The nonchiral bislactim diethoxy ether as a highly stereo-inducing synthon for sterically hindered, γ-branched α-amino acids: A practical, large-scale route to an intermediate of the novel renin inhibitor aliskiren

Article abstract of DOI:10.1002/hlca.200390235

The diastereoselective synthesis of the sterically hindered, γ-branched α-amino acid derivative (2S,4S)-24a and its N-[(tert-butoxy)carbonyl](Boc)-protected alcohol (2S,4S)-19, both key intermediates of a novel class of nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)-17 was obtained by alkylation of the chiral Schoellkopf dihydropyrazine (R)-12a with the dialkoxy-substituted alkyl bromide (R)-11a, which proceeded with explicitly high diastereofacial selectivity (ds > 98%) to give (2S,SR,2′S)-13a (Scheme 4), followed by mild acid hydrolysis and N-Boc protection (Scheme 5). Conversely, the complete lack of stereocontrol and poor yields for the reaction of (R)-11a with the enantiomeric (S)-12b suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion between the MeO-C(6) and the bulky residues of (R)-11a in the proposed transition state, which would strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)-11a was found to provide a 95:5 mixture of diastereoisomers (2S,2′S)-22a and (2R,2′S)-23a in high yield (Scheme 6), which afforded in two steps and after recrystallization enantiomerically pure (2S,4S)-24a. Similarly, the stereochemical course for the alkylation reactions of the related alkyl bromides (S)-28a and (R)-28b with both (R)-12a and (S)-12b as well as with the achiral 21 was investigated (Schemes 7-9). The precursor bromides (R)-11a, (S)-11b, (R)-28a, and (S)-28b were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones (R)-7a and (S)-7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard transformations (Schemes 3 and 7). A practical and economical protocol of the preparation of (2S,4S)-24a on a multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of 21, as a highly stereo-inducing synthon providing rapid access to a N-protected γ-branched α-amino acid with (2S) absolute configuration.

Full text of DOI:10.1002/hlca.200390235

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Helvetica Chimica Acta Vol. 86 (2003)
The Nonchiral Bislactim Diethoxy Ether as a Highly Stereo-Inducing Synthon
for Sterically Hindered, g-Branched a-Amino Acids: A Practical, Large-Scale
Route to an Intermediate of the Novel Renin Inhibitor Aliskiren
by Richard Gˆschke1), Stefan Stutz2), Walter Heinzelmann3) and J¸rgen Maibaum*
Novartis Pharma AG, Novartis Institutes for BioMedical Research, WKL-136.683, CH-4002 Basel
(e-mail: juergen_klaus.maibaum@pharma.novartis.com; tel.: ‡‡ 41616965560; fax: ‡‡ 41616961163)
The diastereoselective synthesis of the sterically hindered, g-branched a-amino acid derivative (2S,4S)-24a
and its N-[(tert-butoxy)carbonyl](Boc)-protected alcohol (2S,4S)-19, both key intermediates of a novel class of
nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)-17
was obtained by alkylation of the chiral Schˆllkopf dihydropyrazine (R)-12a with the dialkoxy-substituted alkyl
bromide (R)-11a, which proceeded with explicitly high diastereofacial selectivity (ds ꢀ 98%) to give
(2S,5R,2'S)-13a (Scheme 4), followed by mild acid hydrolysis and N-Boc protection (Scheme 5). Conversely, the
complete lack of stereocontrol and poor yields for the reaction of (R)-11a with the enantiomeric (S)-12b
suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion
between the MeOÀC(6) and the bulky residues of (R)-11a in the proposed transition state, which would
strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of
the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)-11a was found to provide a 95 :5 mixture of
diastereoisomers (2S,2'S)-22a and (2R,2'S)-23a in high yield (Scheme 6), which afforded in two steps and after
recrystallization enantiomerically pure (2S,4S)-24a. Similarly, the stereochemical course for the alkylation
reactions of the related alkyl bromides (S)-28a and (R)-28b with both (R)-12a and (S)-12b as well as with the
achiral 21 was investigated (Schemes 7 9). The precursor bromides (R)-11a, (S)-11b, (R)-28a, and (S)-28b
were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones
(R)-7a and (S)-7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard
transformations (Schemes 3 and 7). A practical and economical protocol of the preparation of (2S,4S)-24a on a
multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of
21, as a highly stereo-inducing synthon providing rapid access to a N-protected g-branched a-amino acid with
(2S) absolute configuration.
1. Introduction. Several classes of structurally novel hydroxyethylene dipeptide
isostere inhibitors of the aspartyl protease renin, including aliskiren (ˆ(aS,gS,dS,zS)-d-
amino-N-(3-amino-2,2-dimethyl-3-oxopropyl-g-hydroxy-4-methoxy-3-(3-methoxypro-
poxy)-a,z-bis(1-methylethyl)benzeneoctanamide; 1; Scheme 1), have emerged recent-
ly from a target-structure-based-design approach [1]. In vitro, these nonpeptide, small-
molecule inhibitors are highly potent and selective for human renin and are unique with
respect to their specific binding interactions with a nonsubstrate pocket of the enzyme.
Aliskiren (1) induced pronounced and long-lasting reduction in blood pressure after
oral administration in monkeys [2] and is currently under clinical investigation as a new
antihypertensive agent [3].
1
)
)
)
Current address: Felixh‰gli 21, CH-4103 Bottmingen.
Current address: Speedel Experimenta AG, Gewerbestrasse 14, CH-4123 Allschwil.
Current address: PrepLab, CentralTechnologies, Novartis Pharma AG, Basel.
2
3

Helvetica Chimica Acta Vol. 86 (2003)
2849
Scheme 1. retro-Synthesis of the Novel Renin Inhibitor Aliskiren (1)
The synthesis of 1 and related analogues initially relied on efficient stereoselective
access to the N-[(tert-butoxy)carbonyl](Boc)-protected a-amino ester (2S,4S)-17 as
the key intermediate bearing two highly substituted and bulky residues at the branched
g-position (Scheme 1) [2][4]4). Enantiomerically pure (2S,4S)-17 was envisaged to be
readily accessible from the chiral precursor electrophile (R)-11a by the bis-lactim ether
approach developed by Schˆllkopf and co-workers for the synthesis of unnatural a-
amino acids [5][6]. This methodology has been applied by us previously to generate a
variety of analogues of 1 for structureÀactivity-relationship studies [4].
We report herein a highly stereoselective route to (2S,4S)-17 by the preparation of
the fully substituted alkyl bromide (R)-11a from the Evans (4R)-benzyloxazolidinone
(R)-7a, followed by an efficient diastereofacial alkylation step using the chiral
Schˆllkopf auxiliary (R)-12a.
In the course of this work, we discovered an alternative and very practical protocol
for the preparation of crystalline N-Boc-protected (2S,4S)-24a, the ethyl ester analogue
of (2S,4S)-17. This procedure is based on the diastereoselective alkylation reaction of
bromide (R)-11a with the nonchiral 2,5-diethoxy-3,6-dihydropyrazine (21), a crystal-
line synthon readily accessible from cheap starting materials. The rationale for this
previously unprecedented stereo-induction by an achiral dihydropyrazine scaffold was
derived from the unexpected ratios of doubly −matched× and −mis-matched× alkylation
products formed between the sterically demanding electrophile and the chiral
Schˆllkopf auxiliaries (R)-12a and (S)-12b, repectively. The new route turned out to
be highly advantageous as compared to the classical bis-lactim ether approach for the
preparation of (2S,4S)-24a or (2R,4R)-24b and was amenable to up-scaling. The
application of this method to the synthesis of the related g-branched amino acid
(2S,4S)-31 is also described.
2. Results and Discussion. 2.1. Stereoselective Syntheses of Enantiomerically Pure
Alkyl Bromides (R)-11a and (S)-11b. The (R)-configured bromide (R)-11a required
for the synthesis of the targeted N-protected a-amino acid ester, as derived from the
retro-synthetic analysis (Scheme 1), was efficiently accessed by diastereoselective
alkylation of (4R)-3-isovaleroyl-4-benzyl-oxazolidin-2-one ((R)-7a) with the conven-
iently substituted 3,4-dialkoxybenzyl bromide 6 following the method by Evans and co-
workers [7] as the key reaction step (see below, Scheme 3). The intermediate benzyl
bromide 6 was obtained in a straightforward manner on a > 1m reaction scale from 3-
hydroxy-4-methoxybenzaldehyde (2) according to Scheme 2. The 3-methoxypropoxy
side chain was introduced in a two-step procedure, first by alkylation of the phenolic
4
)
For alternative synthesis approaches to aliskiren (1), see the review article by Mealy et al. [3].

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Helvetica Chimica Acta Vol. 86 (2003)
OH group with a large excess of dibromopropane5) in the presence of K2CO3 to give
bromo derivative 3 in high yield (93%). Subsequent replacement of the Br-atom with
NaOMe/MeOH was accompanied by elimination of HBr to give the corresponding 3-
(allyloxy) derivative as a major by-product. Under optimized reaction conditions
(dropwise addition of 30% NaOMe in MeOH at 61 648, followed by brief reflux), a
4 :1 ratio of the desired substitution vs. dehydrohalogenation products were obtained,
providing aldehyde 4 in 72% isolated yield after flash-chromatography (FC)
purification6). Subsequent reduction with NaBH4 to 5 followed by bromination with
Me3SiBr gave crystalline 67) in almost quantitative yield over two steps.
Scheme 2
a) Br(CH2)3Br, K2CO3, MeCN, 19 h reflux; 93%. b) 30% NaOMe soln., MeOH, heat; 72%. c) NaBH4, MeOH,
0
58 to r.t.; 96%. d) Me3SiBr, CHCl3, 20 258; quant.
The reaction of the lithium enolate, generated by deprotonation of the auxiliary
(R)-7a (1.2 equiv.) with LiHMDS (lithium salt of hexamethyldisilazane) at À 758 in
THF, with benzyl bromide 6 according to the method of Evans and co-workers [7] gave
a unique alkylation product (single spot on TLC (silica gel)) (Scheme 3). The 1H-NMR
spectrum, after FC purification, clearly indicated the presence of one major
diastereoisomer (2'R,4R)-8a, besides only trace signals within the detection limit,
which were tentatively assigned to the corresponding (2'S,4R)-isomer. Recrystalliza-
tion from Et2O/hexane eventually afforded the desired (2'R,4R)-8a in 86% yield8).
Removal of the chiral auxiliary was achieved by alkaline hydrolysis of (2'R,4R)-8a
under standard conditions with LiOH/H2O2 [7] to give the carboxylic acid (R)-9a
(95%) as a colorless oil, which could be crystallized from Et2O/hexane at À 2089). (R)-
9a was then smoothly reduced to alcohol (R)-10a with NaBH4 in presence of I2 in THF
[8], followed by bromination with N-bromosuccinimide (NBS) in CH2Cl2 to give solid
(R)-11a (87%, two steps). In a similar fashion, the stereoselective alkylation of (S)-7b
with 6 ( ! (2'S,4S)-8b), followed by straightforward transformation to the acid (S)-9b
and alcohol (S)-10b, without purification of any intermediates, and final NBS
bromination afforded the enantiomeric bromide (S)-11b (Scheme 3).
5
)
)
Excess (10 equiv.) dibromopropane was recovered by evaporation of the reaction mixture.
Alternatively, 4 was obtained from 2 by alkylation with MeO(CH2)3Br (commercially available from
Matrix Scientific (Columbia, SC, USA) and Karl Industries Inc. (Aurora, OH, USA) in presence of K2CO3.
Solid bromide 6 was found to rapidly decompose at the surface of metallic materials. Even short contact
with any metal equipment such as a spatula or metal stirrer should be avoided!
This highly stereoselective alkylation reaction was successfully scaled up to produce several 100-g
quantities of (2'R,4R)-8a without compromising the diastereoisomer purity.
On a larger reaction scale, the chiral Evans oxazolidinones were recovered almost quantitatively and in
optically pure form by extractive separation of (R)-9a or (S)-9b and subsequent recrystallization from
AcOEt/hexane.
6
7
8
9
)
)
)

Helvetica Chimica Acta Vol. 86 (2003)
2851
Scheme 3
a) 1m LiHMDS, THF, À 708 to r.t.; 86% (for (2'R,4R)-8a). b) LiOH, 30% H2O2 soln., THF/H2O 3 :1, 08 to r.t.;
95% ((R)-9a) and 91% ((S)-9b). c) NaBH4, I2, THF, 4 d at r.t.; 90% (for (R)-10a). d) NBS, CH2Cl2, 18h at r.t.;
97% (for (R)-11a).
The enantiomer excess (ee) of alcohols (R)-10a and (S)-10b was determined to be
¾
98.8 and 98.2%, respectively, by HPLC resolution on a Chiralpak AD chiral stationary
phase. Full separation of both enantiomers (R)-11a and (S)-11b was also achieved on
¾
Chiralpak AD under similar elution conditions; however, analysis of the ee for the
first eluting (R)-11a10) was less accurate due to peak tailing (ee > 97%). These results
confirm the very high diastereoisomer ratios of > 99 :1 obtained for the alkylation of
the Evans auxiliary leading to (2'R,4R)-8a and (2'S,4R)-8b, and a negligible
racemization during the alkaline hydrolysis step.
2.2. Stereoselective Alkylation Reactions with Schˆllkopf×s (2R)- and (2S)-2,5-
Dihydro-2-isopropyl-3,6-dimethoxypyrazine as Chiral Auxiliary Reagents. Following
the standard protocol of Schˆllkopf and co-workers [5][6], the enantiomerically pure
alkyl bromide (R)-11a (see Scheme 3) was treated with the lithium enolate of the chiral
dihydropyrazine auxiliary (R)-12a (generated by deprotonation with BuLi at À 758 in
THF) at À 208 for 18h to give the desired (2 S,5R,2'S)-13a besides a small amount of
(2R,5R,2'S)-14a (Scheme 4). Analysis of the crude product after aqueous workup by
TLC (silica gel) and reversed-phase HPLC indicated that (2S,5R,2'S)-13a was formed
with remarkably high diastereoselectivity11). Transformation of the crude material to
the mixture of diastereoisomers (2S,4S)-17 and (2R,4S)-18 (Scheme 5, vide infra)
eventually allowed to determine the exact ratio of (2S,5R,2'S)-13a and its minor C(2)
epimer (2R,5R,2'S)-14a to be > 98:2 by reversed-phase HPLC. Hence, alkylation of
the Schˆllkopf chiral auxiliary (R)-12 with the b-branched and bulky bromide (R)-11a
proceeded with exeptionally high diastereoselectivity. Purification by FC (silica gel)
10
)
)
Note the reverse elution sequence of the (S)- und (R)-enantiomers of alcohols 10 as compared to those of
bromides 11 (cf. Exper. Part).
11
A very faint TLC spot detected at Rf 0.23 (hexane/AcOEt 2:1; UV254) slightly below that of (2S,5R,2'S)-
13a, may have corresponded to the diastereoisomer (2R,5R,2'S)-14a. Reversed-phase HPLC (Nucleosil 5
C18) showed several very minor peaks (each with AUC ꢁ 2%) in addition to the major product peak. The
1H-NMR spectrum of the crude product did not provide clear evidence for the formation of the C(2)
epimer (2R,5R,2'S)-14a due to overlapping signals with (R)-12 (used in excess) and unreacted bromide
(R)-11a.

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Helvetica Chimica Acta Vol. 86 (2003)
eventually provided the diastereomerically pure (2S,5R,2'S)-13a, as demonstrated by
1H-NMR, in excellent 85% yield.
Scheme 4
a) Reagent (R)-12a or (S)-12b, 1 equiv. of BuLi, THF, À 758, 75 min; then bromide (R)-11a or (S)-11b
(0.67 equiv.) in THF, À 758 to À 208, 18 h.
Surprisingly, when bromide (R)-11a was treated under identical conditions with the
lithium enolate of (S)-12b of opposite absolute configuration, complete loss of
diastereoselectivity was observed, i.e., the two stereoisomers (2S,5S,2'S)-16b and
(2R,5S,2'S)-15b were formed as a 43 :57 mixture (separable on silica gel) and in only
moderate 54% isolated yield (Scheme 4). Variation of the reaction time and temper-
ature or addition of alkyl bromide (R)-11a in large excess did not improve the
diastereoselectivity or the overall conversion of reactants. The 1H-NMR spectra of both
FC-purified epimers provided evidence that both products (2S,5S,2'S)-16b and
(2R,5S,2'S)-15b differed in their relative configuration at the dihydropyrazine moiety
(2,5-cis vs. 2,5-trans, resp.) [9]. Conversely, the −doubly matched× diastereoisomeric
product (2R,5S,2'R)-13b (enantiomeric to (2S,5R,2'S)-13a) was obtained in high
diastereomer excess (de ꢀ 99%) from (S)-bromide (S)-11b and auxiliary (S)-12b,
whereas alkylation of (R)-12a with (S)-11b remained incomplete (overall 42% isolated
yield) even after prolonged reaction times, leading to a ca. 1:1 mixture of separable
diastereoisomers (2S,5R,2'R)-15a and (2R,5R,2'R)-16a in a −doubly mismatched×
fashion (Scheme 4; see also the Figure below and Sect. 2.6).
2.3. Transformation to the Diastereoisomeric N-Boc-Protected Amino Esters and
Their Amino Alcohols. Determination of the Absolute Configuration. Mild acidic
hydrolysis of the dihydropyrazine derivative (2S,5R,2'S)-13a and subsequent reaction
with dicarbonic acid di(tert butyl) ester (Boc2O) gave the crystalline N-Boc-protected
methyl ester (2S,4S)-17 (Scheme 5). Reduction of (2S,4S)-17 with LiBH4 in THF

Helvetica Chimica Acta Vol. 86 (2003)
2853
Figure. Proposed mechanism for the diastereoselective alkylation of (R)-12a (R ˆ iPr), (S)-12b (R ˆ iPr), and
21 (R ˆ H; both MeO replaced by EtO) with bromide (R)-11a (the two alkoxy groups of the benzyl moiety are
omitted)
Scheme 5
a) 1n HCl, MeCN, 30 min., r.t.; b) Boc2O, Et3N, CH2Cl2, 18h at r.t.; 74% (2 steps, for (2 S,4S)-17). c) LiBH4,
THF, 16 h, r.t. (95% for (2S,4S)-19).

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Helvetica Chimica Acta Vol. 86 (2003)
provided the crystalline amino alcohol (2S,4S)-19 as a white solid in good yield (82%)
on a multi-g scale.
Similarly, epimer (2R,5S,2'S)-15b was transformed by the two-step sequence to the
corresponding diastereoisomer (2R,4S)-18 (oil) and then to the amino alcohol (2R,4S)-
20, which, in contrast to its epimer (2S,4S)-19, could not be crystallized (Scheme 5). The
1H-NMR spectra (CDCl3) allowed us to clearly distinguish between the pairs of
diastereoisomers (2S,4S)-17 vs. (2R,4S)-18 and (2S,4S)-19 vs. (2R,4S)-20; for example,
(2S,4S)-19 showed a narrow m for both enantiotopic benzylic protons (d 2.48), whereas
(2R,4S)-20 revealed 2 dd (d 2.61 (J ˆ 5, 13 Hz) and 2.21 (J ˆ 8 , 13 Hz)). The
diastereoisomer excess of (2S,4S)-19 was determined to be ꢀ 99.9% by reversed-
phase HPLC (Nucleosil C18)12).
The alcohol (2S,4S)-19 served as a starting material for the synthesis of renin
inhibitor 1 and related analogues as part of our structure-activity relationship studies
[2]. In the course of this work, the X-ray crystal structure of a derivative of 1
unambiguously confirmed that alcohol (2S,4S)-19 and the stereogenic centers of its
precursor intermediates had the desired absolute configuration [10].
2.4. Nonchiral Dialkoxy-Dihydropyrazine as a Stereo-Inducing Template for
Enantioselective Alkylation Reactions. The remarkably high diastereoselectivity of
> 98:1 observed for the alkylation of the chiral bis-lactim ether ( R)-12a with bromide
(R)-11a (vice versa that of (S)-12b with (S)-11b) and, more intriguingly, the complete
lack of stereo-induction observed for the −doubly mismatched× reaction of (R)-12a with
the enantiomeric bromide (S)-11b (Scheme 4) could be rationalized by adapting the
simplified transition-state mechanism proposed previously (Fig.) [5][6]13). Accord-
ingly, the anticipated −matched× situation would involve the lithiated dihydropyrazine
anion, generated from (R)-12a, in a −folded× conformation with one diastereotopic side
being strongly shielded by the relatively large isopropyl group on the C(2) position
(Fig.,a; R ˆ iPr)14). The steric congestion on the bottom side favors the Si attack of the
electrophile (R)-11a from above the plane of the heterocyclic species leading to the
(S)-configuration at the newly formed stereocenter (C(2) in (2S,5R,2'S)-13a, see
Scheme 4). This transition-state model would also suggest that (R)-11a adopts a
preferred low-energy conformation, in which the bulky isopropyl residue at the
stereogenic center is anti-periplanar to the leaving Br-atom when approaching the
center of induction15). This conformation of the electrophile avoids also a steric clash
12
)
)
Compound (2R,4S)-20 showed a de of 70% due to incomplete separation of precursor (2S,5S,2'S)-16b from
(2R,5S,2'S)-15b.
13
The reacting species of nucleophilic lithium enolates derived from bis-lactim ethers is currently unknown.
The X-ray structure of a lithiated bis-lactim ether derived from cyclo-[Ala-Ala] has been resolved as a
dimeric aggregate in which the two Li-atoms are s-bonded to the negatively charged N-atoms and
coordinated to a total of three THF solvent molecules [11]. On the other hand, cryoscopic experiments
have demonstrated that this dimeric aggregate is in equilibrium with a monomeric species in solution at
very low temperatures [12].
14
15
)
)
A violation of the −Schˆllkopf rule× has been observed for the reaction of the lithiated bis-lactim ether
derived from (R)-2-methyl-3-phenylalanine and glycine with 2-haloethyl triflates, as well as for the
subsequent intramolecular ring closure, to give predominantly the cis addition products [13].
We assume an SN2-type mechanism for the displacement reaction. Force-field calculations revealed only
small energy differences of 1-2 kJ/mol for the anti-periplanar vs. both synclinal conformations, suggesting
that electrophile (R)-11a does not adopt a single predominant conformation in solution [14].

Helvetica Chimica Acta Vol. 86 (2003)
2855
between the substituted benzyl group (syn-clinal to the Br-atom) and the MeO group
within the folded plane of the nucleophile, thereby minimizing the overall steric
constraints with the lithium enolate nucleophile (−doubly matched×)16). In contrast,
attack of (R)-11a from the diastereotopic Re side would be even more disfavored
(−doubly mismatched×)16) due to the steric interference of the substituted benzyl group
with the MeO substituent at C(6) of the heterocycle, in addition to the diastereofacial
shielding effect by the iPr group at C(2) of the auxiliary (R)-12a (Fig.,b).
In line with the postulated mechanism, the reaction of auxiliary (S)-12b of opposite
chirality with (R)-11a would result in a −mismatched× situation for both putative
i
transition states, either due to the diastereofacial blockade by the Pr group at C(2)
(Fig.,d), or by considerable steric repulsion between the MeO group at C(6) of the
Schˆllkopf reagent and the bulky substituted benzyl residue of the electrophile (R)-11a
(Fig.,c). The lack of diastereoselectivity observed experimentally for the alkylation of
(S)-12b with (R)-11a giving a 43 :57 product mixture (Scheme 4), as well as the poor
chemical reactivity resulting in only low isolated yields, indicated that both
diastereotopic sides of the heterocyclic anion are markedly congested by steric
constraints. Thus, the alkoxy group at C(6) of the dihydropyrazine could, in principle,
have a major directing effect to a similar extent as the stereocontrol exerted by the
i
−shielding× Pr group at C(2)17). Most importantly, our hypothetical model suggested
that, for the reaction with sterically hindered chiral electrophiles, such as bromides (R)-
11a and (S)-11b, stereodifferentiation could be achieved essentially in the absence of
the alkyl group at C(2) of the chiral Schˆllkopf reagent, leading in the case of (R)-11a
to the desired absolute (S)-configuration at the newly formed stereocenter.
Intrigued by these considerations, we initiated some work to study the stereo-
chemical course of the alkylation reaction between the bromides (R)-11a and (S)-11b
i
and the nonchiral diethoxy-dihydropyrazine 21 lacking the Pr group at C(2) of the
reagents (R)-12a and (S)-12b. To the best of our knowledge, a detailed investigation of
the directing effect of the alkoxy residue neighboring the nucleophilic center of the bis-
lactim ether relative to the directing effect of the C(2) alkyl residue of the classical
Schˆllkopf reagent has not been reported previously.
2.5. Large-Scale Preparation of Bis-Lactim Diethyl Ether 21. A few general
considerations prompted us to select the known bis-lactim diethyl ether 21 (Scheme 6)
for our studies18). The compound is readily accessible from inexpensive starting
materials, in contrast to the corresponding dimethyl ether analogue [15]19). Further-
more, we anticipated a more-pronounced stereo-inducing effect due to the slightly
increased bulkiness of the EtO vs. the MeO group and, hence, an increased
16
)
Referred to as a −doubly matched× or −doubly mismatched× situation, both with respect to the nucleophile
as well as the electrophile, in contrast to the −mismatched× situation evolving either from steric hindrance
induced predominantly by the electrophile, as depicted in the Fig.,c, or by the nucleophile (Fig.,d).
The only moderate isolated yield for the alkylation products (2S,5S,2'S)-16b/(2R,5S,2'S)-15b also reflects
the overall steric constraints exerted by both reaction partners.
17
)
18
19
)
)
For alkylation of 21 with simple alkyl and allyl bromides, see [15] and [16].
Preparation of the dimethyl analogue by O-alkylation of the diketopiperazine with trimethyloxonium
tetrafluoroboate has been reported to proceed with only low yields (see [6], ref. 4 therein). Furthermore,
the commercially available −ethyl× Meerwein salt is less expensive than (Me3O)BF4, allowing economical
production of 21 on a multi-kg scale. For the preparation of the 2,5-bis-(benzyloxy)-3,6-dihydropyrazine,
see [17].

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 6
a) Reagent 21 (1.5 equiv.), 1.4 equiv. of BuLi, THF, À 758; then bromide (R)-11a or (S)-11b (1.0 equiv.) in
THF, À 408 to À 208, 18 h. b) 1n HCl, MeCN, 30 min at r.t. c) Boc2O, Et3N, CH2Cl2, 18h, r.t. (3 steps, 82% for
(2S,4S)-24a). d) LiBH4, THF, 16 h, r.t.; 95% (for (2S,4S)-19).
diastereoselectivity for the alkylation reaction with the enantiomeric bromides (R)-11a
and (S)-11b20).
The diethoxy-dihydropyrazine 21 was efficiently prepared by O-alkylation of
commercially available pyrazine-2,5-dione with 2.5 equiv. of triethyloxonium tetra-
fluoroborate in CH2Cl2 for 18h at room temperature, according to the protocol
described previously [15][16]. The product precipitated from CH2Cl2/hexane to furnish
white crystals in 76% yield on a 2.5-mol reaction scale.
2.6. Diastereoselective Alkylation of Nonchiral 2,5-Diethoxy-3,6-dihydropyrazine
21. The lithium enolate of 21 was smoothly generated by deprotonation with BuLi in
THF at À 758 for 20 min, and then treated in slight excess (1.5 equiv.) with (R)-11a for
1
18h at À 208. After standard aqueous workup, the H-NMR spectra indicated the
formation of two inseparable diastereoisomeric products, (2S,2'S)-22a and (2R,2'S)-23a
in a ca. 95 :5 ratio, which were isolated in excellent yield (Scheme 6). Conversely,
reaction of enantiomeric (S)-11b with 21 gave a 5 :95 ratio of diastereoisomers
(2S,2'R)-23b and (2R,2'R)-22b with almost quantitative conversion of the starting alkyl
bromide21).
The absolute configuration of the major diastereoisomer (2S,4S)-22a was confirmed
by transformation to its N-Boc-protected amino alcohol derivative (Scheme 6) and by
comparing the resulting product with the two diastereoisomeric amino alcohols
(2S,4S)-19 and (2R,4S)-20, which were obtained from the corresponding methyl
carboxylates (2S,4S)-17 and (2R,4S)-18, respectively (Scheme 5). Thus, crude (2S,2'S)-
22a/(2R,2'S)-23a was hydrolyzed with 1n HCl in MeCN followed by N-Boc protection
20
)
)
For the preference for chiral bis-lactim dimethyl ethers over their diethyl analogues as commercial
reagents, see [6], footnote 4 therein.
Condensation of achiral dihydropyrazine 21 (Scheme 6) with achiral aldehydes and ketones has been
reported to give a single (or a major) diastereoisomeric product of unknown configuration [16].
21

Helvetica Chimica Acta Vol. 86 (2003)
2857
to provide the amino ester (2S,4S)-24a in a 94.9 :5.1 mixture (by reversed-phase HPLC
on Nucleosil 5 C18) with its minor (2R,4S) epimer (Scheme 6). A single recrystalliza-
tion from hexane afforded diastereoisomerically pure (2S,4S)-24a with a de > 99%.
LiBH4 reduction then gave in 95% yield the N-Boc-protected amino alcohol (2S,4S)-19
as a crystalline solid, which was identical by 1H-NMR to the product obtained from the
methyl ester (2S,4S)-17 (vide supra). In a similar fashion, the 5 :95 mixture (2S,2'R)-
23b/(2R,2'R)-22b was hydrolyzed and N-Boc-protected to the enantiomeric (2R,4R)-
24b.
The high enantioface preference leading from (R)-11a and 21 to (2S,2'S)-22a as the
predominant isomer (and from (S)-11b to (2R,2'R)-22b, resp.) can be explained by a
transition state analogous to the one depicted in the Figure,a and b (for R ˆ H; MeO
replaced by EtO). In this model, a preferred conformation of the electrophile (R)-11a
would be involved in which the bulkiest group at the b-position, i.e., the iPr residue, is
anti-periplanar to the Br-atom and in which the substituted benzyl group is directed
towards the less-hindered side of the reactant in its folded conformation (Fig.,a). On
the other hand, the Re-facial attack of the electrophile (Fig.,b) would be much less
favored due to steric interference of the substituted benzyl residue with the EtO group
of the heterocyclic anion.
It should be emphasised that the remarkably high diastereoselectivity of 95 :5
obtained for the reaction of 21 with bromides (R)-11a and (S)-11b is at least equally
good as the stereoselectivity that is often achieved for the alkylation of chiral bis-lactim
ethers such as (R)-12a and (S)-12b with different electrophiles [6][18 20]. No
additional attempts were made at this point to further improve the diastereoselectivity
of the alkylation reaction of (R)-11a or (S)-11b with dihydropyrazine 21 as an achiral
a-amino acid synthon.
2.7. Upscaled Synthesis of N-Boc-Protected Amino Ester (2S,4S)-24a with Diethoxy-
dihydropyrazine 21 as a Nonchiral Auxiliary. The stereoselective alkylation of the
lithium enolate of 21 with (R)-11a (vide supra, Sect. 2.6) was readily amenable to a 1m
reaction scale with only minor modifications of the original reaction conditions. Thus,
deprotonation of 21 with BuLi and subsequent addition of bromide (R)-11a was
performed at a slightly higher temperature (À408 instead of À 758) without
compromising the ca. 95 :5 diastereoisomer product ratio of (2S,2'S)-22a vs. (2R,2'S)-
23a and the high overall isolated yield22). Mild acidic hydrolysis (1n HCl in MeCN) of
the crude product mixture afforded the a-amino ethyl ester derivative as an oily
residue. The glycine ethyl ester formed from an excess of synthon 21 was readily
removed by extractive workup due to the high water solubility of this by-product,
thereby avoiding any additional purification step23). Single recrystallization of the
crude N-Boc-protected amino ester (2S,4S)-24a from hexane completely removed the
minor (2R,4S)-diastereoisomer and provided (2S,4S)-24a with high diastereomer
excess (de > 99%) and in 82% overall yield from (R)-11a.
22
)
)
Notable amounts of the dialkylation by-products could not be detected in the crude product, indicating
that (2S,2'S)-22a and (2R,2'S)-23a are not susceptible to further alkylation via lithium enolate formation in
the reaction mixture.
This is in contrast to the hydrolysis of 13 16, requiring bulb-to-bulb distillation under high vacuum or a
tedious FC step to purify the a-amino ester products from the valine methyl ester.
23

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Helvetica Chimica Acta Vol. 86 (2003)
In summary, the new route for the preparation of the enantiomerically pure amino
acid derivative (2S,4S)-24a via the stereoselective alkylation of the achiral dihydropyr-
azine 21 proved to be readily amenable to a larger scale. Moreover, it turned out to be
superior to the classical chiral Schˆllkopf approach in terms of practical and
economical considerations.
2.8. Stereoselective Synthesis of Related g-Branched a-Amino Acids from Achiral
Bis-lactim Diethyl Ether 21. To further explore the potential scope of application for the
achiral synthon 21, we envisaged the synthesis of the g-branched N-Boc-protected a-
amino ester (2S,4S)-37a via enantioselective alkylation of the auxiliary with the
enantiomerically pure bromide (S)-28a (see below, Scheme 9). The O-benzyl-protected
(2S,4S)-37a, and its methyl ester analogue (2S,4S)-31 (see below, Scheme 8), were of
major interest to us as intermediates for the synthesis of a novel series of nonpeptide,
orally active renin inhibitors [21].
The precursor bromide (S)-28a was obtained with high enantiomer purity in four
steps as shown in Scheme 7. Thus, generation of the titanium enolate from (R)-7a by
treatment with TiCl4 in the presence of H¸nig×s base according to the protocol of Evans
and co-workers [22], and subsequent reaction with chloromethyl benzyl ether afforded
in a > 99 :1 diastereoisomer ratio the desired (4R,2'S)-25a and its more polar (TLC)
epimer (4R,2'R)-25b. Purification by silica-gel chromatography and recrystallization
from Et2O/hexane afforded (4R,2'S)-25a with a de > 99% (by reversed-phase HPLC)
and in 50% isolated yield. LiOH/H2O2-Mediated hydrolysis to the carboxylic acid (S)-
26a proceeded smoothly, which then was reduced by NaBH4/I2 to the alcohol (R)-27a in
83% yield (2 steps). Bromination with NBS gave (S)-28a as a colorless oil in 70% yield
(Scheme 7), which was found to be unstable on silica gel (as detected by TLC).
Similarly, the corresponding enantiomer (R)-28b was obtained in 43% overall yield
starting from the chiral auxiliary (S)-7b (not shown). The enantiomer excess of both
alcohol intermediates (R)-27a and (S)-27b was determined by HPLC on a Chiralcel
¾
OJ chiral stationary phase to be > 99.5% within the detection limits.
Scheme 7
a) TiCl4 (1.05 equiv.), H¸nig×s base (1.05 equiv.), CH2Cl2, 08; then BnOCH2Cl (2 equiv.), 08, 20 h; 50%. b)
LiOH, 30% aq. H2O2 soln., THF, 08 to r.t., 18h; 92%. c) NaBH4, I2, THF, 08 to r.t., 72 h; 90%. d) NBS, Ph3P,
CH2Cl2, 08 to r.t., 21 h; 70%.
Alkylation of the chiral Schˆllkopf reagent (R)-12a with bromide (S)-28a
proceeded with very high diastereoselectivity of > 97:3 to give (2S,5R,2'S)-29 as the
major product (Scheme 8). Only traces of the minor isomer (2R,5R,2'S)-30 were
detectable by TLC (more polar on silica gel) and were removed easily by FC to afford

Helvetica Chimica Acta Vol. 86 (2003)
2859
diastereoisomerically pure (2S,5R,2'S)-29 in 90% isolated yield. Standard hydrolysis of
the latter and subsequent N-Boc protection provided the a-amino acid derivative
(2S,4S)-31, which was demonstrated by high-resolution 1H-NMR to be a single
diastereoisomer (de > 99%).
Scheme 8
a) (2R)-12a (1.5 equiv.), BuLi (1.5 equiv.), THF, À 758; then (S)-28a or (R)-28b (1.0 equiv.) in THF, À 758 to
À 188, 64 h; 90% ((2S,5R,2'S)-29/(2R,5R,2'S)-30 and 93% (2S,5R,2'R)-32/(2R,5R,2'R)-33). b) 1n HCl, MeCN,
r.t. c) Boc2O, Et3N, CH2Cl2, r.t., 16 h, 72% ((2S,4S)-31; 2 steps) and 86% (2S,4R)-34).
Interestingly, poor 4 :1 diastereoselectivity was observed for the reaction of (R)-12a
with the bromide (R)-28b of opposite absolute configuration (Scheme 8). Separation
by silica-gel chromatography furnished the major (2S,5R,2'R)-32 and its epimer
(2R,5R,2'R)-33 in 93% overall yield. Transformation of (2S,5R,2'R)-32 to the protected
amino ester (2S,4R)-34, as described above for (2S,4S)-31, eventually afforded a single
diastereoisomeric product (by comparison of its 1H-NMR spectra with that of (2S,4S)-
31). The substantial formation of the −mismatched× alkylation product (2R,5R,2'R)-33
on reaction of the bis-lactim ether (R)-12a and bromide (R)-28b suggested again that
the MeO group at C(6) of the bis-lactim ether plays a role in the diastereofacial control
i
additionally to the −shielding× effect of the Pr group at C(2) (Fig.).
Reaction of bromide (S)-28a with the lithium enolate of the diethoxy-dihydropyr-
1
azine 21 under standard conditions afforded a ca. 2 :1 mixture (by H-NMR) of the
inseparable diastereoisomers (2S,2'S)-35 and (2R,2'S)-36 in 89% isolated yield
(Scheme 9). The absolute configuration of the predominant alkylation product
(2S,2'S)-35 was unambiguously assigned after transformation of (2S,2'S)-35/(2R,2'S)-
36 to the inseparable N-Boc-protected ethyl esters (2S,4S)-37a and (2R,4S)-37b and
1
comparison of the H-NMR spectrum with that of the corresponding methyl ester
analogues (2S,4S)-31 and (2S,4R)-34. In particular, the chemical shifts of the signals for
the NH and C6H5CH2O group of the major isomer (2S,4S)-37a were identical with that

2860
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 9
a) 21 (1.5 equiv.), BuLi (1.4 equiv.), THF, À 408; then (S)-28a (1.0 equiv.) in THF, À 408 to À 188, 16 h; 8 9%
((2S,2'S)-35/(2R,2'S)-36). b) 1n HCl, MeCN, r.t. c) Boc2O, Et3N, CH2Cl2, r.t., 16 h; 94% for (2S,4S)-37a/
(2R,4S)-37b (2 steps).
of (2S,4S)-31, and clearly differed from that of the isomer (2S,4R)-3424). Unfortunately,
compounds (2S,2'S)-35/(2R,2'S)-36 and (2S,4S)-37a/(2R,4S)-37b were obtained only as
oily products, which prohibited further purification by recrystallization.
The moderate diastereoselectivity obtained for the reaction of the benzyloxy
derivative (S)-28a with 21, forming the alkylation products (2S,2'S)-35 and (2R,2'S)-36
in only a 2 :1 ratio, could be simply explained by the lower steric demand of the
electrophile (S)-28a (cf. Fig.), as compared to (R)-11a, although other reasons, such as
electronic effects induced by the side-chain-ether O-atom in (S)-28a, cannot be
excluded.
3. Conclusions and Outlook. The explicitly high diastereoselectivity (ds > 98%)
observed for the −matched× alkylation reaction between the chiral Schˆllkopf
dihydropyrazine (R)-12a and the sterically hindered, enantiomerically pure bromide
(R)-11a, and, conversely, the complete lack of stereo-induction for the same reaction
between (S)-12b and (R)-11a (−mismatched×) strongly suggested that the MeO residue
at C(6) of the reagent exerted a strong diastereofacial control in addition to the
chirality of the auxiliary (Scheme4, Fig.). These considerations provided the rationale
that led us to investigate the stereochemical course for the alkylation of the achiral
auxiliary 21 with alkyl bromides (R)-11a and (S)-11b (Scheme 6), and in addition with
the related sterically less-demanding (S)-28a (Scheme 9). As demonstrated by the high
diastereoisomer ratio of 95 :5 for products (2S,2'S)-22a/(2R,2'S)-23a (vice versa, 5 :95
for the enantiomeric (2S,2'R)-23b/(2R,2'R)-22b), this previously unrecognized direct-
ing effect by the EtO group of 21 may become predominant even over the shielding
effect of the C(2) alkyl residue of the classical Schˆllkopf auxiliary (R)-12a.
No further efforts towards improvement of the alkylation diastereoselectivity by
optimizing the reaction parameters (e.g., variation of the base, solvent, temperature,
etc.) or by changing the leaving group of the electrophile were made at this stage of our
work. The effect of the leaving group on the diastereoselectivity for the alkylation of
the chiral Schˆllkopf auxiliary has been investigated recently by employing various
The absence of rotamer signals was established by temperature-dependent 1H-NMR measurements in
various solvents such as (D6)DMSO and (D6)benzene [9].
24
)

Helvetica Chimica Acta Vol. 86 (2003)
2861
achiral bromide, tosylate, and diphenyl phosphate electrophiles [18], demonstrating the
tosylate to be superior over the bromide with respect to diastereoselectivity and
isolated yield in almost all studied cases. On the other hand, the proper choice of the
dialkoxy substituents of modified dihydropyrazines may be beneficial to improve the
alkylation diastereoselectivity, e.g., by incorporating bulkier branched alkyl groups,
without compromising the overall reactivity of the synthon enolate with a sterically
demanding electrophile.
Furthermore, the achiral synthon 21 may find successful application for the
stereoselective synthesis of optically active unnatural amino acid derivatives by other
transformations, including the aldol reaction with chiral aldehydes, ketones, and
epoxides for the preparation of enantiomerically pure b-hydroxy amino acids
[20][23]25), asymmetric acylation of lithiated bis-lactim ethers [5], and conjugate
addition reactions [24]. In general, a more-detailed study of the structural requirements
which are essential to control the stereoselectivity of reactions with the achiral
dihydropyrazine synthon should confirm this methodology as a potentially versatile
principle in future work.
The highly stereoselective and efficient alkylation of the achiral bis-lactim ether 21
with the highly substituted, enantiomerically pure alkyl bromide (R)-11a, and
subsequent hydrolysis followed by N-Boc protection provided an economic and
practical protocol for the preparation on a multi-100-g scale of the a-amino acid
derivative (2S,4S)-24a, a synthetic intermediate of a novel class of orally active renin
inhibitors such as aliskiren (1), which is currently under clinical investigation.
The authors thank Tammo Winkler for NMR measurements, Paul Richert (Separations Group, Novartis
Central Technologies) for his assistance in the chiral HPLC analyses of enantiomeric intermediates, and
¬
Vincenzo Tschinke for the force field calculations. We also acknowledge Oliver Simic for helpful comments.
Experimental Part
General. All commercial chemicals were reagent grade and used without further purification, if not
otherwise stated. Low-temp. reactions were carried out under Ar. THF was distilled over potassium/
benzophenone. TLC: precoated silica gel 60 F254 glass plates (E. Merck); visualization: UV (254 nm), I2
chamber, or CPS staining (reagent: soln. of phosphomolybdic acid hydrate (25 g), cerium(IV) sulfate (10 g),
and conc. H2SO4 soln. (60 ml) in H2O (1 l). Flash chromatography (FC): silica gel 60 (0.04 0.063 mm; E.
¾
Merck). Reversed-phase HPLC: Kontron-Instruments 322 system with autosampler 465; C18-Nucleosil (5 mm)
column (l ˆ 25 cm; d ˆ 0.46 cm); gradient MeCN/H2O/CF3COOH 20 :80 :0.1 ! 100 :0 :0.1 within 20 min; if not
stated otherwise; tR in min. M.p.: uncorrected; B¸chi 510. [a]d : Perkin-Elmer 291 polarimeter; l ˆ 10 cm, c in g/
100 ml; at 228 or 258. IR Spectra: Perkin-Elmer-983 spectrometer. 1H-NMR Spectra: Varian Gemini-200
(200 MHz) or Gemini-300 (300 MHz) spectrometer; if not otherwise stated, all spectra in CDCl3; d in ppm rel.
to nondeuterated solvent CHCl3 (ˆ 7.27 ppm), J in Hz. 13C-NMR Spectra: Bruker AM-360 spectrometer
(90 MHz); d in ppm rel. to CHCl3 (ˆ 77.0 ppm); 13C multiplicities from DEPT spectra. Fast atom bombardment
(FAB) MS: ZAB-HF mass spectrometer with thioglycerol as matrix; only selected peaks are indicated, in m/z
(%). Elemental analysis: Perkin-Elmer PE-240; measured values are within Æ 0.4% of the calculated values for
C, H, and N.
4-Methoxy-3-(3-methoxypropoxy)benzaldehyde (4). To a mixture of 3-hydroxy-4-methoxybenzaldehyde
(2; 200 g, 1.32 mol) and MeCN were added K2CO3 (272.3 g, 1.973 mol) and 1,3-dibromopropane (1.34 l,
13.2 mol). The resulting mixture was refluxed for 19 h. After cooling, the solid was filtered followed by
evaporation of the solvent and excess 1,3-dibromopropane. The residue was purified by FC (silica gel, AcOEt/
hexane 1 :3): 334 g (93%) of 3-(3-bromopropoxy)-4-methoxybenzaldehyde (3). Solid. M.p. 61 628. TLC
25
)
For aldol-type reactions with zinc or tin(II) aza-enolates of chiral dihydropyrazines, see [23b].

2862
Helvetica Chimica Acta Vol. 86 (2003)
(hexane/AcOEt 3 :1): Rf 0.50. IR (CH2Cl2): 3051w, 2842w, 1687s, 1596m, 1586m, 1510s, 1435m, 1395m, 1135s,
1
1022m. H-NMR ((D6)DMSO): 9.85 (s, 1 H); 7.60 (dd, J ˆ 2, 8, 1 H); 7.44 (d, J ˆ 2, 1 H); 7.21 (d, J ˆ 8 , 1 H);
4.15 (t, J ˆ 7, 2 H); 3.90 (s, 3 H); 3.70 (t, J ˆ 7, 2 H); 2.30 (m, 2 H). Anal. calc. for C11H13BrO3 (273.13): C 48.37,
H 4.80, Br 29.26; found: C 48.61, H 4.84, Br 29.19.
To a soln. of 3 (844 g, 3.09 mol) in MeOH (4.15 l) was added dropwise 30% NaOMe soln. in MeOH (0.86 l,
4.64 mol) at 61 648. After stirring an additional 1.5 h at reflux temp., the mixture was cooled to r.t., and H2O
(180 ml) was added. Subsequently, MeOH (ca. 3 l) was partially removed in vacuo (at 358), and the residue was
partitioned between Et2O (3 Â 3 l) and ice-cooled 4n HCl. The org. phases were washed with H2O and sat. aq.
NaHCO3 soln., combined, dried (MgSO4), and evaporated. The residue was purified by FC (silica gel, hexane/
AcOEt 3 :1): 498g (72%) of pure 4. Oil. TLC (hexane/AcOEt 2 :1): Rf 0.18. IR (CH2Cl2): 3020 2840w, 1686s,
1
1596m, 1586m, 1510s, 1441m, 1135s, 1021m. H-NMR ((D6)DMSO): 9.85 (s, 1 H); 7.57 (dd, J ˆ 8 , 2, 1 H); 7.40
(d, J ˆ 2, 1 H); 7.18( d, J ˆ 8, 1 H); 4.08 (t, J ˆ 7, 2 H); 3.88 (s, 3 H); 3.49 (t, J ˆ 7, 2 H); 3.26 (s, 3 H); 1.95
(m, 2 H).
4-Methoxy-3-(3-methoxypropoxy)benzenemethanol (5). To a soln. of 4 (336 g, 1.50 mol) in MeOH (3.36 l)
at 08 was added in portions NaBH4 (39.7 g, 1.05 mol) while the temp. was maintained at 0 58. The mixture was
stirred for 60 min at r.t. and then evaporated. The residue was partitioned between ice-cooled 2n HCl and
AcOEt (3 Â 2 l). The org. layers were washed with H2O and sat. aq. NaHCO3 soln., combined, dried (MgSO4),
and evaporated. FC (CH2Cl2/MeOH 96 :4) afforded pure 5 (326 g, 96%). Oil. TLC (AcOEt/hexane 2 :1): Rf
0.31. IR (CH2Cl2): 3602w, 3046w, 2935 2880m, 1605w, 1592w, 1515s, 1464m, 1442m, 1426m, 1235m, 1138s,
1
1026m. H-NMR: 6.8 6.95 ( m, 3 H); 4.58( d, J ˆ 5.4, 2 H); 4.11 (t, J ˆ 6.5, 2 H); 3.84 (s, 3 H); 3.56 (t, J ˆ 6.5,
2 H); 2.33 (s, 3 H); 2.11 (m, 2 H); 1.95 (t, J ˆ 5.4, 1 H). Anal. calc. for C12H18O4 (226.27): C 63.70, H 8.02; found:
C 63.70, H 8.24.
4-Methoxy-3-(3-methoxypropoxy)benzyl Bromide (ˆ4-(Bromomethyl)-1-methoxy-3-(3-methoxypropoxy)-
benzene; 6). To a soln. of 5 (111 g, 0.50 mol) in CHCl3 (1.3 l) was added dropwise (5 min) Me3SiBr (97 ml,
0.75 mol) at 20 258 (ice-bath cooling). After stirring for additional 10 min at r.t., the mixture was evaporated
and the residue immediately purified by FC (hexane/AcOEt 3 :1): 144.5 g (quant.) of pure 626). White solid.
M.p. 50 518 (from hexane). TLC (hexane/AcOEt 2 :1): Rf 0.34. IR (CH2Cl2): 2935 2835w, 1604w, 1590w,
1517s, 1464m, 1442m, 1426m, 1240m, 1211s, 1141s, 1025m. 1H-NMR: 6.93 (m, 2 H); 6.80 (d, J ˆ 8, 1 H); 4.48
(s, 2 H); 4.12 (t, J ˆ 7, 2 H); 3.85 (s, 3 H); 3.56 (t, J ˆ 7, 2 H); 3.35 (s, 3 H); 2.10 (m, 2 H). Anal. calc. for
C12H17BrO3 (289.17): C 49.84, H 5.93, Br 27.63; found: C 50.27, H 6.11, Br 27.04.
(2R)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoic Acid (ˆ(aR)-4-Methoxy-3-(3-meth-
oxypropoxy)-a-(1-methylethyl)benzenepropanoic Acid; (R)-9a). To a stirred soln. of 1m LiHMDS in anh. THF
(600 ml, 0.60 mol) at À 708 was added dropwise a soln. of (R)-7a [7] (156.6 g, 0.60 mol) in THF (500 ml). The
mixture was stirred for an additional 75 min at À 708. Then, a soln. of 6 (145 g, 0.50 mol) in THF (500 ml) was
added, and the temp. was raised from À 708 to 08 during 2 h. After stirring for 18h at 0 8, the reaction was
quenched by addition of 10% aq. NH4Cl soln. (250 ml). Volatiles were removed in vacuo, and the product was
extracted with AcOEt (3 Â 1.2 l). The org. layers were washed with brine (1.2 l), dried (MgSO4), and
evaporated. FC (hexane/AcOEt 1:1) and recrystallization gave (4R)-3-{(2R)-2-{[4-methoxy-3-(methoxypro-
poxy)phenyl]methyl}-3-methyl-1-oxobutyl}-4-(phenylmethyl)oxazolidin-2-one ((2'R,4R)-8a; 202 g, 86%). Solid.
M.p. 55 568 (from Et2O/hexane). TLC (hexane/AcOEt 2 :1): Rf 0.29. IR (CH2Cl2): 2960 2840w, 1777s, 1694m,
1605w, 1590w, 1515m, 1442w, 1387m, 1349w, 1234m. 1H-NMR: 7.21 (m, 3 H); 6.75 6.95 (m, 5 H); 4.58( m, 1 H);
4.27 (m, 1 H); 4.07 (t, J ˆ 7, 2 H); 3.9 4.05 (m, 2 H); 3.78( s, 3 H); 3.51 (t, J ˆ 7, 2 H); 3.30 (s, 3 H); 2.75 3.0
(m, 3 H); 2.15 2.25 (dd, J ˆ 14, 11, 1 H); 2.07 (t, J ˆ 6.5, 2 H); 1.95 2.05 (m, 1 H); 1.05 (m, 6 H). Anal. calc. for
C27H35NO6 (469.58): C 69.06, H 7.51, N 2.98; found: C 68.64, H 7.66, N 3.04.
To a soln. of (2'R,4R)-8a (300 g, 0.639 mol) in THF/H2O 3 :1 (4.8l), cooled in an ice bath, were added 30%
aq. H2O2 soln. (434 ml, 3.83 mol) and LiOH (31.2 g, 1.28 mol). The mixture was stirred at 208 for 3 h, followed
by cooling to 08. Then, 1.5m aq. Na2SO3 (2.55 l, 3.83 mol) was added dropwise within 30 min (CAUTION: check
for complete removal of residual peroxides before concentrating the mixture!). After addition of sat. aq. NaHCO3
soln. (1 l), volatiles were evaporated, and the aq. phase was washed with CH2Cl2 (3 Â 3 l). The aq. layer was
adjusted to pH 3 by adding 2n HCl, followed by CH2Cl2 extraction (3 Â 3 l). The org. phase was dried (MgSO4)
and evaporated: (R)-9a (187 g, 94%). Oil; a fraction of this material crystallized from Et2O/hexane at À 208.
25
D
M.p. 43.5 448. TLC (AcOEt/hexane 2 :1): Rf 0.30. ‰aŠ ‡ 42.1 (c ˆ 1, CH2Cl2). IR (CH2Cl2): 3300 3000 (br.),
2962m, 2935m, 2880m, 1740m, 1705s, 1608w, 1590w, 1515s, 1235s, 1140s, 1027m. 1H-NMR: 6.65 6.80 (m, 3 H);
26
)
For the instability of compound 6 on metal surfaces, see Footnote 7.

Helvetica Chimica Acta Vol. 86 (2003)
2863
4.10 (t, J ˆ 7, 2 H); 3.82 (s, 3 H); 3.56 (t, J ˆ 7, 2 H); 3.35 (s, 3 H); 2.78( m, 2 H); 2.40 2.50 (m, 1 H); 2.07
(m, 2 H); 1.85 2.0 (m, 1 H); 1.03 (m, 6 H). Anal. calc. for C17H26O5 (310.39): C 65.78, H 8.44; found: C 65.96, H
8.70.
(2S)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoic Acid ((S)-9b). As described for (R)-
9a, with 1m LiHMDS in THF (72 ml, 72.0 mmol), (S)-7b (18.8 g, 72.0 mmol), and 6 (17.3 g, 60.0 mmol).
Quenching with sat. aq. NH4Cl soln. and extractive workup gave pure (2'S,4S)-8b as a yellow oil (33 g, crude),
which was used in the next step without further purification. TLC (hexane/AcOEt 2 :1): Rf 0.28. 1H-NMR: 7.1
7.2 ( m, 3 H); 6.65 6.90 (m, 5 H); 4.65 (m, 1 H); 4.26 (m, 1 H); 3.95 (t, J ˆ 7, 2 H); 3.95 4.15 (m, 2 H); 3.68
(s, 3 H); 3.41 (t, J ˆ 7, 2 H); 3.19 (s, 3 H); 2.45 2.85 (m, 4 H); 1.8 2.0 ( m, 3 H); 0.98( m, 6 H).
Crude (2'S,4S)-8b (33.0 g) was hydrolyzed as described for (R)-9a: crude (S)-9b (17.0 g, 91%). Pale yellow
1
oil. H-NMR: identical to that of (R)-9a.
(2R)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl Bromide (ˆ4-[(2R)-2-(Bromomethyl)-
3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; (R)-11a). A soln. of (R)-9a (186 g, 0.60 mol) in THF
(0.50 l) was added to a suspension of NaBH4 (27.2 g, 0.72 mol) in THF (1.50 l) at r.t. over 10 min. The mixture
was stirred until gas evolution ceased (45 min). A soln. of I2 (76.2 g, 0.30 mol) in THF (1.0 l) was added slowly,
and the mixture was then stirred for 4 days at r.t. MeOH (1.0 l) was added carefully over 20 min, followed by
stirring for 30 min and evaporation of volatiles. The residue was extracted with AcOEt (3 Â 2 l). The org. layers
were washed with 2n HCl (2 l), H2O (2 l), sat. aq. Na2S2O3 soln. (2 l), H2O (2 l), 0.1n NaOH (1 l), and brine and
evaporated. The crude product was purified by FC (silica gel, AcOEt/hexane 1:1): 160 g (90%) of (aR)-4-
methoxy-3-(3-methoxypropoxy)-a-(1-methylethyl)benzenepropanol (R)-10a. Oil. TLC (AcOEt/hexane 1:1): Rf
0.27; IR (CH2Cl2): 3618w, 2959m, 2930m, 2870m, 1589w, 1514s, 1465m, 1442m, 1422m, 1234m, 1140m, 1030m. 1H
NMR: 6.70 6.8( m, 3 H); 4.10 (t, J ˆ 7, 2 H); 3.85 (s, 3 H); 3.70 (m, 4 H); 3.35 (s, 3 H); 2.65 (dd, J ˆ 13, 4, 1 H);
2.45 (dd, J ˆ 13, 8, 1 H); 2.10 (m, 2 H); 1.8 6 (m, 1 H); 1.62 (m, 1 H); 1.15 (t, J ˆ 7, 1 H); 0.96 (m, 6 H). Anal.
calc. for C17H28O4 (296.41): C 68.89, H 9.52; found: C 68.34, H 9.49.
To a soln. of (R)-10a (102.2 g, 0.345 mol) in CH2Cl2 (2 l) at 08, Ph3P (108.6 g, 0.414 mol) and NBS (73.7 g,
0.414 mol) were added in portions. After stirring for 18h at r.t., the mixture was evaporated and the residue
purified by FC (silica gel, hexane/AcOEt 4 :1): 120.2 g (97%) of 11a. White solid. M.p. 52 538 (from Et2O/
hexane). TLC (AcOEt/hexane 1:1): Rf 0.56. IR (CH2Cl2): 2960m, 2935m, 2878m, 1589w, 1514s, 1465m, 1442m,
1236m, 1140m, 1119m, 1028m. 1H NMR (CDCl3): 6.7 6.85 (m, 3 H); 4.10 (t, J ˆ 7, 2 H); 3.84 (s, 3 H); 3.58
(t, J ˆ 7, 2 H); 3.26 3.45 (m, 2 H); 3.35 (s, 3 H); 2.77 (dd, J ˆ 15, 3, 1 H); 2.48( dd, J ˆ 15, 8, 1 H); 2.10 (m, 2 H);
1.86 (m, 1 H); 1.60 (m, 1 H); 1.00 (m, 6 H). Anal. calc. for C17H27BrO3 (359.30): C 56.83, H 7.57, Br 22.24; found:
C 56.81, H 7.34, Br 22.06.
(2S)-2-[4-Methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl Bromide ((S)-11b). As described for (R)-
11a, with crude (S)-9b (16.5 g, 53.2 mmol), THF (220 ml), NaBH4 (2.41 g, 63.8mmol), and I 2 (6.75 g,
26.6 mmol): (S)-10b (15.5 g, 100%). Pale yellow oil. TLC (AcOEt/hexane 1:1): Rf 0.27.
Crude (S)-10b (14.8g, 50.0 mmol) was treated without further purification with NBS (10.7 g, 60 mmol),
CH2Cl2 (290 ml), and Ph3P (15.7 g, 60.0 mmol): (S)-11b (16.6 g, 100%). Colorless oil, which solidified on
storage. 1H-NMR ((D6)DMSO): 6.87 (d, J ˆ 11, 1 H); 6.78( d, J ˆ 1.5, 1 H); 6.70 (q, J ˆ 11, 1.5, 1 H); 3.98( t, J ˆ
7.5, 2 H); 3.73 (s, 3 H); 3.44 3.48( m, 3 H; t at 3.46, J ˆ 7.5); 3.34 (dd, J ˆ 13, 7, 1 H); 3.23 (s, 3 H); 2.71 (dd, J ˆ
17, 7.5, 1 H); 2.38( dd, J ˆ 17, 9.5, 1 H); 1.93 (m, 2 H); 1.76 (m, 1 H); 1.71 (m, 1 H); 0.94 (t, J ˆ 7.5, 6 H).
Enantiomer-Excess (ee) Determination by Chiral HPLC. Complete enantiomer separation of the alcohol
intermediates (R)-10a and (S)-10b, as well as of the bromides (R)-11a and (S)-11b, was achieved by HPLC
¾
(Chiralpak AD column (25 cm  4.6 mm), flow rate 1.0 ml/min, 30 bar pressure, UV detection at 230 nm).
Eluent hexane/iPrOH 95 :5: tR 17.8for ( S)-10b and tR 19.4 for (R)-10a. Eluent hexane/iPrOH 98:2: tR 7.6 for
(R)-11a and tR 8.4 for (S)-11b. The ee of (R)-10a and (S)-10b, prepared as described above, was determined by
HPLC analyses to be 98.8 and 98.2%, resp. A similar ee (> 97%) was determined for (R)-11a.
(2S,5R)-2,5-Dihydro-3,6-dimethoxy-2-{(2S)-2-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-meth-
ylbutyl}-5-(1-methylethyl)pyrazine ((2S,5R,2'S)-13a). To a soln. of (2R)-2,5-dihydro-3,6-dimethoxy-2-(1-meth-
ylethyl)pyrazine ((R)-12a; 51.3 g, 0.279 mol) in THF (0.5 l) at À 758 was added dropwise 1.6m BuLi in hexane
(174 ml, 0.279 mol) during 45 min. After additional stirring for 30 min at À 758, a soln. of (R)-11a (66.8g,
0.186 mol) in THF (0.3 l) was added dropwise over 30 min. The mixture was stirred for 2 h at À 758 and then for
18h at À 208. After evaporation, the residue was partitioned between AcOEt (3 Â 1 l) and H2O (3 Â 1 l). The
org. layers were washed with brine (1 l), combined, dried (MgSO4), and evaporated. The residue was dried
under high vacuum (508/0.02 bar) to remove excess (R)-12 and purified by FC (AcOEt/hexane 1 :5): crude
(2S,5R,2'S)-13a (78.0 g, 91%). Reversed-phase HPLC: only traces of (2R,5R,2'S)-14a present in the crude
1
product. Oil. TLC (hexane/AcOEt 2 :1): Rf 0.34. H-NMR: 6.65 6.80 (m, 3 H); 4.10 (t, J ˆ 7, 2 H); 3.90 4.0

2864
Helvetica Chimica Acta Vol. 86 (2003)
(m, 2 H); 3.83 (s, 3 H); 3.69 (s, 6 H); 3.57 (t, J ˆ 7, 2 H); 3.35 (s, 3 H); 2.70 (dd, J ˆ 4, 13.5, 1 H); 2.42 (dd, J ˆ 7.5,
13.5, 1 H); 2.28( m, 1 H); 2.10 (m, 2 H); 1.8 5 (m, 1 H); 1.45 1.70 (m, 3 H); 1.04 (d, J ˆ 7, 3 H); 0.80 (m, 6 H);
‡
0.65 (d, J ˆ 7, 3 H). FAB-MS: 463 (100, [M ‡ H] ), 419 (60), 209 (35), 183 (60), 141 (85).
(2S,5S)- and (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-{(2S)-2-{[4-methoxy-3-(3-methoxypropoxy)phenyl]-
methyl}-3-methylbutyl}-5-(1-methylethyl)pyrazine ((2S,5S,2'S)-16b and (2R,5S,2'S)-15b, resp.). As described
for (2S,5R,2'S)-13a, with (S)-12b (2.4 g, 13.3 mmol), THF (20 ml), 1.6m BuLi in hexane (8.2 ml, 13.3 mmol),
(R)-11a (3.2 g, 9.9 mmol), and THF (20 ml); at À 758 for 2 h and at À 208 for 48h: (2 S,5S,2'S)-16b/(2R,5S,2'S)-
15b 43 :57 as a yellow oil (5.9 g) containing unreacted starting materials. Separation of both diastereoisomers
was achieved by FC (hexane/AcOEt 5 :1) of the crude product and repeated chromatography of enriched
fractions.
Data of (2S,5S,2'S)-16b: Pale yellow oil (1.05 g, 26%). TLC (hexane/AcOEt 4 :1): Rf 0.18. 1H-NMR: 6.7
6.8( m, 3 H); 4.09 (t, J ˆ 6.5, 2 H); 3.9 4.0 (m, 2 H); 3.83 (s, 3 H); 3.66 (s, 3 H); 3.65 (s, 3 H); 3.56 (t, J ˆ 6.5,
2 H); 3.48( s, 3 H); 2.69 (dd, J ˆ 4.5, 14, 1 H); 2.46 (dd, J ˆ 7.5, 14, 1 H); 2.0 2.15 (m, 4 H); 1.65 1.75 (m, 2 H);
1.36 (m, 1 H); 1.03 (d, J ˆ 7, 3 H); 0.81 (d, J ˆ 7, 3 H); 0.80 (d, J ˆ 7, 3 H); 0.73 (d, J ˆ 7, 3 H ) . 13C-NMR (CDCl3):
164.4; 162.5; 148.0; 147.3; 134.4; 121.1; 114.4; 111.6; 69.2 (CH2); 65.8(CH 2); 60.8; 58;3; 55.8; 53.5; 51.9; 51.8;
41.3; 36.6 (CH2); 35.8(CH 2); 31.3; 29.4 (CH2); 28.1; 19.9 (Me); 19.2 (Me); 17.4 (Me); 16.9 (Me). FAB-MS: 463
‡
(100, [M ‡ H] ), 419 (70), 209 (45), 183 (50), 141 (85).
Data of (2R,5S,2'S)-15b: Pale yellow oil (1.13 g, 28%; containing 10 15% of (2S,5S,2'S)-16b by 1H-NMR).
TLC (hexane/AcOEt 4 :1): Rf 0.13. 1H-NMR: 6.65 6.8( m, 3 H); 4.06 (t, J ˆ 6.5, 2 H); 4.02 (m, 1 H); 3.69
(m, 1 H); 3.84 (s, 3 H); 3.65 (s, 3 H); 3.62 (s, 3 H); 3.58( t, J ˆ 6.5, 2 H); 3.35 (s, 3 H); 2.51 (dd, J ˆ 4, 14, 1 H);
2.36 (dd, J ˆ 7.5, 14, 1 H); 2.27 (m, 1 H); 2.10 (m, 2 H); 1.75 1.9 (m, 3 H); 1.35 (m, 1 H); 1.03 (d, J ˆ 7, 3 H ) ;
0.91 (d, J ˆ 7, 3 H); 0.86 (d, J ˆ 7, 3 H); 0.68( d, J ˆ 7, 3 H ) . 13C-NMR (CDCl3): 164.4; 163.0; 148.2; 147.5; 134.8;
121.3; 114.4; 111.9; 69.4 (CH2); 66.1 (CH2); 60.5; 58.6; 56.2; 54.3; 52.2 (2C); 41.6; 36.6 (CH2); 34.8(CH 2); 31.5;
‡
29.7 (CH2); 27.8; 19.1 (Me); 16.6 (2 Me); 16.2 (Me). FAB-MS: 463 (90, [M ‡ H] ), 419 (100), 209 (45), 183
(35), 141 (95).
(2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-{(2R)-2-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-meth-
ylbutyl}-5-(1-methylethyl)pyrazine ((2R,5S,2'R)-13b). As described for (2S,5R,2'S)-13a, with (S)-12b (553 mg,
3.0 mmol), THF (10 ml), 1.6m BuLi in hexane (1.88 ml, 3.0 mmol), (S)-11b (719 mg, 2.0 mmol), and THF
(6 ml); at À 758 for 2 h and at À 208 for 16 h. FC (silica gel (20 g), hexane/AcOEt 2 :1) afforded pure
1
(2R,5S,2'R)-13b (630 mg, 68%). Pale yellow oil. TLC (hexane/AcOEt 2 :1): Rf 0.71. H-NMR ((D6)DMSO):
6.6 6.9 (m, 3 H); 3.9 4.0 (m, 4 H); 3.71 (s, 3 H); 3.64 (s, 3 H); 3.60 (s, 3 H); 3.46 (t, J ˆ 7, 2 H); 3.24 (s, 3 H);
2.60 (dd, J ˆ 4.5, 15, 1 H); 2.38( dd, J ˆ 8, 15, 1 H); 2.20 (m, 1 H); 3.92 (m, 2 H); 1.55 1.8( m, 3 H); 1.46
(m, 1 H); 1.00 (d, J ˆ 7, 3 H); 0.78( d, J ˆ 7, 3 H); 0.74 (d, J ˆ 7, 3 H); 0.60 (d, J ˆ 7, 3 H ) .
(2S,5R)- and (2R,5R)-2,5-Dihydro-3,6-dimethyl-2-{(2R)-2-{[4-methoxy-3-(3-methoxypropoxy)phenyl]-
methyl}-3-methylbutyl}-5-(1-methylethyl)pyrazine ((2S,5R,2'R)-15a and (2R,5R,2'R)-16a, resp.). As described
for (2S,5R,2'S)-13a; with (R)-12a (8.29 g, 45 mmol), THF (70 ml), 1.6m BuLi in hexane (28.1 ml, 45 mmol), (S)-
11b (10.8g, 30 mmol), and THF (70 ml); at À 758 for 2 h and at À 208 for 16 h. FC (0.5 kg, CH2Cl2/Et2O 20 :1)
afforded (2S,5R,2'R)-15a (2.72 g, 20%) and (2R,5R,2'R)-16a (3.07 g, 22%). Pale yellow oils. 1H-NMR: identical
to those of the corresponding enantiomers (2R,5S,2'S)-15b and (2S,5S,2'S)-16b, resp.
Compounds (2R,5R,2'R)-16a and (2S,5R,2'R)-15a were derivatized to the N-Boc-protected amino alcohols
25
D
(2R,4R)-19 (white crystals; ‰aŠ ˆ À5.1 (c ˆ 1, CHCl3)) and (2S,4R)-20 (colorless oil), as described below for
(2S,4S)-19 and (2R,4S)-20.
Methyl (2S,4S)-2-{[(tert-Butoxy)carbonyl]amino}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methyl-
hexanoate (ˆ Methyl (aS,gS)-a-{[(1,1-Dimethylethoxy)carbonyl]amino}-4-methoxy-3-(3-methoxypropoxy)-g-
(1-methylethyl)benzenepentanoate; (2S,4S)-17). To a stirred soln. of (2S,5R,2'S)-13a (77.5 g, 0.167 mol) in
MeCN (0.67 l) at r.t. was added 1n HCl (0.67 l, 0.670 mol), and stirring was continued for 1.5 h. The mixture was
poured into ice-cooled sat. aq. NaHCO3 soln. and extracted with CH2Cl2 (3 Â 1 l). Evaporation of the org. phase
gave 82 g of a pale yellow oil. The valine methyl ester by-product was removed by evaporation under high
vacuum (508/0.02 bar). FC (CH2Cl2/MeOH/conc. NH3 soln. 950 :50 :1) of the oily residue gave methyl (2S,4S)-2-
amino-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate (55.5 g, 90%). Oil. TLC (CH2Cl2/
MeOH/conc. NH3 soln. 700 :50 :1): Rf 0.41. 1H-NMR: 6.65 6.80 (m, 3 H); 4.10 (t, J ˆ 7, 2 H); 3.83 (s, 3 H);
3.67 (s, 3 H); 3.57 (t, J ˆ 7, 2 H); 3.34 (s, 3 H); 3.32 (m, 1 H); 2.50 (m, 2 H); 2.10 (m, 2 H); 1.75 (m, 2 H); 1.2
1.65 (m, 4 H); 0.86 (m, 6 H).
To a stirred soln. of this material (55.0 g, 0.149 mol) in CH2Cl2 (450 ml) at 08 were added Et3N (35.6 ml,
0.208mol) and Boc 2O (42.3 g, 0.194 mol) in CH2Cl2 (100 ml). The mixture was stirred for 20 h at r.t.
Evaporation and FC (CH2Cl2 ! CH2Cl2/Et2O 8:2) afforded, after recrystallization, pure (2 S,4S)-17 (57.0 g,

Helvetica Chimica Acta Vol. 86 (2003)
2865
22
D
82%). White solid. TLC (AcOEt/hexane 1:1): Rf 0.45. M.p. 70 718 (from Et2O/hexane). ‰aŠ ˆ ‡8.3 (c ˆ 1,
CHCl3). IR (CH2Cl2): 3433w, 2957m, 2940m, 2880m, 1741s, 1712s, 1589w, 1514s, 1367m, 1235m, 1162s, 1140m,
1027m. 1H-NMR: 6.66 6.79 (m, 3 H); 4.87 (d, 1 H); 4.36 (m, 1 H); 4.10 (t, J ˆ 7, 2 H); 3.83 (s, 3 H); 3.67
(s, 3 H); 3.57 (t, J ˆ 7, 2 H); 3.34 (s, 3 H); 2.64 (m, 1 H); 2.44 (m, 1 H); 2.10 (m, 2 H); 1.50 1.78( m, 4 H); 1.45
(s, 9 H); 0.83 (m, 6 H). Anal. calc. for C25H41NO7 (467.61): C 64.25, H 8.84, N 3.00; found: C 64.20, H 8.97, N
3.22.
Methyl (2R,4S)-2-{[(tert-Butoxy)carbonyl]amino}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methyl-
hexanoate ((2R,4S)-18). As described for (2S,4S)-17, with (2R,5S,2'S)-15b (1.1 g, 2.37 mmol), 1n HCl (9.5 ml),
and MeCN (9.5 ml); for 90 min at r.t. FC (silica gel (100 g), CH2Cl2/MeOH/conc. NH3 soln. 800 :50 :1) gave
610 mg (70%) of a yellow oil. TLC (CH2Cl2/MeOH/conc. NH3 soln. 700 :50 :1): Rf 0.50. 1H-NMR: 6.65 6.8
(m, 3 H); 4.09 (t, J ˆ 7, 2 H); 3.84 (s, 3 H); 3.69 (s, 3 H); 3.58( t, J ˆ 7, 2 H); 3.35 (s, 3 H); 3.3 3.4 (m, 1 H); 2.60
(dd, J ˆ 4, 15, 1 H); 2.31 (dd, J ˆ 7.5, 15, 1 H); 2.11 (m, 2 H); 1.25 1.85 (m, 6 H); 0.95 (d, J ˆ 7, 3 H); 0.85
(d, J ˆ 7, 3 H ) .
This material (605 mg, 1.64 mmol) was treated in CH2Cl2 (20 ml) with Boc2O (465 mg, 2.13 mmol) in the
presence of H¸nig×s base (392 ml, 2.29 mmol) for 16 h at r.t. FC (silica gel (100 g), CH2Cl2 and CH2Cl2/Et2O 9 :1)
gave (2R,4S)-18 (700 mg, 91%; containing 10 15% of isomer (2S,4S)-17 by 1H-NMR). Oil. TLC (CH2Cl2/Et2O
9 :1): Rf 0.28. 1H-NMR: 6.6 6.8( m, 3 H); 4.61 (br. d, J ˆ 9, 1 H); 4.28( m, 1 H); 4.10 (t, J ˆ 7, 2 H); 3.74
(s, 3 H); 3.70 (s, 3 H); 3.58( t, J ˆ 7, 2 H); 3.35 (s, 3 H); 2.61 (dd, J ˆ 5.5, 13, 1 H); 2.24 (dd, J ˆ 9, 13, 1 H); 2.11
(m, 2 H); 1.5 1.9 (m, 4 H); 1.42 (s, 9 H); 0.95 (d, J ˆ 7, 3 H); 0.86 (d, J ˆ 7, 3 H ) .
(2S,4S)-2-{[(tert-Butoxy)carbonyl]amino}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexan-1-
ol (ˆ(aS,gS)-a-{[(1,1-Dimethylethoxy)carbonyl]amino}-4-methoxy-3-(3-methoxypropoxy)-g-(1-methylethyl)-
benzenepentanol; (2S,4S)-19). To a mixture of (2S,4S)-17 (53.8g, 0.115 mol) in THF (800 ml) at r.t. was added
LiBH4 (5.6 g, 0.258mol) in portions. The mixture was stirred for 16 h, followed by dropwise addition of MeOH
(800 ml). Solvents were evaporated at 408, followed by addition of MeOH (800 ml). The mixture was again
evaporated, and ice-cooled 1n HCl (800 ml) was added carefully. After extraction with CH2Cl2 (3 Â 800 ml), the
org. phase was dried (MgSO4) and evaporated: diastereoisomerically pure (2S,4S)-19 (48.0 g, 95%). A sample
of this material was recrystallized from Et2O/hexane. White crystals. TLC (CH2Cl2/AcOEt 7 :3): Rf 0.30. M.p.
25
64 66827). ‰aŠ ‡ 5.1 (c ˆ 1, CHCl3). 1H-NMR: 6.65 6.8( m, 3 H); 4.53 (br. d, 1 H); 4.10 (t, J ˆ 7, 2 H); 3.82
D
(s, 3 H); 3.4 3.75 (m, 3 H); 3.56 (t, J ˆ 7, 2 H); 3.35 (s, 3 H); 2.48( m, 2 H); 2.09 (m, 2 H); 1.43 (s, 9 H); 1.15
1.8( m, 4 H); 0.88 (d, J ˆ 7, 3 H); 0.87 (d, J ˆ 7, 3 H ) .
(2S,4S)-19 from (2S,4S)-24a: Reduction of (2S,4S)-24a (28.9 g, 61.8 mmol) with LiBH4 (3.0 g, 138mmol) in
THF (430 ml) afforded, after recrystallization from Et2O/hexane, (2S,4S)-19 (25.2 g, 93%), identical to (2S,4S)-
19 from (2S,4S)-17 by 1H-NMR and TLC (CH2Cl2/AcOEt 7:3). White solid. M.p. 66 678. TLC (AcOEt/hexane
22
D
1:1): Rf 0.19. ‰aŠ ‡ 5.7 (c ˆ 1, CHCl3). IR (CH2Cl2): 3434w, 2959m, 2938m, 2880m, 1708s, 1589w, 1513s, 1465m,
1367m, 1235m, 1163m, 1028m. 1H-NMR ((D6)DMSO, 808): 6.82 (d, J ˆ 8, 1 H); 6.80 (d, J ˆ 2, 1 H); 6.70
(dd, J ˆ 8, 2, 1 H); 5.98 (br. d, 1 H); 4.19 (t, J ˆ 6, 1 H); 4.01 (t, J ˆ 6.4, 2 H); 3.74 (s, 3 H); 3.35 3.55 (m, 1 H);
3.49 (t, J ˆ 6.4, 2 H); 3.25 3.35 (m, 2 H); 3.26 (s, 3 H); 2.57 2.6 (m, 1 H); 2.30 2.35 (m, 1 H); 1.93 (m, 2 H);
1.58 1.65 ( m, 2 H); 1.41 (s, 9 H); 1.23 1.42 (m, 2 H); 0.80 (m, 6 H). Anal. calc. for C24H41NO6 (439.59): C
65.58, H 9.40, N 3.19; found: C 65.39, H 9.68, N 3.11.
(2R,4S)-2-{[(tert-Butoxy)carbonyl]amino}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexan-1-
ol ((2R,4S)-20). As described for (2S,4S)-19, with (2R,4S)-18 (18.9 mg, 0.04 mmol), LiBH4 (14.0 mg, 0.6 mmol),
25
D
and THF (5 ml); at r.t. overnight. Colorless oil. TLC (CH2Cl2/AcOEt 7 :3): Rf 0.28. ‰aŠ À 7.8( c ˆ 1, CHCl3).
1H-NMR: 6.6 6.8( m, 3 H); 4.16 (br. m, 1 H); 4.10 (t, J ˆ 7 H, 2 H); 3.79 (s, 3 H); 3.33 (s, 3 H); 3.75 3.4
(m, 3 H); 3.54 (t, J ˆ 7, 2 H); 2.61 (dd, J ˆ 5, 13, 1 H); 2.21 (dd, J ˆ 8, 13, 1 H); 2.10 (m, 2 H); 1.9 1.2 (m, 4 H);
1.39 (s, 9 H); 0.96 (d, J ˆ 7, 3 H); 0.84 (d, J ˆ 7, 3 H ) .
The diastereomer purity of alcohols (2S,4S)-19 and (2R,4S)-20 was determined by reversed-phase HPLC
(Nucleosil-5-C18 anal. column, 30 ! 90% MeCN/H2O ‡ 0.1% CF3COOH over 60 min): tR 36.1 for (2S,4S)-19
and 37.2 for (2R,4S)-20. (2S,4S)-19 obtained from (2S,4S)-17, as well as from (2S,4S)-24a after recrystallization,
was diastereoisomerically pure (single HPLC peak); (2R,4S)-20 contained 14.5% of the (2S,4S)-isomer.
2,5-Diethoxy-3,6-dihydropyrazine (21). To the soln. of glycine anhydride (256.7 g, 2.25 mol) in CH2Cl2
(2.5 l) in a 20-l reaction vessel was added at r.t. and under N2 a soln. of triethyloxonium tetrafluoroborate
(Fluka; 1.07 kg, 5.53 mol) in CH2Cl2 (5.0 l) in one portion with stirring. The turbid mixture was stirred for 64 h at
r.t., followed by cooling to 08 with a CO2/EtOH bath. An aq. phosphate buffer soln. of pH 7.36 (prepared from
27
)
Material obtained from a 0.7m-scale reaction showed a slightly higher melting point of 70 718.

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Helvetica Chimica Acta Vol. 86 (2003)
K2HPO4 (3.29 kg, 4.19 mol) and KH2PO4 (0.945, 1.54 mol) dissolved in 11.2 l of distilled H2O) was then added
over 5 min by keeping the temp. of the mixture < 108. Stirring was continued for 30 min, followed by filtration of
the suspension/emulsion through Hyflo¾. After washing the precipitate with CH2Cl2 (3.0 l), the org. phase of
the combined filtrates was separated and the aq. phase extracted twice with CH2Cl2 (2 l). The combined org.
phase was washed with brine (2 l), filtered through a cotton pad, and evaporated. The residue was dissolved in
CH2Cl2 (400 ml), and hexane (4 l) was added with stirring. The precipitate was filtered off and washed with
hexane and the combined filtrate evaporated (bath. temp. 408) until the product began to crystallize. The
suspension was cooled in an ice bath with stirring and then filtered and the solid washed with small amounts of
cold hexane and finally dried at 308 under high vacuum. 21 (291 g, 76%). White crystalline solid. M.p. 82 838
([25]: m.p. 848). 1H-NMR: 4.08( q, J ˆ 7, 4 H); 3.98( s, 4 H); 1.23 (t, J ˆ 7, 6 H). Anal. calc. for C8H14N2O2
(170.2): C 56.45, H 8.29, N 16.45; found: C 56.42, H 8.47, N 16.50.
(2S)- and (2R)-3,6-Diethoxy-2,5-dihydro-2-{(2S)-2-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-
methylbutyl}pyrazine ((2S,2'S)-22a and (2R,2'S)-23a). To a soln. of 21 (229.8g, 1.35 mol) in THF (3.0 l) at À 408
was added dropwise 1.6m BuLi in hexane (0.788 l, 1.26 mol) during 20 min. After stirring for 15 min at À 408, a
soln. of (R)-11a (323.4 g, 0.90 mol) in THF (1.0 l) was added dropwise over 20 min, and stirring was continued at
À 208 for 18h. The mixture was evaporated, the residue partitioned between AcOEt (3 Â 3 l) and H2O (3 Â 3 l),
and the org. layers were washed with brine (1 l), combined, dried (MgSO4), and evaporated. The residue was
dried for 1 h at 358 under high vacuum: crude (2S,2'S)-22a/(2R,2'S)-23a (472 g; containing excess 21) in the ratio
94.9 :5.1 (determined by reversed-phase HPLC after transformation to (2S,4S)-24). Oil. TLC (hexane/AcOEt
2 :1): Rf 0.20. 1H-NMR28): 6.65 6.80 (m, 3 H); 3.93 4.18( m, 9 H); 3.83 (s, 3 H); 3.57 (t, J ˆ 6.4, 2 H); 3.35
(s, 3 H); 2.34 2.70 (m, 2 H); 2.03 2.18( m, 2 H); 1.52 1.88 (m, 4 H); 1.3 1.25 (m, 6 H); 0.74 0.94 (m, 6 H).
(2S)- and (2R)-3,6-Diethoxy-2,5-dihydro-2-{(2R)-2-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-
methylbutyl}pyrazine ((2S,2'R)-23b and (2R,2'R)-22b). As described for (2S,2'S)-22a/(2R,2'S)-23a, with 21
(511 mg, 3.00 mmol), THF (6 ml), 1.6m BuLi in hexane (1.75 ml, 2.80 mmol), (S)-11b (719 mg, 2.00 mmol), and
THF (10 ml) at À 208 for 18h: (2 S,2'R)-23b/(2R,2'R)-22b (1.0 g; containing excess 21), in the ratio 5 :95
(determined by reversed-phase HPLC after transformation to crude (2R,4R)-24b). Oil. TLC (hexane/AcOEt
1
2 :1): Rf 0.20. H-NMR: identical to that of the enantiomers (2S,2'S)-22a/(2R,2'S)-23a.
Ethyl (2S,4S)-2-{[(tert-Butoxy)carbonyl]amino}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methyl-
hexanoate (ˆ Ethyl (aS,gS)-a-{[(1,1-Dimethylethoxy)carbonyl]amino}-4-methoxy-3-(3-methoxypropoxy)-g-
(1-methylethyl)benzenepentanoate; (2S,4S)-24a). To a stirred soln. of crude (2S,2'S)-22a/(2R,2'S)-23a (472 g,
0.90 mol) in MeCN (3.6 l) at r.t. was added 1n HCl (3.6 l, 3.60 mol). After 30 min at r.t., the mixture was poured
into ice-cooled sat. aq. NaHCO3 soln. and extracted with CH2Cl2 (3 Â 4 l). The org. layers were washed several
times with H2O and evaporated: 351 g of crude a-amino ester. Oil. TLC (CH2Cl2/MeOH/conc. NH3 soln.
850 :50 :1): Rf 0.34. 1H-NMR: 6.65 6.85 (m, 3 H); 4.03 4.20 (m, 4 H); 3.83 (s, 3 H); 3.57 (t, J ˆ 6.4, 2 H); 3.34
(s, 3 H); 3.23 3.34 (m, 1 H); 2.38 2.60 ( m, 2 H); 2.10 (m, 2 H); 1.30 1.90 (m, 6 H); 1.20 1.32 (m, 3 H);
0.80 0.98 (m, 6 H).
To a stirred soln. of the crude a-amino ester (351 g, 0.90 mol) in CH2Cl2 (2.7 l) at 08 were added Et3N
(200 ml, 1.17 mol) and Boc2O (216 g, 0.99 mol) in CH2Cl2 (0.3 l), followed by stirring for 18h at r.t. The mixture
was evaporated and the residue dried under high vacuum for 30 min at 358 and purified by filtration through
silica gel (2.5 kg) with hexane/AcOEt 4 :1 (1 l) to 2 :1 (1 l) to afford a pale-colored oil. Recrystallization from
hexane afforded pure (2S,4S)-24a (353 g, 82%). White solid. M.p. 59 608. TLC (AcOEt/hexane 1:1): Rf 0.47.
22
D
‰aŠ ˆ ‡8.1 (c ˆ 1, CHCl3). IR (CH2Cl2): 3434w, 2959m, 2936m, 2878m, 1738s, 1712s, 1589w, 1514s, 1368m,
1236m, 1162s, 1140m, 1027m. 1H-NMR ((D6)DMSO; 808): 6.84 (d, J ˆ 8, 1 H); 6.75 (d, J ˆ 2, 1 H); ); 6.68
(dd, J ˆ 8, 2, 1 H); 6.66 (br. s, 1 H); 3.99 4.10 (m, 3 H); 4.00 (t, J ˆ 6.4, 2 H); 3.74 (s, 3 H); 3.49 (t, J ˆ 6.4, 2 H);
3.27 (s, 3 H); 2.45 (d, J ˆ 6, 2 H); 1.93 (m, 2 H); 1.51 1.72 (m, 4 H); 1.39 (s, 9 H); 1.18( t, J ˆ 7, 3 H); 0.84
(m, 6 H). Anal. calc. for C26H43NO7 (481.63): C 64.84, H 9.00, N 2.91; found: C 65.00, H 9.16, N 3.04.
Ethyl (2R,4R)-2-{[(tert-Butoxy)carbonyl]amino}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methyl-
hexanoate ((2R,4R)-24b). As described for (2S,4S)-24a, with (2S,2'R)-23b/(2R,2'R)-22b 5 :95 (0.96 g,
2.00 mmol) and final FC purification (silica gel (100 g), hexane/AcOEt 3 :1). The major (2R,4R)-24b was
obtained as pale yellow oil (0.82 g, 88%), contaminated with 5.4% of its (2S,4R)-epimer (determined by
reversed-phase HPLC).
(4R)-3-{(2S)-3-Methyl-1-oxo-2-[(phenylmethoxy)methyl]butyl}-4-(phenylmethyl)oxazolidin-2-one
((4R,2'S)-25a). To a stirred soln. of (R)-7a (209 g, 0.80 mol) in abs. CH2Cl2 (3.2 l; filtered through basic Al2O3),
28
)
Only the signals for the major diastereoisomer are indicated.

Helvetica Chimica Acta Vol. 86 (2003)
2867
cooled to 08 and under Ar, TiCl4 (92.2 ml, 0.84 mol) was added dropwise over 15 min ( ! orange suspension).
After 5 min, H¸nig×s base (148ml, 0.864 mol) was added at 0 8 over 15 min, and stirring of the dark mixture was
continued for 1 h. Then, benzyl chloro methyl ether (222 ml, 1.60 mol; Fluka) was slowly added over 90 min at
08. The orange-brown soln. was stirred for 20 h at 08, and then sat. aq. NH4Cl soln. (0.8l) over 5 min and H 2O
(1.6 l) were added. The aq. phase was extracted with CH2Cl2 (2 Â 2 l) and the combined org. phase washed with
H2O (4 l), dried (MgSO4), and evaporated. The yellow oil was purified by FC (2 Â 2.5 kg (two portions),
hexane/AcOEt 4 :1) and by final recrystallization from Et2O/hexane: pure (4R,2'S)-25a (152 g, 50%). White
1
solid. M.p. 74 758. TLC (hexane/AcOEt 3 :1; 2 Â developed): Rf 0.32. H-NMR: 7.15 7.35 (m, 10 H); 4.65
4.8( m, 1 H); 4.54 (m, AB, 2 H); 4.05 4.25 (m, 3 H); 3.88 (t, J ˆ 8, 1 H); 3.71 (dd, J ˆ 4, 8, 1 H); 3.22 (dd, J ˆ 2,
13, 1 H); 2.61 (dd, J ˆ 9, 13, 1 H); 2.04 (m, 1 H); 0.96 (t, J ˆ 7, 6 H). Anal. calc. for C23H27NO4 (381.47): C 72.42,
H 7.13, N 3.67; found: C 72.31, H 7.12, N 3.82.
Small quantities of the more-polar (TLC) isomer (4R,2'R)-25b were obtained from corresponding
combined FC fractions. TLC (hexane/AcOEt 3 :1; 2 Â developed): Rf 0.21. 1H-NMR: 7.15 7.4 (m, 10 H); 4.7
4.8( m, 1 H); 4.58( m, AB, 2 H); 4.05 4.25 (m, 3 H); 4.01 (t, J ˆ 9, 1 H); 3.83 (dd, J ˆ 3, 8, 1 H); 3.28 (dd, J ˆ 2,
14, 1 H); 2.79 (dd, J ˆ 9, 14, 1 H); 2.05 (m, 1 H); 0.95 1.0 (m, 6 H).
(2S)-3-Methyl-2-[(phenylmethoxy)methyl]butanoic Acid ((2S)-26a). To a stirred soln. of (4R,2'S)-25a
(103.8g, 0.272 mol) in THF (1.5 l) and H 2O (0.52 l), cooled to 08, were added 30% aq. H2O2 soln. (186 ml,
1.63 mol), dropwise over 5 min, and LiOH (13.1 g, 0.544 mol) by keeping the temp. at 0 28. The mixture was
slowly warmed to r.t., and stirring was continued for 18h. Then, a soln. of sodium sulfite (206 g, 1.63 mol) in H 2O
(1.15 l) was added at 0 108 over 10 min (Exothermic! CAUTION: check for complete removal of residual
peroxides before concentrating the mixture!). The suspension was filtered, the residue washed with cold H2O,
and the combined filtrate (pH 10 11) was concentrated in vacuo at 408 to remove excess THF. The aq. phase
was washed with CH2Cl2 (3 Â 1 l), then adjusted to pH 2 by addition of ice-cold 4n HCl and extracted with
CH2Cl2 (3 Â 800 ml). The org. phase was dried (MgSO4) and evaporated and the residue dried under high
vacuum at r.t.: (2S)-26a (55.5 g, 92%). Pale yellow oil. TLC (hexane/AcOEt 2 :1): Rf 0.25. 1H-NMR: 7.25 7.4
(m, 5 H); 4.54 (s, 2 H); 3.73 (dd, J ˆ 9, 16, 1 H); 3.63 (dd, J ˆ 5, 9, 1 H); 3.68( m, 1 H); 2.00 (m, 1 H); 0.99
(d, J ˆ 7, 3 H); 0.96 (d, J ˆ 7, 3 H). Anal. calc. for C13H18O3 (222.28): C 70.24, H 8.16; found: C 69.95, H 8.15.
(2R)-3-Methyl-2-[(phenylmethoxy)methyl]butan-1-ol ((R)-27a). To the mixture of NaBH4 (11.3 g,
0.299 mol) in abs. THF (60 ml), cooled to 108, a soln. of (2S)-26a (55.4 g, 0.249 mol) in abs. THF (150 ml)
was added over 15 min. Stirring was continued for 40 min at 10 208, followed by dropwise addition of I2 (31.7 g,
0.125 mol) in abs. THF (330 ml) at 208 over 15 min. After stirring the mixture for 72 h at r.t., MeOH (220 ml)
was slowly added over 10 min (gas evolution), and stirring was continued for an additional 60 min at r.t. The
mixture was evaporated in vacuo at 408 and the residue partitioned between ice-cold 2n HCl (800 ml) and
AcOEt (3 Â 800 ml). The combined org. phase was subsequently washed with brine/H2O 1:1 (800 ml), sat. aq.
Na2S2O3 soln. (800 ml), brine/H2O 1 :1 (800 ml), 0.1n NaOH (800 ml), and brine (800 ml), dried (MgSO4), and
evaporated. FC (silica gel (500 g), hexane/AcOEt 3 :1) afforded, after drying under high vacuum (R)-27a
(47.9 g, 92%). Pale yellow oil. TLC (hexane/AcOEt 2 :1): Rf 0.39. 1H-NMR: 7.25 7.4 (m, 5 H); 4.53 (m, 2 H);
3.55 3.8( m, 4 H); 2.70 (t, J ˆ 5, 1 H); 1.78( m, 1 H); 1.65 (m, 1 H); 0.92 (d, J ˆ 7, 3 H); 0.90 (d, J ˆ 7, 3 H ) .
Anal. calc. for C13H20O2 (208.30): C 74.96, H 9.68; found: C 74.92, H 9.69.
¾
Determination of the Enantiomer Excess (ee) of (‡)-(R)-27a and (À)-(S)-27b. By HPLC (Chiralcel-OJ
column (25 cm  4.6 mm), flow rate 1.0 ml/min, 30 bar pressure, UV detection at 210 nm, hexane/iPrOH 98:2):
tR 21.2 for (‡)-(R)-27a (ee > 99%) and 24.4 for (À)-(S)-27b (ee > 99.5%).
(2S)-2-[(Benzyloxy)methyl]-3-methylbutyl Bromide (ˆ1-Bromo-3-methyl-2-[(phenylmethoxy)methyl]bu-
tane; (S)-28a). To a soln. of (R)-27a (47.9 g, 0.229 mol) in CH2Cl2 (1 l), cooled to 08, Ph3P (72.6 g, 0.276 mol) and
NBS (49.2 g, 0.276 mol) were added in portions over 15 min, keeping the temp. at 0 58. After stirring overnight
at r.t., the mixture was poured into an ice-cold sat. aq. NaHCO3 soln. (800 ml) and extracted with CH2Cl2 (2 Â
800 ml). The combined org. phase was dried (MgSO4) and evaporated and the residue stirred at r.t. for 1 h in
hexane (400 ml). The suspension was filtered, the solid washed, and the combined filtrate concentrated to
200 ml. An additional filtration gave a clear soln. of the crude product. FC (silica gel (2 kg), hexane/AcOEt
10 :1) gave (S)-28a (43.2 g, 70%). Pale yellow oil. TLC (hexane/CH2Cl2 4 :1): Rf 0.17. 1H-NMR: 7.25 7.4
(m, 5 H); 4.53 (s, 2 H); 3.43 3.75 (m, 4 H); 1.8 4 (m, 1 H); 1.71 (m, 1 H); 0.96 (d, J ˆ 7, 3 H); 0.92 (d, J ˆ 7, 3 H ) .
Anal. calc. for C13H19BrO (271.20): C 57.58, H 7.06, Br 29.46; found: C 57.84, H 7.03, Br 29.22.
(2R)-2-[(Benzyloxy)methyl]-3-methylbutyl Bromide ((R)-28b). As described for (4R,2'S-25a, (S)-26a,
(R)-27a, and (S)-28a, with (S)-7b (60.0 g, 0.230 mol) at 0 58, abs. CH2Cl2 (960 ml; filtered through basic
Al2O3), TiCl4 (26.4 ml, 0.241 mol) (over 10 min), Et3N (42.5 ml, 0.248mol) (stirring at 0 5 8 for 60 min), and
benzyl chloro methyl ether (63.8ml, 0.460 mol) (overnight). FC (silica gel (2 kg), CH 2Cl2/hexane 1:1) and

2868
Helvetica Chimica Acta Vol. 86 (2003)
recrystallization gave a white solid (50.7 g, 53%). M.p. 73 748; TLC (CH2Cl2/hexane 2 :1; 2 Â developed): Rf
22
0.40. ‰aŠ ˆ ‡64.8( c ˆ 1, CH2Cl2). 1H-NMR: 7.15 7.4 (m, 10 H); 5.85 (m, 1 H); 5.53 (m, 2 H); 4.05 4.25
D
(m, 3 H); 3,88 (dd, J ˆ 11, 9.5, 1 H); 3.73 (dd, J ˆ 9.5, 5, 1 H); 3.23 (dd, J ˆ 12.5, 4, 1 H); 2.65 (dd, J ˆ 12.5, 9,
1 H); 2.04 (m, 1 H); 0.95 (m, 6 H). Anal. calc. for C23H27NO4 (381.47): C 72.42, H 7.13, N 3.67; found: C 72.71, H
7.07, N 3.73.
Hydrolysis of the white solid (50.6 g, 0.133 mol) in THF (0.7 l) with LiOH (6.4 g, 0.266 mol) and 30% H2O2
soln. (90.5 ml, 0.798mol) afforded (2R)-2-[(phenylmethoxy)methyl]butanoic acid ((R)-26b; 28.5 g, 97%). Pale
25
D
yellow oil. ‰aŠ ˆ À10.6 (c ˆ 1, CH2Cl2). Anal. calc. for C13H18O3 (222.28): C 70.24, H 8.16; found: C 69.80, H
8.26.
Reduction of (R)-26b with NaBH4 (5.81 g, 0.154 mol) in the presence of I2 (16.3 g, 0.064 mol) in THF
(550 ml) afforded, after FC purification (silica gel (700 g), hexane/AcOEt 5 :1) (S)-27b (23.0 g, 86%). Pale
25
D
yellow oil. ‰aŠ ˆ À15.7 (c ˆ 1, CH2Cl2). Anal. calc. for C13H20O2 (208.30): C 74.96, H 9.68; found: C 74.72, H
9.51.
Reaction of (S)-27b (15.0 g, 72.0 mmol) with NBS (15.4 g, 86.6 mmol) in CH2Cl2 (310 ml) in the presence of
Ph3P (22.8g, 86.6 mmol) and FC purification (silica gel (310 g), hexane/AcOEt 10 :1) gave ( R)-28b (18.9 g,
25
97%). Pale yellow oil. TLC (hexane/AcOEt 9 :1): Rf 0.73. ‰aŠ ˆ À9.7 (c ˆ 1, CH2Cl2). 1H-NMR: 4.49, 4.55 (2d,
D
AB, J ˆ 13, 2 H); 3.70 (dd, J ˆ 10, 4.5, 1 H); 3.63 (dd, J ˆ 9.5, 4.5, 1 H); 3.57 (dd, J ˆ 10, 6, 1 H); 3.49 (dd, J ˆ 9.5,
7, 1 H ) ; 1.84 ( m, 1 H); 1.71 (m, 1 H); 0.96 (d, J ˆ 7, 3 H); 0.94 (d, J ˆ 7, 3 H); Anal. calc. for C13H19BrO (271.20):
C 57.58, H 7.06, Br 29.46; found: C 57.65, H 6.88, Br 29.01.
(2S,5R)-2-{(2S)-2-[(Benzyloxy)methyl]-3-methylbutyl}-2,5-dihydro-5-isopropyl-3,6-dimethoxypyrazine
(ˆ(2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(1-methylethyl)-5-{(2S)-3-methyl-2-[(phenylmethoxy)methyl]butyl}-
pyrazine; (2S,5R,2'S)-29). As described for (2S,5R,2'S)-13a; with (R)-12a (29.5 g, 160 mmol), THF (530 ml),
1.6m BuLi in hexane (100 ml, 160 mmol), (S)-28a (29.0 g, 107 mmol), and THF (130 ml); at À 708 for 2 h and at
À 188 for 64 h. FC (silica gel (2.4 kg), hexane/AcOEt 15 :1) gave pure (2S,5R,2'S)-29 (36.2 g, 90%). Pale yellow
oil. TLC (hexane/AcOEt 4 :1): Rf 0.58. 1H-NMR: 7.25 7.35 (m, 5 H); 4.50 (s, 2 H); 3.9 4.1 (m, 2 H); 3.69
(s, 3 H); 3.63 (s, 3 H); 3.50 (m, 2 H); 2.25 (m, 1 H); 1.2 2.0 (m, 4 H); 0.65 1.1 (m, 12 H). Anal. calc. for
C22H34N2O3 (374.52): C 70.55, H 9.15, N 7.48; found: C 70.80, H 9.34, N 7.17.
Methyl (2S,4S)-4-[(Benzyloxy)methyl]-2-{(tert-butoxy)carbonyl]amino}-5-methylhexanoate ((2S,4S)-31).
As described for (2S,4S)-24a; with (2S,5R,2'S)-29 (36.2 g, 96.7 mmol), MeCN (400 ml), 1n HCl (400 ml); at r.t.
for 2 h. FC (silica gel (2.4 kg), CH2Cl2/MeOH/conc. NH3 soln. 950 :50 :1) afforded methyl (2S,4S)-2-amino-4-
[(benzyloxy)methyl)-5-methylhexanoate (21.9 g, 80%). Colorless oil. TLC (CH2Cl2/MeOH/conc. NH3 soln.
700 :50 :1): Rf 0.34. 1H-NMR: 7.25 7.35 (m, 5 H); 4.49 (m, 2 H); 3.71 (s, 3 H); 1.4 1.9 (m, 6 H); 1.35 1.6 (m, 3 H);
0.85 0.9 (m, 6 H). Anal. calc. for C16H25NO3 (279.23): C 68.79, H 9.02, N 5.01; found: C 68.72, H 9.10, N 5.11.
Then with this a-amino ester (21.9 g, 78.4 mmol), CH2Cl2 (0.5 l), Et3N (17.4 ml, 102 mmol), Boc2O (18.8 g,
86.2 mmol), and CH2Cl2 (100 ml); for 16 h at r.t. FC (silica gel (2.4 kg), hexane/AcOEt 6 :1) gave (2S,4S)-31
(27.0 g, 91%). Colorless oil. TLC (hexane/AcOEt 4 :1): Rf 0.34. 1H-NMR: 7.26 7.35 (m, 5 H); 5.45 (d, NH,
1 H); 4.51 (m, 2 H); 4.32 (m, 1 H); 3.71 (s, 3 H); 3.35 3.5 (m, 2 H); 1.55 1.9 (m, 4 H); 1.41 (s, 9 H); 0.8 0.9
(m, 6 H).
(2S,5R)- and (2R,5R)-2-{(2R)-2-[(Benzyloxy)methyl]-3-methylbutyl}-2,5-dihydro-5-isopropyl-3,6-dimeth-
oxypyrazine ((2S,5R,2'R)-32 and (2R,5R,2'R)-33, resp.). As described for (2S,5R,2'S)-29a, with (2R)-12a (13.0 g,
70.6 mmol), THF (230 ml), 1.6m BuLi in hexane (44 ml, 70.4 mmol), (R)-28b (12.8g, 47.0 mmol), and THF
(60 ml). FC (silica gel (1.0 kg), hexane/AcOEt 20 :1) gave the major (2S,5R,2'R)-32 (12.9 g, 73%). Pale yellow
25
oil. TLC (hexane/AcOEt 6 :1): Rf 0.62. ‰aŠ ˆ ‡26.0 (c ˆ 1, CH2Cl2). 1H-NMR: 7.25 7.35 (m, 5 H); 4.46
D
(s, 2 H); 4.01 (m, 1 H); 3.92 (m, 1 H); 3.63 (s, 6 H); 3.38( m, 2 H); 2.26 (m, 1 H); 1.75 2.0 (m, 3 H); 1.47
(m, 1 H); 1.03 (d, J ˆ 7, 3 H); 0.87 (d, J ˆ 7, 3 H); 0.86 (d, J ˆ 7, 3 H); 0.67 (d, J ˆ 7, 3 H). Anal. calc. for
C22H34N2O3 (374.52): C 70.55, H 9.15, N 7.48; found: C 70.49, H 9.26, N 7.34.
The minor (2R,5R,2'R)-33 (3.49 g, 20%) was also isolated as a pale yellow oil. TLC (hexane/AcOEt 6 :1):
Rf 0.50. 1H-NMR: 7.25-7.35 (m, 5 H); 4.53 (s, 2 H); 3.9 4.2 (m, 2 H); 3.67 (s, 3 H); 3.63 (s, 3 H); 3.57 (m, 1 H);
3.49 (m, 1 H); 1.75 2.25 (m, 4 H); 1.20 (m, 1 H); 1.06 (d, J ˆ 7, 3 H); 0.87 (d, J ˆ 7, 3 H); 0.80 (d, J ˆ 7, 3 H ) ;
0.76 (d, J ˆ 7, 3 ) .
Methyl (2S,4R)-4-[(Benzyloxy)methyl]-2-{[(tert-butoxy)carbonyl]amino}-5-methylhexanoate ((2S,4R)-
34). As described for (2S,4S)-17, with diastereoisomerically pure (2S,5R,2'R)-32 (15.7 g, 41.9 mmol), MeCN
(180 ml), and 1n HCl (176 ml); at r.t. for 2 h. FC (silica gel (1.0 kg), CH2Cl2/MeOH/conc. NH3 soln. 97:3 :0.1)
afforded a pale yellow oil (10.9 g, 93%). TLC (CH2Cl2/MeOH/conc. NH3 soln. 9 :1:0.1): Rf 0.59.
Then as described for (2S,4S)-24a, with this yellow oil (8.8 g, 31.5 mmol), CH2Cl2 (35 ml), Boc2O (7.56 g,
34.6 mmol), and Et3N (7.0 ml, 40.9 mmol). FC (silica gel (1.0 kg), hexane/AcOEt 6 :1) gave (2S,4R)-34 (11.1 g,

Helvetica Chimica Acta Vol. 86 (2003)
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25
93%). Pale yellow oil. TLC (hexane/AcOEt 3 :1): Rf 0.43. ‰aŠ ˆ ‡6.24 (c ˆ 1, CH2Cl2). 1H-NMR: 7.3 7.4
D
(m, 5 H); 5.38(br. d, J ˆ 8, 1 H); 4.49 (s, 2 H); 4.21 (m, 1 H); 3.70 (s, 3 H); 3.48( dd, J ˆ 9, 5, 1 H); 3.28( dd, J ˆ
9, 8, 1 H); 1.55 1.9 (m, 4 H); 1.43 (s, 9 H); 0.89 (d, J ˆ 7, 3 H); 0.87 (d, J ˆ 7, 3 H). Anal. calc. for C21H33NO5
(379.50): C 66.46, H 8.76, N 3.69; found: C 66.49, H 8.97, N 3.69.
(2S)- and (2R)-2-{(2S)-2-[(Benzyloxy)methyl]-3-methylbutyl}-3,6-diethoxy-2,5-dihydropyrazine ((2S,2'S)-
35 and (2R,2'S)-36, resp.). Similarly to the method described above for (2S,5R,2'S)-13a: To a soln. of (S)-28a
(1.09 g, 4.0 mmol) in THF (20 ml), cooled to À 408, was added 1.6m BuLi in hexane (3.5 ml, 5.6 mmol) over
15 min with stirring, followed by addition of 21 (1.02, 6.0 mmol) in THF (25 ml) over 10 min at À 408. The
colored mixture was warmed to À 188, and stirring was continued for 16 h. FC (silica gel (100 g), hexane/AcOEt
4 :1) gave (2S,2'S)-35/(2R,2'S)-36 ca. 2 :1 (by 1H-NMR) (1.28g, 89%). Pale yellow oil. Rf 0.32. 1H-NMR: 7.25
7.4 ( m, 5 H); 4.47, 4.49 (2s, ca. 2 :1, 2 H); 3.96 4.16 (m, 7 H); 3.35 3.55 (m, 2 H); 1.4 2.06 (m, 4 H); 1.2 1.35
(m, 6 H); 0.76 0.92 (m, 6 H).
Ethyl (2S,4S)- and (2R,4S)-4-[(Benzyloxy)methyl]-2-{[(tert-butoxy)carbonyl]amino}-5-methylhexanoate
((2S,4S)-37a and (2R,4S)-37b, resp.). As described for (2S,4S)-24a, with (2S,2'S)-35/(2R,2'S)-36 ca. 2 :1 (1.20 g,
3.33 mmol), MeCN (12 ml), 1n HCl (12 ml); at r.t. for 20 min. Then with Et3N (0.73 ml, 4.29 mmol), Boc2O
(0.79 g, 3.63 mmol), and CH2Cl2 (20 ml); at r.t. for 16 h. FC (silica gel (100 g), hexane/AcOEt 6 :1) gave (2S,4S)-
37a/(2R,4S)-37b ca. 2 :1 (by 1H-NMR) (1.23 g, 94%). Colorless oil. TLC (hexane/AcOEt 4 :1): Rf 0.34.
1H-NMR: 7.25 7.40 (m, 5 H); 5.43 (d, 0.67 H, NH); 5.35 (d, 0.33 H, NH); 4.45 4.55 (m, 2 H); 4.10 4.35
(m, 3 H); 3.25 3.52 (m, 2 H); 1.55 1.90 (m, 4 H); 1.42 (s, 9 H); 1.24 1.29 (m, 3 H); 0.83 0.90 (m, 6 H). Anal.
calc. for C22H34N2O3 (393.52): C 67.15, H 8.96, N 3.56; found: C 66.88, H 8.67, N 3.50.
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Received March 6, 2003