requirescarefreeprevent attentionanypolluting acetic acid that hydrolyzesthere OB 0 -Ester.
Both Boc-Ser-OB0 2.44 ester and Boc-Thr-OB0 2-45 esterthey were stored at room temperature for more than a year, with the optical activity slowly declining, mainly due to ring opening of the O B 0 ester. aldehyde2.46tends to lose its optical activity rapidly due to racemization even when stored-20 °C.
2.2.2 additivevonVarios GrignardreagentsABoc-Serpha1d)OBO-Ester 2.46jBoc-
2S,3R=importantTomorrow morning 2.49R=CH3 2,50R=et 2.51R=Vinyl 2,52 R=Ph
Ifsummarized in table2.1,IsTypGrignard reagent, solvent and temperature were all studied to optimize addition. little difference in performanceEraswere obtained with different halide counterions and therefore MeMgBr was usedas the reagent of choiceescommercial availability. Temperature and solvent played a greater role in the determinationbothYield relationships and diastereomenc. Elevated temperatures resulted in lower yields due to the formation of complex mixtures ofvon-Products that have not been isolated. The moderate increase in the reactivity of theGrignardImplementation in tolueneC(Entry 5) is an anomaly, although not without itprevious?This reactivity was enhanced by using a nonpolar and noncoordinating solvent.hatwas it described above? However, if the encoreErasmade in tolueneIn-78 "C,the highest reactivity experienced inC Erasnot observed, although the srereoselectivityErasIncrease. Even with long reaction times (entry 10), the reaction was not complete for all solvents at -78°C.
The main by-product of the additivesErasunreacted Boc-Ser(a1d)OBO ester 2.46. One ofIsThe most common side reaction with Grignard reagents is enolization. Formation of the 2,46-aldehyde/2,47-ketone enolate would compete with the addition reaction and produce the aldehyde after processing, albeit racemic. In
62
To examine this as a possible side reaction, the reactionseemed to haveended itErasout and theresidual aldehyde reduced with NaB&
since it is known that the aldehyderacenizefertilizeaction of silica gel.
Is
specific rotation of the ester Boc-Ser-OB0 2.44(-40,2)generated by reductionErasIt was found to be close to the specific rotation of pure 2A4(-41,8)indicating minimal enolization of unreacted aldehydeoccurs during Grignard addition. This was consequently removedEnolization as a possible side reaction preventing the reactionIsAldehydes.
Mesa2.1:
additive
from MeMgX to BocSer(ald)OBO ester 2m46.
Input reagent solvent(CHEF
J
To produce
(%Lb
Thretxerythro y G
1MeMgCl THFÖ 30
- -
2 MeMgBrTHFO 427O:3Oe
-
5 MeMgBr-TolueneÖ5571:29'
-
6 MeMgBr
THF
-7860(75) 79:21 96
10MeMgBr-Toluene-7851(85) 82:18 98
'
Added 3 equivalent Grignard reagents.
BYield for 2 stages (up from 2.44).
bravery
in brackets is the yield based on the starting material obtained.
relationship determined byHPLCAnalysis unless otherwise noted.
DMinimumCH2ClzErasused to dissolve the liquid.
relationship determined by'H-RMN.
After optimizing the addition of MeMgBr, we turned our attention to the addition of other Grignard reagents to the Boc-Ser(a1d)OBO ester.2.46(Scheme 2.21, Table 2.2). Inal1Cases caused the addition littleracemizationwith the unprotected dl-amino acids possessing297%And.The diastereoselectivity of the crude product ranged from 84:16 to 88:12 directions: erythro andIncome from40-6695.cleaningvonflash chromatography followed by deprotection andHPLCAnalysis ofIsThe amino acid purified by ion exchange showed a slight increase in diastereoselectivity. In fact, although the
Radiofrequenz
since both diastereomers were typically similar, diastereomeric enrichment seemed apparentbethis occurs after flash chromatography, although values are determined by'H-RMNIntegration is the issueAexperimental error. steric volume ofIsThe Grignard reagent does not appear to play an important role in stereoselectivity since similar tre0:erytht-o ratios are obtained for all reagents.ts.
Table 2.2: Additions
von
RMgBrABoc-Ser(ald)OBOEster2.46.
protected aa unprotectedAA 9%
%ds ratio (s,R:s,S)~ ds ratio% generally VerbotenRMgBr Crude Oil Revenue Product
(s$:s,S)C
EEC performance
1 year 2.50 49 84:sixteen 87: 13 98 24
2 Weinj1 2,51 40 87:13 89:1197 16
3 phases2.52 66 88:12 90:10 98 40
AReported performance for 2 passes
(von
2.44).
certain ratiovon'H-RMNrelationship determined byHPLCAnalyse
Addition of MeMgBr to Boc-Throcet)-OB0 Ester 2.47 afforded protection
Be
Hydroxyvalin 2,57 (Schema2.22,Table 2.3). The reaction proceeded in good yield.(7246,in two steps), but as for the additions to the aldehyde2.46, AT3analysis indicated residual ketone of 2.47.
Is
recovered ketone 2.47, theErasstable on silica,
64
kept its lookactivitywhich indicates refinementIsThe a-hydrogen was not responsible for preventing the complete reaction of the ketone, but the enolization of the methyl ketone cannotbeignoredeci. However, a similar observation of incompetent response failsGrignardreactive with2.46suggests that another phenomenon prevents the ketone from fully reacting.
Schema 2-22
2S13R=importantDiastereomero 2-57R=CH3 2.58R=et
Outstanding stereoselectivity of nucleophilic additionErasobserved with the most voluminousEtMgBr (98:2 Address: erythro)Grignard reagent whenreactedcon2-47.The stereochemistry of the adduct 2.58Erasassigned to 49 by spectroscopic comparison with literature values and is consistent with the direction of attack observed in Senne Aidehyde 2-46. This model is discussedfurtherDetails in Section 2.2.5. Yields for both MeMgBr and EtMgBr addition were generally good; however, the longer response times required for optimal performanceIsFall of EtMgBr led to the formation ofvon-Product2-61in less than 5% yield. Thehappens likecompetition resultattackof the Grignard reagent on the carbamateand hask e n previously reportedhappenwith bulky Grignard reagents and long reaction time~.'~ Although the carbamate probably exists as the magnesium enolate, the slow equilibration to the carbonyl and the subsequent attack ofEtMgBris the likely formation mechanism.
Mesa
23:
RMgBr additiveABoc-Thr(lcet)OBOEster2.47.
protectedAAunprotectedAA % 96 ds ratio (S&:S,S)~ DSRelationship %generally
Verboten
R.MgBr Productproduces a blank(S&:S,S)c CEEto produce
IMich2.57 72
- -
99 38
2 et 22% Sixty-five 98:2 99:1 99 37
AReported performance for2 steps (from 2.45).
relationship determined by'H-RMNrelationship determined by
HPLC
Analyse
2.2.3 deprotectionvonFDiaIkyl-jPHydroxry-a-Aminoacids
Anecessary part ofanyThe synthetic route is the Straighdonvardeliminationof protecting groups. However, this isthe phase in which many methods failforDifferent reason. Once the various B had hydroxy-α-amino acidsConditionsynthesized.
unprotectionErasneeded forevaluate both diastereomeric and enantiomeric Punty.
2.2.3.1 Boc Distance
Is
Boc protecting groupEraseasily removed with wet trifluoroacetic acid(TFA)in CH2C12 under standard conditions andErastypically completed in less than 30 minutes(The plan2.23)?
2.2.3.2vegetable gardenEstercutout
Simultaneous cleavage of the orthoesterhappenDunng Boc neckline withExposure to wet TFA what the2-Methyl-2-hydroxymethyl-1,3-propandiolEsterderivat (mphd)2.62.
Have several multi-step proceduresConditionreportedthe literature on the removal of bicyclic orthoesters (Sect1.4.1).One uses acid hydrolysis to initially open the orthoester and generate base hydrolysisIsAcid or transesterification ofIsRing open ortho ester to a methyl ester followedvonbasic hydrolysis of methyl esterAenter the acid with normal yields~ 6 0 % . ~ 'Elimination of the mphd ester according to the methodsdescribed above, it was found thatbeunsuccessiÙl.62 However, alkali carbonatesCondition
be showmore efficient at ester hydrolysis thanBicarbonate ^^^ and the combination of Cs2C03 in MeOH:H2O was very effective in cleaving the ring rnhpd ester 2-62 to the acid2.53.
Schema 2.23
Is
optimizedstewThe procedure consists of the simultaneous excision of the Bocprotective group and the OB0 ester to thernhpd-Ester2,62 con
ATF.
By evaporation to dryness the residue was dissolved in methanol to which a 10% solution was added.C s K 0 3Erasaddedan amount to ensure at least 5 base equivalentsErasAggregate.
2.2.3.3 Compliance with the punishment
Once the amino acidErasdeprotected ion exchange chromatographyErasused to clean the product from the cleavage reaction salts. cation cleaningErascommonly used forelCs2C03based cleavages and volatile bases (5% Et3N inHDÖ0,5Norte
N B H )
used for elution, allowing isolation of the free amino acid. The solutionvonIsC is a 3cutoutEraspreviously leavenedloadont0 the resin. Most commonly, contamination resulted from incomplete hydrolysis of the rnhpd 2.62 ester. Anion exchange chromatography effectively removed the rnhpd ester during loading and washing of the column, leaving elution with 0.5N acetic or formic acid freeauthorizedacid toobeisolated. anion exchange chromatographyErasmost commonly used in cleaning ofIsp-dialcyl-p-hydroxyamino acids to minimize exposureIs
p-dialkyl-p-hydroxy moiety susceptible to dehydration under basic conditions. Although strong anion exchange resins contain a polymer-supported basic tetraalkylammonium hydroxide,NOracemizationhas beenobserved in previous reports from this laboratory."
Cnide yields after ion exchange chromatography ranged from 40-8 L%,but generally in the range of 50%.
Manyof the synthesized aminothe acids weredifficult to recrystallize, although spectroscopic techniques indicated high purity after ion exchange chromatography.
The diastereomeric ratios couldbedetermined by'H NMR and AmbosAssigned diastereoisomeric and enantiomeric ratios after derivatization and
HPLC
Analysis (Section 2.2.4).
Good matchErasfound between the twomethods.