tnt
`
`Pep/ide Protein Re.s 32 1988 279291
`
`Synthesis of functionalized non-natural amino acid derivatives via
`amidoalkylation transformations
`
`PHILIPPE LEGALL KAILASII
`
`SAWHNEY JUDITH
`
`CONLEY and HAROLD KOHN
`
`Department of Chemistry University of Houston Houston TX USA
`
`Received
`
`16 February accepted for publication
`
`May 1988
`
`for the preparation of functionalized amino
`Synthetic routes have been developed
`acid derivatives in which the a-substitucnt at carbon
`is either an aromatic or
`heteroaromatic group The -substituent was introduced using an amidoalkylation
`reaction using boron trifluoride
`in moderate yield with
`etherate and proceeded
`regioselectivity This protocol permitted the employment of the acid sen
`excellent
`sitive heterocycles pyrrole benzofuran and indole The scope and limitations of this
`procedure have been evaluated
`
`amido alkylation
`Key words a-substituted
`natural amino acids
`
`transformations aromatic heteroaromatic
`
`non-
`
`Recent studies conducted
`in our
`laboratory
`have drawn attention to the importance of
`c-functionalized
`derivatives of N-acetylgly-
`cine-N-benzylamide
`as potential
`for the treatment of epilepsy
`drug candidates
`In an effort
`to delineate
`the structure
`activity relationship of this novel class of anti
`were re-
`convulsants
`select derivatives of
`quired in which the csubstituent
`was either
`an aromatic or
`heteroaromatic moiety Un-
`fortunately relatively few methods exist for
`the preparation of
`the corresponding free
`amino acidsi
`thereby diminishing the likeli
`hood of employing these substrates
`as start-
`
`In this
`ing materials for the synthesis of
`paper we describe the use and limitations of
`transformations
`for the
`arnidoalkylation
`preparation of functionalized derivatives of
`amino acids in which the
`substituent
`is an
`aromatic moiety
`
`II
`
`CH
`
`RESULTS AND DISCUSSION
`
`Two different strategies Scheme
`Methods
`and
`were investigated
`for the prepara
`The approaches
`tion of
`differ primarily in
`the sequence of reactions employed for the
`the desired compound
`In
`synthesis of
`
`For excellent discussions of this reaction see ref
`
`279
`
`Abstracted
`
`from the Masters dissertation
`author Additional structure proof and experimental and
`spectra data may be found in this reference
`
`of
`
`this
`
`The 2- and 3-thienyl compounds are commercially
`abailable Aldrich Chemical Company For leading ref
`erences for procedures for the preparation of non-natural
`amino acides and related studies see ref
`
`Breckenridge Exhibit 1016
`Breckenridge v. Research Corporation Technologies, Inc.
`
`

`
`LeGal ct of
`
`Method
`
`the initial
`
`thesis of
`
`target was the 2sub-
`Our
`stituted alk\l 2-acetamidoacetate
`n-
`this compound \\ as patterned after
`described b\ Bcn-ishai Satat
`the procedure
`the preparation of meth
`Bernstein
`N-benzyloxycarhonI--i-furanglycinate
`with glvoxvlic acid
`
`for
`
`Reaction of acetamide
`
`aromatic
`
`substrate
`
`and boron
`
`trifluoride
`
`etherate This synthetic route permitted the
`preparation of compounds lali Moderate
`yields 2894% for this step were observed
`furan
`2meihvlfuran
`
`for
`
`pyrrole
`benzofuran
`thiophene
`niethvlpyrrole
`indole phenol p-cresol anisole and thio
`4% yield was obtained
`phenol while only
`yielded
`in near quantitati\e
`which upon dissolution in either methanol or
`Employ
`and
`the correspondine ment of prazole iniidazole pyridine 3- and
`ethanol
`acid
`gave
`and
`henvene
`alkyl 2-acetamido-2-alkoxyacetates
`4-hvdroxypyridine
`naphthalene
`5a
`5b Treatment of
`and N-acetylaniline as the aromatic substrate
`with either
`furan or
`pyrrole in the presence of boron trifluoride
`led to no detectable product
`in this procedure
`formation No signifIcant effort was made to
`etherate gave
`the v-substituted product
`in
`moderate yield 5162% In the case of
`varr either the acid or the solvent employed
`in which
`furan only 6a was observed
`sub-
`in the amidoalkylation
`step in order
`to
`stitution had occurred at the 2-position of the
`improve the efficiency of this transformation
`interesting observations were noted
`aromatic ring Correspondinelr with pvrrole
`Several
`3.41 binary rnixtLire of the aromatic 26c1
`concerning the conversion of
`the 2-ethoxy
`the employed con
`and 36c2- substituted compounds
`derivative 8b to
`First
`respec-
`ditions boron trifluoride etherate ether per-
`tively was obtained Unfortunately attempts
`the acid sensitive hetero
`to convert
`to the corresponding benzyl
`mitted the use of
`Low
`amide adduct
`cycles pyrrole benzofuran and indole These
`proved unsatisfactor\
`yields were obtained for the condensation of
`substrates have found limited use in previous
`henzvlamine with
`amidoalkylation transformations Zaugg
`Similarly unacceptable
`were experienced
`Second in the reaction of pyrrole only
`for the
`trace amount of the 3-substituted pyrrole
`conversion
`of
`to the acid
`product was detected tic analysis
`much
`of
`the
`corresponding
`larger
`percentage
`adduct was observed
`\vhen ester 5b was em-
`the starting material Scheme
`This synthetic obstacle was expeditiously
`ployed as
`Method
`The
`high regioselectivity wit-
`circumvented
`the
`the
`second
`use of
`by
`pathway Method
`nessed in the former transformation was also
`outlined in Scheme
`In
`reaction was mirrored in the other reactions with hetero
`the coupling
`this procedure
`conducted
`one
`aromatic
`substrates Typically
`the amidoalkylation
`only
`prior
`to
`isomer was observed This result was par
`transformation Treatment of alkyl 2-aceta-
`ticularlv surprising in he reactions
`and
`Sa
`5b with
`involving
`mido-2-alkoxyacetates
`benzofuran
`benzylamine in alcoholic solution produced
`benzofuran only the 2-substituted aromatic
`the corresponding 2-acetamido-N-henzvl-2-
`the known
`and 8b respectively
`derivative was observed
`alkoxyacetamidcs 8a
`despite
`Higher yields and cleaner product mixtures
`to undergo
`of
`this heterocycle
`tendency
`alkylation at both the 2- and 3-positions
`were noted for the synthesis of ethoxy adduct
`8b versus the methoxy derivative 8a Corn-
`pound 8b was converted
`by treatment
`with the appropriate
`aromatic or hetero-
`
`yield
`
`for benzo Table
`
`overall yields for
`
`sequential
`
`KOH HO followed by the coupling of the
`i.e. C1COR EtN DCC
`
`N-protected amino acid
`
`with benzvlamine
`
`and benzo With
`
`while with benzo none of the ex
`
`3-substituted
`benzobthiophene
`pected
`product was observed
`but
`rather only
`4% yield of
`the 2-substituted adduct was
`starting mat
`isolated along with unreacted
`four substituted benzene sub
`erial Third all
`strates phenol p-cresol anisole and thio
`phenol
`reacted to give
`single product
`t.l.c
`analysis In the case of phenol and anisole
`
`to
`
`ss as hrieiv examined
`
`Ihe direct cons ersiori or4 to
`Addition
`of either
`
`furan or heneoluran
`
`to
`presence of Less is acids sielded the correspondine a-sub-
`ields 1420
`amino acid derivatises in loss
`siOuted
`For additional details see f.ytnote
`
`in the
`
`280
`
`

`
`Functionalized non-natural amino acid derivatives
`
`Selected physical and spectral data fr 2-acetamido-N-benvl-2-suhstituted
`
`acetamides
`
`TABLE
`
`No
`
`Ia
`
`lb
`
`Ic
`
`Id
`
`le
`
`If
`
`02
`
`CHt.1
`
`3a
`
`Yield
`
`M.p
`
`M/eC
`
`n.m.r
`
`s-CH
`
`3C n.m.r
`
`s-C
`
`58
`
`61
`
`35
`
`62
`
`37
`
`178179
`
`273
`
`5.50
`
`79
`
`50.95
`
`148-150
`
`286
`
`5.49
`
`8.0
`
`53.23
`
`174175
`
`27 12
`
`5.42
`
`69
`
`5265
`
`179181
`
`285 17
`
`5.52
`
`7.8
`
`49.20
`
`167169
`
`289 21
`
`5.74
`
`7.9
`
`52.20
`
`51.22
`
`0i2
`
`S2
`
`7a
`
`HO.3j2
`
`CHO4
`
`Hi.L.L
`
`Ig
`
`lb
`
`Ii
`
`Ij
`
`1k
`
`33
`
`28
`
`195196
`
`322
`
`5.77
`
`213214
`
`321
`
`5.72
`
`7.2
`
`49.98
`
`226227
`
`338
`
`5.86
`
`52.70
`
`56
`
`232235
`
`299
`
`5.34
`
`7.4
`
`55.90
`
`62
`
`67
`
`196198
`
`313
`
`5.42
`
`7.8
`
`55.78
`
`183185
`
`313 7f
`
`5.63
`
`7.6
`
`51.54
`
`94
`
`165-167
`
`315 11
`
`5.90
`
`9.0
`
`57.65
`
`from 2-acetamido-N-benzyl-2-ethoxyacetamide Sb Melting points
`The
`are uncorrected
`Purified yields
`ion peak in the mass spectrum was obtained at an ionizing voltage of 70ev The number in the parentheses
`molecular
`indicates the relative intensity of this ion relative to the base peak in the spectrum dThe 300MHz
`n.m.r spectra
`were taken in DMSO-d6 unless otherwise indicated The number in each entry is the chemical shift value
`observed
`in parts per million relative to TMS The information in parentheses
`is the multiplicity of the signal
`followed by the
`in Hertz The 75MHz 3C n.m.r spectra were taken in DMSO-d6 unless otherwise indicated
`coupling constant
`in each entry is the chemical shift value in parts per million relative to TMS 1The
`The number
`peak was
`observed McLafferty F.W Interpretation of Mass Spectra 2nd edn W.A Benjamin Reading MA 1973
`N.m.r spectrum was taken in CD3CN
`
`281
`
`

`
`LeGal et al
`
`CH3CNHCCOOR
`
`CH3CNHCCOOH
`
`/RH
`8F3.Et20
`
`aR
`c1R
`
`2- Furan
`2- Furan
`
`2- Pyrrole
`3- Pyrrok
`
`CH
`CHCH
`CHCH
`CHCH
`
`2- Furan
`
`2- Pvrrale
`
`3- Pyrrole
`
`CER
`cR
`
`CHCNHCCONHCH2Ph
`
`OR
`CHC NHCCONHCHPh
`
`II
`
`RH
`
`BF3.Et20
`
`CH
`CHCH
`
`CH3CNH
`
`00
`HCCOH
`
`OH
`CH3CNHCCOOH
`
`II
`
`OR
`CH3CNHCCOOR
`
`II
`
`SCHEME
`
`the para-substituted adducts Ii and lj
`respec-
`lively were observed while with p-cresol only
`1k was isolated in which reaction had oc-
`curred ortho- to the phenolic group Finally
`than carbon substitution was
`sulfur
`rather
`observed with thiophenol Fourth in the
`reaction involving indole the indole trimer
`was obtained along with the desired
`product 1g Indole is known to undergo
`trimerization in the presence of both mineral
`and Lewis acids
`
`Fl
`
`CHCH2
`
`ii
`
`NH
`
`282
`
`aR
`
`Cl-I
`CH Cl-I
`
`Characteristic
`were
`properties
`spectra
`noted for the newly prepared functionalized
`amino acid derivatives
`in agreement with
`the proposed structural assignments 10 11
`In particular the chemical shift value for the
`a-carbon proton ranged from 55.34 to 5.90 in
`n.m.r spectra while the correspond-
`the
`between
`ing methine carbon signal appeared
`57.65 ppm Evidence
`and
`the
`for
`49.20
`proposed site of aromatic substitution was
`and 3C n.m.r
`secured from both the
`spectra In each case the proton chemical
`values
`as well
`as the proton-proton
`shift
`coupling patterns were in excellent agreement
`with previously reported compounds of corn
`12 More
`parable substitution patterns
`in the 3C n.m.r spectra the chemical
`over
`for the substituted aro
`shift values observed
`matic carbon atoms were always downfield
`6.020.Oppm versus
`corresponding
`the
`in the unsubstituted heterocycle 11
`signal
`cases compounds
`Ii and 1k the
`In several
`3C n.m.r assignments were aided by per-
`
`

`
`Functionalized non-natural amino acid derivatives
`
`forming the corresponding APT n.m.r ex-
`periment 13
`
`CONCLUSIONS
`
`chemicals were of the highest grade available
`and were used without
`further purification
`The mixed anhydride reactions as well as the
`transformations
`amidoalkylation
`using
`boron trifluoride
`etherate were run under
`
`all
`
`croscope
`21521
`
`facile procedure has been developed for the
`anhydrous conditions
`In these cases
`synthesis of non-natural amino acid deriva-
`glassware was flame-dried under N2 the solid
`tives containing an electron-rich aromatic or
`starting materials were dried in vacuo prior to
`heteroaromatic -substituent using an amido-
`under
`use and the reactions were conducted
`The
`alkylation transformation
`reaction
`positive pressure of N2 Preparative flash
`proceeded with high regioselectivity and per-
`column
`was
`chromatography
`run
`using
`mitted the use of the acid sensitive hetero-
`Merck silica gel grade 60 230240 mesh 60
`cycles pyrrole benzofuran and indole Sig-
`Company
`from Aldrich Chemical
`nificantly this approach should be applicable
`Milwaukee Wisconsin Thin-layer chromato
`for the preparation of peptides in which the
`graphic analyses were run on precoated silica
`peptide bond is formed prior to the introduc-
`10 cm Analtech
`microscope slides 2.5
`tion of the aromatic or heteroaromatic sub- No 01521 or on precoated silica GHLF mi
`reaction
`the general
`strate Optimization of
`20cm Analtech No
`slides 10
`conditions i.e Lewis acid solvent should
`allow the synthesis of other a-substituted
`functionalized amino acid derivatives
`
`EXPERIMENTAL PROCEDURES
`
`Sulfuric
`
`Preparation of methyl
`2-acetamido-2-methoxyacetate 5a
`acid 95% 4mL 7Ommol was
`added to methanolic solution 230 mL of
`
`283
`
`146
`
`131
`
`General methods
`acid
`2-acetamido-2-hydroxyacetic
`points were determined with
`13.30g 100 mmol The solution was stirred
`Melting
`Thomas-Hoover melting point apparatus and
`at room temperature 48
`neutralized with
`are uncorrected Infrared spectra jr were
`solid NaHCO3 filtered and then the metha
`Perkin-Elmer
`run on either
`1330 or
`nol was removed in vacuo The pink oil was
`Perkin-Elmer
`and
`distilled under vacuum 70120 0.6 torr to
`spectrophotometer
`the 1601cm band of
`calibrated against
`colorless oil which was recrystallized
`give
`from petroleum ether 3560 to yield 5.20
`polystyrene Absorption values are expressed
`in wavenumbers cm- Proton
`n.m.r 32% of the desired product RfO.52 982
`300MHz and carbon 3C n.m.r 75MHz
`chloroform/methanol m.p 4446 i.r
`spectra were KBr 3270 2820 1735 1650 br 1505 1205
`nuclear magnetic
`resonance
`Nicolet NT-300 or
`on either
`taken
`1010 930 900cm-
`1110
`1090
`n.m.r
`General Electric QE300 instrument Chemi- CDCI3 2.08
`CH3CO 3.46
`OCH3
`9.3 Hz CH
`values
`cal shifts are in parts per million
`COOCH1 5.54
`3.81
`tetramethylsilane TMS and
`NH 13C n.m.r CDCI3
`relative
`to
`6.706.80 br
`values are in Hertz
`22.98 CH3CO 52.69 COOCH3 56.48
`coupling constants
`Mass spectra were performed at the Eli Lilly CH3O 78.16 CH 168.49 CH3CO
`Corporation Indianapolis Indiana or by
`170.67 COOCH3 ppm mass spectrum m/e
`Dr John Chinn at the Department of Chem-
`relative intensity 162
`102 46 88 25 60100
`istry University of Texas at Austin Elemen-
`118
`tal analyses were conducted
`Anal calc for C6HN04
`the Eli Lilly
`at
`6.88
`44.72
`Corporation Indianapolis Indiana Acetoni-
`8.69 Found
`8.72
`44.46
`7.14
`true and triethylamine were distilled from
`and ethyl ether
`CaH2 and tetrahydrofuran
`from Na/benzophenone
`were
`distilled
`Furan pyrrole benzofuran
`ethyl chloro-
`formate and isobutyl
`chloroformate were
`fractionally distilled prior to use All other
`
`Preparation of ethyl
`2-acetamido-2-ethoxyacetate
`
`Sb
`Sulfuric acid 95% 8mL 140 mmol was
`added
`ethanolic solution
`
`to
`
`an
`
`ice
`
`cold
`
`283
`
`

`
`LeGall ci
`500 mL of
`Data for all new compounds prepared by
`2-acetamido-2-hydroxyacetic
`26.6g 200 mmol and the solu-
`are ised below
`acid
`this technique
`tion was stirred at room temperature for 72
`Meth%-l -acetaniido-J-/uranacetare 6a The
`The yellow colored solution was cooled
`desired compound was purified in 62% yield
`and neutralized with
`cold aqueous
`urated NaHCO3 solution 400rnL The re-
`by flash chromatoeraphy 991 chloroform/
`with ethyl methanol R0.32 991 chioroform/metha
`suiting mixture was extracted
`SOOmL The organic layers nol m.p 8081 i.r KBr 3200 1740 1620
`acetate
`were combined and the volatile materials br 1530 br 1205
`900
`1090
`1020
`Hn.m.r CDC13
`890cm
`The
`removed
`in vacuo
`remaining
`ö2.03
`acetate CH3CO 3.75
`OCH3 5.77
`was
`extracted
`with
`7.8 Hz CH 6.356.36
`500mL and the extract dried NaSO4 and
`C5H C4H 7.02
`7.8 Hz NH 7.36 br
`C5H 3C
`in vacuo
`The
`to dryness
`evaporated
`27.69 CH3CO 50.43
`n.m.r CDCI1
`residue was purified
`by distillation
`to give 2l.04g OCH 52.88 CH 108.72 C1 110.78
`vacuum 7095 0.30.8torr
`white waxy solid RfO.53 982 C4 142.84 C5 148.89 C2 169.57
`55% of
`i.r CHICO 169.96 COOCHCH1 ppm mass
`m.p 3536
`chloroform/methanol
`KBr 3400 br 1735 1655 br 1200 1085
`relative intensity 197 14
`spectrum rn/c
`br 1010 930 890cm
`165 35 154 78 l3 36 96100 9493
`n.rn.r CDCI1
`7.3 Hz OCH1CH 1.32
`6916
`l.23
`CH1CO Anal calc for C9H NO4
`7.3 Hz OCH2CHI 2.08
`7.3Hz OCHCH1 4.25
`7.10 Found
`54.96
`COOCH.CHI
`7.3 Hz
`5.60
`6a
`9.6 Hz CH 6.96 br
`9.6 Hz Ethil
`-acetanthio-2-fiiranacetate
`NH 3C n.m.r CDCI5 13.78 OCH2CH3
`Compound 6a was isolated in 51% yield
`14.75 OCHCH1 22.91 CHICO 61.74
`after two successive flash chromatographies
`COOCHCH1 64.72 OCHCHI
`100% chloroform
`7030 ethyl ether/
`CH 168.25 CH1CO 170.48 COOCH2-
`973 chloroform/methanol
`then
`pentane
`CH1ppm mass spectrum me relative in-
`R.0.17 lOO% chloroform m.p 6970 jr
`tensity 1905 1602 14438 11698 102 KBr 3200 1750 l635br 1530 1380 1335
`890 745 595 cm
`92 74 100 high resolution mass spectrum
`1205
`1180
`1020
`n.m.r CDCI1
`C8H6N04
`7.2 Hz
`190.1079
`found
`CH1CO 4.144.32
`OCH2CH1 2.04
`8.1 Hz CH 6.34
`OCH2CH3 5.75
`6.35 rn C5H C4H 6.356.54 br
`8.1 Hz NH 7.357.36
`C5H 3C n.m.r
`CDCI1 13.91 OCHCH1 22.81 CH5CO
`50.33 CH 62.08 OCHCH 108.49 C3
`General procedure The alkyl 2-acetamido-2-
`110.62 Ca 142.64 Ci 148.85 C2 168.89
`equiv was suspended in
`alkoxyacetate
`anhydrous ethyl ether 6OmL lOmmol
`CH1CO 169.43 COOCHCH3ppm mass
`then boron trifluoride
`etherate 1.6equiv
`spectrum rn/c relative intensity 2118 168
`was added in one portion followed by the 32 138
`96100 9427
`The
`equiv.
`solution was
`heterocycle
`caic for C0HNO4
`stirred at room temperature 72h and then
`6.63 Found
`56.98
`poured into an
`ice-cold
`saturated aqueous
`solution of NaHCO1
`tem
`ice
`stirred at
`perature 20mm and then extracted with Er/u -acerarnido-2-pvrroieacetate 6c1 and
`6c
`method The organic
`er/ni
`ethyl acetate
`-acetarnido-3-pirro1rucetate
`layers were combined dried Na2SO4 and Tic analysis at
`the conclusion of the reac
`lion indicated the presence of two major com
`to dryness in vacuo The result-
`concentrated
`and RO.19 982 chloroform/
`pounds110.33
`ing oil was purified by flash chromatography
`methanol which were isolated by flash chro
`or recrystallization
`
`Preparation of a/kvi-suhctiruied-r-
`acetamidoacetates
`
`sat-
`
`yellow
`
`ethyl
`
`oily
`under
`
`76.85
`
`liquid
`
`3.70
`
`calc
`for
`190.1087
`
`284
`
`54.82
`5.40
`7.27
`
`5.62
`
`5l.24
`
`.1
`
`56.87
`6.19
`
`6.20
`6.83
`
`

`
`Functionalized non-natural amino acid derivatives
`
`flash
`
`6.72
`
`C5
`
`8.48
`
`5.33
`
`106
`
`5.53
`
`room tern-
`stirred at
`The
`reaction was
`con-
`and the residue diluted
`
`982
`solution
`chloroform/methanol
`matography
`resulting
`fraction R1 0.33 982 chloroform/
`perature 48
`The initial
`second
`methanol was further purified by
`centrated
`in vacuo
`with HO and then washed with either ethyl
`973
`chromatography
`dichioro-
`6c in 4l% acetate or ethyl ether The aqueous layer was
`methane/methanol
`to produce
`yield m.p 104106 i.r KBr 3310 3200
`then made acidic with 8.5% H3P04 and cx-
`1715 1635 br 1515 br 1220 1180 1085
`The organic
`tracted with ethyl acetate
`dried NaS04
`n.m.r DMSO-d6 51.16
`1010 890cm
`combined
`layers were
`7.2 Hz OCHCH3 1.88
`CH3CO evaporated
`to dryness in vacuo and then re
`OCHCH3
`4.014.16
`crystallized to yield the desired product
`6.9 Hz CH 5.965.99
`C3H C4H 6.69
`Data for all new compounds prepared by
`6.9 Hz CONH
`are listed below
`this technique
`10.8010.99 br NH 3C n.m.r CDCI
`acid 7a Corn
`13.93 OCH2CH5 22.79 CH3CO 50.73
`c1-Acetamido-2-furanacetic
`CH 61.38 OCH2CH2 106.35 C3 107.52
`pound 7a was isolated in 51% yield after
`C4 118.07 C5 125.28 C3 169.24
`from acetonitrile
`recrystallization
`RfO.37
`CH3CO 170.11 COOCHCH3ppm mass
`811 isopropanol/NH4OH/HO m.p 171
`spectrum m/e relative intensity 210 22
`172 i.r KBr 3320 3100 1705 1580br
`167 36 137 54 121
`95100 93
`1530
`1410
`1360
`1320
`1280
`1270
`1225
`97 79
`68 53
`1010 890 660 640 610
`1210 1145
`1100
`570 400cm
`Anal caic for C0H4N03
`n.m.r DMSO-d6 c51.88
`6.71
`57.13
`7.8 Hz CH 6.39
`CH3CO 5.45
`13.33 Found
`6.55
`57.20
`13.13
`C3H C4H 7.65
`CSH 8.69
`fraction R0.19
`982
`The
`second
`6.45
`7.8 Hz NH
`chloroform/methanol was further purified
`carboxyl proton
`3C n.m.r DMSO-d6
`second flash chromatography 955 di-
`was not detected
`by
`22.10 CH3 50.16 CH 108.17 C3 110.66
`to give 6c in 12%
`chlorornethane/methanol
`yield m.p 9293 i.r KBr 3320 3240 C4 142.83 C5 149.75 C2 169.21
`1720 1640 br 1510 1400 br 1210 1180 CH3CO 170.01 COOHppm mass spec-
`165 10
`1010 890 crn
`n.m.r CDC13 51.25
`trurn rn/c relative intensity 183
`6.9Hz OCH.CH5 2.02
`CH5CO 14024 12319 1091961009443.80
`OCHCH5
`4.104.30
`69
`7.2 Hz CH 6.176.30 rn C4H 6.25
`Anal calc for CH9N04
`7.2 Hz CONH 6.706.75
`C5H
`7.65 Found
`52.61
`8.458.60 br NH 3C
`6.786.80
`n.m.r CDCI3 13.93 OCH2CH3 22.79
`acid 7c The
`CH3CO 50.73 CH 61.38 OCHCH3
`c-Acetamido-2-pyrro/eacetic
`06.78 C4 116.56
`118.25 C3 118.63
`was
`product
`chloroform/
`recrystallized
`to give 7c 29% yield
`C5 169.79 CH3CO 171.76 COOCI-L-
`methanol/hexanes
`811 isopropanol/NH4OH/HO
`CH3ppm mass spectrum rn/c
`137 31 rn.p 112-114 i.r KBr 3340 3300 1710
`tensity 210 12 167 16 152
`1590br
`1530br
`1220
`1080
`95100 93100 805 6871 high
`725cm
`n.m.r DMSO-d6
`resolution mass spectrum calc for CH4- CHSCO 5.31
`7.2Hz CH 5.96
`C4H 6.87
`7.2Hz CONH 10.7910.85brs NH
`3C
`carboxyl proton was not detected
`n.m.r DMSO-d 22.16 CH3CO 50.45
`CH 106.21 C3 107.45 C4 117.83
`Genera/procedure The alkyl 2-substituted-a- C5 126.11
`169.13 CH3CO 171.56
`COOH ppm mass spectrum rn/c
`equiv was dissolved
`1647 151 45 138 100
`in 9010 ethanol/water 9mL/l mmol and
`intensity 182
`95 98 93 10 9146
`137 25 121
`then KOH 1.1 equiv was added and the
`
`52.46
`4.93
`
`4.95
`7.94
`
`relative in-
`
`R10.55
`
`121
`
`N205210.l004
`
`found 210.1015
`
`Preparation of substituted
`-acetamidoacetic acids
`
`substituted-x-acetamjdoacetates
`
`from a/kr-
`
`acetamidoacetate
`
`885
`51.87
`
`C3
`
`5.97
`
`C5
`
`8.40
`
`relative
`
`285
`
`

`
`LeGall Ct
`
`Preparation 0.1
`i-Acetamido-N-beny-2-furanacetamide
`la
`
`to
`
`C5
`
`8.58
`
`relative intensity 273
`
`230
`
`5.83
`10.15
`
`acid 7c The
`6.0 Hz CH7
`CH3CO 4.31
`61.90
`-Acetarnido-3-pvrroIeacetic
`Hz CH 6.276.33
`beige residue was recrystallized chloroform 5.58
`Ph
`C4H 7.207.36
`methanol/hexanes to furnish 7c 38% yield C3
`6.406.44
`8.1 Hz
`811
`isopropanoiNH4OH/HO
`7.607.64
`R10.28
`m.p 135138 i.r KBr 3340 3300 1700 NH 8.73
`6.0Hz NH 3C n.m.r
`DMSO-d 22.35 CH3 CO 42.27 CH2
`1585 br 1525 br 1240 br 920 895cm
`50.95 CH 107.60 C3 110.55 C4 126.82
`CHSCO 5.05
`n.m.r DMSO-d6 61.85
`2C2 or 2C 127.08 2C or 2C5 128.27
`7.0Hz CH 6.04
`C4H 6.69
`CH 6.76
`7.0 Hz C4 139.05
`142.58 C5 151.16 C2
`C5H 8.23
`CONH 10.6810.86 br NH
`168.02 CH3CO 169.30 CONH ppm mass
`car-
`3C n.m.r
`boxyl proton was not detected
`22.18 CHSCO 50.57 CH
`spectrum rn/c
`139 100 96 94 9151 65
`DMSO-d6
`106.98 C4 116.28
`Anal calc for C5HN205
`117.83 C3 and
`66.16
`C5 169.13 CH3CO 173.00 COOH ppm
`10.29 Found
`65.92
`5.83
`mass spectrum mje relative intensity 182
`138 100 124
`164
`157
`Preparation oJ
`121
`38 95 19 93 33 80 94 68 91 high
`2-acetamido-N-beniI-2-methoxyacetarnide
`resolution mass spectrum caic for C8H0- Ba
`To methanolic solution l8OmL of methyl
`N-O 182.0691
`found 182.0688
`2-acetamido-2-meihoxyacetate 5a 8.73
`54 mmol was
`rapidly added benzylamine
`8.68g 8.80 mL 81 mmol
`and
`then
`the
`mixture was stirred at 50
`days during
`acid 7a 0.47
`beige precipitate appeared The
`which time
`z-Acetamido-2-furanacetic
`2.56 mmol was combined with acetonitrile
`solvent was removed in vacuo and the result
`lOmL and cooled
`ing precipitate was recrystallized from tetra
`ice/salt water
`to give 7.67 32% of the
`bath Triethylamine 0.26g 0.36 mmol was
`hydrofuran
`desired product as beige crystals RfO.35 955
`then rapidly added and the mixture stirred at
`mm Ethyl chloroformate
`chloroform/methanol m.p 145146 i.r
`0.28
`dropwise KBr3260 1625hr 1550 1505 1435 1390
`0.25mL 2.S6mmol was added
`890 740
`between
`and
`and the resulting sus-
`935
`1370
`1230
`1120
`1060
`n.rn.r CDC13
`pensionwasstirredat 420min.andthen
`690cm
`62.06
`an acetonitrile solution 2mL of benzyla- CH3CO 3.39
`CH3O 4.354.40
`mine 0.30g 0.31 mL 2.82mmol was care- CH 5.52
`8.7Hz CH 7.12
`8.7 Hz NH 7.207.40 rn Ph NH 3C
`fully added During the addition of benzyla-
`n.m.r CDCI3 23.03 CH3CO 43.51 CH2
`mine the temperature of the solution did not
`55.84 CH3O 78.94 CH 127.62 C4
`The mixture was stirred at
`go above
`127.70 2C or 2C 128.70 2C or 2C5
`room temperature 18h and
`and at
`167.91 CH5CO 171.57
`in vacuo The residue was
`then concentrated
`CONH ppm mass spectrum rn/c
`then
`triturated with
`hot
`tetrahydrofuran
`16 3h and the result-
`5rnL cooled at
`205
`intensity 237
`10626 102 94
`1461 1341 121
`ing white precipitate was filtered and iden-
`9195 7713 61100
`as
`tified
`triethylamine
`hydrochloride
`Anal calc for CHN2O 61.00
`n.m.r analysis The filtrate was evaporated
`to dryness in cacao and the resulting oil pun-
`982
`by
`chromatography
`fled
`flash
`13% yield
`chloroform/methanol
`to give
`982 chloroform
`la R10.30
`of
`0.09
`methanol m.p 178179 i.r KBr 3230
`1625 br 1525 br 1375 br 1230
`1090
`890 740 690cmH n.rn.r DMSO-d5
`
`8h
`An ethanolic solution 420mL of ethyl 2-
`5b
`27.92g
`acetamido-2-ethoxyacetate
`
`137.45
`
`193
`
`relative
`163
`
`177
`
`11.86 Found
`
`60.91
`
`6.85
`
`6.83
`11.66
`
`Preparation qf
`
`2-acetamido-N-heniI-2-ethoxiacetarnide
`
`286
`
`

`
`Functionalized non-natural amino acid derivatives
`
`drofuran/hexanes
`
`R10.59
`
`151.20
`
`4.54
`
`127.69
`
`23.25
`
`163
`
`to
`
`relative
`
`11.24
`
`from
`
`2-acetamido-N-benzyl-2-ethoxyacetamide
`
`8b
`
`147 mmol and benzylamine 23.70g 24mL
`to yield the title compound in
`zene/acetone
`58% yield as white crystals RfO.30 982
`221 mmol was stirred at 4045 for
`days
`chloroform/methanol m.p 178179 mixed
`The reaction mixture was evaporated
`in vacuo
`and the residue recrystallized 3.51 tetrahy- melting point with sample prepared by mixed
`anhydride method m.p 178179
`to yield 25.80g
`70% of the desired product as beige crystals
`955 chloroform/methanol m.p
`153155 i.r KBr 3260 1630 br 1550
`a-A cetamido-N-benzyl-2- 5-methylfuran
`acetamide ib The reaction mixture was
`sh 1505 br 1380 1360 1230 1115 1065
`lOIS 890 740 690cmH n.m.r CDC13
`poured into an aqueous saturated NaHCO3
`7.0Hz OCH2CH3 2.07
`solution and extracted with ethyl acetate
`OCHCH3 4.40
`CH3CO 3.603.76
`The ethyl acetate extracts were corn-
`8.7 Hz CH bined dried Na2SO4
`CH2NH 5.60
`and evaporated
`in
`8.7Hz NH 7.00 br NH vacuotogiveabeigesolidwhichwaspurified
`6.63
`Ph 3C n.m.r CDCI3 15.06
`by flash chromatography 982 chloroform
`7.267.36
`CH3CO 43.60 methanol
`OCH2CH1
`yield 61% of
`the
`desired
`CHNH 64.51 OCH2CH3 77.43 CH product as
`white crystalline solid R10.25
`2C2 or 2C3 C4 128.79
`982 chloroform/methanol m.p 148150
`2C2 or
`2C3 137.57 C1 168.13 CH3CO 171.29
`i.r KBr 3270 1620 br 1520 br 1440
`1360 1210 1010 cm1H n.m.r DMSO-d6
`CONH ppm mass spectrum rn/c
`116 98 106 34 151.88
`CH3CO 2.23
`CH3 4.244.36
`intensity 251
`8.0 Hz CH 6.01 br
`CH2 5.49
`9198 74 100
`7.25 CH 6.14
`2.4Hz C4H 7.207.31
`Anal caic for C14H1N2O 62.38
`8.0Hz NH 8.69
`Ph 8.52
`11.19 Found
`62.49
`7.27
`5.6 Hz NH 3C n.m.r DMSO-d6
`13.44 CH3 22.35 CH3CO 44.11 CH2
`53.23 CH 107.51 C3 or C4 110.40 C3 or
`C4 128.13 C4 128.18 2C2 or 2C3 129.43
`2C2 or 2C3 139.69 C1 149.18 C2 or C5
`153.81 C2 or C5 170.78 CH3CO 173.03
`CONH ppm mass spectrum rn/c
`153 57 152 57
`intensity 286
`11123 110 100 97 23 9131
`Anal calc for C16H18N203
`9.78 Found
`66.92
`
`Preparation of 2-substituted
`a-acetamido-N-henzylacetamides
`
`179
`
`relative
`
`6.34
`9.52
`
`67.12
`
`6.52
`
`General procedure 2-Acetarnido-N-benzyl-2-
`ethoxyacetamide Sb
`equiv was suspend-
`ed in anhydrous ethyl ether and then boron
`l.66.3equiv
`was
`etherate
`trifluoride
`rapidly added and the resulting solution was
`stirred for 15mm The aromatic substrate
`6l6equiv was then added and the reac
`room temperature
`tion was stirred at
`days The
`experimental workup
`varied
`slightly for each compound and is described
`below
`observed
`along with the
`spectral
`properties
`
`a-A ceramido-IV-henzyl-2-furanacetamide
`
`chloroform/methanol
`green
`solid This material was purified by flash
`chromatography 955 chloroform/methanol
`la The reaction mixture was poured into
`in 35% yield as
`to yield the desired product
`solution of white solid Rf 0.29 964 chloroform/metha
`saturated aqueous
`ice-cold
`an
`rn.p 174175 i.r KBr 3230 1610
`NaHCO3andthenstirredatO20minand
`nol
`then the mixture was extracted with ethyl br 1500 1470 br 1330 1230 1070 950
`890 860 740 710 685 655 cm n.m.r
`The organic layers were corn-
`acetate
`to CDICN 151.93
`CH1CO 4.35
`bined dried Na2SO4 and evaporated
`6.9 Hz CH
`6.0 Hz CH2 5.42
`dryness in vacuo The product was further
`C3H C4H 6.686.72
`purified by flash chromatography 7030 ben-
`6.006.18
`
`ct-A cetamido-N-benzyl-2-pvrroleaceramide
`1c1 Hexanes were added to the reaction
`and the mixture was filtered and the brown
`955
`was
`triturated
`with
`semi-solid
`
`to
`
`furnish
`
`287
`
`

`
`LeGall et
`
`Anal
`65.29
`6.74
`
`caic
`
`H20
`65.42
`
`-Acetaniido-N-hensI-2-thiopIieneaeeiamide
`
`for C15F19N5O0.5
`14.28 Found
`6.85
`14.04
`
`6.9Hz NH 7.17
`CSH 7.04
`6.0Hz NH 7.10-7.47
`Ph 925
`9.35 br NH 3C n.m.r CDCN 22.02
`CH5CO 43.83 CH 52.65 CH 10757
`C5 108.85 C4 119.33 Cs 127.96
`128.09 2C or 2C le The mixture was cooled in an ice bath
`128.01 2C2 or 2C5
`129.49 Cv 140.01
`170.94 CHSCO and cold
`saturated NaHCO3 was
`aqueous
`171.21 CONHppm mass spectrum me
`added and the aqueous
`layer was extracted
`relative intensity 27112 228
`The
`with
`213
`acetate
`ethyl
`organic
`1802 1649 13794 10820.95100.91
`and the original ether
`washings
`layer were
`38 82 35 68 15 high resolution mass
`combined dried NaSO4 and concentrated
`In vacuo The residue was purified by flash
`spectrum calc for C1.H1-NSO 271.1321
`946
`column
`found 271.1314
`chromatography
`using
`as an eluent and then
`chloroform/methanol
`recrystallized from benzene to give le in 37%
`acetarnide id The thick brown residue that
`yield R1 0.70 946 chloroform/methanol
`n.ni.r DMSO-d6 151.91
`deposited during the reaction was separated m.p 167169
`6.0 Hz CH 5.74
`CH5CO 4.31
`and
`layer was poured into an
`the ether
`7.9 Hz CH 6.99-7.44
`saturated NaHCO solution The
`Ph
`aqueous
`7.9 Hz NH 8.85
`chloroform C4HSS 8.64
`mixture was
`with
`extracted
`6.0 Hz NH
`n.m.r DMSO-d5
`and the chloroform extracts were corn-
`22.4 CHCO 42.3 CH 5.22 CH 125.6
`bined dried Na2SO4 and concentrated
`C5 or C4 125.8 C5 or C4 126.6 C5 126.9
`give id 44%
`The oily residue which formed during the C4 127.3 2C or 2Cr 128.3 2C or 2C1
`169.2 CHSCO 169.3
`reaction was treated with an aqueous
`CON ppm mass spectrum m/e relative
`urated NaHCO5 solution and then extracted
`155 100 112
`with chloroform
`The
`chloroform
`intensity 289
`100 91100 85 34 74 24
`extracts were combined dried Na2 SO4 and
`Anal calc for C1H6N2OS
`brown
`the chloroform removed to yield
`9.71 Found
`residue which was purified by flash column
`5.59
`62.64
`chromatography 982 chloroform/methanol
`to give id 8% The desired compound was
`-A cetaniido-N-benil-2-henofuranaceta-
`from nude if The reaction mixture was poured
`by
`further
`purified
`recrystallization
`R10.20 982 chloroform metha-
`methanol
`into an ice-cold saturated aqueous solution of
`nol m.p 179181 i.r KBr 3240 3060
`NaHCO5 and then the mixture was main-
`1620 br 1540 br 1440
`1360 1320 1290
`tamed at
`this temperature for an additional
`15mm The mixture was extracted with ethyl
`n.m.r DMSO-d5 51.87
`1220cm
`NCHS 4.30
`CHSCO 3.51
`and the organic layers were
`acetate
`5.6 Hz CH 5.52
`7.8 Hz CH 5.90
`combined dried NaSO4 and evaporated
`in
`br C5H C4H 6.68 CSH 7.227.3
`macno The residue was purified by flash chro
`7.8 Hz NH 8.56
`Ph 8.32
`matography 100% chloroform then
`991
`5.6Hz NH 3C n.m.r DMSO-d5
`in 33%
`chloroformmethanol
`to yield if
`CH5CO 33.42 NCH5 42.23 CH2 49.20
`982 chloroform/methanol
`CH 106.13
`or C4 107.58 C5 or C4 m.p 195196 i.r KBr 3230 1625 br
`122.66 C5 126.66 C4 127.18
`1520 br 1440
`2C2 or
`1090
`1085
`890
`735
`128.93 C2 690cm
`2C5 128.09 2C2 or
`n.m.r DMSO-d6 15 1.94
`139.18 C1 168.84 CONH 169.42 CH5CO 4.34
`5.7 Hz CH2 5.77
`8.1 Hz CH 7.24-7.32
`CH5CO ppm mass spectrum me relative
`C5H C5H
`178 15 152 94 CH Ph 7.54
`intensity 285 17 227
`7.0 Hz C4H or C7H
`151 100 135 97 11038 109 100 107
`7.0 Hz C4H or C7H 8.74
`8.1 Hz NH 8.86
`5.7 Hz NH
`62 96 35 95 25 93 85 82 92
`
`y.-Acetanido-N-henv/-2-1-niethylp.vrrole-
`
`to
`
`sat-
`
`139.0
`
`141.4
`
`.J
`
`181
`
`62.48
`5.73
`9.61
`
`22.23
`
`yield R10.30
`
`2C5
`
`7.62
`
`288
`
`

`
`cx-Acetamideo-N-benzyl-3-indoleacetamide
`
`1000 890 735cm
`nm.r DMSO-d6 22.27 CH3CO 42.30
`CR 51.22 CH 104.34 C3 110.90 C7 DMSO-d6
`n.m.r
`CH2 4.794.86
`3.323.36
`121.05 C4 122.90 C5 124.28 C6 126.73
`CH 6.34 dd
`7.5 Hz
`7.5 Hz
`Cia 127.01 2C or 2C3 127.69 2C2 or CS.H 6.57
`7.5 Hz C6.H 6.78 dd
`2C1 128.14 C4 138.87 C1 154.10 C7a
`7.5 Hz C4.H 6.82
`7.5 Hz
`154.30 C2 167.40 CH3CO 169.26
`7.5 Hz C3.H 6.86 dd
`7.8 Hz
`CONH ppm mass spectrum rn/e
`6.97 dd
`7.8 Hz C5.H
`or C6
`relative
`2791 264
`2341 215
`7.8 Hz
`7.8 Hz C5.
`or C6.H 7.24
`intensity 322
`189 45 146 100 130 11 1187 91
`C2H 7.26
`7.8 Hz C7.H or C4..H
`87 65 16 high resolution mass spectrum
`7.8 Hz C7..H or C4..H 10.58
`found NH
`for C9 H8N2 03
`signal for the NH2 protons was not
`322.1317
`caic
`322.1318
`detected and may have overlapped with the
`n.m.r DMSO-d6
`aromatic
`protons.3
`32.57 CH 36.01 CR2 111.45 C6 114.91
`ig Petroleum ether 3560 was added to C3 or C3 116.43 C3 or C3 117.76 C2
`118.63 C5 118.93 C4 or C7 120.44 C4 or
`the reaction and the resulting semisolid mat-
`filtered and washed with petroleum C7 122.12 C5. 124.88 C3a 125.99 C4 or
`erial
`the reaction C6 126.66 C4 or C6 129.24
`ether 3560 Purification of
`by flash chroma- C7a 145.71 C2 ppm mass spectrum m/e
`mixture was accomplished
`relative intensity 351 100 145
`982 chloroform/methanol
`tography
`to
`white solid in 18% yield
`produce
`Ig as
`RfO.I4 955 chloroform/methanol m.p
`.r KBr 3260 1610 br 1515
`a-Acetamido-N-benzy1-2-benzo
`213214
`acetamide lh The solution was poured into
`br 1450 1420 1370 1350 1235 1095 895
`n.m.r DMSO-
`735 715 695 600cm-
`an ice-cold
`solution of
`saturated aqueous
`CH3CO 4.36
`NaHCO3 and then stirred for 15mm at
`6.0 Hz
`d6 51.90
`7.2 Hz CH 6.907.37
`CH2 5.72
`The mixture was extracted with ethyl acetate
`7.02 dd
`7.5 Hz
`Ph
`and the organic layers were combined
`7.5 Hz C5H or C6H 7.12 dd
`dried Na2 SO4 and evaporated
`in vacuo
`to
`7.5
`7.5 Hz C5H or C6H 7.39
`give an orange oil The oil was triturated with
`7.5 Hz C4H or C7H 7.65
`7.5 Hz
`crystalline product
`ethyl ether
`to yield
`7.2 Hz NHCH which was filtered and further purified by
`C4H or C7
`6.0Hz NHCH2 10.3010.80
`991
`chloroform
`chromatography
`8.13
`NH 3C n.m.r DMSO-d6
`in 4%
`22.32 m