

di-O-benzyl-^D-iditol (32) in three steps in 60% overall

yield. One of the primary hydroxyls of 32 was tosylated

and then treated with NaN₃to give the azido derivative

34, in 72% yield from 32. Reduction of the azido group

converted it to the amine 35 that was protected in situ

with Boc₂O to get the intermediate 36. Finally, PDC

oxidation of the remaining hydroxyl of 36, followed by

treatment with CH₂N₂resulted in the formation of the

protected Iaa 38, in 70% yield from 34.

For the synthesis of the 3,4-dideoxy congener 6 of Iaa

(Scheme 4), the starting material chosen was 28 of

Scheme 3. Opening of the benzylidene rings of 28 gave

selectively primary O-benzylated diol 39 as the major

product in 60% yield. Treatment of 39 with Ph₃P/I₂/

imidazole led to the formation of an olefin intermediate

40 in 62% yield that was hydrogenated to get the 2,5-

anhydro-3,4-dideoxy-1,6-diol framework 41, prepared

earlier by resolution methods.¹⁵Conversion of 41 to the

(14) (a) Delft, F. L. van; Valentijn, A. R. P. M.; Marel, G. A. van

der; Boom, J . H. van J . Carbohydr. Chem. 1999, 18, 191-207. (b)

Rafka, R. J .; Morton, B. J . Carbohydr. Res. 1994, 260, 155-158. (c)

Rao, V. S.; Perlin, A. S. Can. J . Chem. 1984, 62, 886-890.

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6445

Sch em e 4. Syn th esis of N-Boc-6-a m in o-

Sch em e 6. Syn th esis of En k ep h a lin An a logu es

2,5-a n h yd r o-3,4,6-tr id eoxy-D-id on ic Acid (46)

8-11

N-Boc-protected ddIaa 46 followed the same route de-

scribed above for the synthesis of 38 from 32. Monoto-

sylation of 41 gave 42, in 46% yield from 40, from which

the azido compound 43 was made (90% yield). Transfor-

mation of 43 to the Boc-protected amine 45 was carried

out in two steps (yield 74%): hydrogenation and in-situ

Boc-protection. Finally, 45 was oxidized using RuCl₃‚

3H₂O/NaIO₄to get the dideoxy sugar amino acid 46, in

92% yield, which was used directly in the subsequent

peptide coupling step.

The 2,5-anhydro-3,4-di-O-benzyl-^D-iditol (32) of Scheme

3 served as the starting material for the synthesis of Idac

7. Oxidation of 32 with an excess of PDC in DMF gave

the diacid 47 (Scheme 5) which was treated with CH₂N₂

in ether, for easy purification, to get the dimethyl ester

of 2,5-anhydro-3,4-di-O-benzyl-^D-idaric acid (48) in 60%

yield (from 32).

Finally, hydrogenation using H₂/Pd(OH)₂-C in EtOAc

yielded the side-chain deprotected compound Boc-Tyr-

Gaa-Phe-Leu-OMe (8a ). A similar reaction sequence

starting with Boc-protected sugar amino acids 22, 37, and

46 led to the formation of their corresponding enkephalin

analogues, 9a , 10a , and 11a , respectively.

For the synthesis of the reverse-turn mimetic 12

(Scheme 7), the dibenzyl derivative of idaric acid (47),

prepared from the diester 48 by saponification, was

reacted with an excess of H₂N-Phe-Leu-OMe under the

coupling conditions described in Scheme 6 to get the

coupled product 51 in 74% yield. Hydrogenation of 51

gave a quantitative yield of the target molecule 12.

Sch em e 7. Syn th esis of Rever se-tu r n Mim etic 12

Sch em e 5. Syn th esis of 2,5-a n h yd r o-

3,4-d i-O-ben zyl-D-id a r ic Acid Dim eth yl Ester (48)

Syn th esis of th e P ep tid om im etics. All the pepti-

domimetic molecules were synthesized by standard solu-

tion methods using 1-ethyl-3-(3-(dimethylamino)propyl)-

carbodiimide hydrochloride (EDCI) and 1-hydroxybenzo-

triazole (HOBt) as coupling agents and amine-free dry

DMF and/or dry CH₂Cl₂as solvent. The protocol followed

for the synthesis of the enkephalin analogues 8-11 is

depicted in Scheme 6. Reaction of Boc-Gaa(Bn₂)-OH (18),

prepared from the ester 20 by simple saponification, with

H₂N-Phe-Leu-OMe gave the protected peptide Boc-Gaa-

(Bn₂)-Phe-Leu-OMe (49i), which was deprotected at the

N-terminus with trifluoroacetic acid (TFA) in dichlo-

romethane and subsequently coupled with Boc-Tyr(Br-

Z)-OH to give Boc-Tyr(Br-Z)-Gaa(Bn₂)-Phe-Leu-OMe (50i).

Con for m a t ion a l An a lysis. Cir cu la r Dich r oism

Stu d ies. The conformational analysis of the peptidomi-

metics 8-12 were carried out by studying their circular

dichroism (CD) spectra in trifluoroethanol (TFE). The CD

spectrum of 8a having a “2,5-cis” geometry in the sugar

amino acid exhibits a strong positive band at 216 nm

(Figure 1) characteristic of a type II â-turn.¹⁶The

corresponding deprotected peptide H₂N-Tyr-Gaa-Phe-

(15) (a) Naemura, K.; Fukuda, R.; Takahashi, N.; Konishi, M.;

Hirose, Y.; Tobe, Y. Tetrahedron Asymmetry 1993, 4, 911-918. (b)

Naemura, K.; Ebashi, I.; Matsuda, A. Bull. Chem. Soc. J pn. 1985, 58,

3057-3058. (c) Nakazaki, M.; Naemura, K.; Makimura, M.; Matsuda,

A.; Kawano, T.; Ohta, Y. J . Org. Chem. 1982, 47, 2429-2435.

(16) Woody, R. W. In The Peptides: Analysis, Synthesis, Biology;

Udenfriend, S. J ., Meienhofer, J ., Hruby, V. J ., Eds.; Academic Press:

New York, 1985; Vol. 7, pp 15-114.

6446 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

F igu r e 1. CD spectra (in TFE) of 8a (a), 8b (b), 9a (c), and

9b (d).

F igu r e 2. CD spectra (in TFE) of 10a (a), 11a (b), and 12 (c).

Leu-OMe (8b) also shows a positive band although of

reduced ellipticity at ∼217 nm. The spectra of the Maa-

containing analogues, both protected (9a ) and depro-

tected H₂N-Tyr-Maa-Phe-Leu-OMe (9b), indicate a lower

tendency to form turn structures. The CD spectra of 10a ,

11a , and 12 are shown in Figure 2. While 10a shows a

positive band at ∼218 nm, the spectrum of 11a indicates

the absence of any prominent structure. Of all the

substrates studied here, the most ordered structure is

observed in the CD spectrum of the reverse turn mimetic

12 with a very strong positive band of high ellipticity at

∼212 nm, indicating the presence of a very predominant

â-turn structure in the molecule.

used for obtaining the restraints in the MD calculations.

The cross-peak intensities were semiqualitatively char-

acterized as strong, medium, weak, and very weak,

corresponding to internuclear distances in the range of

2.0-2.7 Å, 2.0-3.3 Å, 2.0-4.0 Å, and 2.0-5.0 Å, respec-

tively. The temperature coefficient of amide proton

chemical shift (∆δ/∆Τ) is a measure of their involvement

in the hydrogen bonding. Most of the amide protons,

leaving apart the LeuNH in some of the peptides, showed

a large magnitude of temperature coefficients.

The ³J _HNCRHare large (>8 Hz) for Phe and Tyr residues,

whereas for Leu residues they are between 7 and 8 Hz.

This corresponds to a value of æ in the vicinity of -120°.

The existence of a complete set of sequential CRH-NH

NOE connectivities, wherever possible, implies propen-

sity of structures with large population of conformers in

the â-region of the æ-ψ space (æ ) -180° to -60° and ψ

) 60° to 180°). However, observation of weak NH-NH

Con for m a tion a l An a lysis. NMR Stu d ies. The NMR

spectra of the peptides described here are quite well

resolved, and most of the spectral parameters could be

obtained and are reported in the Tables 1-6. The cross-

peak intensities in the NOESY and ROESY spectra were

Ta ble 1. ¹H Ch em ica l Sh ifts (δ) in p p m , Cou p lin g Con sta n ts (J ) in Hz, a n d Tem p er a tu r e Coefficien ts (∆δ/∆T, in p p b/K)

of th e Am id e P r oton s of 8a (500 MHz, DMSO-d ₆)

protons

Tyr

Phe

Leu

NH

6.89 (d)

8.41 (d)

7.93 (d)

J _NH-RH) 8.7

J _NH-RH) 9.3

J _NH-RH) 7.3

CRH

4.04 (ddd)

4.60 (ddd)

4.24 (ddd)

CâH(pro-S)

2.82 (dd)

J _R-â(pro-S)) 4.4

2.64 (dd)

3.36 (dd)

J _R-â(pro-S)) 3.1

3.06 (dd)

1.43 (ddd)

J _R-â(pro-S)) 4.6

1.51 (ddd)

CâH(pro-R)

J _R-â(pro-R)) 10,

J _{â(pro-S)-â(pro-R)}) 13.7

J _R-â(pro-R)) 10.4,

J _{â(pro-S)-â(pro-R)}) 14

J _R-â(pro-R))11.4,

J _{â(pro-S)-â(pro-R)}) 13.6

1.73 (m)

J _â(pro-S)-γ) 9.6,

J _â(pro-R)-γ) 4.6

0.81 (d, CH₃(pro-R)),

0.77 (d, CH₃(pro-S))

J _γ-δ(pro-S), J _γ-δ(pro-R)) 6.5

CγH

CδH

CꢀH

7.01 (d)

6.61 (d)

J _δ-ꢀ) 8.4

others

-∆δ/∆T (ppb/K) for NH

9.15 (s, OH), 1.29 (s, Boc)

7.14-7.22 (m, ArH)

5.0

3.6 (s, CO₂CH₃)

1.3

7.6

Gaa: 8.21 (t, NH, J _NH-6,6′) 3.5), 5.97 (d, OH(3), J _H3-OH) 3.8), 5.34 (d, OH(4), J _H4-OH) 3.5), 4.26 (d, H2),

4.05 (d, H3, J _2-3) 3.8), 3.76 -3.84 (H6_pro-R,H5, H4), 2.92 (H6_pro-S, J _6-6′) 11.4); -∆δ/∆T (ppb/K) for NH ) 4.2

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6447

Ta ble 2. ¹H Ch em ica l Sh ifts (δ) in p p m , Cou p lin g Con sta n ts (J ) in Hz, a n d Tem p er a tu r e Coefficien ts (∆δ/∆T, in p p b/K)

of th e Am id e P r oton s of 9a (500 MHz, DMSO-d ₆)

protons

Tyr

Phe

Leu

NH

6.74 (d)

7.58 (d)

8.41 (d)

J _NH-RH) 8.7

J _NH-RH) 8.6

J _NH-RH) 7.7

CRH

4.08 (ddd)

4.54 (ddd)

4.30 (ddd)

CâH(pro-S)

2.82 (dd)

J _R-â(pro-S)) 3.8

2.60 (dd)

2.93 (dd)

J _R-â(pro-S)) 5.4

2.96 (dd)

1.49 (ddd)

J _R-â(pro-S)) 5.3

1.56 (ddd)

CâH(pro-R)

J _R-â(pro-R)) 10.5,

J _{â(pro-S)-â(pro-R)}) 13.8

J _R-â(pro-R)) 7.8,

J _{â(pro-S)-â(pro-R)}) 13.7

J _R-â(pro-R)) 9.5,

J _{â(pro-S)-â(pro-R)}) 13.7

CγH

CδH

1.59 (m)

J _â(pro-S)-γ) 8.9,

J _â(pro-R)-γ) 4.9

0.88 (d, CH₃(pro-R)),

0.82 (d, CH₃(pro-S))

J _γ-δ(pro-S), J _γ-δ(pro-R)) 6.5

7.02 (d)

CꢀH

6.60 (d)

J _δ-ꢀ) 8.4

Others

-∆δ/∆T (ppb/K) for NH

9.12 (s, OH), 1.30 (s, Boc)

7.15-7.24 (m, ArH)

2.5

3.6 (s, CO₂CH₃)

4.2

6.1

Maa: 8.01 (dd, NH, J _NH-6,6′) 5.1, 7.1), 5.55 (d, OH(4), J _H4-OH) 3.5), 5.25 (d, OH(3), J _H3-OH) 3.5),

4.08 (d, H2, J _2-3) 2.9), 3.96 (t, H3), 3.84 (H5, J _4-5) 3.7), 3.72 (dd, H4, J _3-4) 2.9),

3.25-3.31 (H6_pro-S, H6_pro-R, J _6-6′) 13.7), -∆δ/∆T (ppb/K) for NH ) 5.2

Ta ble 3. ¹H Ch em ica l Sh ifts (δ) in p p m , Cou p lin g Con sta n ts (J ) in Hz, a n d Tem p er a tu r e Coefficien ts (∆δ/∆T, in p p b/K)

of th e Am id e P r oton s of 10a (400 MHz, DMSO-d ₆)

protons

Tyr

Phe

Leu

NH

6.84 (d)

7.72 (d)

8.02 (d)

J _NH-RH) 8.4

J _NH-RH) 9.0

J _NH-RH) 7.2

CRH

4.06 (ddd)

4.60 (ddd)

4.17 (ddd)

CâH(pro-S)

2.80 (dd)

J _R-â(pro-S)) 4.1

2.61 (dd)

3.16 (dd)

J _R-â(pro-S)) 4.2

2.88 (dd)

1.43 (ddd)

J _R-â(pro-S)) 5.4

1.49 (ddd)

CâH(pro-R)

J _R-â(pro-R)) 10.5,

J _{â(pro-S)-â(pro-R)}) 13.8

J _R-â(pro-R)) 9.2,

J _{â(pro-S)-â(pro-R)}) 14.1

J _R-â(pro-R)) 9.7,

J _{â(pro-S)-â(pro-R)}) 13.6

1.58 (m)

J _â(pro-S)-γ) 8.8,

J _â(pro-R)-γ) 5.1

0.84 (d, CH₃(pro-R)),

0.81 (d, CH₃(pro-S))

J _γ-δ(pro-S), J _γ-δ(pro-R))6.4

CγH

CδH

CꢀH

7.02 (d)

6.63 (d)

J _δ-ꢀ) 8.4

others

-∆δ/∆T (ppb/K) for NH

9.14 (s, OH), 1.29 (s, Boc)

7.14-7.23 (m, ArH)

4.9

3.60 (s, CO₂CH₃)

2.0

6.3

Iaa: 7.95 (t, NH, J _NH-6,6′) 5.5), 5.71 (d, OH(3), J _H3-OH) 4.1), 5.26 (d, OH(4), J _H4-OH) 3.6),

4.27 (d, H2, J _2-3) 3.7), 4.11 (dd, H3), 4.11 (H5, J _4-5) 2.7), 3.84 (dd, H4, J _3-4) 1.2), 3.24,

3.30 (H6_pro-S, H6_pro-R, J _6-6′) 11.4); -∆δ/∆T (ppb/K) for NH ) 4.4

ROESY cross-peaks between Tyr-Saa and Phe-Leu is

rotamers about CR-Câ is further supported by much

stronger ROESY cross-peaks between NH-CâH(pro-R)

than between NH-CâH(pro-S).

consistent with some, but significant, populations of the

molecules with æ and ψ values in the R-region of the æ-ψ

space (æ ) -120° to -10° and ψ ) -120° to 20°). The

populations of side-chain conformations about CR-Câ (ø₁)

for all the peptides are shown in Table 7. There is a clear-

cut dominance of g^-rotamers, while the populations of

g⁺rotamers is invariably small. These general comments

serve as a prelude to the following detail individual

discussion on the structures and conformations of all the

peptides 8-11a , 51, and 12.

Con for m a tion a l An a lysis of 8a . The side-chains of

Tyr, Phe, and Leu of 8a are quite rigid and show larger

than 70% rotamer population of g^-about ø₁. The rigidity

of the Leu side-chain is also observed between Câ-Cγ

(ø₂) bond, with about 68% population of rotamers having

anti relationship between âH(pro-S) and γH. The cross-

peak in the ROESY spectrum between the LeuCRH-

LeuδCH₃(pro-S) provide additional evidence of the rigid-

ity of the Leu side-chain. The predominance of the g^-

The small J _2-3of 3.8 Hz and ROESY cross-peak

between GaaC2-H and C5-H support an envelope (C_2′-

exo or C_3′-endo) conformer for the sugar ring. The pres-

ence of cross-peaks between LeuCâH(pro-R)-GaaC3-OH,

LeuδCH₃(pro-R)-GaaC3-OH, LeuCγH-GaaC6-H(pro-R),

LeuδCH₃(pro-R)-GaaC6-H(pro-R) show that Leu and Gaa

ring come close to each other resulting in the propensity

of a single major conformation of Leu. This conformation

is further stabilized by a unique H-bonding between

LeuNH f GaaC3-OH leading to a nine-membered â-turn-

like ring structure. The sugar-hydroxyl can also possibly

act as H-bond donor to Leu carbonyl or solvent molecules.

There is a downfield shift of sugarC3-hydroxyl proton by

1

0.44 ppm compared to its chemical shift in the H NMR

spectrum of Boc-Gaa-OMe in DMSO-d₆(10 mM), whereas

the C4-OH signal did not show any appreciable shift.

Amino acids with hydroxyl groups in their side-chains

6448 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

Ta ble 4. ¹H Ch em ica l Sh ifts (δ) in p p m , Cou p lin g Con sta n ts (J ) in Hz, a n d Tem p er a tu r e Coefficien ts (∆δ/∆T, in p p b/K)

of th e Am id e P r oton s of 11a (400 MHz, DMSO-d ₆)

protons

Tyr

Phe

Leu

NH

6.81 (d)

7.69 (d)

8.40 (d)

J _NH-RH) 8.6

J _NH-RH) 8.8

J _NH-RH) 7.8

CRH

4.03 (ddd)

4.56 (ddd)

4.28 (ddd)

CâH(pro-S)

2.76 (dd)

J _R-â(pro-S)) 4.4

2.59 (dd)

J _R-â(pro-R)) 10.1,

J _{â(pro-S)-â(pro-R)}) 13.7

3.02 (dd)

J _R-â(pro-S)) 4.6

2.84 (dd)

J _R-â(pro-R)) 9.6,

J _{â(pro-S)-â(pro-R)}) 13.9

1.50-1.52 (m)

J _R-â(pro-S)) 5.2

1.50-1.52 (m)

J _R-â(pro-R)) 9.5

CâH(pro-R)

CγH

CδH

1.50-1.52 (m)

7.02 (d)

0.89 (d, CH₃(pro-R)),

0.83 (d, CH₃(pro-S))

J _γ-δ(pro-S), J _γ-δ(pro-R)) 6.5

CꢀH

6.62 (d)

J _δ-ꢀ) 8.4

others

-∆δ/∆T (ppb/K) for NH

9.14 (s, OH), 1.29 (s, Boc)

7.14-7.24 (m, ArH)

3.7

3.6 (s, CO₂CH₃)

4.6

6.4

ddIaa: 7.90 (t, NH, J _NH-6,6′) 5.8), 4.23 (dd, H2, J ) 7.8, 5.3), 4.08 (m, H5), 3.23 (ddd, H6_pro-S, J ) 13.8, 5.8, 4.4),

3.06 (ddd, H6_pro-R, J ) 13.8, 5.8, 4.4), 2.01-1.5 (m, H3, H4); -∆δ/∆T (ppb/K) for NH ) 4.8

Ta ble 5. ¹H Ch em ica l Sh ifts (δ) in p p m , Cou p lin g Con sta n ts (J ) in Hz, a n d Tem p er a tu r e Coefficien ts (∆δ/∆T, in p p b/K)

of th e Am id e P r oton s of 51 (400 MHz, DMSO-d ₆)

protons

Phe

Leu

NH

CRH

CâH(pro-S)

CâH(pro-R)

7.80 (d, J _NH-RH) 8.5)

4.64 (ddd)

3.04 (dd, J _R-â(pro-S)) 4.6)

2.86 (dd, J _R-â(pro-R)) 8.7),

J _{â(pro-S)-â(pro-R)}) 13.8)

8.35 (d, J _NH-RH) 7.6)

4.26 (q)

1.47 (m, J _R-â(pro-S)) 7.6)

1.47 (m, J _R-â(pro-R)) 7.6)

CγH

CδH

1.56 (m)

0.84 (d, CH₃(pro-R)), 0.77 (d, CH₃(pro-S))

J _γ-δ(pro-S), J _γ-δ(pro-R)) 6.6

3.58 (s, CO₂CH₃)

others

-∆δ/∆T

(ppb/K) for NH

7.12-7.26 (m, ArH)

3.7

3.9

Idac(Bn₂): 7.16-7.11 (m, Ph), 4.54 (d, H2, H5, J _2-3) 3.5), 4.17 (d, H3, H4), 4.34 and 4.28 (ABq, J ) 12.5, PhCH₂O-)

Ta ble 6. ¹H Ch em ica l Sh ifts (δ) in p p m , Cou p lin g Con sta n ts (J ) in Hz, a n d Tem p er a tu r e Coefficien ts (∆δ/∆T, in p p b/K)

of th e Am id e P r oton s of 12 (400 MHz, DMSO-d ₆)

protons

Phe

Leu

NH

CRH

CâH(pro-S)

CâH(pro-R)

8.03 (d, J _NH-RH) 9.2)

4.61 (ddd)

3.21 (dd, J _R-â(pro-S)) 3.6)

2.91 (dd, J _R-â(pro-R)) 10.4),

J _{â(pro-S)-â(pro-R)}) 14.3

7.93 (d, J _NH-RH) 7.2)

4.17 (ddd)

1.43 (ddd, J _R-â(pro-S)) 5.1)

1.49 (ddd, J _R-â(pro-R)) 10.2),

J _{â(pro-S)-â(pro-R)}) 13.7)

1.64 (m, J _â(pro-S)-γ) 9.0,

J _â(pro-R)-γ) 5.1)

0.86 (d, CH₃(pro-R)), 0.81 (d, CH₃(pro-S))

J _γ-δ(pro-S), J _γ-δ(pro-R)) 6.7

3.59 (s, CO₂CH₃)

CγH

CδH

Others

-∆δ/∆T

(ppb/K) for NH

7.17-7.27 (m, ArH)

6.3

1.2

Idac: 5.99 (d, OH(3), OH(4), J _H-OH) 3.7), 4.50 (d, H2, H5, J _2-3) 3.2), 4.13 (d, H3, H4).

Ta ble 7. P op u la tion s of Va r iou s Rota m er s a bou t Cr-Câ

Bon d (ø₁) in P ep tid es 8-11a , 51, a n d 12

very rare, mainly because of the free rotation about ø₁in

these amino acids. In sugar amino acids, unlike in serine

and threonine, the hydroxyls are conformationally re-

stricted, forcing one of them to participate in the forma-

tion of an unusual secondary structure. This pseudo

â-turn is probably responsible for the strong positive band

at 216 nm in the CD spectrum of the molecule (Figure

1). Another long-range ROESY cross-peak between Tyrâ-

protons and Phe aromatic protons suggests their close

proximity.

Tyr

Phe

Leu

peptides g^-

g⁺

t

g^-

g⁺

t

g^-

g⁺

t

8a

9a

10a

11a

51

0.72 0.08 0.20 0.82 0.10 0.08 0.76 0.04 0.20

0.77 0.07 0.16 0.51 0.17 0.32 0.67 0.05 0.28

0.77 0.07 0.16 0.64 0.16 0.20 0.69 0.03 0.28

0.73 0.08 0.19 0.68 0.10 0.22 0.67 0.06 0.27

0.59 0.17 0.24 0.49 0.02 0.49

12

0.76 0.11 0.13 0.74 0.01 0.25

(serine, threonine) serve as acceptors only ∼30% of the

time.¹⁷Moreover, a H-bond between main-chainNH f

side-chainOH leading to this type of turn structure is also

Several long-range restraints, derived from the ROESY

experiments, were used in the MD calculations. These

MD simulations resulted in four families of structures

based on the RMS deviations of the nonhydrogen atoms,

and the average structures from each of these families

(I-IV) are shown in Figure 3, while the superimpositions

(17) (a) McDonald, I. K.; Thornton, J . M. J . Mol. Biol. 1994, 238,

777-793. (b) Burley, S. K.; Petsko, G. A. Adv. Protein Chem. 1988,

39, 125-189.

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6449

The values of æ(Tyr), æ(Phe), and æ(Leu) are around

3

-100°, consistent with the observed J _HNCRH. A close look

at the superimposed structures shows that the peptide

follows a turn-like structure stabilized by aromatic-

aromatic as well as hydrophobic interaction between the

Leu side-chain and the Gaa sugar ring. This structure

has very strong resemblance with the conformation of

enkephalins in the presence of SDS micelles¹⁰which is

also stabilized by hydrophobic aromatic-aromatic inter-

action and corresponds to one of the two theoretical

binding conformations¹⁹that enkephalin may adopt while

interacting with cell membranes in which opioid recep-

tors are located. We find that such a structure is

preintroduced in 8a making it a potential ligand for the

δ-receptor which require folded conformations with close

proximity (<10 Å) of the two aromatic rings having

nearly parallel orientation.²⁰

Con for m a tion a l An a lysis of 9a . In the Maa-contain-

ing peptide 9a , the large magnitude of ∆δ/∆T for LeuNH

(-4.2 ppb/K) indicates the absence of any intramolecular

H-bonding. PheNH on the other hand, with a medium

∆δ/∆T of -2.5 ppb/K, is probably involved in a weak

intramolecular H-bond. The side-chain of Leu, however,

shows that it exists predominantly in a single conforma-

tion, g^-about CR-Câ having a population of 67%. The

population profile of Leu side-chain in 9a is very similar

to that in 8a , with slight reduction in the population of

predominant rotamers about CR-Câ and Câ-Cγ. Though

Tyr shows a large population of g^-rotamer, the same

for Phe is much smaller in 9a than in other peptides.

On the other hand, the population of t rotamer for Phe

is quite significant in 9a (32%).

F igu r e 3. The average structures (I-IV) of the four families

from the 100 structures sampled during 100 ps MD simula-

tions of 8a .

3

All the J s in the sugar ring of Maa in 9a have very

small values (J _2-3, J _3-4) 2.9 Hz; J _4-5) 3.7 Hz). These

couplings are consistent with a twisted sugar ring

4

conformation, ₃T with P ≈ 180°. The Maa sugar ring

leads to a conformation of the molecule where the two

aromatic rings do not come close to each other, a

prerequisite for imparting activity to the molecule.

Con for m a tion a l An a lysis of 10a . The small magni-

tude of ∆δ/∆T for LeuNH (-2.0 ppb/K) in 10a indicates

its involvement in an intramolecular H-bonding, though

it is believed to be somewhat weaker than that in the

Gaa-containing peptide 8a where the temperature coef-

ficient for LeuNH was -1.3 ppb/K. The cross-peaks in

the ROESY spectrum between LeuCγH-IaaC3-H, LeuCγH-

IaaC3-OH, LeuCδH(pro-R)-IaaC3-OH, and a downfield

shift of about 0.21 ppm of the IaaC3-OH compared to its

F igu r e 4. Stereoview of the superimposed average structures

of the four families from the 100 structures sampled during

100 ps MD simulations of 8a .

of I-IV are presented in Figure 4. These structures differ

in their sugar puckers, æ(Tyr), ψ(Tyr), and æ(Gaa).

Tyrosine being the terminal residue, variation in æ(Tyr)

and ψ(Tyr) is not unexpected. Interestingly, the ψ(Tyr)

and æ(Gaa) variations are coupled and two of the four

average structures show amide plane flip. The ψ(Tyr) and

æ(Gaa) of both I and II are around -80° and 85°,

respectively, while the same for both III and IV are

around 105° and -92°, respectively. Thus, the flip of the

amide bond takes place through a 180° change of

sequential ψ and æ dihedral angles. Such flips are

responsible for changes in conformations of proteins

through switch in turn structures.¹⁸

The four families show variations in the sugar pucker

as well. The values of pseudorotation phase angle (P) and

maximum angle of pucker (ν_max) are (109°, 26°), (113°,

23°), (17°, 32°), and (162°, 31°). These values of P refer

to approximate sugar puckers of C_2′-exo, C_2′-exo, C_4′-endo,

and C_3′-endo. The broadening of the spectral lines from

the Gaa residue seems to support the observations from

MD calculations that show the existence of the confor-

mational equilibrium between several structural families

involving the sugar moiety.

1

chemical shift in the H NMR spectrum of Boc-Iaa-OMe

in DMSO-d₆(10 mM), imply the presence of LeuNH f

IaaC3-O(H) H-bond. The side-chains of Tyr, Phe, and Leu

take predominantly g^-conformation about ø₁. While Tyr

has a larger population of g^-rotamers, Phe has a smaller

percentage of it compared to their counterparts in 8a .

Similarly, the predominance of a single conformer about

Câ-Cγ is not as prominent as in 8a .

MD calculations show five families of structures (Fig-

ure 5) arising mainly due to variations in the terminal

and side chain conformations. The only notable variation

in the backbone conformation is around æ(Tyr) and æ-

(Iaa) (it is a pseudo æ angle). Sugar pucker for all the

(19) (a) Behnam, B. A.; Deber, C. M. J . Biol. Chem. 1984, 259,

14935-14940. (b) Deber, C. M.; Behnam, B. A. Biopolymers 1985, 24,

105-116.

(20) Yamazaki, T.; Mierke, D. F.; Said-Nejad, O. E.; Felder, E. R.;

Goodman, M. Int. J . Pep. Protein Res. 1992, 39, 161-181.

(18) (a) Brunger, A. T.; Kaplus, M. Acc. Chem. Res. 1991, 24, 54-

61. (b) F. van Gunsteren, W.; Berendsen, H. J . C. Angew. Chem., Int.

Ed. Engl. 1990, 29, 992-1023.

6450 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

Ta ble 8. An a lgesic Activity Assa y by Hot P la te Meth od

analgesic activity

ED₅₀

peak

relative

peptides

(µmol/animal)

(min)

(Leu-enk Me ester ) 1)

8a

8b

9a

9b

10a

11a

12

Leu-enk

Me ester

1.14

1.48

2.51

2.22

2.80

2.49

2.70

1.35

90

30

60

90

60

1.18

0.91

0.54

0.61

0.48

0.54

0.50

1.00

F igu r e 5. Stereoview of the superimposed average structures

of the five families from the 100 structures sampled during

100 ps MD simulations of 10a .

Ta ble 9. An a lgesic Activity Assa y by Ta il Clip Meth od

analgesic activity

ED₅₀

(µmol/animal)

duration

(min)

relative

(Leu-enk Me ester ) 1)

families has P of about 225°, corresponding to C_5′-endo

and an unusually large ν_maxof about 47°. The average

value of æ for all the residues is between -95° to -118°,

in conformity with large ³J _HNCRHobserved experimentally.

The structures also reveal that the aromatic rings in 10a

are orthogonal and pointing away from each other.

Con for m a tion a l An a lysis of 11a . As discussed al-

ready, the Gaa and Iaa containing peptides, 8a and 10a ,

respectively, due to the syn disposition of SaaC3-OH and

Phe-Leu amide chain, have an unusual nine-membered

â-turn-like structure stabilized by LeuNH f SaaC3-O(H)

H-bond. Such a turn structure is expected to be absent

in the dideoxy congener of these peptides, due to the

absence of the H-bond accepting OH group. The observa-

tion of large magnitudes of ∆δ/∆T for all amide protons

in 11a supports the above presumption. There is a similar

predominance of g^-conformer about the CR-Câ bond for

Tyr, Phe, and Leu residues. Due to spectral overlap, it

was not possible to get information on sugar pucker and

rotamer preferences about Câ-Cγ in the Leu side-chain.

Con for m a tion a l An a lysis of 51. To further substan-

tiate the participation of LeuNH f SaaC3-O(H) H-bond

in the unusual â-turn-like structure, the protected Idac

containing peptide 51 was investigated in detail by NMR

spectroscopy. A large value of ∆δ/∆T for LeuNH is

consistent with the absence of the said H-bond. This can

be attributed to the presence of a bulky protective group

on C3-oxygen that also effects the rigidity of the Leu side-

chain. The Leu side-chain in 51 shows the existence of

equal population (about 50%) of g^-and t rotamers about

CR-Câ, whereas for Phe, despite the dominance of g^-

rotamers, other rotamers have sizable populations.

Con for m a tion a l An a lysis of 12. The turn structure

observed in some of the above peptides where sugar

amino acids have “cis-â-hydroxycarboxyl” moiety, was

manifested in more ordered form in Idac-bearing reverse

turn mimetic 12. The anticipated nucleation of â-turn-

peptides

8a

8b

9b

Leu-enk

Me ester

1.17

1.33

2.45

2.06

90

120

90

1.76

1.55

0.84

1.00

like structures at both ends of this C₂-symmetric as-

sembly involving identical intramolecular H-bonding, as

observed earlier in 8a and 10a , between LeuNH f

sugarC3(C4)-O(H) was realized as expected. A very small

∆δ/∆T for LeuNH (-1.2 ppb/K) and a very low-field shift

of 5.99 ppm of IdacC3(C4)-OH support the formation of

a strong intramolecular LeuNH f IdacC3(C4)-O(H)

H-bond. The side-chains of Phe and Leu point to the

existence of large population of a single conformation.

The 2-fold symmetry of the molecule was also evident in

its ¹³C NMR spectrum which showed peaks for only half

of the molecule.

The MD calculations show the presence of seven

families of conformations (Figure 6), largely differing due

to different orientations of terminal groups. The sugar

pucker has a twist conformation with P ) 180° and

maximum puckering amplitude of about 35°. The average

values of æ from MD simulations are consistent with the

3

observed J _HNCRH

.

Biologica l Assa ys. The analgesic activities of the

enkephalin analogues²¹8-11 and 12 were tested in vivo

by mouse hot-plate²²and tail-clip²³assays following

intraperitoneal (ip) administration of the test substrates

and compared to that of Leu-enkephalin methyl ester.

The results of the assays are summarized in Tables 8

and 9, respectively. In the hot-plate test (Table 8)

compounds 8a ,b showed activities (ED₅₀) 1.14 and 1.48

µmol/animal, respectively), similar to that of Leu-en-

kephalin methyl ester (ED₅₀) 1.35 µmol/animal). The

same trend was observed when analgesic activities were

F igu r e 6. Stereoview of the superimposed average structures of the seven families from the 100 structures sampled during 100

ps MD simulations of 12.

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6451

Ta ble 10. Com p a r ison of th e ¹H Ch em ica l Sh ifts (δ, in

p p m ) in DMSO-d ₆(7-10 m M) of th e OH Gr ou p s in

Va r iou s Su ga r Am in o Acid s a n d th e Cor r esp on d in g

P ep tid es^a

C2-C1(O) dihedral angle of ∼60° (e,e relationship in a

chair conformation) was probably unable to bring LeuNH

and C3-OH close enough to initiate any H-bond forma-

tion. It can be stated here that the strength of the H-bond

depends largely on the nature of the sugar amino acids

and their ring size. The intramolecular H-bond inducing

the cis-â-hydroxycarboxyl structural motif appropriately

anchored on five-membered sugar rings described herein

is considered as the key element to bestow folded

conformations in linear peptides and may find applica-

tions in designing useful compounds.

Gaa in

8a

Maa in

9a

Iaa in

10a

Idac in

12 D

protons

A

B

C

OH(3)

OH(4)

5.97 5.53 5.25 5.17 5.71 5.50 5.99 5.72

5.34 5.27 5.55 5.61 5.26 5.12 5.99 5.72

a

A ) Boc-Gaa-OMe; B ) Boc-Maa-OMe; C ) Boc-Iaa-OMe;

D ) MeO-Idac-OMe.

tested by the tail-clip method (Table 9). Compounds 9a ,b,

10a , 11a , and 12 showed lower actvities than Leu-

enkephalin methyl ester.

Con clu sion s

An interesting rearrangement observed in a hexose-

derived acyclic aziridinyl compound, involving an in-

tramolecular 5-exo S_N2 opening of the terminal aziridine

ring by γ-benzyloxy oxygen with concomitant debenzyl-

ation under remarkably mild conditions, led to the

development of a new class of molecular scaffolds with a

2,5-anhydro sugar framework. The various functional

groups on each of these designed scaffolds, specially their

amino and carboxyl termini, besides serving as facile

adapters for solid-phase synthetic methods, may provide

opportunities to create libraries of multifaceted molecules

that can emulate structural diversities of natural prod-

ucts and their properties. The nonproteinogenic proper-

ties of sugar amino acids will make compounds physi-

ologically more stable. They will find wide ranging

applications in peptidomimetics, especially in designing

bioactive conformations of small peptides and in creating

de novo molecular entities with architecturally beautiful

structures and useful properties.

Discu ssion

The spectroscopic data strongly support the proposed

turn structures in 8a , 10a , and 12. The cis-â-hydroxy-

carboxyl moieties present on the sugar rings of these

molecules engage their LeuNH residues in intramolecu-

lar H-bonds with sugar-OH which is somewhat weaker

in 10a than in 8a and 12. It is noteworthy to mention

here that in these peptides, the chemical shifts of LeuNH

show about 0.4 ppm downfield shift in substrates where

intramolecular H-bonds are absent (9a , 11a , and 51).

This indicates that in the absence of intramolecular

H-bond, the LeuNH is solvent exposed and participates

in stronger H-bonds with DMSO. At the same time, the

sugarC3-OH protons show substantial downfield shifts

(Table 10) in some of these peptides (0.44 ppm for 8a ,

0.21 ppm for 10a , and 0.27 ppm for 12), where the OH

oxygen acts as H-bond acceptor resulting in the decreased

electron density on the proton.²⁴The changes in the

sugarC4-OH proton chemical shifts are less pronounced.

The two aromatic rings in 8a come close enough to each

other resulting in its biological activity. This is in

conformity with earlier observations that in enkephalins

the C-terminal address segment stabilizes the bioactive

conformation of the N-terminal message segment in

which the two aromatic rings remain in close proximity

with nearly parallel orientation.¹⁰While the higher

temperature coefficient of LeuNH and the absence of any

significant ROESY cross-peaks between the aromatic

rings in 10a , resulting in their divergent disposition as

revealed by MD simulations, can possibly explain its

reduced activity, the inability of 9a and 11a to exhibit

any detectable folded conformation makes them biologi-

cally less active. The reverse turn mimetic 12, despite

showing a highly ordered structure, also exhibits reduced

analgesic activity possibly for lacking the essential phar-

macophoric framework.

Exp er im en ta l Section

Gen er a l P r oced u r es. All reactions were carried out in

oven- or flame-dried glassware with magnetic stirring under

nitrogen atmosphere using dry, freshly distilled solvents,

unless otherwise noted. Reactions were monitored by thin-

layer chromatography (TLC) carried out on 0.25 mm silica gel

plates with UV light, I₂, 7% ethanolic phosphomolybdic acid-

heat, and 2.5% ethanolic anisaldehyde (with 1% AcOH and

3.3% concentrated H₂SO₄)-heat as developing agents. Silica

gel finer than 200 mesh was used for flash column chroma-

tography. Yields refer to chromatographically and spectro-

scopically homogeneous materials unless otherwise stated.

IR spectra were recorded as neat liquids or KBr pellets.

Mass spectra were obtained under electron impact (EI) and

liquid secondary ion mass spectrometric (LSIMS) techniques,

respectively. For LSIMS, m-nitrobenzyl alcohol was used as a

matrix. Melting points are uncorrected.

The CD spectra were recorded in quartz cells of 1 mm path

length at 25 °C using peptide concentrations of 0.2 mM in TFE.

An a lgesic Activity Assa y. (a) Effect of enkephalin and its

analogues on mechanically induced pain (heat; hot plate

method) in mice: Albino Swiss mice weighing between 20 and

22 g were subjected to the hot plate test. The test substances

dissolved/suspended in physiological solution (0.1 mL/mg) were

administered in varying doses (0.5, 1.0, 2.0 mg/animal) by

intraperitoneal (ip) route with a 24 gauge needle using 10

animals for each group (N ) 10). The hot plate (Socrel, model

DS-37, Italy) was adjusted to the temperature of 55.0 ( 0.1

°C. The individual reaction time (licking of paws) was recorded

before administering the test substances. The cut-off point of

reaction was about 12 s to avoid the thermal injury to the paw.

Analgesic response was calculated as the percent increase in

reaction time before and after administration of test sub-

stances measured at intervals of 30, 60, 90, and 120 min taking

95% confidence limit. An initial gap of 30 min was given after

The small HO-C3-C2-C1(O) dihedral angles on

sugar rings in 8a , 10a , and 12 with average values of

26°, 16°, and 41°, respectively, explains the failure to

exhibit any significant turn structure by the biologically

inactive pyranoid sugar amino acid-containing enkepha-

lin analogues reported earlier,^4j,4mwhere the HO-C3-

(21) Kieffer, B. L. Trends Pharmacol. Sci. 1999, 20, 19-26.

(22) Dutta, A. S.; Gormley, J . J .; Hayward, C. F.; Morley, J . S.; Shaw,

J . S.; Stacey, G. J .; Turnbull, M. T. Life Sci. 1977, 21, 559-562.

(23) Bobrova, I.; Abissova, N.; Mishlakova, N.; Rozentals, G.;

Chipens, G. Eur. J . Med. Chem. 1998, 33, 255-266 and the references

therein.

(24) (a) Martin, T. W.; Derewenda, Z. S. Nature Struct. Biol. 1999,

6, 403-406. (b) Arunan, E. Curr. Sci. 1999, 77, 1233-1235 and the

references therein.

6452 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

each administration before starting the measurements. The

ED₅₀values were calculated using the probit analysis and

compared to that of Leu-enkephalin methyl ester. The results

are summarized in Table 8.

subjected to MD simulations. A number of interatomic distance

and torsional angle constraints²⁷obtained from NMR data

were used as restraints in the minimization as well as MD

runs. For MD runs, a temperature of 300 K was used. The

assemblies of molecules soaked in solvents were initially

equilibrated for 10 ps and subsequently subjected to a 100 ps

dynamics with a step size of 1 fs, sampling the trajectory at

equal intervals of 1 ps. The samples were minimized using

above-mentioned energy minimization protocol and analyzed

for similarities in their structures by comparing the RMS

deviations between each possible pair of structures. The RMS

deviations were plotted in a 100 × 100 matrix with the x- and

y-axes representing the structure numbers. The plot revealed

a number of areas of clusters along the diagonal, indicating

that several families of distinct structures were visited during

the simulation period. The average structures from various

families were compared and superimposed as shown in Figures

4-6.

(b) Effect of enkephalin and its analogues on the mechani-

cally induced pain (Tail clip method) in mice: Albino Swiss

mice weighing between 20 and 22 g were used for the

experiment. The pain was induced by applying an artery clip

to the base of the mouse tail. The animals which responded

by biting the clip or attempting to remove the clip within 2-3

s were selected a day prior to experiment. The test substances

dissolved in physiological solution (0.1 mL/mg) were admin-

istered in varying doses (0.5, 1.0, 2.0 mg/animal) by i.p. route

with 24 gauge needle using 10 animals for each group (N )

10). Measurements were made after 30 min at intervals of 30,

60, 90, 120 min. The analgesic activity was expressed as a

percent of mice not showing the biting response or attempt to

remove the clip. The confidence limit was 95% and the cut-off

time was about 6-8 s to avoid mechanical injury to the mice.

The ED₅₀values were calculated using the probit analysis and

compared to that of Leu-enkephalin methyl ester. The results

are summarized in Table 9.

NMR Sp ectr oscop y. NMR spectra were recorded on 200,

400, and 500 MHz spectrometers at room temperature of ∼21

°C (unless otherwise mentioned) with 7-10 mM solutions in

appropriate solvents using tetramethylsilane as internal

standard or the solvent signals as secondary standards, and

the chemical shifts are shown in δ scales. Multiplicities of NMR

signals are designated as s (singlet), d (doublet), t (triplet), q

(quartet), br (broad), m (multiplet, for unresolved lines), etc.

¹³C NMR spectra were recorded with complete proton decou-

pling. The assignments were carried out with the help of two-

dimensional double quantum filtered correlation spectroscopy

(DQF COSY) and total correlation spectroscopy (TOCSY).²⁵For

some cases the nuclear Overhauser effect spectroscopy (NOE-

SY) or rotating frame nuclear Overhauser effect spectroscopy

(ROESY) experiments,²⁵which provide the information on the

proximity of protons, were additionally used to confirm the

assignments made. All the experiments were carried out in

the phase-sensitive mode using the procedure of States et al.²⁶

The spectra were acquired with 2 × 256 or 2 × 192 free

induction decays (FID) containing 8-32 transients with

relaxation delays of 1.5 to 2.0 s. The NOESY and ROESY

experiments were performed with mixing time of 0.1 to -0.5

s. For ROESY experiments a spin locking field of about 2 kHz

and pulsed field locking with 30° pulses were used. The

TOCSY experiments were performed with the spin locking

fields of about 10 kHz and a mixing time of 0.08 s. The two-

dimensional data were processed with Gaussian apodization

in both the dimensions. The chemical shifts, coupling constants

and temperature coefficients (∆δ/∆T) of amide proton chemical

shifts are given in Tables 1-6. To obtain the temperature

coefficients of NH-chemical shifts, the spectra were recorded

between room temperature and 70 °C.

6-Deoxy-6-a zid o-2,3,4-tr i-(O-ben zyl)-^D-glu citol (15). To

a solution of 13 (9 g, 18.4 mmol) in glacial acetic acid (60 mL)

was added dilute HCl (2 M, 14 mL), and the reaction mixture

was heated with stirring for 8 h at 80-85 °C. It was then

cooled to room temperature, diluted with EtOAc, washed

sequentially with water, saturated NaHCO₃, and brine, dried

(Na₂SO₄), and concentrated in vacuo. Column chromatography

(SiO₂, 5-20% EtOAc in petroleum ether eluant) gave unre-

acted 13 (3.6 g) and the desired lactol 14 (4.32 g, 83%) as a

syrupy liquid which was used without characterization in the

next step. To a solution of the lactol 14 (4.32 g, 9.09 mmol) in

dry MeOH (25 mL) was added NaBH₄(3.4 g, 90 mmol)

portionwise at 0 °C. The reaction mixture was slowly brought

to room temperature and stirred under nitrogen atmosphere

for 6 h. It was then cooled to 0 °C and quenched by slow

addition of saturated NH₄Cl solution. The aqueous solution

was extracted with EtOAc. The combined organic extracts were

washed with brine, dried (Na₂SO₄), and concentrated in vacuo.

Purification by column chromatography (SiO₂, 10-25% EtOAc

in petroleum ether eluant) afforded pure diol 15 (3.76 g, 87%)

as a syrupy liquid. R_f) 0.4 (silica, 25% EtOAc in petroleum

ether); [R]²⁰_D35.9 (c 1, CHCl₃); IR (neat): ν_max3450, 2100, 1450

cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ 7.45-7.2 (m, 15 H, ArH),

4.65 (s, 4 H, PhCH₂O-), 4.51 (s, 2 H, PhCH₂O-). 3.95 (m, 1 H,

C5-H), 3.78 (br s, 2 H, CH₂OH), 3.74-3.55 (m, 2 H, C3-H, C4-

H), 3.44 (dd, J ) 12.6, 3 Hz, 1 H, C6-H), 3.35 (m, 1 H, C2-H),

3.25 (dd, J ) 12.6, 5 Hz, 1 H, C6-H′); ¹³C NMR (CDCl₃, 50

MHz): δ 137.69, 137.3, 137.25, 128.45, 128.14, 128.06, 127.94,

78.89, 78.73, 76.75, 74.11, 73.44, 73.10, 71.42, 61.60, 53.52;

MS (LSIMS): m/z (%): 478 [M⁺], 450 [M⁺- N₂]. HRMS

(LSIMS): calcd for C₂₇H₃₁N₃O₅[M⁺]: 478.2342, found: 478.2355.

(2S)-N-Boc-2-[(1R,2S,3S)-1,2,3-tr iben zyloxy-4-h yd r oxy-

bu t-1-yl]a zir id in e (17). To a solution of 15 (3.5 g, 7.32 mmol)

in dry toluene (30 mL) was added Ph₃P (3.84 g, 14.64 mmol)

at room temperature. The reaction mixture was refluxed under

nitrogen atmosphere for 24 h. After cooling to room temper-

ature, Boc₂O (3.19 g, 14.64 mmol) was added to it followed by

stirring for an additional 6 h. It was then diluted with EtOAc,

washed with brine, dried (Na₂SO₄), and concentrated in vacuo.

Column chromatography (SiO₂, 10-30% EtOAc in petroleum

ether eluant) gave pure Boc-protected aziridine 17 (3.32 g,

85%) as a syrupy liquid. R_f) 0.45 (silica, 30% EtOAc in

Molecu la r Dyn a m ics. All molecular mechanics/dynamics

calculations were carried out using Insight II (97.0)/Discover

program on a Silicon Graphics Octane workstation. The cvff

force field with default parameters was used throughout the

simulations. In the calculations, the peptides were soaked with

three shells of DMSO solvent molecules with the radii of 18,

7, and 10 Å, respectively. The first shell solvent molecules were

allowed to move freely along with the peptides, while in the

second shell, they were tethered with respect to the hydrogen

atoms. In the third shell, all atoms of the solvent molecules

were fixed. Minimizations were done first with steepest decent,

followed by conjugate gradient methods for a maximum of 1000

iterations each or RMS deviation of 0.01 kcal/mol, whichever

was earlier. The energy-minimized structures were then

petroleum ether); [R]²⁰-52.1 (c 1, CHCl₃); IR (neat): ν_max

D

1

3450, 1720, 1450 cm^-1; H NMR (CDCl₃, 200 MHz): δ 7.4-

7.05 (m, 15 H, ArH), 4.98-4.57 (three ABq, 6 H, PhCH₂O-),

3.84 (dt, J ) 4.0, 2.5 Hz, 1 H, C2-H), 3.68 (ddd, J ) 12.8, 6.4,

2.5 Hz, 1 H, C1-H), 3.62 (t, J ) 4.0 Hz, 1 H, C3-H), 3.43 (ddd,

J ) 12.8, 6.4, 4.0 Hz, 1 H, C1-H′), 3.21 (dd, J ) 6.8, 4.0 Hz, 1

H, C4-H), 2.52 (ddd, J ) 6.8, 6.8, 3.7 Hz, 1 H, C5-H), 2.16 (t,

J ) 6.4 Hz, 1 H, CH₂OH), 1.93 (d, J ) 6.8 Hz, 1 H, C6-H),

1.78 (d, J ) 3.7 Hz, 1 H, C6-H′), 1.44 (s, 9 H, Boc); ¹³C NMR

(CDCl₃, 50 MHz): δ 161.98, 138.26, 137.93, 137.83, 128.54,

128.34, 128.25, 127.87, 127.72, 127.65, 81.41, 80.00, 79.41,

(25) (a) Cavanagh, J .; Fairbrother, W. J .; Palmer, A. G., III; Skelton,

N. J . Protein NMR Spectroscopy, Academic Press: San Diego, 1996.

(b) Wu¨thrich, K. NMR of Proteins and Nucleic Acids; Wiley: New York,

1986.

(26) States, D. J .; Haberkorn, R. A.; Ruben, D. J . J . Magn. Reson.

1982, 48, 286-292.

(27) Kessler, H.; Griesinger, C.; Lautz, J .; Mu¨ller, A.; F. van

Gunsteren, W.; Berendsen, H. J . C. J . Am. Chem. Soc. 1988, 110,

3393-3396.

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6453

78.61, 74.55, 72.77, 71.59, 61.31, 38.77, 27.87, 27.19; MS

(LSIMS): m/z (%): 534 [M⁺+ H], 434 [M⁺+ H - 100]; HRMS

(LSIMS): calcd for C₃₂H₄₀NO₆[M⁺+ H]: 534.2855, found:

534.2842.

and 3.38 (two m, 2 H, C6-H₂), 1.42 (s, 9 H, Boc); ¹³C NMR

(CDCl₃, 50 MHz): δ 169, 156.1, 138.25, 128.37, 127.88, 127.68,

82.68, 78.65, 75.91, 75.41, 72.68, 71.68, 71.28, 66.93, 41.62,

28.4; MS (LSIMS): m/z (%): 494 (16) [M⁺+ Na], 472 (10) [M⁺

+ H], 372 (100) [M⁺+ H - 100].

Meth yl N-Boc-6-a m in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-6-

d eoxy-^D-glu con a te (20). To a solution of 17 (3 g, 5.63 mmol)

in dry DMF (10 mL) was added PDC (10.59 g, 28.15 mmol) at

0 °C. The reaction mixture was stirred at room temperature

for 12 h. It was then diluted with EtOAc, washed with

saturated CuSO₄and brine, dried (Na₂SO₄), and concentrated

in vacuo. The crude product was dissolved in ether (30 mL),

and an ethereal solution of diazomethane was added dropwise

at 0 °C till the esterification was complete as shown by TLC.

The reaction mixture was then concentrated in vacuo and

chromatographed (SiO₂, 5-25% EtOAc in petroleum ether

eluant) to get pure ester 20 (1.35 g) and the bicyclic product

19 (0.6 g). A solution of 19 (0.6 g, 1.36 mmol) in dry MeOH (5

mL) was treated with anhydrous K₂CO₃(0.188 g, 1.36 mmol)

at 0 °C, and the reaction mixture was stirred for 1 h at the

same temperature. It was then diluted with EtOAc, washed

with brine, dried (Na₂SO₄), and concentrated in vacuo. Puri-

fication by column chromatography (SiO₂, 5-25% EtOAc in

petroleum ether eluant) afforded the ester 20 (0.54 g), as a

syrupy liquid, leading to an overall yield of 72% from 17. Data

for 19: R_f) 0.6 (silica gel, 30% EtOAc in petroleum ether);

1,3:4,6-Di-O-ben zylid en e-2-O-tosyl-^D-m a n n itol (25). To

a solution of 24 (15 g, 41.89 mmol) and Et₃N (6.37 mL, 46.07

mmol) in CH₂Cl₂:DMF (4:1, 150 mL) was added TsCl (8.83 g,

46.07 mmol) under nitrogen atmosphere, and the reaction

mixture was stirred at room temperature for 5 h. It was then

diluted with EtOAc, washed with saturated NH₄Cl and brine,

dried (Na₂SO₄), and concentrated in vacuo. Purification by

column chromatography (SiO₂, 20-35% EtOAc in petroleum

ether eluant) afforded the monotosylate 25 (17.19 g, 80%) as

a white solid. R_f) 0.5 (silica gel, 40% EtOAc in petroleum

ether); [R]²⁰-23.2 (c 1, CHCl₃); IR (KBr): ν_max3500, 1600,

D

1350, 1175, 975 cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ 7.76 and

7.12 (two d, J ) 8.5 Hz, 4 H, tosyl), 7.5-7.3 (m, 10 H, ArH),

5.52 (s, 1 H, benzylideneCH), 5.0 (s, 1 H, benzylideneCH), 4.85

(dt, J ) 11.2, 5.6 Hz, 1 H, C2-H), 4.42 (dd, J ) 11.2 and 5.6

Hz, 1 H, C1-H), 4.3-4.0 (m, 3 H, C6-H, C4-H, C5-H), 3.85 (t,

J ) 11.2 Hz, 1 H, C1-H′), 3.65 (dd, J ) 11.2, 2 Hz, 1 H, C4-H),

3.54 (t, J ) 11.2 Hz, 1 H, C6-H′), 2.25 (s, 3 H, tosyl-CH₃); ¹³C

NMR (CDCl₃, 50 MHz): δ 145.38, 137.36, 136.82, 132.61,

129.99, 129.16, 128.75, 128.19, 127.98, 127.87, 126.18, 126.08,

101.31, 100.48, 77.3, 75.03, 71.05, 68.55, 67.29, 59.71, 21.47;

MS (LSIMS): m/z (%): 513 (100) [M⁺+ H]; HRMS (LSIMS):

calcd for C₂₇H₂₉O₈S [M⁺+ H]: 513.1583, found: 513.1589.

Th e Keto Com p ou n d 26. A solution of oxalyl chloride (4.09

mL, 46.7 mmol) in dry CH₂Cl₂(140 mL), cooled to -78 °C,

was treated with DMSO (6.64 mL, 93.5 mmol). After 5 min,

the alcohol 25 (16 g, 31.25 mmol) dissolved in CH₂Cl₂(40 mL)

was added to the reaction mixture at the same temperature.

After stirring for 1 h at -78 °C, the reaction mixture was

treated with Et₃N (19.41 mL, 140.35 mmol), slowly warmed

to 0 °C, and stirred at this temperature for 15 min. It was

then poured into a cold saturated aqueous NH₄Cl solution and

extracted with EtOAc. The combined organic extracts were

washed with brine, dried (Na₂SO₄), filtered, and concentrated

in vacuo. Purification by column chromatography (SiO₂, 20%

EtOAc in petroleum ether eluant) afforded the ketone 26 (14.34

g, 90%) as a white solid. R_f) 0.4 (silica gel, 30% EtOAc in

[R]²⁰_D-18.4 (c 1, CHCl₃); IR (neat): ν_max1780, 1725, 1470 cm^-1

;

¹H NMR (CDCl₃, 400 MHz): δ 7.4-7.28 (m, 10 H, ArH), 4.77

and 4.45 (ABq, 2 H, PhCH₂O-), 4.76 (d, J ) 5 Hz, 1 H, C2-H),

4.5 (ABq, 2 H, PhCH₂O-), 4.44 (d, J ) 5 Hz, 1 H, C3-H), 4.3

(dd, J ) 5.3, 2.2 Hz, 1 H, C5-H), 4.04 (d, J ) 2.2 Hz, 1 H,

C4-H), 3.83 (dd, J ) 12.8, 5.3 Hz, 1 H, C6-H), 3.55 (d, J )

12.8 Hz, 1 H, C6-H′), 1.54 (s, 9 H, Boc); ¹³C NMR (CDCl₃, 50

MHz): δ 166.2, 152, 137.1, 136.9, 128.5, 128.4, 128.1, 128,

127.8, 86.8, 86.3, 83.6, 79.6, 77.8, 72.9, 71.7, 48.9, 28; MS

(LSIMS): m/z (%): 439 (10) [M⁺], 384 (100) [M⁺+ H - CH₂d

C(CH₃)₂]; HRMS (LSIMS): calcd For C₂₁H₂₂NO₆[M⁺+ H -

CH₂dC(CH₃)₂]: 384.1447, found: 384.1462. Data for 20: R_f

) 0.4 (silica gel, 30% EtOAc in petroleum ether); [R]²⁰9.4 (c

D

1, CHCl₃); IR (neat): ν_max1765, 1705 cm^-1; H NMR (CDCl₃,

1

200 MHz): δ 7.4-7.2 (m, 10 H, aromatic), 5.3 (m, 1 H, NHBoc),

4.68 (d, J ) 5 Hz, 1 H, C2-H), 4.48 (ABq, 4 H, PhCH₂O-), 4.22

(dd, J ) 5, 2 Hz, 1 H, C3-H), 4.13 (m, 1 H, C5-H), 3.88 (dd, J

) 3, 2 Hz, 1 H, C4-H), 3.72 (s, 3 H, CO₂CH₃), 3.4 (m, 2 H,

C6-H), 1.42 (s, 9 H, Boc); ¹³C NMR (CDCl₃, 50 MHz): δ 169.6,

156.1, 137.3, 137.1, 128.5, 128.4, 128, 127.8, 127.7, 83.6, 83.2,

82.7, 80, 79.1, 72.4, 72.1, 52, 42.2, 28.4; MS (LSIMS): m/z

petroleum ether); [R]²⁰-60.2 (c 1, CHCl₃); IR (KBr): ν_max

D

1740, 1600, 1365, 1175 cm^-1; H NMR (CDCl₃, 200 MHz): δ

1

7.75 and 7.15 (two d, J ) 8.5 Hz, 4 H, tosyl), 7.5-7.2 (m, 10

H, ArH), 5.58 (s, 1 H, benzylideneCH), 5.48 (s, 1 H, ben-

zylideneCH), 4.82 (dt, J ) 11.2, 5.6 Hz, 1 H, C2-H), 4.5 (s, 1

H, C4-H), 4.45-4.3 (m, 2 H, C1-H, C3-H), 4.35 (ABq, 2 H, C6-

H, C6-H′), 3.7 (t, J ) 11.2 Hz, 1 H, C1-H′), 2.3 (s, 3 H, tosyl-

CH₃); ¹³C NMR (CDCl₃, 50 MHz): δ 203.6, 145.44, 136.78,

136.46, 132.52, 129.98, 129.23, 129.12, 128.23, 128.15, 127.94,

126.21, 126.05, 101.24, 98.57, 78.8, 76.99, 72.03, 68.43, 67.03,

21.53; MS (LSIMS): m/z (%): 511 (100) [M⁺+ H]; HRMS

(LSIMS): calcd for C₂₇H₂₇O₈S [M⁺+ H]: 511.1426, found:

511.1436.

(%): 494 (25) [M⁺+ Na], 472 (20) [M⁺+ H], 372 (100) [M⁺

+

H - 100]. HRMS (LSIMS): calcd for C₂₆H₃₄NO₇[M⁺+ H]:

472.2335, found: 472.2363.

(2S)-N-Boc-2-[(1R,2S,3R)-1,2,3-tr iben zyloxy-4-h yd r oxy-

bu t-1-yl]a zir id in e (21). It was synthesized following the

same method as described above for the synthesis of 17. Data

for 21: R_f) 0.5 (silica gel, 30% EtOAc in petroleum ether);

[R]²⁰-78.4 (c 1, CHCl₃); IR (neat): ν_max3430, 1720 cm^-1; ¹H

D

NMR (CDCl₃, 200 MHz): δ 7.4-7.1 (m, 15 H, ArH), 4.9, 4.7,

and 4.3 (three ABq, 6 H, PhCH₂O-), 3.9-3.55 (m, 4 H, C1-H₂,

C2-H, C3-H), 3.15 (dd, J ) 8.4, 2.3 Hz, 1 H, C4-H), 2.55 (ddd,

J ) 8.4, 6.8, 3.7 Hz, 1 H, C5-H), 2.05 (broad t, 1 H, CH₂OH),

1.85 (d, J ) 6.8 Hz, 1 H, C6-H), 1.7 (d, J ) 3.7 Hz, 1 H, C6-

H′), 1.44 (s, 9 H, Boc); ¹³C NMR (CDCl₃, 50 MHz): δ 138.3,

137.95, 137.87, 128.56, 128.36, 128.21, 127.92, 127.73, 127.54,

81.49, 79.26, 78.81, 74.10, 72.03, 71.14, 60.24, 39.54, 27.9,

27.13; MS (LSIMS): m/z (%): 534 (5) [M⁺+ H], 434 (30) [M⁺

+ H - 100]; HRMS (LSIMS): calcd for C₃₂H₄₀NO₆[M⁺+ H]:

534.2855, found: 534.2847.

D-Glu citol In ter m ed ia te 27. To a solution of 26 (12 g,

23.52 mmol) in dry MeOH (120 mL) was added NaBH₄(4.437

g, 117.25 mmol) portionwise at 0 °C. The reaction mixture was

stirred at the same temperature for 1 h. It was then quenched

by careful addition of cold saturated aqueous NH₄Cl solution.

After removal of MeOH under reduced pressure, the aqueous

solution was extracted with EtOAc. The combined organic

extracts were washed with brine, dried (Na₂SO₄), and concen-

1

trated in vacuo. H NMR of the crude residue indicated it as

a mixture of 25 and 27 (ca. 1:6 ratio). The mixture was used

as such in the next step.

Meth yl N-Boc-6-a m in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-6-

d eoxy-^D-m a n n on a te (23). Following the same method as

described above for the conversion of 17 to 20, the mannonate

congener 23 was prepared from 21 in 78% yield by PDC

oxidation. Data for 23: R_f) 0.45 (silica gel, 30% EtOAc in

petroleum ether); [R]²⁰_D14.3 (c 1, CHCl₃); IR (neat): ν_max1770,

1,3:4,6-Di-O-ben zylid en e-2,5-a n h yd r o-^D-id itol (28). The

residue from the previous step (11 g, 21.56 mmol), dissolved

in dry MeOH (125 mL), was treated at 0 °C with anhydrous

K₂CO₃(5.926 g, 42.88 mmol). The reaction mixture was stirred

under nitrogen atmosphere at room temperature for 12 h. It

was then cooled to 0 °C and quenched by slow addtion of a

cold saturated aqueous NH₄Cl solution. After removal of

MeOH under reduced pressure, the aqueous solution was

extracted with EtOAc. The combined organic extracts were

1

1700 cm^-1; H NMR (CDCl₃, 400 MHz): δ 7.4-7.2 (m, 10 H,

ArH), 5.0 (m, 1 H, NH), 4.6 and 4.47 (two ABq, 4 H, PhCH₂O-

), 4.65 (s, 1 H, C2-H), 4.33 (s, 1 H, C3-H), 4.3 (m, 1 H, C5-H),

3.88 (d, J ) 1.8 Hz, 1 H, C4-H), 3.72 (s, 3 H, CO₂CH₃), 3.48

6454 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

washed with brine, dried (Na₂SO₄), and concentrated in vacuo.

Purification by column chromatography (SiO₂, 8-12% EtOAc

in petroleum ether eluant) afforded the cyclic product 28 (5 g,

62% from 26) as a white solid. R_f) 0.5 (silica gel, 20% EtOAc

in petroleum ether); [R]²⁰_D21.5 (c 1.02, CHCl₃); IR (KBr): ν_max

H, C₃-H, C₄-H), 3.78 and 3.68 (two dd, J ) 11.5, 4.5 Hz, 4 H,

C₁-H₂, C₆-H₂), 3.8 (d, J ) 3.2 Hz, 2 H, OH); ¹³C NMR (CDCl₃,

50 MHz): δ 197.3, 128.45, 128, 127.56, 82.52, 79.9, 72.22,

61.54; MS (LSIMS): m/z (%): 345 (95) [M⁺+ H], 367 (100)

[M⁺+ Na]; HRMS (LSIMS): calcd for C₂₀H₂₅O₅[M⁺+ H]:

345.1702, found: 345.1738.

1425, 1390, 1150, 1100, 975 cm^{-1 1}H NMR (CDCl₃, 200

;

MHz): δ 7.5-7.3 (m, 10 H, ArH), 5.45 (s, 2 H, benzylideneCH),

4.5 (m, 2 H, C₂-H, C₅-H), 4.45 (d, J ) 17.6 Hz, 2 H, C₆-H), 4.32

(br s, 2 H, C₃-H, C₄-H), 4.08 (dd, J ) 17.6, 1 Hz, 2 H, C₆-H′);

¹³C NMR (CDCl₃, 50 MHz): δ 137.94, 128.95, 128.11, 126.22,

98.97, 96.22, 79.86, 73.56, 68.08; MS (LSIMS): m/z (%): 341

(100) [M⁺+ H]; HRMS (LSIMS): calcd for C₂₀H₂₀O₅[M⁺]:

340.1310, found: 340.1293.

2,5-An h yd r o-^D-id itol (29). To a solution of 28 (5 g, 14.7

mmol) in MeOH:EtOAc (1:1, 40 mL) was added 10% Pd on C

(1 g). It was hydrogenated under atmospheric pressure using

a H₂balloon. The reaction mixture was then filtered through

a short pad of Celite, and the filter cake was washed with

MeOH. The filtrate and washings were combined and concen-

trated in vacuo. The residue was azeotroped with dry toluene

to afford pure 29 in quantitative yield, which was used directly

in the next step without further purification.

2,5-An h yd r o-1,6-d i-O-(ter t-b u t yld ip h en ylsilyl)-^D-id i-

tol (30). The tetrol 29 from the previous step (2.41 g, 14.7

mmol), dissolved in dry DMF (50 mL), was treated at 0 °C

under nitrogen atmosphere sequentially with imidazole (2 g,

29.4 mmol) and TBDPSCl (7.52 mL, 29.4 mmol). After stirring

for 12 h at room temperature, the reaction mixture was diluted

with EtOAc, washed with saturated NH₄Cl and brine, dried

(Na₂SO₄), and concentrated in vacuo. Purification by column

chromatography (SiO₂, 10-20% EtOAc in petroleum ether

eluant) afforded the product 30 (8.47 g, 90%) as a syrupy

liquid. R_f) 0.45 (silica gel, 30% EtOAc in petroleum ether);

2,5-An h yd r o-3,4-d i-O-ben zyl-6-O-tosyl-^D-id itol (33). To

a solution of 32 (1.8 g, 5.23 mmol) in dry THF (20 mL) under

nitrogen atmosphere at 0 °C was added NaH (60% dispersion,

209 mg, 5.24 mmol) portionwise. After stirring for 15 min at

the same temperature, TsCl (1 g, 5.23 mmol) was added to it

and stirring continued for 1 h. It was quenched with saturated

NH₄Cl solution, extracted with EtOAc. The combined organic

extracts were washed with brine, dried (Na₂SO₄), and concen-

trated in vacuo. Purification by column chromatography (SiO₂,

20-30% EtOAc in petroleum ether eluant) gave the desired

monotosylated compound 33 (2.08 g, 80%) as a syrupy liquid,

which was used directly in the next step.

2,5-An h yd r o-6-a zid o-6-d eoxy-3,4-d i-O-b en zyl-^D-id it ol

(34). To a solution of 33 (1.8 g, 3.6 mmol) in dry DMF (10 mL)

was added NaN₃(468 mg, 7.2 mmol), and the reaction mixture

was heated with stirring at 80 °C for 3 h. After cooling to room

temperature, it was diluted with EtOAc, washed with water

and brine, dried (Na₂SO₄), and concentrated in vacuo. Purifi-

cation by column chromatography (SiO₂, 16-18% EtOAc in

petroleum ether eluant) gave the azide 34 (1.1 g, 90%) as a

syrupy liquid. R_f) 0.5 (silica gel, 30% EtOAc in petroleum

ether); [R]²⁰_D27.2 (c 1, CHCl₃); IR (neat): ν_max3450, 2300, 1485

cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ 7.45-7.2 (m, 10 H, ArH),

4.55 and 4.5 (two ABq, 4 H, PhCH₂O-), 4.25 (m, 2 H, C2-H,

C5-H), 4.05 (m, 2 H, C3-H, C4-H), 3.8 (m, 2 H, C1-H₂), 3.52

and 3.45 (two dd, J ) 11.5, 4.5 Hz, 2 H, C6-H₂), 2 (broad, 1 H,

OH); ¹³C NMR (CDCl₃, 50 MHz): δ 137.34, 137.23, 128.63,

128.54, 128.36, 128.17, 128.08, 127.76, 127.67, 82.32, 81.67,

79.96, 78.62, 72.46, 72.34, 61.65, 50.1; MS (LSIMS): m/z (%):

392 (20) [M⁺+ Na].

[R]²⁰_D-10.6 (c 1, CHCl₃); IR (neat): ν_max3375, 1425, 1400 cm^-1

;

¹H NMR (CDCl₃, 200 MHz): δ 7.75-7.3 (m, 20 H, ArH), 4.34

(t, J ) 3.6 Hz, 2 H, C3-H, C4-H), 4.22 (dd, J ) 3.6, 3.2 Hz, 2

H, C2-H, C5-H), 4.03 (d, J ) 3.6 Hz, 4 H, C1-H₂, C6-H₂), 3.8

(d, J ) 3.2 Hz, 2 H, OH), 1.02 (s, 18 H, tert-butyl); ¹³C NMR

(CDCl₃, 50 MHz): δ 135.66, 135.51, 132.71, 132.4, 129.97,

129.91, 127.86, 79.69, 79.12, 63.67, 26.75, 19.1; MS (LSIMS):

m/z (%): 663 (30) [M⁺+ Na].

N-Boc-6-Am in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-6-d eoxy-^D-

id itol (36). To a solution of 34 (1 g, 2.71 mmol) in MeOH (20

mL) was added Ph₃P (1.42 g, 5.42 mmol), and the reaction

mixture was stirred for 12 h at room temperature. This was

followed by the addtion of Boc₂O (1.24 mL, 5.42 mmol) to the

reaction and stirring continued for an additional 1 h. It was

then diluted with EtOAc, washed with brine, dried (Na₂SO₄),

and concentrated in vacuo. Column chromatography (SiO₂,

25-30% EtOAc in petroleum ether eluant) gave pure Boc-

protected amino alcohol 36 (1.08 g, 90%) as a syrupy liquid.

R_f) 0.3 (silica gel, 40% EtOAc in petroleum ether); [R]²⁰_D30.6

2,5-An h ydr o-3,4-di-O-ben zyl-1,6-di-O-(ter t-bu tyldiph en -

ylsilyl)-^D-id itol (31). To a solution of 30 (7.5 g, 11.71 mmol)

in THF-DMF (2:1, 30 mL) was added benzyl bromide (3.5 mL,

29.27 mmol). The reaction mixture was cooled to 0 °C and

treated by dropwise addition with a solution of NaHMDS in

THF (2 M, 14.63 mL, 29.27 mmol). After stirring for 15 min

at 0 °C, it was quenched by careful addition of a cold saturated

aqueous NH₄Cl solution. The aqueous layer was extracted with

EtOAc. The combined organic extracts were washed with

brine, dried (Na₂SO₄), and concentrated in vacuo. Purification

by column chromatography (SiO₂, 1-2% EtOAc in petroleum

ether eluant) afforded the product 31 (6.73 g, 70%) as a syrupy

liquid. R_f) 0.45 (silica gel, 6% EtOAc in petroleum ether);

1

(c 1, CHCl₃); IR (neat): ν_max3400, 1700, 1512 cm^-1; H NMR

(CDCl₃, 200 MHz): δ 7.4-7.2 (m, 10 H, ArH), 4.8 (m, 1 H,

NHBoc), 4.6 and 4.3 (m, 4 H, PhCH₂O-), 4.2 (m, 2 H, C2-H,

C5-H), 4.05 (m, 2 H, C3-H, C4-H), 3.75 (m, 2 H, C1-H₂), 3.5

and 3.2 (two m, 2 H, C6-H₂), 2.03 (broad, 1 H, OH), 1.45 (s, 9

H, Boc); ¹³C NMR (CDCl₃, 50 MHz): δ 156.01, 137.38, 137.27,

128.57, 128.25, 128.1, 128.04, 127.67, 82.61, 82.03, 79.61,

79.14, 78.85, 72.31, 72.23, 61.65, 40.47, 28.36; MS (LSIMS):

m/z (%): 344 (100) [M⁺+ H - 100], 444 (15) [M⁺+ H], 466

[R]²⁰_D3.96 (c 1.2, CHCl₃); IR (neat): ν_max3062, 1475, 1425 cm^-1

;

¹H NMR (CDCl₃, 200 MHz): δ 7.65 (d, J ) 7 Hz, 8 H, ArH),

7.4-7.2 (m, 22 H, ArH), 4.56 (s, 4 H, PhCH₂O-), 4.25 (m, 2 H,

C2-H, C5-H), 4.22 (d, J ) 3.6 Hz, 2 H, C3-H, C4-H), 3.92 (dd,

J ) 10.5, 7 Hz, 2 H, C1-H, C6-H), 3.8 (dd, J ) 10.5, 5.6 Hz, 2

H, C1-H′, C6-H′), 1.05 (s, 18 H, tert-butyl); ¹³C NMR (CDCl₃,

50 MHz): δ 138.21, 135.58, 133.73, 133.5, 129.53, 128.37,

127.6, 81.75, 80.35, 72.6, 61.88, 26.89, 19.2; MS (LSIMS): m/z

(%): 843 (10) [M⁺+ Na].

(20) [M⁺+ Na]; HRMS (LSIMS): calcd for C₂₅H₃₄NO₆[M⁺

H]: 444.2386, found: 444.2376.

+

Meth yl N-Boc-6-a m in o-2,5-a n h yd r o-3,4-d i-O-ben zyl-6-

d eoxy-^D-id on a te (38). To a solution of 36 (0.9 g, 2.03 mmol)

in dry DMF (10 mL) was added PDC (3.81 g, 10.15 mmol) at

0 °C. The reaction mixture was stirred at room temperature

under nitrogen atmosphere for 12 h. It was then worked up

in the same way as described above for the preparation of 20

to get the idonate 38 (0.7 g, 78%). R_f) 0.4 (silica gel, 25%

2,5-An h yd r o-3,4-d i-O-ben zyl-^D-id itol (32). A solution of

31 (5 g, 6.09 mmol) in THF (30 mL) was treated at 0 °C with

TBAF (1 M in THF, 15.2 mL, 15.2 mmol). The reaction mixture

was stirred at room temperature for 12 h, quenched with

saturated NH₄Cl solution, and extracted with EtOAc. The

combined organic extracts were washed with brine, dried (Na₂-

SO₄), and concentrated in vacuo. Purification by column

chromatography (SiO₂, 60-80% EtOAc in petroleum ether

eluant) afforded the product 32 (2.0 g, 95%) as a syrupy liquid.

R_f) 0.5 (silica gel, EtOAc); [R]²⁰_D33.2 (c 1.61, CHCl₃); ¹H NMR

(CDCl₃, 200 MHz): δ 7.35-7.15 (m, 10 H, ArH), 4.46 (ABq, 4

H, PhCH₂O-), 4.2 (m, 2 H, C₂-H, C₅-H), 4.05 (d, J ) 4.5 Hz, 2

EtOAc in petroleum ether); [R]²⁰10.1 (c 1.25, CHCl₃); IR

D

(neat): ν_max1762, 1712, 1500 cm^-1

;

¹H NMR (CDCl₃, 200

MHz): δ 7.45-7.22 (m, 10 H, ArH), 4.85 (m, 1 H, NHBoc), 4.8

(d, J ) 4.5 Hz, 1 H, C2-H), 4.5 (s, 2 H, PhCH₂O-), 4.48 (ABq,

2 H, PhCH₂O-), 4.4 (m, 1 H, C5-H), 4.28 (m, 1 H, C3-H), 3.97

(m, 1 H, C4-H), 3.78 (s, 3 H, CO₂CH₃), 3.55 and 3.32 (two m,

2 H, C6-H₂), 1.45 (s, 9 H, Boc); ¹³C NMR (CDCl₃, 50 MHz): δ

169.98, 155.91, 137.17, 128.6, 128.46, 128.34, 128.13, 128.04,

127.78, 82.69, 81.34, 80.54, 79.7, 72.76, 72.23, 51.87, 40.28,

28.37; MS (LSIMS): m/z (%): 372 (60) [M⁺+ H - 100], 472

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6455

(6) [M⁺+ H], 494 (14) [M⁺+ Na]; HRMS (LSIMS): calcd for

EtOAc in petroleum ether); [R]²⁰-12.6 (c 1.24, CHCl₃); IR

D

C

₂₆H₃₄NO₇[M⁺+ H]: 472.2335, found: 472.2327.

(neat): ν_max3450, 1600, 1487, 1350, 1175 cm^-1

;

¹H NMR

2,5-An h yd r o-1,6-d i-O-ben zyl-^D-id itol (39). To a solution

(CDCl₃, D₂O exchanged, 200 MHz): δ 7.8 and 7.35 (two d, J

) 9.5 Hz, 4 H, ArH), 4.18 (m, 1 H, C2-H), 4.1-3.9 (m, 3 H,

C6-H₂, C5-H), 3.62 (dd, J ) 11.6, 4 Hz, 1 H, C1-H), 3.4 (dd, J

) 11.6, 5.6 Hz, 1 H, C1-H′), 2.47 (s, 3 H, ArCH₃), 2.15-1.6 (m,

4 H, C3-H₂, C4-H₂); ¹³C NMR (CDCl₃, 50 MHz): δ 144.8,

132.85, 129.75, 127.83, 80.04, 76.22, 71.51, 64.46, 28.07, 26.0,

21.51; MS (LSIMS): m/z (%): 133 (24) [M⁺+ H - Ts].

2,5-An h yd r o-3,4,6-tr id eoxy-6-a zid o-^D-id itol (43). To a

solution of 42 (0.4 g, 1.39 mmol) in dry DMF (5 mL) was added

NaN₃(0.271 g, 4.18 mmol), and the reaction mixture was

heated with stirring for 3 h at 70-80 °C. It was then brought

to room temperature, diluted with EtOAc, washed with water

and brine, dried (Na₂SO₄), and concentrated in vacuo. Column

chromatography (SiO₂, 25-30% EtOAc in petroleum ether

eluant) gave the desired azido compound 43 (0.2 g, 90%) as a

colorless liquid. R_f) 0.45 (silica gel, 50% EtOAc in petroleum

of compound 28 (4 g, 11.76 mmol) in CH₂Cl₂:Et₂O (1:1, 30 mL)

was added LAH (2.67 g, 70.56 mmol) at 0 °C under nitrogen

atmosphere. Then the reaction mixture was heated to 40 °C

and AlCl₃(6.27 g, 47.04 mmol) dissolved in ether (15 mL) was

added to the reaction mixture at the same temperature. After

stirring for 1 h at 40 °C, the reaction mixture was cooled to 0

°C and quenched with a saturated aqueous solution of Na₂-

SO₄. The aqueous layer was extracted with EtOAc. The

combined organic extracts were washed with brine, dried (Na₂-

SO₄), filtered, and concentrated in vacuo. Purification by

column chromatography (SiO₂, 20% EtOAc in petroleum ether

eluant) afforded the diol 39 (2.42 g, 60%) as a white solid. R_f

) 0.5 (silica gel, 60% EtOAc in petroleum ether); [R]²⁰-2.9

D

(c 1, CHCl₃); IR (KBr): ν_max3425, 1500, 1430, 1100, 750 cm^-1

;

¹H NMR (CDCl₃, D₂O exchanged, 200 MHz): δ 7.4-7.25 (m,

10 H, ArH), 4.65 and 4.58 (ABq, 4 H, PhCH₂O-), 4.32 (q, J )

4 Hz, 2 H, C2-H, C5-H), 4.25 (d, J ) 4 Hz, 2 H, C3-H, C4-H),

3.88 (d, J ) 4 Hz, 4 H, C1-H₂, C6-H₂); ¹³C NMR (CDCl₃, 50

MHz): δ 137.37, 128.44, 127.86, 127.73, 79.0, 78.39, 73.88,

69.17; MS (LSIMS): m/z (%): 367 (20) [M⁺+ Na]; MS (EI):

m/z (%): 253 (90) [M⁺- Bn]; HRMS (LSIMS): calcd for

ether); [R]²⁰-50.85 (c 0.7, CHCl₃); ¹H NMR (CDCl₃, 200

D

MHz): δ 4.3-4.1 (m, 2 H, C2-H, C5-H), 3.7 (dd, J ) 11.5, 3.5

Hz, 1 H, C1-H), 3.5 (dd, J ) 11.5, 5.5 Hz, 1 H, C1-H′), 3.38

(dd, J ) 11.5, 3.5 Hz, 1 H, C6-H), 3.22 (dd, J ) 11.5, 5.5 Hz,

1 H, C6-H′), 2.15-1.7 (m, 4 H, C3-H₂, C4-H₂); ¹³C NMR (CDCl₃,

50 MHz): δ 79.98, 78.28, 64.68, 54.58, 29.19, 27.41; MS (EI):

m/z (%): 101 (50) [M⁺- CH₂N₃], 57 (100) [CH₃N₃].

C

₂₀H₂₅O₅[M⁺+ H]: 345.1702, found: 345.1700.

Dih yd r ofu r a n In ter m ed ia te 40. A mixture of compoumd

N-Boc-6-a m in o-2,5-a n h yd r o-3,4,6-tr id eoxy-^D-id itol (45).

To a solution of 43 (0.17 g, 1.08 mmol) in MeOH (4 mL) was

added 10% Pd on C (20 mg). It was hydrogenated under

atmospheric pressure using H₂balloon. After 1 h, Boc₂O (0.5

mL, 2.165 mmol) was added to the reaction mixture and stirred

for 5 h. The reaction mixture was then filtered through a short

pad of Celite, and the filter cake was washed with MeOH. The

filtrate and washings were combined and concentrated in

vacuo. Purification by column chromatography (SiO₂, 50-60%

EtOAc in petroleum ether eluant) afforded 45 (0.16 g, 74%).

39 (2.3 g, 6.68 mmol), triphenylphosphine (7 g, 26.72 mmol),

and imidazole (1.81 g, 26.72 mmol) were refluxed in toluene

(150 mL) with stirring. Iodine (5.08 g, 20.04 mmol) was added

in small portions. The white, finely dispersed complex initially

formed was transformed into a clear yellow solution that

darkened as iodine was liberated. At the bottom of the reaction

vessel, a dark tarry complex was formed from which the

product was gradually dissolved. After 3 h, the reaction

mixture was cooled and iodine (1.695 g, 6.68 mmol) was added,

followed by aqueous sodium hydroxide (2.40 g, 60.12 mmol in

45 mL H₂O). The mixture was stirred until virtually all of the

tarry red deposits were dissolved. The mixture was transferred

to a separating funnel. The aqueous layer was separated, and

the organic layer was washed successively with water, satu-

rated aqueous sodium thiosulfate, saturated aqueous NaHCO₃,

and brine. The organic layer was dried (Na₂SO₄), filtered, and

concentrated in vacuo. Purification by column chromatography

(SiO₂, 1.5-2% EtOAc in petroleum ether eluant) afforded 40

(1.3 g, 62%). R_f) 0.5 (silica gel, 4% EtOAc in petroleum ether);

[R]²⁰_D183.4 (c 1, CHCl₃); IR (neat): ν_max2850, 1462, 1350, 1100

cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ 7.4-7.25 (m, 10 H, ArH),

5.9 (s, 2 H, C3-H, C4-H), 5.03 (m, 2 H, C2-H, C5-H), 4.6 and

4.5 (ABq, 4 H, PhCH₂O-), 3.55 (dd, J ) 11.5, 5.6 Hz, 2 H, C1-

H, C6-H), 3.48 (dd, J ) 11.5, 4.5 Hz, 2 H, C₁-H′, C₆-H′); ¹³C

NMR (CDCl₃, 50 MHz): δ 138.27, 128.84, 128.28, 127.58,

127.51, 85.46, 73.41, 72.75; MS (LSIMS): m/z (%): 333 (40)

[M⁺+ Na], 309 (10) [M⁺- H]; HRMS (LSIMS): calcd for

R_f) 0.35 (silica gel, 80% EtOAc in petroleum ether); [R]²⁰

D

-16.9 (c 0.3, CHCl₃); IR (neat): ν_max3350, 1700, 1525 cm^-1

;

¹H NMR (CDCl₃, 200 MHz): δ 4.9 (m, 1 H, NHBoc), 4.15-4.0

(m, 2 H, C2-H, C5-H), 3.62 (dd, J ) 11.5, 3.5 Hz, 1 H, C1-H),

3.45 (dd, J ) 11.5, 5.5 Hz, 1 H, C1-H′), 3.35 and 3.1 (m, 2 H,

C6-H₂), 2.1-1.6 (m, 4 H, C3-H₂, C4-H₂), 1.45 (s, 9 H, Boc); ¹³

C

NMR (CDCl₃, 125 MHz): δ 156.13, 79.65, 79.21, 78.42, 64.82,

44.34, 28.92, 28.34, 27.4; MS (LSIMS): m/z (%): 254 (12) [M⁺

+ Na], 232 (20) [M⁺+ H].

N-Boc-6-am in o-2,5-an h ydr o-3,4,6-tr ideoxy-^D-idon ic Acid

(46). A mixture of NaIO₄(0.256 g, 1.2 mmol) and RuCl₃‚3H₂O

(1.5 mg, 0.006 mmol) in CH₃CN:CCl₄:H₂O (1:1:1.5, 4.5 mL) was

stirred at room temperature for 0.5 h and then added into an

CH₃CN solution of the alcohol 45 at 0 °C. After stirring for

0.5 h, an additional amount of NaIO₄was added to the reaction

mixture. After 10 min, it was diluted with EtOAc, washed with

saturated aqueous NH₄Cl, brine, dried (Na₂SO₄), and concen-

trated in vacuo. The residue was azeotroped with dry toluene

to afford pure acid 46 in quantitative yield, which was used

directly in the next step without further purification.

C

₂₀H₂₁O₃[M⁺- H]: 309.1491, found: 309.1505.

2,5-An h yd r o-3,4-d id eoxy-^D-id itol (41). To a solution of

40 (1.2 g, 3.87 mmol) in EtOAc (12 mL) was added 10% Pd on

C (200 mg). It was hydrogenated for 1 h under atmospheric

pressure using a H₂balloon. The reaction mixture was then

filtered through a short pad of Celite, and the filter cake was

washed with MeOH. The filtrate and washings were combined

and concentrated in vacuo. The residue was azeotroped with

dry toluene to afford 41, which was used directly in the next

step without further purification.

2,5-An h yd r o-3,4-d id eoxy-6-O-tosyl-^D-id itol (42). The diol

41 from the previous step (0.5 g, 3.78 mmol), dissolved in dry

THF (10 mL), was treated at 0 °C under nitrogen atmosphere

with NaH (60% suspension, 0.151 g, 3.78 mmol). After 15 min,

TsCl (0.72 g, 3.78 mmol) was added to the reaction mixture

and stirred for 1 h at 0 °C. The reaction mixture was then

quenched with saturated aqueous NH₄Cl solution and ex-

tracted with EtOAc. The combined organic extracts were

washed with brine, dried (Na₂SO₄), and concentrated in vacuo.

Purification by column chromatography (SiO₂, 36-40% EtOAc

in petroleum ether eluant), afforded the monotosylated product

42 (0.5 g, 46%) as a colorless liquid. R_f) 0.4 (silica gel, 50%

2,5-An h yd r o-3,4-d i-O-ben zyl-^D-id a r ic Acid Dim eth yl

Ester (48). To a solution of 32 (0.4 g, 1 mmol) in dry DMF (6

mL) were added PDC (3.76 g, 10 mmol) and 4 Å mol sieves

(3.76 g) at 0 °C. The reaction mixture was stirred at room

temperature for 12 h under nitrogen atmosphere. After cooling

to 0 °C, an ethereal solution of CH₂N₂was added to it until

all the acids were converted into the diester. It was then

diluted with EtOAc and filtered through a short pad of Celite,

and the filter cake was washed with EtOAc. The filtrate and

washings were combined, washed with brine, dried (Na₂SO₄),

and concentrated in vacuo. Column chromatography (SiO₂,

20-25% EtOAc in petroleum ether eluant) gave pure idaric

acid diester 48 (0.24 g, 60%) as a syrupy liquid. R_f) 0.5 (silica

gel, 45% EtOAc in petroleum ether); [R]²⁰_D11.2 (c 0.9, CHCl₃);

1

IR (neat): ν_max1762, 1737, 1462 cm^-1; H NMR (CDCl₃, 200

MHz): δ 7.4-7.15 (m, 10 H, ArH), 4.95 (d, J ) 4.5 Hz, 2 H,

C2-H, C5-H), 4.48 (ABq, 4 H, PhCH₂O-), 4.24 (d, J ) 4.5 Hz,

2 H, C3-H, C4-H), 3.74 (s, 6 H, CO₂CH₃); ¹³C NMR (CDCl₃, 50

MHz): δ 169.1, 136.9, 128.47, 128.1, 127.76, 82.1, 80.79, 72.74,

52; MS (LSIMS): m/z (%): 399 (20) [M⁺- H], 423 (34) [M⁺

+

6456 J . Org. Chem., Vol. 65, No. 20, 2000

Chakraborty et al.

Na]; HRMS (LSIMS): calcd for C₂₂H₂₄O₇[M⁺]: 400.1522,

found: 400.1504.

(CDCl₃, 50 MHz): δ 172.52, 170.21, 168.78, 155.82, 137.15,

136.94, 136.28, 129.52, 128.54, 128.06, 127.65, 127, 81.5, 80.79,

79.39, 73.14, 71.01, 53, 52.01, 50.93, 40.93, 40.09, 37.3, 28.38,

Boc-Ga a (Bn ₂)-P h e-Leu -OMe (49i). A solution of Cbz-Phe-

Leu-OMe (0.4 g, 0.93 mmol) in MeOH:1 N HCl (4:1, 5 mL)

was hydrogenated under atmospheric pressure using Pd on C

(10%, 0.2 g) for 0.5 h. The reaction mixture was then filtered

through a short pad of Celite, and the filter cake was washed

with EtOAc. The combined filtrate and washings were con-

centrated in vacuo to get the hydrochloride of the deprotected

amine.

24.77, 22.58, 21.82; MS (LSIMS): m/z (%): 754 (20) [M⁺

+

Na], 732 (24) [M⁺+ H]; HRMS (LSIMS): calcd for C₄₁H₅₄N₃O₉

[M⁺+ H]: 732.3860, found: 732.3868.

Boc-d d Ia a -P h e-Leu -OMe (49iv). R_f) 0.5 (silica, 40%

EtOAc in petroleum ether); IR (neat): ν_max1750, 1710, 1660,

1

1525 cm^-1; H NMR (CDCl₃, 500 MHz): δ 7.3-7.15 (m, 5 H,

ArH), 7.06 (d, J ) 7.9 Hz, 1 H, PheNH), 6.18 (d, J ) 7.9 Hz,

1 H, LeuNH), 4.71 (br t, J ) 6 Hz, 1 H, ddIaaNH), 4.53 (q, J

) 7.9 Hz, 1 H, PheCRH), 4.43 (m, 1 H, LeuCRH), 4.29 (t, J )

7.9 Hz, 1 H, ddIaaCRH), 4.03 (m, 1 H, ddIaaC5-H), 3.62 (s, 3

H, CO₂CH₃), 3.32-3.0 (m, 4 H, PheCâH₂, ddIaaC6-H₂), 2.3-

2.2, 1.97-1.83 and 1.62-1.38 (m, 7 H, LeuCâH₂, LeuCγH,

ddIaaC3-H₂, ddIaaC4-H₂), 1.4 (s, 9 H, Boc), 0.81 (d, J ) 6.0

Hz, 6 H, Leu-CH₃); ¹³C NMR (CDCl₃, 125 MHz): δ 173.07,

172.7, 170.3, 156, 136.42, 129.24, 128.68, 127.1, 79.9, 78.5,

53.93, 52.26, 50.93, 44.14, 41.37, 37.63, 30.08, 29.7, 28.4, 28.23,

24.8, 22.68, 21.9; MS (LSIMS): m/z (%): 542 (60) [M⁺+ Na],

520 (80) [M⁺+ H].

Saponification of 20 (0.4 g, 0.85 mmol) was carried out in

THF:MeOH:H₂O (3:1:1, 5 mL) at 0 °C using LiOH‚H₂O (0.107

g, 2.55 mmol). After 1 h, the reaction mixture was acidified

by adding 1 N HCl till pH 2. It was then diluted with EtOAc,

washed with brine, dried (Na₂SO₄), and concentrated in vacuo.

The residue was dissolved in dry CH₂Cl₂(3 mL), cooled to 0

°C, and treated sequentially with HOBt (0.114 g, 0.85 mmol)

and EDCI (0.164 g, 0.85 mmol). After 0.25 h, the hydrochloride

of the amine, HCl‚H₂N-Phe-Leu-OMe, prepared above and

dissolved in dry DMF (2 mL), was added to the reaction

mixture followed by the addition of DIPEA (0.3 mL, 1.72

mmol). After stirring for 6 h at room temperature, the reaction

mixture was diluted with EtOAc, washed with saturated NH₄-

Cl and brine, dried (Na₂SO₄), and concentrated in vacuo.

Column chromatography (SiO₂, 10-40% EtOAc in petroleum

ether eluant) gave pure tripeptide 49i (0.41 g, 66%) as a white

Boc-Tyr (Br -Z)-Ga a (Bn ₂)-P h e-Leu -OMe (50i). To a solu-

tion of 49i (0.4 g, 0.55 mmol) in dry CH₂Cl₂(4 mL) was added

trifluoroacetic acid (2 mL) at 0 °C and stirred under nitrogen

for 0.5 h. The reaction mixture was then concentrated in vacuo.

In another round-bottom flask, Boc-Tyr(Br-Z)-OH (0.298 g, 0.6

mmol), dissolved in dry CH₂Cl₂(4 mL), was sequentially

treated with HOBt (0.082 g, 0.6 mmol) and EDCI (0.116 g,

0.6 mmol) at 0 °C. After 0.25 h, TFA‚H₂N-Gaa(Bn₂)-Phe-Leu-

OMe, prepared above and dissolved in dry DMF (2 mL), was

added to the reaction mixture, followed by the addition of

DIPEA (0.21 mL. 1.2 mmol). After stirring for 6 h at room

temperature, the reaction mixture was diluted with EtOAc,

washed with saturated NH₄Cl and brine, dried (Na₂SO₄), and

concentrated in vacuo. Column chromatography (SiO₂, 10-

50% EtOAc in petroleum ether eluant) gave pure tetrapeptide

50i (0.39 g, 64%) as a white solid. R_f) 0.45 (silica, 40% EtOAc

in petroleum ether); [R]²⁰_D23.0 (c 1, CHCl₃); mp 54-55 °C; IR

(KBr): ν_max1765, 1715, 1650, 1500 cm^-1; ¹H NMR (DMSO-d₆,

400 MHz): δ 8.31 (t, J ) 5.6 Hz, 1 H, GaaNH), 8.23 (d, J )

7.5 Hz, 1 H, LeuNH), 7.9 (d, J ) 8.5 Hz, 1 H, PheNH), 7.69

(dd, J ) 7.6, 1 Hz, 1 H, Br-Z-H3), 7.55 (dd, J ) 7.6, 1.6 Hz, 1

H, Br-Z-H6), 7.45 (dt, J ) 7.6, 1 Hz, 1 H, Br-Z-H5), 7.35 (dt, J

) 7.6, 1.6 Hz, 1 H, Br-Z-H4), 7.32-7.12 (m, 19 H, aromatic),

7.01 (d, J ) 8.6 Hz, 1 H, TyrNH), 5.3 (s, 2 H, Br-Z-CH₂O-),

4.7 (dt, J ) 8.5, 4.6 Hz, 1 H, PheCRH), 4.45 (ABq, 2 H,

PhCH₂O-), 4.43 (s, 2 H, PhCH₂O-), 4.35 (d, J ) 4.2 Hz, 1 H,

GaaC2-H), 4.27 (q, J ) 7.5 Hz, 1 H, LeuCRH), 4.14 (m, 1 H,

TyrCRH), 4.12 (d, J ) 4.2 Hz, 1 H, GaaC3-H), 4.01 (m, 1 H,

GaaC4-H), 3.94 (m, 1 H, GaaC5-H), 3.55 (s, 3 H, CO₂CH₃), 3.4

and 3.3 (m, 2 H, GaaC6-H₂), 3.12 (dd, J ) 14.1, 4.6 Hz, 1 H,

PheCâH), 2.98-2.92 (m, 2 H, TyrCâH, PheCâH′), 2.74 (dd, J

) 13.8, 10.5 Hz, 1 H, TyrCâH′), 1.59 (m, 1 H, LeuCγH), 1.46

(m, 2 H, LeuCâH₂), 1.27 (s, 9 H, Boc), 0.81 and 0.75 (two d, J

) 6.4 Hz, 6 H, Leu-CH₃); ¹³C NMR (CDCl₃, 50 MHz): δ 172.59,

172.15, 170.91, 168.38, 155.7, 153.34, 150.01, 137.08, 136.79,

132.93, 130.46, 130.13, 130.01, 129.32, 128.56, 128.48, 128.37,

128.21, 128.12, 127.93, 127.60, 127.48, 126.92, 120.95, 84.08,

82.52, 81.24, 80.14, 73.0, 71.47, 69.54, 53.74, 52.10, 51.05,

42.25, 41.19, 38.35, 38.21, 28.19, 24.67, 22.64, 22.04; MS

(LSIMS): m/z (%): 1109 (20) [M⁺(⁸¹Br) + H], 1107 (18) [M⁺(⁷⁹-

Br) + H], 1009 (60) [M⁺(⁸¹Br) + H - 100], 1007 (54) [M⁺(⁷⁹Br)

+ H - 100].

solid. R_f) 0.5 (silica, 40% EtOAc in petroleum ether); [R]²⁰

D

7.4 (c 1, CHCl₃); mp 32-33 °C; IR (KBr): ν_max1760, 1665, 1625,

1530 cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ 7.52 (d, J ) 9.4 Hz,

1 H, PheNH), 7.4-7.05 (m, 15 H, ArH), 6.6 (d, J ) 8.5 Hz, 1

H, LeuNH), 4.8 (m, 2 H, Gaa-NH, PheCRH), 4.55 and 4.2 (two

ABq, 4 H, PhCH₂O), 4.52 (d, J ) 5 Hz, 1 H, GaaC2-H), 4.5 (m,

1 H, LeuCRH), 4.22 (dd, J ) 5, 2 Hz, 1 H, GaaC3-H), 4.13 (m,

1 H, GaaC5-H), 4.0 (m, 1 H, GaaC4-H), 3.6 (s, 3 H, CO₂CH₃),

3.4-3.1 (m, 2 H, GaaC6-H), 3.15 (d, J ) 7.4 Hz, 2 H, PheCâH₂),

1.8-1.3 (m, 3 H, LeuCâH₂, CγH), 1.45 (s, 9 H, Boc), 0.84 and

0.8 (two d, J ) 6.5 Hz, 6 H, Leu-CH₃); ¹³C NMR (CDCl₃, 50

MHz): δ 172.68, 170.66, 168.38, 156.32, 137.14, 136.97, 129.45,

128.59, 128.50, 128.13, 127.96, 127.53, 126.85, 85.68, 83.44,

82.54, 81.93, 79.70, 72.86, 71.53, 53.43, 52.05, 50.87, 43.41,

41.23, 37.63, 28.49, 24.64, 22.69, 21.86; MS (LSIMS): m/z

(%): 754 (10) [M⁺+ Na], 732 (50) [M⁺+ H], 632 (100) [M⁺

+

H - 100]. HRMS (LSIMS): calcd for C₄₁H₅₄N₃O₉[M⁺+ H]:

732.3860, found: 732.3876.

Boc-Ma a (Bn ₂)-P h e-Leu -OMe (49ii). R_f) 0.5 (silica, 40%

EtOAc in petroleum ether); [R]²⁰1.3 (c 1, CHCl₃); mp 118-

D

120 °C; IR (KBr): ν_max1750, 1710, 1650, 1515 cm^-1; ¹H NMR

(CDCl₃, 200 MHz): δ 7.4-7.05 (m, 16 H, ArH, PheNH), 6.23

(d, J ) 8.2 Hz, 1 H, LeuNH), 4.84 (t, J ) 5.6 Hz, 1 H, MaaNH),

4.62 (ABq, 2 H, PhCH₂O-), 4.6-4.5 (m, 2 H, PheCRH, MaaC2-

H), 4.35 (m, 3 H, PhCH₂O-, MaaC3-H), 4.0 (m, LeuCRH), 3.77

(m, 1 H, MaaC4-H), 3.7 (s, 3 H, CO₂CH₃), 3.45-3.15 (m, 2 H,

MaaC6-H₂), 3.0 (dd, J ) 13.7, 5.9 Hz, 1 H, PheCâH), 2.75 (dd,

J ) 13.7, 7.2 Hz, 1 H, PheCâH′), 1.7-1.4 (m, LeuCâH₂, CγH),

1.46 (s, 9 H, Boc), 0.91 and 0.88 (two d, J ) 6.5 Hz, 6 H, Leu-

CH₃); ¹³C NMR (CDCl₃, 50 MHz): δ 172.74, 170.43, 170.15,

155.85, 137.26, 137.06, 136.19, 129.4, 128.56, 128.46, 128.41,

127.96, 127.89, 126.95, 85.34, 83.9, 83.32, 79.44, 71.97, 71.64,

53.73, 52.18, 50.89, 42.32, 41.41, 37.48, 28.38, 24.71, 22.64,

21.94; MS (LSIMS): m/z (%): 754 (10) [M⁺+ Na], 732 (40)

[M⁺+ H]; HRMS (LSIMS): calcd for C₄₁H₅₃N₃O₉[M⁺]:

731.3782, found: 731.3771.

Boc-Ia a (Bn ₂)-P h e-Leu -OMe (49iii). R_f) 0.5 (silica, 40%

EtOAc in petroleum ether); [R]²⁰13.3 (c 0.9, CHCl₃); IR

Boc-Tyr (Br -Z)-Ma a (Bn ₂)-P h e-Leu -OMe (50ii). R_f) 0.45

(silica, 40% EtOAc in petroleum ether); [R]²⁰_D5.4 (c 1, CHCl₃);

mp 59-60 °C; IR (KBr): ν_max1770, 1650, 1540 cm^-1; ¹H NMR

(DMSO-d₆, 400 MHz): δ 8.51 (d, J ) 7.6 Hz, 1 H, LeuNH),

8.25 (t, J ) 5.6 Hz, 1 H, MaaNH), 7.69 (dd, J ) 7.7, 1 Hz, 1 H,

Br-Z-H3), 7.64 (d, J ) 8.5 Hz, 1 H, PheNH), 7.55 (dd, J ) 7.7,

1.2 Hz, 1 H, Br-Z-H6), 7.45 (dt, J ) 7.7, 1 Hz, 1 H, Br-Z-H5),

7.35 (dt, J ) 7.7, 1.2 Hz, 1 H, Br-Z-H4), 7.32-7.07 (m, 19 H,

aromatic), 6.96 (d, J ) 8.5 Hz, 1 H, TyrNH), 5.3 (s, 2 H, Br-

Z-CH₂O-), 4.7 (ddd, J ) 8.5, 8, 5 Hz, 1 H, PheCRH), 4.51 (ABq,

2 H, PhCH₂O-), 4.41 (ABq, 2 H, PhCH₂O-), 4.39 (s, 1 H,

MaaC2-H), 4.27 (m, 1 H, LeuCRH), 4.2 (m, 1 H, TyrCRH), 4.13

D

(KBr): ν_max1750, 1725, 1675, 1525 cm^-1; ¹H NMR (CDCl₃, 200

MHz): δ 7.4-7.05 (m, 15 H, ArH), 7.0 (d, J ) 9.1 Hz, 1 H,

PheNH), 6.45 (d, J ) 8.2 Hz, 1 H, LeuNH), 4.84 (dd, J ) 9.1,

6.8 Hz, 1 H, IaaNH), 4.68 and 4.48 (ABq, 2 H, PhCH₂O-), 4.6

(d, J ) 4.5 Hz, 1 H, IaaC2-H), 4.6-4.4 (m, 2 H, IaaC5-H,

PheCRH), 4.35 and 4.05 (ABq, 2 H, PhCH₂O-), 4.28 (d, J )

4.5 Hz, 1H, IaaC3-H), 4.18 (m, 1 H, LeuCRH), 3.72 (d, J ) 4.5

Hz, 1 H, IaaC4-H), 3.64 (s, 3 H, CO₂CH₃), 3.5-3.15 (m, 3 H,

PheCâH, IaaC6-H₂), 3.05 (dd, J ) 13.7, 6.8 Hz, 1 H, PheCâH′),

1.7 (m, 1 H, LeuCγH), 1.5 (s, 9 H, Boc), 1.5-1.15 (m, 2 H,

LeuCâH₂), 0.91 (d, J ) 6.5 Hz, 6 H, Leu-CH₃); ¹³C NMR

Peptidomimetics Containing Furanoid Sugar Amino Acids

J . Org. Chem., Vol. 65, No. 20, 2000 6457

(s, 1 H, MaaC3-H), 3.94 (m, 2 H, MaaC4-H, MaaC5-H), 3.61

(s, 3 H, CO₂CH₃), 3.4 and 3.3 (two, m, 2 H, MaaC6-H₂), 2.98-

2.82 (m, 4 H, TyrCâH₂, PheCâH₂), 1.59-1.46 (m, 3 H,

LeuCâH₂, CγH), 1.22 (s, 9 H, Boc), 0.87 and 0.84 (two d, J )

6.4 Hz, 6 H, Leu-CH₃); ¹³C NMR (CDCl₃, 50 MHz): δ 172.96,

171.77, 170.9, 170.63, 155.9, 153.35, 149.89, 137.22, 137.1,

136.7, 135.11, 134.25, 132.9, 130.42, 130.11, 130.04, 129.4,

128.45, 128.38, 127.88, 127.60, 126.78, 123.43, 120.82, 85.53,

83.6, 83.38, 83.31, 79.98, 71.98, 71.51, 69.52, 54.25, 52.18, 51.0,

41.27, 38.6, 37.94, 29.64, 28.27, 24.7, 22.57, 22.02; MS

(LSIMS): m/z (%): 1108 (54) [M⁺(⁷⁹Br) + H₂], 1110 (52) [M⁺(⁸¹-

Br) + H₂], 1130 (82) [M⁺(⁷⁹Br) + H + Na], 1132 (100) [M⁺(⁸¹-

Br) + H + Na].

78.06, 77.92, 77.84, 56.42, 53.01, 51.94, 50.55, 41.64, 37, 36.19,

28.24, 23.79, 22.83, 21.16; MS (LSIMS): m/z (%): 737 (34) [M⁺

+ Na], 715 (36) [M⁺+ H], 615 (100) [M⁺+ H - 100]; HRMS

(LSIMS) calcd for C₃₆H₅₁N₄O₁₁[M⁺+ H]: 715.3554, found:

715.3557.

Boc-Tyr -Ma a -P h e-Leu -OMe (9a ). R_f) 0.35 (silica gel,

EtOAc); [R]²⁰91.2 (c 1, MeOH); mp 119-120 °C; IR (KBr):

D

ν_max3360, 1740, 1660, 1525 cm^-1

;

¹H NMR (DMSO-d₆, 500

MHz): see Table 2; ¹³C NMR (DMSO-d₆, 100 MHz): δ 172.81,

172.13, 170.7, 170.32, 155.74, 155.26, 137.2, 130.17, 129.58,

128.33, 128.08, 126.38, 114.82, 84.37, 80.28, 78.15, 77.94, 56.0,

52.93, 51.95, 50.3, 40.83, 39.79, 37.54, 37.15, 28.21, 24.19,

22.79, 21.36; MS (LSIMS): m/z (%): 715 (28) [M⁺+ H], 615

(100) [M⁺+ H - 100]; HRMS (LSIMS) calcd for C₃₆H₅₁N₄O₁₁

[M⁺+ H]: 715.3554, found: 715.3523.

Boc-Tyr (Br -Z)-Ia a (Bn ₂)-P h e-Leu -OMe (50iii). R_f) 0.35

(silica, 50% EtOAc in petroleum ether); [R]²⁰_D16.2 (c 1, CHCl₃);

1

IR (KBr): ν_max1700, 1662, 1500 cm^-1; H NMR (CDCl₃, 400

Boc-Tyr -Ia a -P h e-Leu -OMe (10a ). R_f) 0.4 (silica gel,

MHz): δ 7.6 (dd, J ) 7.7, 1 Hz, 1 H, Br-Z-H3), 7.5 (dd, J )

7.7, 1.2 Hz, 1 H, Br-Z-H6), 7.37-7.07 (m, 22 H, aromatic,

PheNH), 6.33 (d, J ) 7.8 Hz, 1 H, LeuNH), 6.1 (t, J ) 5.8 Hz,

1 H, IaaNH), 5.36 (s, 2 H, Br-Z-CH₂O-), 4.9 (m, 1 H, TyrNH),

4.79 (dt, J ) 8.7, 6.5 Hz, 1 H, PheCRH), 4.66 and 4.48 (two d,

ABq, 2 H, PhCH₂O-), 4.55 (d, J ) 3.8 Hz, 1 H, IaaC2-H), 4.44

(m, 1 H, IaaC5-H), 4.36 and 4.05 (two d, ABq, 2 H, PhCH₂O-

), 4.28 (d, J ) 3.8 Hz, 1 H, IaaC3-H), 4.2 (m, 1 H, LeuCRH),

4.16 (m, 1 H, TyrCRH), 3.72 (d, J ) 3.8 Hz, 1 H, IaaC4-H),

3.63 (s, 3 H, CO₂CH₃), 3.52 and 3.38 (two m, 2 H, IaaC6-H₂),

3.2 and 3.14 (two dd, J ) 13.8, 6.4 Hz, 2 H, PheCâH₂), 3.01

and 2.94 (two dd, J ) 14, 6.7 Hz, 2 H, TyrCâH₂), 1.5-1.2 (m,

3 H, LeuCâH₂, CγH), 1.4 (s, 9 H, Boc), 0.8 (d, J ) 6.5 Hz, 6 H,

Leu-CH₃); ¹³C NMR (CDCl₃, 50 MHz): δ 172.55, 171.13,

170.19, 168.71, 155.19, 153.31, 150.02, 137.23, 136.91, 136.46,

134.57, 132.91, 130.26, 130.13, 130.03, 129.41, 128.66, 128.57,

128.28, 128.08, 127.96, 127.89, 127.6, 126.95, 123.41, 121,

81.73, 81.55, 81.29, 80.16, 79.41, 73.08, 71.98, 69.56, 53.52,

52.06, 50.94, 41.06, 38.59, 37.72, 37.64, 28.25, 24.75, 22.55,

21.92; MS (LSIMS): m/z (%): 1007 (30) [M⁺(⁷⁹Br) + H - 100],

1009 (32) [M⁺(⁸¹Br) + H - 100]; HRMS (LSIMS): calcd for

EtOAc); [R]²⁰-13.5 (c 1.63, CHCl₃); ¹H NMR (400 MHz,

D

DMSO-d₆): see Table 3; ¹³C NMR (CDCl₃, 100 MHz): δ 173.84,

172.92, 171.0, 170.78, 155.5, 155.48, 135.83, 130.36, 129.23,

128.71, 127.37, 127.2, 115.7, 81.67, 80.34, 77.5, 75.93, 56.31,

53.24, 52.39, 51.08, 40.28, 37.8, 37.7, 37.0, 28.28, 24.65, 22.62,

21.64; MS (LSIMS): m/z (%): 715 (18) [M⁺+ H], 615 (100)

[M⁺+ H - 100]; HRMS (LSIMS) calcd for C₃₆H₅₁N₄O₁₁[M⁺

+

H]: 715.3554, found: 715.3553.

Boc-Tyr -d d Ia a -P h e-Leu -OMe (11a ). R_f) 0.4 (silica gel,

80% EtOAc in petroleum ether); [R]²⁰-3.4 (c 1, CHCl₃); IR

D

1

(KBr): ν_max3400, 1650, 1525 cm^-1; H NMR (DMSO-d₆, 400

MHz): see Table 4; ¹³C NMR (CDCl₃, 50 MHz): δ 172.57,

172.51, 171.24, 171.12, 155.98, 155.25, 135.0, 130.27, 129.34,

128.58, 127.76, 127.1, 115.62, 80.04, 79.4, 78.15, 53.88, 52.34,

51.1, 42.96, 41.07, 38.77, 38.37, 29.77, 28.31, 24.75, 22.6, 21.83;

MS (LSIMS): m/z (%): 583 (100) [M⁺+ H - 100], 683 (48)

[M⁺+ H], 705 (30) [M⁺+ Na], 815 (14) [M⁺+ Cs]; HRMS

(LSIMS): calcd for C₃₆H₅₁N₄O₉[M⁺+ H]: 683.3656, found:

683.3655.

MeO-Leu -P h e-Id a c(Bn ₂)-P h e-Leu -OMe (51). The diben-

zyl derivative of idaric acid (47), prepared from the diester 48

(100 mg, 0.25 mmol) by saponification, was reacted with H₂N-

Phe-Leu-OMe obtained from Cbz-Phe-Leu-OMe (276 mg, 0.645

mmol) under the same coupling conditions described above for

the synthesis of 49i to get the reverse turn mimetic 51 (170

mg, 74%). R_f) 0.4 (silica, 50% EtOAc in petroleum ether);

C

₅₃H₆₀79BrN₄O₁₁[M⁺(⁷⁹Br) + H - C₅H₈O₂]: 1007.3442,

found: 1007.3457; calcd for C₅₃H₆₀81BrN₄O₁₁[M⁺(⁸¹Br) + H

- C₅H₈O₂]: 1009.3421, found: 1009.3430.

Boc-Tyr (Br -Z)-ddIaa-P h e-Leu -OMe (50iv). R_f) 0.5 (silica,

70% EtOAc in petroleum ether); [R]²⁰_D-29.5 (c 1.1, CHCl₃);

IR (KBr): ν_max1765, 1750, 1650, 1525 cm^-1; ¹H NMR (CDCl₃,

400 MHz): δ 7.62 (dd, J ) 7.7, 1 Hz, 1 H, Br-Z-H3), 7.5 (dd, J

) 7.7, 1.2 Hz, 1 H, Br-Z-H6), 7.36 (dt, J ) 7.7, 1.2 Hz, 1 H,

Br-Z-H5), 7.35-7.07 (m, 11 H, ArH, PheNH), 6.2 (d, J ) 7.8

Hz, 1 H, LeuNH), 6.18 (m, 1 H, ddIaaNH), 5.38 (s, 2 H, Br-

Z-CH₂O-), 5.05 (d, J ) 8.5 Hz, 1 H, TyrNH), 4.79 (q, J ) 7.5

Hz, 1 H, PheCRH), 4.5 (m, 1 H, ddIaaC2-H), 4.4-4.25 (m, 2

H, ddIaaC5-H, LeuCRH), 4.0 (m, 1 H, TyrCRH), 3.7 (s, 3 H,

CO₂CH₃), 3.32 (t, J ) 7 Hz, 2 H, ddIaaC6-H₂), 3.12 and 3.08

(two d, J ) 7.5 Hz, 4 H, PheCâH₂, TyrCâH₂), 2.5-1.4 (m, 7 H,

ddIaaC3-H₂, ddIaaC4-H₂, LeuCâH₂, CγH), 1.42 (s, 9 H, Boc),

0.88 (d, J ) 6.5 Hz, 6 H, Leu-CH₃); ¹³C NMR (CDCl₃, 50

MHz): δ 172.9, 172.7, 171.42, 170.4, 155.4, 153.3, 150.0, 136.4,

134.7, 134.2, 132.9, 130.3, 130.1, 130.0, 129.2, 128.5, 127.5,

126.9, 123.4, 121.0, 80.3, 79.0, 78.3, 69.5, 56.0, 54.0, 52.1, 50.8,

42.4, 41.1, 37.8, 29.7, 28.2, 24.7, 22.6, 21.8; MS (LSIMS): m/z

(%): 795 (34) [M⁺(⁷⁹Br) + H - 100], 797 (33) [M⁺(⁸¹Br) + H -

100], 917 (5) [M⁺(⁷⁹Br) + Na], 919 (5) [M⁺(⁸¹Br) + Na], 1027

(96) [M⁺(⁷⁹Br) + Cs], 1029 (100) [M⁺(⁸¹Br) + Cs].

[R]²⁰3.8 (c 1, CHCl₃); IR (KBr): ν_max1750, 1650, 1512 cm^-1

;

D

¹H NMR (DMSO-d₆, 400 MHz): see Table 5; ¹³C NMR (CDCl₃,

50 MHz): δ 172.44, 169.95, 167.61, 136.7, 136.25, 129.37,

128.62, 128.48, 128.03, 127.64, 127.1, 82.77, 81.4, 72.76, 53.47,

52.1, 50.94, 41.03, 37.87, 24.73, 22.49, 21.91; MS (LSIMS): m/z

(%): 921 (100) [M⁺+ H], 943 (50) [M⁺+ Na]; HRMS

(LSIMS): calcd for C₅₂H₆₄N₄O₁₁Na [M⁺+ Na]: 943.4469,

found: 943.4442.

MeO-Leu -P h e-Id a c-P h e-Leu -OMe (12). The intermediate

51 (120 mg, 0.112 mmol) was hydrogenated in the usual way

using Pd-C/H₂-balloon to get a quantitative yield of compound

12 (100 mg). R_f) 0.5 (silica, EtOAc); [R]²⁰21.2 (c 1, CHCl₃);

D

IR (KBr): ν_max3375, 1725, 1662, 1512 cm^-1; ¹H NMR (DMSO-

d₆, 400 MHz): see Table 6; ¹³C NMR (CDCl₃, 50 MHz): δ 174.1,

170.04, 168.91, 135.84, 129.09, 128.7, 127.3, 83.33, 77.63,

53.16, 52.33, 50.77, 40.87, 36.86, 24.6, 22.62, 21.64; MS

(LSIMS): m/z (%): 741 (90) [M⁺+ H], 763 (40) [M⁺+ Na];

HRMS (LSIMS): calcd for C₃₈H₅₃N₄O₁₁[M⁺+ H]: 741.3711,

found: 741.3725.

Boc-Tyr -Ga a -P h e-Leu -OMe (8a ). To a solution of 50i (o.3

g, 0.27 mmol) in EtOAc (4 mL), Pd(OH)₂on C (10%, 0.03 g)

was added and the mixture was hydrogenated under atmo-

spheric pressure using a H₂-filled balloon for 4 h. It was then

filtered through a short pad of Celite and the filter cake was

washed with EtOAc. The combined filtrate and washings were

concentrated in vacuo to get 8a (0.181 g, 94%) as a white solid.

Ack n ow led gm en t. We thank Dr. M. Vairamani for

mass spectroscopic assistance and CSIR, New Delhi for

research fellowships (S.G. and S.J .) and a Young

Scientist Award Research Grant (T.K.C.).

Su p p or tin g In for m a tion Ava ila ble: ¹H, ¹³C, TOCSY,

ROESY, ¹H VT NMR and mass (LSIMS) spectra of 8-11a ,

51, and 12. This material is available free of charge via the

Internet at http://pubs.acs.org.

R_f) 0.4 (silica, EtOAc); [R]²⁰-4.8 (c 0.5, MeOH); mp 159-

D

160 °C; IR (KBr): ν_max3325, 1725, 1655, 1510 cm^-1; ¹H NMR

(DMSO-d₆, 500 MHz): see Table 1; ¹³C NMR (DMSO-d₆, 100

MHz): δ 173, 172.66, 170.97, 169.34, 155.77, 155.23, 138.74,

130.12, 128.97, 128.24, 128.13, 126.17, 114.87, 87.72, 82.52,

J O000408E

Article Doi

Synthesis and Conformational Studies of Peptidomimetics Containing Furanoid Sugar Amino Acids and a Sugar Diacid

DOI: 10.1021/jo000408e

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Full text of DOI:10.1021/jo000408e

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