Synthesis of orthogonally protected (2S)-2-amino-adipic acid (α-AAA) and (2S,4 R)-2-amino-4-hydroxyadipic acid (Ahad)

Article abstract of DOI:10.1021/jo400558t

(2S,4R)-2-Amino-4-hydroxyadipic acid (Ahad) building block 45 was synthesized in 11 steps and 6.5% overall yield from commercially available materials. Key steps in stereocontrol were an asymmetric conjugate addition employing a proline-based catalyst and a syn-selective intramolecular-conjugate addition of an oxygen nucleophile to an α,β-unsaturated ester. To enable incorporation of α-amino-adipic acid (α-AAA) and Ahad into peptides, a truly orthogonal protecting group scheme was developed, encompassing an allyloxycarbonyl (Alloc) carbamate for Nα, a tert-butyl ester for the δ-COOH, an acetol ester for the α-COOH, and a tert- butyldimethylsilyl ether for the γ-hydroxy group of Ahad.

Full text of DOI:10.1021/jo400558t

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Article
Synthesis of Orthogonally Protected (2S)-2-Aminoadipic
Acid and (2S,4R)-2-Amino-4-Hydroxyadipic Acid (Ahad)
Saroj Yadav, and Carol M. Taylor
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400558t • Publication Date (Web): 01 May 2013
Downloaded from http://pubs.acs.org on May 3, 2013
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Synthesis of Orthogonally Protected (2S)-2-Amino-Adipic Acid
(α-AAA) and (2S,4R)-2-Amino-4-Hydroxyadipic Acid (Ahad)
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Saroj Yadav and Carol M. Taylor*
Department of Chemistry, Louisiana State University, Baton Rouge, LA, 70803.
Corresponding Author Email: cmtaylor@lsu.edu
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Table of Contents Graphic
Abstract
(2S,4R)ꢀ2ꢀAminoꢀ4ꢀhydroxyadipic acid (Ahad) building block 45 was synthesized
in 11 steps and 6.5% overall yield from commercially available materials. Key steps in
stereocontrol were an asymmetric conjugate addition employing a prolineꢀbased catalyst
and a synꢀselective intramolecularꢀconjugate addition of an oxygen nucleophile to an α,βꢀ
unsaturated ester. With a view to incorporating αꢀaminoadipic acid (αꢀAAA) and Ahad
into peptides, a truly orthogonal protecting group scheme was developed, encompassing
an allyloxycarbonyl (Alloc) carbamate for Nα, a tertꢀbutyl ester for the δꢀCOOH an
acetol ester for the αꢀCOOH and a tertꢀbutyldimethylsilyl ether for the γꢀhydroxy group
of Ahad.
Background and Introduction
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(2S,4R)ꢀ2ꢀAminoꢀ4ꢀhydroxyadipic acid (Ahad) is a constituent amino acid of
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theonellamides AꢀF (Figure 1), bicyclic peptides isolated by Fusetani’s group.1 These
compounds have been shown to inhibit the growth of prototypical fungi and cancer cell
lines. Watabe et al. reported that theonellamide F induced vacuole formation in 3Y1 rat
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embryonic fibroblasts;2 this is the first low molecular weight compound demonstrated to
induce extraordinarily large vacuoles without causing cell death, suggesting potential as
good molecular probes to investigate intracellular membrane structures.3
Figure 1. Theonellamide C (1) with the Ahad residue circled.
(2S)ꢀαꢀAminoꢀadipic acid (αꢀAAA, 3, Scheme 1), which lacks the γꢀhydroxy
group, occurs in theonegramide4 and theopalauamide,5 bicyclic compounds closely
related to the theonellamides. Theopalauamide was shown to be produced by symbiotic,
filamentous bacteria living within sponges of the Theonella genus.6 Theopalauamide was
recently demonstrated to inhibit the growth of Saccharomyces cerevisaie at 0.4 nM and
the molecular target was shown to be ergosterol.7,8
(3S)ꢀ3ꢀHydroxyadipic acid (6) is an oxidative degradation product of adipic acid
(5) (Scheme 1) and is excreted in urine,9 while αꢀAAA (3) is a normal metabolite in the
degradation of lysine (2).10 Aside from the appearance of Ahad in the theonellamides
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(vide supra) the only other report of this amino acid was from Blass and Macheboeuf
who proposed, without spectroscopic evidence, the occurrence of Ahad in cultures of
Vibrio cholerae.11 This αꢀaminoꢀγꢀhydroxy acid would appear to be of novel or mixed
biogenesis.
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Scheme 1. Biogenesis of adipic acids.
Kristensen et al. reported the synthesis of a mixture of all four stereoisomers of
Ahad in 1980,12 as analytical standards for analysis. The synthesis was performed by
analogy to Benoiton’s protocol13 for the synthesis of γꢀhydroxyglutamic acids (Scheme
2). Condensation of the anion of ethyl acetamidocyanoacetate (7) with 3ꢀacetoxyꢀ4ꢀ
chlorobutyronitrile (8), followed by hydrolysis and decarboxylation yielded a mixture of
four isomers; the two racemates were separated by ion exchange chromatography. In
1994, Tohdo, Hamada and Shioiri reported the synthesis of Ahad in the context of their
efforts toward theonellamide F.14 They made intelligent use of the chiral pool,
employing aspartic acid as the source of the Cα stereocenter. The acyl imidazole
generated from the free acid in compound 11 was used to acylate the magnesium enolate
of the malonate half ester 12. The ketone was then reduced stereoselectively by
hydrogenation under high pressure with Ruꢀ(R)ꢀBINAP. Unfortunately, upon generation
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of the secondary alcohol, spontaneous cyclization occurs to give a γꢀlactone (c.f., 9)
which is ultimately not a useful intermediate in peptide synthesis (vide infra).
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Scheme 2. Previous syntheses of Ahad.
It is important to note that Ahad and αꢀAAA are incorporated into the cyclic
peptides via their αꢀamino (Nα) and the side chain carboxylate (δꢀCOOH). The αꢀ
carboxylic acid is not part of the peptide backbone and may be important for stabilization
of an imidazolium cation in the natural products (Figure 1). During acidic degradation of
the theonellamides, Ahad was isolated as the corresponding γꢀlactone. As described
above, Tohdo et al. used the γꢀlactone functionality as “intramolecular protection” in
building block 9. On the basis of our experience with 4,5ꢀdihydroxyleucine,15 we believe
that it would have been impossible to open the γꢀlactone without epimerization at Cα.
Michl had shown earlier that Nαꢀacyl and Nαꢀcarbamoyl γꢀlactones are susceptible to
epimerization, most likely via an oxazolone.16 We therefore sought to avoid the γꢀlactone
moiety during our synthesis. The development of a sophistocated protecting group
scheme that would support theonellamide synthesis became an integral goal of this work.
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Results and Discussion
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For the synthesis of Ahad, we initially explored an approach based on the the
CoreyꢀLygo protocol wherein a glycine enolate is alkylated in the presence of the
cinchona alkaloidꢀderived phase transfer catalyst 15 (Scheme 3).17 While we were able
to reproduce alkylations, as reported in the literature, for allyl bromide and nꢀbutyl
iodide, we were never able to isolate any alkylation product for reaction with electrophile
14. It seems that the best electrophiles are allylic or benzylic, and used in fiveꢀfold
excess. Electrophile 14 was synthesized in five steps from Dꢀmalic acid according to
Scheme 3. Formation of the dibenzyl ester according to Lee et al.18 was followed by
chemoselective reduction of the αꢀhydroxyester19 to give 18. Selective tosylation of the
primary alcohol under standard conditions20 was not very rewarding, but was successfully
achieved via the stannylene acetal.21 Protection of the remaining secondary alcohol gave
19. The tosylate was readily converted to iodide 14. Even with suitable excesses of 14,
no alkylation was observed, under a variety of reaction conditions. We are forced to
conclude that this is due to low reactivity in combination with steric hinderance of the
center undergoing nucleophilic attack in 14 and related electrophiles that we investigated.
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Scheme 3
We next turned to the generation of the synꢀ1,3ꢀaminoalcohol following an
approach reported by MacMillan and coworkers in the context of their enantioselective
organocatalytic amine conjugate additions.22 According to Scheme 4, the γꢀhydroxy
group would be installed intramolecularly; exposure to a source of fluoride ion would
generate an oxyanion from compound 20 that would add in a conjugate manner to the
α,βꢀunsaturated ester. Conjugate addition of CbzꢀNHOTBS to a chiral iminium ion
generated from aldehyde 21 would occur enantioselectively to generate the first
stereocenter. Wittig homologation with commerically available 22 would convert the
aldehyde to the α,βꢀunsaturated ester 20. We opted to perform the reactions implied in
Scheme 4 using commercially available hydroxycarbamate and phosphorane reagents,
cognisant of the fact that this would require some protecting group manipulations at a
later stage. As noted previously, Ahad is incorporated into the cyclic peptides via the
side chain carboxylate. Thus, the free acid depicted in the generic structure (Scheme 4)
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would ultimately be coupled with the appropriate amine of the bridging τꢀ
histidinoalanine residue. Our theonellamide synthetic strategy involves a final global
deprotection using fluoride, hence our choice of the TBS ether for the γꢀhydroxy group.
Candidates for temporary protection of the αꢀamino and δꢀcarboxy groups will be
discussed in due course.
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Scheme 4
The execution of this plan is illustrated in Scheme 5.
Diethyl
(benzyloxycarbonylmethyl)phosphonate was prepared by hydrolysis of the carboxylate
ester of triethylphosphonoacetate (23) and conversion to the benzyl ester 24. A Hornerꢀ
Emmons reaction was conducted in a biphasic reaction mixture of cyclohexane and an
aqueous solution of glyoxal dimethyl acetal (25) afforded Eꢀ26.23 Hydrolysis of the
dimethyl acetal to give aldehyde 21 was best accomplished according to Iesce et al.;24
other conditions led to isolation of the hydrate. Conjugate addition of CbzNHOTBS (27)
to (E)ꢀbenzyl 4ꢀoxobutꢀ2ꢀenote (21) in the presence of catalyst 28 led to no isolable
product. Fortunately, employing catalyst 29, according to Cordova et al.25 afforded 30 in
good yield that was then subjected to a Wittig reaction to obtain 20. In practice, direct
addition of the phosphorane to the reaction mixture containing 30 led to 20 directly in
good overall yield. Treatment of compound 20 with fluoride ion facilitated silyl group
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removal with concomitant, intramolecular oxyꢀMichael addition to afford isooxazolidine
32a.
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While MacMillan and coꢀworkers had employed samarium diiodide to reductively
cleave the NꢀO bond in a compound analogous to 29, we anticipated that exposure of 29
to standard hydrogenolysis conditions would simultaneously remove the Cbz and benzyl
ester protecting groups, along with cleavage of the NꢀO bond.26 This was borne out by
experiment to give 33a ready for introduction of a suitable suite of protecting groups.
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Scheme 5
We began our search for a combination of protecting groups that might be
compatible with the total synthesis of a theonellamide, with αꢀAAA as this congener is
not hydroxylated at Cγ. Acetol27 and 2ꢀ(trimethylsilyl)ethoxymethyl (SEM)28 esters were
entertained as possible protective groups for the αꢀcarboxylate as these functionalities
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appear likely to survive the various reaction conditions in the synthesis and have been
shown to be cleaved using tetrabutylammonium fluoride.
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Racemic αꢀAAA (±)ꢀ3 was protected as its allyloxycarbamate29 by analogy to a
procedure for the Cbzꢀprotection of adipic acid by Hachisako et al.30 We explored a
number of strategies to selectively protect one of the carboxylic acids in αꢀAAA,
including the intermediacy of copper(II) complexes.31 The approach that was most
fruitful was based on the observation of Baldwin and others who have demonstrated that
it is possible to selectively esterify the αꢀcarboxylic acid of adipic acid,32 since its pKa is
about one unit lower than that of the δꢀcarboxylic acid. Regioselective esterification of
the αꢀacid in compound 34 was attempted by the addition of half an equivalent of cesium
carbonate to form the putative monoꢀcesium carboxylate salt and reacting with SEMꢀCl.
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The
product
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trimethylsilyldiazomethane to afford a mixture of compounds 35ꢀ37 from which 35 could
be isolated by flash chromatography. A low yield of compound 35 was obtained due to
poor regioselectivity and the inability to purify the intermediate acid by flash
chromatography due to their high polarity. Acetol ester 38 was obtained via an analogous
series of reactions, in similarly low yield.
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Scheme 6
Nicolaou reported impressive chemoselectivity of trimethyltin hydroxide for the
hydrolysis of methyl esters, even in the presence of ethyl esters.33 We hoped we would
similarly be able to cleave the methyl esters in compounds 35 and 38, in the presence of
acetol and SEM esters respectively. When compound 38 was treated with Me3SnOH,
complex product mixtures were obtained, regardless of the number of equivalents of
reagent and reaction temperature. Analysis of the product mixture by LCMS showed that
the major product arose from hydrolysis of the acetol ester (giving compound 39) instead
of the methyl ester (minor product 40). The starting diester 38 and diacid 34 were also
observed, revealing a reaction that is not synthetically useful. Similar results were
obtained upon attempted hydrolysis of the SEM group from 35.
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We decided to substitute a tertꢀbutyl ester for the illꢀfated methyl ester.
Cognizant of the acidꢀlability of SEM esters, the acetol ester now became the clear
choice. Thus, a mixture containing acid (±)ꢀ40 was treated with isobutylene under acidic
conditions to give diester (±)ꢀ41 (Scheme 7). The selective cleavage of the tertꢀbutyl
ester and the acetol ester were demonstrated using TFA and TBAF respectively (Scheme
7). Optically active (ꢀ)ꢀ41 was prepared from Lꢀαꢀaminoadipic acid.
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Scheme 7
Following these protecting group studies with αꢀAAA, Ahad building block 33b,
bearing a δꢀCOOtBu group, was synthesized via analogous reactions to those described
earlier for the δꢀCOOMe building block 33a (Scheme 5). The tertꢀbutyl ester was
introduced
using
commercially
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(tertꢀbutoxycarbonylmethylene)ꢀ
triphenylphosphorane during the Wittig reaction to produce 31. Chiral HPLC analysis
showed that compound 31 was obtained in 87.4% e.e. We base our assignment of the Sꢀ
configuration at Cα on the transitionꢀstate model of Córdova and coworkers in which the
amine nucleophile attacks the face of the conjugated pyrrolidinium ion opposite the bulky
CPh2(OTMS) substituent.25 Their model was vindicated by conversion of some
intermediates to known compounds for comparison. Treatment of compound 31 with
fluoride ion facilitated cyclization at room temperature to afford isooxazolidine 32b in a
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3.8:1.0 d.r. favoring the syn diastereomer. In attempts to improve the diastereoselectivity
of the conjugate addition, we conducted the reaction at lower temperatures. For example,
at 0 °C, a 10% yield of isooxazolidine 32b was obtained with 4.2:1.0 d.r. Confirmation
of the syn relative stereochemistry was confirmed by a NOESY experiment that showed a
cross peak between the Hα and Hγ protons of 32b (5.6% nOe). The syn diastereomer
could be further purified by normal phase HPLC, although in practice the minor
diastereomer was gradually removed during chromatography following the next few
reaction steps.
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The free amine 33b was protected as its allyloxycarbamate 43 (Scheme 8) by
analogy to the procedure for αꢀAAA. Esterification of the αꢀacid was attempted in two
ways: firstly, via reaction of the cesium salt with chloroacetone; and secondly, via
coupling to acetol in the presence of activating agents. The only product isolated from
various reaction conditions was the lactone 44 (Scheme 8). This undesired product
afforded further confirmation of the 2S,4R stereochemistry since the Hβ protons gave rise
to a multiplet at 2.4ꢀ2.8 ppm, consistent with a transꢀ1,4ꢀdisubstituted γꢀlactone.34
Various activated acyl species, including the acetol ester, were susceptible to nucleophilic
attack by the γꢀOH, mandating that we protect the secondary alcohol before the
carboxylic acid.
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Scheme 8
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Lajoie and coworkers had shown that a free alcohol can be masked as a TBS ether
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in the presence of free amine and free acid functional groups.35 We applied their
conditions, involving stoichiometric TBSCl and 2,6ꢀlutidine, to compound 43.
Carbodiimideꢀmediated coupling of the resulting crude acid with acetol gave rise to 45 in
reasonable overall yield. We expect this building block to be useful in the synthesis of
theonellamides. The scope for chemoselective cleavage of the tertꢀbutyl ester with tertꢀ
butyldimethylsilyl triflate,36 liberation of the αꢀNH2 with palladium(0) and ultimately
cleavage of the silyl ether and acetol ester side chain protecting groups with fluoride
provides an adaptable building block.
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Conclusion
In summary, a robust, stereoselective synthesis of orthogonally protected (2S,4R)ꢀ
αꢀaminoꢀ ꢀhydroxyadipic acid has been developed starting from commercially available
triethylphosphonoacetate (23), glyoxal dimethyl acetal (25), benzyl Nꢀhydroxycarbamate
and (tertꢀbutoxycarbonylmethylene)triphenylphosphorane.
The two stereoselective
conjugate addition reactions represent a potentially general approach to 1,3ꢀsyn
aminoalcohols. Incorporation of the αꢀAAA and Ahad building blocks, described herein,
into the western hemisphere of theonellamides is currently underway in our laboratory.
Experimental Procedures
(S)-Benzyl 3,4-dihydroxybutanoate (18).
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(a)
(S)-Dibenzyl 2-hydroxysuccinate. Benzyl alcohol (1.50 mL, 1.61 g, 14.90 mmol)
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and pꢀtoluenesulfonic acid monohydrate (14 mg, 0.074 mmol) were added to a solution
of Dꢀmalic acid (17) (1.00 g, 7.46 mmol) in dry toluene (12 mL). The reaction mixture
was heated under reflux with a DeanꢀStark apparatus to effect the azeotropic removal of
water. When no more water appeared in the distillate, the mixture was allowed to cool to
rt and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic
layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash
column chromatography on silica gel with Hex:EtOAc (4:1) as eluent to give the
dibenzyl ester as a colorless oil (80%). Rf 0.42 (4:1 HexꢀEtOAc). [α]D25 +42.98 (c 2.5,
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CHCl3) [Lit.18 [α]D25 +18.2 (c 2, CHCl3)]. H NMR (CDCl3, 400 MHz) δ 2.80 (dd, J =
16.4, 6.1 Hz, 1H), 2.86 (dd, J = 16.4, 4.7 Hz, 1H), 3.41 (br s, 1H), 4.52 (dd, J = 5.9, 4.8
13
Hz, 1H), 5.06 (s, 2H), 5.13 (s, 2H), 7.24ꢀ7.33 (m, 10H); C NMR (CDCl3, 100 MHz) δ
38.8, 66.8, 67.5, 67.6, 128.3, 128.4, 128.5, 128.6, 128.7, 135.2, 135.6, 170.3, 173.2.
HRMS (ESIꢀTOF) calcd for C18H19O5 (M+H)+ 315.1227, obsd 315.1220.
(b)
(S)-Benzyl 3,4-dihydroxybutanoate. Boraneꢀdimethylsulfide complex (175 ꢁL,
0.350 mmol, 2.0 M solution in THF, 1.1 equiv.) was added dropwise over 15 min to a
solution of (S)ꢀdibenzylꢀ2ꢀhydroxysuccinate (100 mg, 0.318 mmol, 1 equiv.) in dry THF
(1 mL) at 0 °C under N2. After 1 h of stirring, sodium borohydride (0.6 mg, 0.016 mmol,
0.05 equiv.) was added and the mixture was stirred overnight at rt. The mixture was
quenched by the addition of methanol (1.5 mL) and stirring continued for 30 min. The
solvent was evaporated and the residue purified by column chromatography on silica gel
(1:1 HexꢀEtOAc) to obtain diol 18 as a colorless oil (41 mg, 61%). Rf 0.31 (1:1 Hexꢀ
25
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EtOAc). [α]D +18.84 (c 1, CHCl3). H NMR (CDCl3, 400 MHz) δ 2.49 (dd, J = 16.3,
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4.3 Hz, 1H) 2.55 (dd, J = 16.3, 8.4 Hz, 1H), 3.35 (br s, 2H) 3.48 (dd, J = 11.4, 6.4 Hz,
1H) 3.62 (dd, J = 11.4, 3.5 Hz, 1H), 4.08ꢀ4.17 (m, 1H), 5.13 (s, 1H), 7.30ꢀ7.35 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ 37.8, 65.7, 66.7, 68.6, 128.3, 128.4, 128.6, 135.6, 172.3.
HRMS (ESIꢀTOF) calcd for C11H14NaO4 (M+Na)+ 233.0784, obsd 233.0793.
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(S)-Benzyl 3-[(tert-butyldimethylsilyl)oxy]-4-(tosyloxy)butanoate (19).
(a) (S)-Benzyl 3-hydroxy-4-(tosyloxy)butanoate. To a solution of diol 18 (200.0 mg,
n
0.95 mmol, 1.00 equiv.) in dry CH2Cl2 (2.5 mL) was added successively Bu2SnO (7.0
mg, 0.03 mmol, 0.03 equiv.), a solution of Et3N (135 ꢁL, 98.4 mg, 0.97 mmol, 1.02
equiv.) in dry CH2Cl2 (2.5 mL) and pꢀtoluenesulfonyl chloride (190.7 mg, 0.97 mmol,
1.02 equiv.) at rt. The mixture was stirred for 6 h, then treated with brine (10 mL) The
aqueous layer was extracted with CH2Cl2 (4 x 15 mL). The combined organic layers were
dried with anhydrous MgSO4, filtered and concentrated. The residue was purified by
silica gel column chromatography (2:1 HexꢀEtOAc) to obtained the tosylate (222 mg,
25
1
64%), Rf 0.43 (1:1 HexꢀEtOAc). [α]D +7.34 (c 1.5, CHCl3). H NMR (CDCl3, 400
MHz) δ 2.00 (bs, 1H), 2.45 (s, 3H), 2.53 (dd, J = 16.6, 4.8 Hz, 1H), 2.62 (dd, J = 16.7,
7.5 Hz, 1H), 4.04 (d, J = 8.3 Hz, 2H), 4.25ꢀ4.28 (m, 1 H), 5.14 (s, 2H), 7.26ꢀ7.39 (m,
7H), 7.78 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.7, 37.4, 66.0, 66.9, 71.9,
128.0, 128.2, 128.5, 128.7, 130.0, 132.5, 135.3, 145.2, 171.4. HRMS (ESIꢀTOF) calcd for
C18H21O6S (M+H)+ 365.1053, obsd 365.1043.
(b)
(S)-Benzyl 3-[(tert-butyldimethylsilyl)oxy]-4-(tosyloxy)butanoate (19).
2,6ꢀ
Lutidine (178 ꢁL, 163 mg, 1.5 mmol, 3.0 equiv.) was added dropwise to a solution of (S)ꢀ
benzyl 3ꢀhydroxyꢀ4ꢀ(tosyloxy)butanoate (185 mg, 0.5 mmol, 1.0 equiv.) in dry CH2Cl2
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(7.5 mL) under N2 at rt. The mixture was stirred for 30 min before the dropwise addition
of TBDMSOTf (140 ꢁL, 161 mg, 0.6 mmol, 1.2 equiv.). The mixture was stirred
overnight, the solvent evaporated and the residue purified by silica gel chromatography,
eluting with 2:1→1:1 (HexꢀEtOAc), to give the TBS ether 19 (206 mg, 85%); Rf 0.38
(1:1 HexꢀEtOAc). [α]D25 +8.01 (c 1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.02 (s, 3H),
0.03 (s, 3H), 0.81 (s, 9H), 2.45 (s, 3H), 2.49 (dd, J = 15.4, 6.9 Hz, 1H), 2.56 (dd, J = 15.4,
5.2 Hz, 1H), 3.93ꢀ4.00 (m, 2H), 4.3ꢀ4.35 (m, 1H), 5.06 (d, J = 12.3 Hz, 1H), 5.12 (d, J =
12.3 Hz, 1H), 7.32ꢀ7.38 (m, 5H), 7.77ꢀ7.79 (m, 4H), 13C NMR (CDCl3, 100 MHz) δ ꢀ5.1,
ꢀ4.7, 17.9, 21.6, 25.6, 39.5, 66.5, 67.2, 72.3, 128.0, 128.2, 128.3, 128.6, 129.9, 132.8,
135.6, 144.9, 170.3. HRMS (ESIꢀTOF) calcd for C24H35O6SSi (M+H)+ 479.1918, obsd
479.1925.
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(S)-Benzyl 3-[(tert-butyldimethylsilyl)oxy]-4-iodobutanoate (14). Sodium iodide (392
mg, 2.08 mmol, 8.0 equiv.) was added to a solution of (S)ꢀbenzyl 3ꢀ[(tertꢀ
butyldimethylsilyl)oxy]ꢀ4ꢀ(tosyloxy)butanoate (19) (125 mg, 0.26 mmol, 1.0 equiv.) in
acetone (5 mL). The mixture was stirred and heated at reflux overnight. Saturated
aqueous NaHCO3 (10 mL) was added and the mixture extracted with diethyl ether (5 x 15
mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4,
filtered and concentrated. Flash chromatography on silica gel (HexꢀEtOAc 5:1) afforded
14 as a brownish yellow oil (88 mg, 78%). Rf 0.58 (2:1 HexꢀEtOAc). [α]D25 +10.01 (c 1,
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.04 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 2.60 (dd,
J = 15.4, 7.1 Hz, 1H), 2.73 (dd, J = 15.4, 4.9 Hz, 1H), 3.21ꢀ3.30 (m, 2H), 4.05 (app. pent,
J = 5.5 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H), 7.25ꢀ7.35 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ ꢀ4.9, ꢀ4.5, 12.8, 17.9, 25.7, 42.6, 66.5, 68.4, 128.3, 128.4,
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128.6, 135.7, 170.7. HRMS (ESIꢀTOF) calcd for C17H28IO3Si (M+H)+ 435.0847, obsd
435.0831.
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Benzyl 2-(diethoxyphosphoryl)acetate (24). Triethylphosphonoacetate (500 ꢁL, 560
mg, 2.49 mmol, 1.00 equiv.) was dissolved in 1M NaOH (1 mL, 2.49 mmol, 1.00 equiv.)
and stirred at 60 °C overnight. The ethanol formed in reaction was evaporated and
aqueous layer was acidified to pH 2 with 10% KHSO4. The aqueous layer was extracted
with CH2Cl2 (4 x 15 mL) and dried over MgSO4, filtered and concentrated to give the
carboxylic acid (373 mg) which was dissolved in dry MeOH (5 mL). Cesium carbonate
(310 mg, 0.95 mmol, 0.5 equiv.) was added and the mixture stirred for 2 h under N2. The
mixture was concentrated, dissolved in DMF (5 mL) and cooled to 0 °C. Benzyl bromide
(274 ꢁL, 391 mg, 2.28 mmol, 1.2 equiv.) was added, the mixture warmed to rt, stirred
overnight, diluted with EtOAc (10 mL), washed with water (15 mL) and brine (15 mL).
The organic layer was dried over MgSO4, filtered and concentrated. Flash
chromatography on silica gel (EtOAcꢀHex 1:1→2:1) afforded 24 as a colorless oil (536
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mg, 75%). Rf 0.48 (EtOAcꢀHex 2:1). H NMR (CDCl3, 400 MHz) δ 1.29 (t, J = 7.1 Hz,
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6H), 2.99 (d, JHꢀP = 21.5 Hz, 2H), 4.09ꢀ4.16 (m, 4H), 5.18 (s, 2H), 7.30ꢀ7.40 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ 16.3 (3J = 16.3 Hz), 34.4 (1JCꢀP = 134.2 Hz), 62.7 (2J = 6.3
Hz), 67.3, 128.3, 128.4, 128.5, 135.4, 165.6. HRMS (ESI, ꢀve, TOF) calcd for C13H18O5P
(MꢀH)ꢀ 285.0897, obsd 285.0897.
(2E)-Benzyl 4,4-dimethoxybut-2-enoate (26). Cesium carbonate (2.20 g, 6.75 mmol,
1.5 equiv.) was added to a solution of benzyl 2ꢀ(diethoxyphosphoryl)acetate 24 (1.28 g,
4.5 mmol, 1.0 equiv.) in cyclohexane (20 mL). The suspension was heated to 65 °C and
then 2,2ꢀdimethoxyacetaldehyde 25 (15.6 mL of a 60 wt.% solution in H2O, 937 mg, 9.0
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mmol, 2.0 equiv.) was added. The biphasic mixture became clear pale yellow and stirred
for 2 h at 65 °C. Saturated aqueous NH4Cl (25 mL) was added and the mixture was
extracted with EtOAc (4 x 25 mL). The combined organic layers were washed with brine
(25 mL), dried over MgSO4, filtered and concentrated. Flash chromatography on silica
gel (HexꢀEtOAc 2:1) afforded the dimethyl acetal 26 as a colorless oil (947 mg, 89%). Rf
0.56 (1:1 HexꢀEtOAc). 1H NMR (CDCl3, 400 MHz) δ 3.32 (s, 6H), 4.94 (d, J = 3.0, 1H),
5.19 (s, 2H), 6.19 (d, J = 15.9 Hz, 1 H), 6.81 (dd, J = 15.8, 3.9 Hz, 1H), 7.30ꢀ7.37 (m,
5H); 13C NMR (CDCl3, 100 MHz) δ 52.8, 66.4, 100.5, 124.4, 128.2, 128.3, 128.6, 135.8,
143.2, 165.6. HRMS (ESIꢀTOF) calcd for C13H17O4 (M+H)+ 237.1160, obsd 237.1153.
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(E)-Benzyl 4-oxobut-2-enoate (21). A solution of 26 (150 mg, 0.635 mmol) in acetone
(30 mL) was treated with 2M HCl (0.3 mL) and stirred at rt for 2 d. The acetone was
evaporated and residue was treated with water (5 mL) and extracted with CHCl3 (3 x 15
mL). The combined organic layers were dried over MgSO4, filtered and concentrated.
Flash chromatography on silica gel (HexꢀEtOAc 2:1) afforded aldehyde 21 as a colorless
oil (90 mg, 75%). Rf 0.46 (1:1 HexꢀEtOAc). 1H NMR (CDCl3, 400 MHz) δ 5.26 (s, 2H),
6.74 (d, J = 15.9 Hz, 1H), 6.98 (dd, J = 15.9, 7.6 Hz, 1H), 7.32ꢀ7.39 (m, 5H), 9.72 (d, J =
7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 67.5, 128.5, 128.7, 135.0, 140.0, 140.6,
164.7, 192.43. HRMS (ESIꢀTOF) calcd for C11H11O3 (M+H)+ 191.0712, obsd 191.0719.
Benzyl (tert-butyldimethylsilyl)oxycarbamate (27). Triethylamine (249 ꢁL, 181 mg,
1.79 mmol, 1.2 equiv.) was added to a solution of benzylꢀNꢀhydroxycarbamate (250 mg,
1.49 mmol, 1 equiv.) in dry CH2Cl2 (5 mL) under N2. The mixture was cooled to 0 °C
and TBSCl (270 mg, 1.79 mmol, 1.2 equiv.) was added. The reaction mixture was
warmed to rt and stirred overnight. The mixture was washed with water (5 mL) and brine
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(5 mL) and the organic layer was dried over MgSO4, filtered and concentrated. Flash
chromatography on silica gel (HexꢀEtOAc 4:1→1:2) afforded 27 as a clear oil (321 mg,
77%). Rf 0.66 (2:1 HexꢀEtOAc). 1H NMR (CDCl3, 400 MHz) δ 0.15 (s, 6H), 0.94 (s, 9H),
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5.16 (s, 2H), 7.02 (s, 1H), 7.30ꢀ7.35 (m, 4H); C NMR (CDCl3, 100 MHz) δ ꢀ5.8, 18.0,
25.9, 67.6, 128.3, 128.4, 128.5, 135.7, 158.6. HRMS (ESIꢀTOF) calcd for C14H24NO3Si
(M+H)+ 282.1520, obsd 282.1516.
(S)-Benzyl
2-[(benzyloxycarbonyl)(tert-butyldimethylsilyloxy)]amino-4-oxo-
butanoate (30). A solution of benzyl (tertꢀbutyldimethylsilyl)oxycarbamate (27) (207.0
mg, 0.736 mmol, 1.4 equiv.) in chloroform (1 mL) was treated with (S)ꢀ2ꢀ
{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine (34.0 mg, 0.105 mmol, 0.2 equiv) and
acetic acid (9 ꢁL, 9.4 mg, 0.105 mmol, 0.2 equiv.) and stirred for 10 min at rt. Benzyl 4ꢀ
oxoꢀbutꢀ2ꢀenoate (21) (100.0 mg, 0.525 mmol, 1.0 equiv.) was added and the reaction
mixture was stirred for 3.5 h at rt, concentrated and residue subjected to silica gel
chromatography (HexꢀEtOAc 5:1) provided the aldehyde 30 as a colorless oil (239 mg,
69%). Rf 0.30 (2:1 HexꢀEtOAc). [α]D ꢀ13.5 (c 0.9, CHCl3). 1H NMR (CDCl3, 400
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MHz) δ 0.08 (s, 3H), 0.12 (s, 3H), 0.87 (s, 9H), 2.87 (dd, J = 17.7, 5.8 Hz, 1H), 3.26 (dd,
J = 17.7, 5.7 Hz, 1H), 5.07ꢀ5.18 (m, 5H), 7.26ꢀ7.40 (m, 10H), 9.81 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ ꢀ4.8, ꢀ4.7, 18.1, 25.8, 42.7, 60.1, 67.5, 68.6, 128.1, 128.3, 128.5,
128.5, 128.6, 135.3, 159.2, 169.1, 198.2. HRMS (ESIꢀTOF) calcd for C25H34NO6Si
(M+H)+ 472.215, obsd 472.2139.
(2S,4E)-1-Benzyl-2-[(benzyloxycarbonyl)(tert-butyldimethylsilyloxy)-amino]-6-
methyl-hex-4-enedioate (20) from 30. A solution of aldehyde 30 (137.0 mg, 0.290
mmol, 1.0 equiv.) in chloroform (2.5 mL) was treated with methyl
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(triphenylphosphorylidine)acetate (164.0 mg, 0.435 mmol, 1.5 equiv.) at 0 °C and
allowed to warm to rt. The reaction mixture was stirred for 1.5 h, concentrated to a
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viscous oil. Flash chromatography on silica gel (HexꢀEtOAc 5:1) afforded the α,βꢀ
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unsaturated ester as colorless oil 20 (140 mg, 91%). Rf 0.30 (2:1 HexꢀEtOAc); [α]D
ꢀ
1
41.2 (c 0.4, CHCl3). H NMR (CDCl3, 400 MHz) δ 0.07 (s, 3H), 0.09 (s, 3H), 0.85 (s,
9H), 2.78ꢀ2.93 (m, 2H), 3.73 (s, 3H), 4.64 (dd, J = 8.9, 6.1 Hz, 1H), 5.07 (d, J = 12.0 Hz,
1H), 5.10 (d, J = 12.2 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 5.16 (d, J = 12.0 Hz, 1H), 5.94
(d, J = 15.7 Hz, 1H), 6.97 (dt., J = 15.7, 7.0 Hz, 1H), 7.26ꢀ7.40 (m, 10H); 13C NMR
(CDCl3, 100 MHz) δ ꢀ4.8, ꢀ4.7, 18.1, 25.8, 31.1, 51.5, 64.2, 67.2, 68.5, 123.6, 128.2,
128.3, 128.4, 128.5, 128.5, 128.6, 135.2, 144.3, 159.2, 166.1, 168.8. HRMS (ESIꢀTOF)
calcd for C28H38NO7Si (M+H)+ 528.2412, obsd 528.2420.
(2S,4E)-1-Benzyl-2-[(benzyloxycarbonyl)(tert-butyldimethylsilyloxy)-amino]-6-
methyl-hex-4-enedioate (20) - one–pot procedure from 21. A solution of benzyl (tertꢀ
butyldimethylsilyl)oxycarbamate (305.00 mg, 1.05 mmol, 1.4 equiv.) in chloroform (1
mL) was treated with (S)ꢀ2ꢀ{diphenyl[(trimethylsilyl)ꢀoxy]methyl}pyrrolidine (50.35 mg,
0.15 mmol, 0.2 equiv), followed by the addition of acetic acid (10 ꢁL, 9.28 mg, 0.15
mmol, 0.2 equiv.) and stirred for 10 min at rt. Benzyl 4ꢀoxoꢀbutꢀ2ꢀenoate (21) (147.20
mg, 0.77 mmol, 1.0 equiv.) was added and the reaction mixture was stirred for 3.5 h at rt.
Upon completion (determined by TLC), methyl (triphenylphosphorylidine)acetate
(357.00 mg, 0.75 mmol, 1.5 equiv.) was added in one portion. The reaction mixture was
stirred for 2.5 h and then concentrated to afford a viscous oil. Flash chromatography on
silica gel (HexꢀEtOAc 5:1) afforded the α,βꢀunsaturated ester 20 as colorless oil (280
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mg, 71%). Rf 0.30 (2:1 HexꢀEtOAc). NMR data was identical to that obtained via the
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butyl-hex-4-enedioate (31).
A solution of benzyl (tertꢀbutylꢀdimethylsilyl)ꢀ
oxycarbamate (27) (250.0 mg, 0.88 mmol, 1.4 equiv.) in chloroform (1 mL) was treated
with (S)ꢀ2ꢀ{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine (41.0 mg, 0.12 mmol, 0.2
equiv), followed by the addition of acetic acid (7 ꢁL, 7.5 mg, 0.12 mmol, 0.2 equiv.) and
stirred for 10 min at rt. Benzyl 4ꢀoxoꢀbutꢀ2ꢀenoate (21) (121.0 mg, 0.63 mmol, 1.0
equiv.) was added and the reaction mixture was stirred for 3.5 h at rt. Upon completion
(determined by TLC), tertꢀbutylꢀ2ꢀ(triphenylphosphoranylidene)acetate (237.0 mg, 0.63
mmol, 1.0 equiv.) was added in one portion. The reaction mixture was stirred for 1.5 h
and then concentrated to a viscous oil. The triphenylphosphine oxide byproduct was
precipitated by the addition of Et2O. The solid was removed by filtration and the filtrate
concentrated. Flash chromatography on silica gel (HexꢀEtOAc 8:1→4:1) afforded the
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α,βꢀunsaturated ester 31 as colorless oil (354 mg, 70%). Rf 0.30 (2:1 HexꢀEtOAc). [α]D
ꢀ37.2 (c 0.5, CHCl3). The enantiomeric excess was determined on a Chiracel ODꢀH
column (4.6 x 25 cm), eluting with 95% hexane, 5% isopropanol, flow rate 0.5 mL minꢀ1
with detection at 218 nm. RT (major) 21 min (93.7%); RT (minor) 36 min (6.3%) for an
e.e. of 87.4%. 1H NMR (CDCl3, 400 MHz) δ 0.08 (s, 3H), 0.10 (s, 3H), 0.85 (s, 9H), 1.47
(s, 9H), 2.76ꢀ2.91 (m, 2H), 4.57 (dd, J = 8.7, 6.2 Hz, 1H), 5.06ꢀ5.18 (m, 4H), 5.84 (d, J =
15.6 Hz, 1H), 6.86 (dt, J = 7.0, 15.6 Hz, 1H), 7.26ꢀ7.36 (m, 10H); 13C NMR (CDCl3, 100
MHz) δ ꢀ4.8, ꢀ4.7, 18.1, 25.8, 28.1, 31.2, 64.5, 67.2, 68.4, 80.3, 125.8, 128.1, 128.2,
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128.4, 128.5, 128.5, 128.6, 135.3, 142.6, 159.1, 165.4, 168.9. HRMS (ESIꢀTOF) calcd for
C31H44NO7Si (M+H)+ 570.2412, obsd 570.2420.
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(3S,5R)-Benzyl-5-[(methoxycarbonyl)methyl]-3-benzyloxycarbonyl-isooxazolidine-2-
carboxylate (32a). To a solution of compound 20 (105 mg, 0.198 mmol, 1.0 equiv.) in
CHCl3 (1 mL) was added acetic acid (17 ꢁL, 17 mg, 0.297 mmol, 1.5 equiv.). The
mixture was cooled to 0 °C and TBAF (297 ꢁL, 1 M in THF with 5% H2O, 0.297 mmol,
1.5 equiv.) was added. The reaction was allowed to stir at 0 °C for 4 d. Reaction was
monitored by TLC and upon completion, the reaction mixture was concentrated and
applied directly to a flash column, eluting with 4:1→2:1 (HexꢀEtOAc), to obtain
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compound 32a (50 mg, 65%); Rf 0.23 (2:1 HexꢀEtOAc). [α]D25 ꢀ33.9 (c 0.5, CHCl3). H
NMR (CDCl3, 400 MHz) δ 2.23 (ddt, J = 12.8, 7.9, 4.8 Hz, 1H), 2.60 (dd, J = 16.4, 7.8
Hz, 1H), 2.83ꢀ2.93 (m, 2H), 3.68 (s, 3H), 4.35 (app. p, J = 7.1 Hz, 1H), 4.88 (dd, J = 9.5,
5.7 Hz, 1H), 5.19 (dd, J = 2.4 Hz, 2 H), 5.21 (s, 2H), 7.33ꢀ7.36 (m, 10H); 13C NMR
(CDCl3, 100 MHz) δ 36.9, 37.9, 52.0, 60.6, 67.4, 68.4, 128.1, 128.2, 128.4, 128.5, 128.5,
128.6, 135.2, 135.5, 156.9, 170.0. HRMS (ESIꢀTOF) calcd for C22H24NO7 (M+H)+
414.1547, obsd 414.1548.
(3S,5R)-Benzyl-5-[(tert-butoxycarbonyl)methyl]-3-benzyloxycarbonyl-
isooxazolidine-2-carboxylate (32b). To a solution of compound 31 (500.0 mg, 0.88
mmol, 1.0 equiv.) in CH2Cl2 (3 mL) was added acetic acid (0.078 mL, 78.9 mg, 1.32
mmol, 1.5 equiv.). The mixture was cooled to 0 °C and TBAF (1.3 mL, 1 M in THF, 1.32
mmol, 1.5 equiv.) was added and allowed to stir at 0 °C for 30 min. The reaction mixture
was warmed to rt and monitored by TLC. Upon completion (2.5 d) the mixture was
concentrated and applied directly to a flash column, eluting with 4:1 (HexꢀEtOAc), and
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then syn diatereomer was further purified by normal phase HPLC {(on a 25 x 10 mm
Altima 10 ꢀ silica column), with 5% EtOAc, 95% hexanes at 3 mL minꢀ1 and dual
wavelength detection at 218 and 254 nm} to obtain compound 32b (344 mg, 55%). Rf
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0.25 (2:1 HexꢀEtOAc). [α]D25 ꢀ23.25 (c 0.5, CHCl3). H NMR (CDCl3, 400 MHz) δ 1.42
(s, 9H), 2.20 (ddt, J = 12.7, 9.1, 5.9 Hz, 1 H), 2.48 (dd, J = 16.0, 8.0 Hz, 1H), 2.77ꢀ2.88
(m, 2H), 4.24ꢀ4.31 (m, 1H), 4.86 (dd, J = 9.6, 5.9 Hz, 1H), 5.16 (d, J = 4.9 Hz, 1 H), 5.18
(d, J = 2.0 Hz, 1 H), 5.19 (d, J = 1.0 Hz, 1 H), 5.22 (d, J = 4.0 Hz, 1 H), 7.26ꢀ7.37 (m,
10H); 13C NMR (CDCl3, 100 MHz) δ28.0, 38.0, 38.4, 60.6, 67.4, 68.4, 81.5, 128.2,
128.3, 128.4, 128.5, 128.6, 135.2, 135.5, 157.0, 168.8, 170.1. HRMS (ESIꢀTOF) calcd for
C25H30NO7 (M+H)+ 456.5547, obsd 456.5548.
2-(Allyloxycarbonylamino)adipic acid (34). Racemic αꢀaminoadipic acid (250 mg,
1.55 mmol, 1.0 equiv.) was added to a solution of sodium hydroxide (223 mg, 5.60
mmol, 3.6 equiv.) in water (12.5 mL) at 0 °C. Allyl chloroformate (247 ꢁL, 281 mg, 2.35
mmol, 1.5 equiv.) was added dropwise over 30 min and stirring continued for 4 h in an
ice bath. The mixture was washed with diethyl ether (20 mL). The aqueous layer was
acidified to pH 2 by the addition of conc. HCl and extracted with EtOAc (4 x 20 mL).
The combined extracts were dried over MgSO4, filtered and concentrated to give (±)ꢀNꢀ
allyloxycarbonylꢀ2ꢀaminoꢀadipic acid (34) (350 mg, 92%). Lꢀ2ꢀAminoadipic acid (100
mg) was subjected to the same procedure to give (L)ꢀNꢀallyloxycarbonylꢀ2ꢀaminoꢀadipic
acid (ꢀ)ꢀ34 (130 mg, 89%). [α]D25 ꢀ7.82 (c 1.0, MeOH). The following data was obtained
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for the racemic compound: Rf 0.29 (6:4:1 CHCl3ꢀMeOHꢀH2O). H NMR (CD3OD, 400
MHz) δ 1.67ꢀ1.74 (m, 3H), 1.87ꢀ190 (m, 1H), 2.33 (t, J = 6.8 Hz, 2H), 4.14 (dd, J = 8.0,
4.4 Hz, 1H), 4.54 (d, J = 5.3 Hz, 2H), 4.97 (br s, 1H), 5.18 (dd, J = 10.5, 1.4 Hz, 1H),
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5.31 (dd, J = 17.2, 1.5 Hz, 1H), 5.93 (ddt, J = 15.9, 10.6, 5.3 Hz, 1H); 13C NMR
(CD3OD, 100 MHz) δ 19.4, 29.1, 31.2, 52.0, 63.5, 114.5, 131.3, 155.6, 172.7, 174.0.
HRMS (ESIꢀTOF) calcd for C10H15NNaO6 (M+Na)+ 268.0792, obsd 268.0786.
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(±)-2-(Allyloxycarbonylamino)-6-methyl-1-(2-trimethylsilylethoxy-methyl)-adipate
(35) and other products. Cesium carbonate (173 mg, 0.53 mmol, 0.5 equiv.) was added
to a solution of (±)ꢀ2ꢀ(allyloxycarbonylamino)adipic acid (34) (261 mg, 1.10 mmol, 1.0
equiv.) in dry MeOH (3 mL). The mixture was stirred for 2.5 h under N2 at rt. The
mixture was concentrated, the residue dissolved in DMF (3 mL) and cooled to 0 °C. 2ꢀ
(Trimethylsilyl)ethoxymethyl chloride (226 ꢁL, 213 mg, 1.30 mmol, 1.2 equiv.) was
added, the mixture warmed to rt, stirred overnight and partitioned between brine (20 mL)
and EtOAc (25 mL). The brine was further extracted with EtOAc (3 x 25 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated to give a
colorless oil that was dissolved in acetonitrile (2.5 mL) and methanol (250 ꢁL).
Trimethylsilyldiazomethane (900 ꢁL, 2 M solution in Et2O, 1.80 mmol, 1.6 equiv.) esd
added dropwise and the mixture stirred for 2.45 h at rt under N2. The mixture was
concentrated, applied to a flash column and eluted with 3:1 hexanesꢀEtOAc to give diꢀ
SEM ester (36) (Rf 0.62, 2:1 hexanesꢀEtOAc) (19 mg, 3.5%), mixed ester 35 (Rf 0.49, 2:1
hexanesꢀEtOAc) (99 mg, 25%) and dimethyl ester 37 (Rf 0.33, 2:1 hexanesꢀEtOAc) (116
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mg, 40%), Data for (±)ꢀ35: H NMR (CDCl3, 400 MHz) δ 0.01 (s, 9H) 0.95 (app.t, J =
8.4 Hz, 2H), 1.68ꢀ1.73 (m, 3H), 1.87ꢀ1.92 (m, 1H), 2.31ꢀ2.38 (m, 2H), 3.65 (s, 3H), 3.66ꢀ
3.73 (m, 2H), 4.35ꢀ4.38 (m, 1H), 4.56 (d, J = 5.4 Hz, 2H), 5.20 (dd, J = 10.4, 1.3 Hz,
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2H), 5.26ꢀ5.36 (m, 3H), 5.90 (ddt, J = 16.1, 10.6, 5.4 Hz, 1H); C NMR (CDCl3, 100
MHz) δ ꢀ1.5, 18.0, 20.6, 31.8, 33.3, 51.6, 53.6, 65.8, 68.2, 89.9, 117.8, 132.6, 155.8,
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171.9, 173.3. HRMS (ESIꢀTOF) calcd for C17H31NNaO7Si (M+Na)+ 412.1762, obsd
412.1748.
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(±)-2-(Allyloxycarbonylamino)-6-methyl-1-(2-oxopropyl)-adipate (38).
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(a)
2ꢀ(Allyloxycarbonylamino)-1-(2-oxopropyl)-adipic acid. Cesium carbonate (166
mg, 0.51 mmol, 0.5 equiv.) was added to a solution of (±)ꢀ2ꢀ(allyloxycarbonylamino)ꢀ
adipic acid (34) (250 mg, 1.02 mmol, 1.0 equiv.) in dry MeOH (1 mL). The mixture was
stirred for 2 h under N2 at rt. The mixture was concentrated, dissolved in DMF (2 mL)
and cooled to 0 °C. Chloroacetone (97 ꢁL, 113 mg, 1.22 mmol, 1.2 equiv.) was added,
the mixture warmed to rt, stirred overnight, diluted with H2O (15 mL) and extracted with
EtOAc (3 x 25 mL). The combined organic layers were dried over MgSO4, filtered and
concentrated to give a colorless oil (300 mg).
(b) 2-(Allyloxycarbonylamino)-6-methyl-1-(2-oxopropyl)-adipate (38). The oil was
dissolved in acetonitrile (3 mL) and methanol (300 ꢁL). Trimethylsilyldiazomethane
(498 ꢁL, 2 M solution in Et2O, 0.99 mmol, 1.1 equiv.) added dropwise and the mixture
stirred for 2.5 h at rt under N2. The mixture was concentrated and applied to a flash
column. Elution with a gradient of 3:1→1:1 (HexꢀEtOAc) gave compound 38 as a
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colorless oil (64 mg, 20%). Rf 0.40 (2:1 EtOAcꢀHex). H NMR (CDCl3, 400 MHz) δ
1.73ꢀ1.82 (m, 3H), 1.97ꢀ2.02 (m, 1H), 2.15 (s, 3H), 2.37 (t, J = 6.4 Hz, 2H), 3.66 (s, 3H),
4.42ꢀ4.46 (m, 1H), 4.56 (d, J = 5.5 Hz, 2H), 4.63 (d, J = 16.8 Hz, 1H), 4.88 (d, J = 16.8
Hz, 1H), 5.21 (dd, J = 10.4, 1.3 Hz, 2H), 5.28ꢀ5.35 (m, 2H), 5.90 (ddt, J = 16.1, 10.5, 5.5
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Hz, 1H); C NMR (CDCl3, 100 MHz) δ 20.5, 26.0, 31.7, 33.3, 51.6, 53.5, 65.9, 68.7,
117.9, 132.5, 155.8, 171.7, 173.5, 200.6. HRMS (ESIꢀTOF) calcd for C14H21NNaO7
(M+Na)+ 338.1216, obsd 338.1220.
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(±)-2-(Allyloxycarbonylamino)-6-(tert-butyl)-1-(2-oxopropyl)-adipate (41).
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(±)-2-(Allyloxycarbonylamino)-1-(2-oxopropyl)-adipate. Cesium carbonate (332
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mg, 1.02 mmol, 0.5 equiv.) was added to a solution of (±)ꢀ2ꢀ(allyloxycarbonylamino)ꢀ
adipic acid 34 (500 mg, 2.04 mmol, 1.0 equiv.) in dry MeOH (4 mL). The mixture was
stirred for 2 h under N2 at rt. The mixture was concentrated, dissolved in DMF (5 mL)
and cooled to 0 °C. Chloroacetone (194 ꢁL, 226 mg, 2.44 mmol, 1.2 equiv.) was added,
the mixture warmed to rt, stirred overnight, diluted with H2O (30 mL) and extracted with
EtOAc (3 x 40 mL). The combined organic layers were dried over MgSO4, filtered and
and concentrated to give a colorless oil (500 mg).
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(b)
(±)-2-(Allyloxycarbonylamino)-6-(tert-butyl)-1-(2-oxopropyl)-adipate (41). The
oil was dissolved in CH2Cl2 (10 mL) and added to condensed isobutylene (10 mL) and pꢀ
TsOH (663 mg, 3.49 mmol, 2.1 equiv.). The flask was stoppered and the mixture stirred
at rt for 3 d, diluted with CH2Cl2 (20 mL), washed with sat’d aq. NaHCO3 (25 mL). The
aqueous layer was further extracted with CH2Cl2 (2 x 30 mL) and the combined organic
layers dried over MgSO4, filtered, concentrated and applied to a flash column, eluting
with a gradient of 3:1→1:1 (HexꢀEtOAc) gave compound 41 as a colorless oil (198 mg,
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34%). Rf 0.32 (2:1 EtOAcꢀHex). H NMR (CDCl3, 400 MHz) δ 1.41 (s, 9H), 1.64ꢀ1.79
(m, 2H), 1.91ꢀ2.02 (m, 2H), 2.14 (s, 3H) 2.25 (t, J = 6.9 Hz, 2H), 4.42 (dd, J = 12.4, 7.4
Hz, 1H), 4.55 (d, J = 5.4 Hz, 2H), 4.62 (d, J = 16.8 Hz, 1H), 4.75 (d, J = 16.8 Hz, 1H),
5.19 (dd, J = 10.4, 1.2 Hz, 1H), 5.26ꢀ5.39 (m, 1H), 5.89 (ddt, J = 16.2, 10.6, 5.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 20.7, 26.0, 28.1, 31.6, 34.7, 53.4, 65.9, 68.7, 80.4, 117.8,
132.6, 155.8, 171.8, 172.4. HRMS (ESIꢀTOF) calcd for C17H28NO7 (M+H)+ 358.1820,
obsd 358.1826.
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(L)ꢀNꢀallyloxycarbonylꢀ2ꢀaminoꢀadipic acid (50 mg) was subjected to the same
procedures to give (ꢀ)ꢀ41 (20 mg, 30% over 2 steps). [α]D25 ꢀ7.75 (c 1.0, MeOH).
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2-(Allyloxycarbonylamino)-1-(2-oxopropyl)-adipic acid (40). To a solution of diester
41 (25 mg, 0.069 mmol, 1.0 equiv.) in dry CH2Cl2 (2 mL) was added trifluoroacetic acid
(2 mL) at 0 °C and allowed to stir at 0 °C for 1 hr. The reaction mixture was warmed to rt
and stirred overnight, concentrated and applied to a flash column. Elution with a gradient
of 3:1→4:1 (EtOAcꢀHex) gave compound 40 (15 mg, 65 %). Rf 0.23 (3:1 EtOAcꢀHex).
1H NMR (CDCl3, 400 MHz) δ 1.20ꢀ1.29 (m, 2H), 1.78ꢀ1.84 (m, 2H), 2.17 (s, 3H), 2.43
(t, J = 7.1 Hz, 2H), 4.43ꢀ4.50 (m, 1H), 4.58 (d, J = 5.0 Hz, 2H), 4.65 (d, J = 16.8 Hz, 1H),
4.80 ( d, J = 16.8 Hz, 1H), 5.22 (dd, J = 10.4, 1.1 Hz, 1H), 5.29 (d, J = 2.6 Hz, 1H), 5.34
(s, 1H), 5.91 (ddt, J = 16.2, 10.7, 5.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.4, 26.0,
31.7, 32.9, 53.4, 66.0, 68.7, 118.0, 132.5, 155.9, 171.6, 176.6. HRMS (ESIꢀTOF) calcd
for C13H19NNaO7 (M+Na)+ 324.1054, obsd 324.1054.
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2-(Allyloxycarbonylamino)-6-(tert-butyl)adipate (42). TBAF (111 ꢁL, 1 M in THF,
0.112 mmol, 2.0 equiv.) was added to a solution of compound 41 (20 mg, 0.056 mmol,
1.0 equiv.) in dry THF (1 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, warmed
to rt and stirred overnight. The mixture was concentrated and applied to a flash column,
eluting with a gradient of 3:1→4:1 (EtOAcꢀHex) to give compound 42 (11 mg, 68 %). Rf
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0.25 (2:1 EtOAcꢀHex). H NMR (CDCl3, 400 MHz) δ 1.41 (s, 9H), 1.64ꢀ1.79 (m, 2H),
1.91ꢀ2.02 (m, 2H), 2.25 (t, J = 6.9 Hz, 2H), 4.42 (dd, J = 12.4, 7.4 Hz, 1H), 4.55 (d, J =
5.4 Hz, 2H), 5.19 (dd, J = 10.4, 1.2 Hz, 1H), 5.26ꢀ5.39 (m, 1H), 5.89 (ddt, J = 16.2, 10.6,
5.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.7, 28.1, 31.6, 34.7, 53.4, 65.9, 80.4,
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117.8, 132.6, 155.8, 171.8, 172.4. HRMS (ESIꢀTOF) calcd for C14H23NNaO6 (M+Na)+
324.1424, obsd 324.1418.
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hydrofuran (44).
(a)
(2S,4R)-2-Amino-6-tert-butyl-4-hydroxy-adipic acid (33b). Compound 32b (100
mg, 0.219 mmol, 1.0 equiv.) was dissolved in dry MeOH (2 mL) and 10 % PdꢀC (93 mg,
0.879 mmol, 4.0 equiv.) was added. The suspension was stirred at rt overnight under an
atmosphere of H2. The reaction mixture was filtered through Celite® and the filtrate
concentrated to give the amino acid 33b as a colorless oil (40 mg). Rf 0.56 (6:4:1 CHCl3ꢀ
MeOHꢀH2O).
(b)
(2S,4R)-2-(Allyloxycarbonylamino)-6-tert-butyl-4-hydroxy-adipic acid (43). The
amino acid 33b was dissolved in a solution of sodium hydroxide (32 mg, 0.788 mmol,
3.6 equiv.) in water (2 mL) at 0 °C and followed by dropwise addition of allyl
chloroformate (28 ꢁL, 32 mg, 0.263 mmol, 1.2 equiv.) at 0 °C. The mixture was stirred
an additional 1 h at 0 °C and then warmed to RT and stirred overnight. The reaction
mixture was washed with diethyl ether (5 mL) to remove unreacted allylchloroformate.
The aqueous layer was cooled to 0 °C and then acidified to ~pH 4 by the dropwise
addition of 0.5 M HCl. The aqueous layer was extracted with EtOAc (5x10 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated to obtain
compound 43. Rf 0.54 (9:1 CH2Cl2ꢀMeOH).
(c)
(3S,5R)-3-(Allyloxycarbonylamino)-5-[(tert-butoxycarbonyl)methyl]-2-oxo-tetra-
hydrofuran (44). Cesium carbonate (36 mg, 0.109 mmol, 0.5 equiv.) was added to a
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solution of acid 43 in dry MeOH (4 mL). The mixture was stirred for 2 h under N2 at rt.
The mixture was concentrated, dissolved in DMF (5 mL) and cooled to 0 °C.
Chloroacetone (21 ꢁL, 24 mg, 0.263 mmol, 1.2 equiv.) was added, the mixture warmed
to rt, stirred overnight, diluted with H2O (5 mL) and extracted with EtOAc (3 x 5 mL).
The combined organic layers were dried over MgSO4, filtered and and concentrated to
give a colorless oil that was dissolved in CH2Cl2 (2 mL) and added 2,6ꢀlutidine (254 ꢁL,
235 mg, 2.190 mmol, 10.0 equiv.) and TBSOTf (402 ꢁL, 463 mg, 1.752 mmol, 8.0
equiv.). Reaction mixture was stirred and concentrated to remove the CH2Cl2. Water (2
mL) was added to the reaction mixture which was then cooled to 0 °C and acidified to
~pH 4 by the dropwise addition of 0.5 M HCl. The acidic solution was then extracted
with EtOAc (4 x 10 mL). The combined organic layers were dried over MgSO4, filtered
and then concentrated to afford a viscous oil. Flash chromatography on silica gel (Hexꢀ
EtOAc 3:1) afforded the lactone 44 as a colorless oil (57 mg, 45% over 4 steps). Rf 0.54
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(1:1 HexꢀEtOAc). [α]D ꢀ8.47 (c 2.5, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 1.45 (s,
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9H), 2.14ꢀ2.17 (m, 1H), 2.38ꢀ2.79 (m, 3H), 4.48 (dd, J = 16.1, 9.3 Hz, 1H), 4.58 (d, J =
5.3 Hz, 2H), 4.98 (dd, J = 16.1, 9.3 Hz, 1H), 5.22 (app. d, J = 10.4 Hz, 1H), 5.30 (app. d,
13
J = 16.4 Hz, 1H), 5.46 (d, J = 5.7 Hz, 1H), 5.90 (ddt, J = 16.4, 10.8, 5.6 Hz, 1H); C
NMR (CDCl3, 100 MHz) δ 28.0, 33.6, 40.6, 49.5, 66.2, 74.2, 81.9, 118.2, 132.3, 155.9,
168.5, 174.6. HRMS (ESIꢀTOF) calcd for C14H21NNaO6 (M+Na)+ 322.1261, obsd
322.1270.
(2S,4R)-2-(Allyloxycarbonylamino)-6-(tert-butyl)-4-(tert-butyldimethyl-silyloxy)-1-
(2-oxopropyl)-adipic acid (45).
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