New scalable asymmetric aminomethylation reaction for the synthesis of β2-amino acids

Article abstract of DOI:10.1002/ejoc.200600926

β-Amino acids are useful tools in the design of peptidomimetics, and the development of new methods for their syntheses, particularly the synthesis of β²-amino acids, remains an important challenge. Here we report a new scalable route based on the aminomethylation of silyl ketene N,O-acetals by Mannich-type iminium electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600926

FULL PAPER
DOI: 10.1002/ejoc.200600926
New Scalable Asymmetric Aminomethylation Reaction for the Synthesis of
β2-Amino Acids
Roba Moumné,[a,b] Bernard Denise,[c][†] Karine Guitot,[a] Henri Rudler,[c] Solange Lavielle,[a]
and Philippe Karoyan*[a]
Keywords: β2-Amino acids / Aminomethylation / Silyl ketene acetals / Mannich-type iminium electrophiles / Scalable
synthesis
β-Amino acids are useful tools in the design of peptidomi-
metics, and the development of new methods for their syn-
theses, particularly the synthesis of β2-amino acids, remains
an important challenge. Here we report a new scalable route
based on the aminomethylation of silyl ketene N,O-acetals
by Mannich-type iminium electrophiles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
have been reported,[7] including a recent elegant organocat-
alytic one developed by Gellman et al.,[8] but none of them
seems amenable to large-scale synthesis, especially in view
of the purification steps required. The most widely used
route involves aminomethylation of an enolate equivalent
bearing the side chain of the amino acid. Many aminometh-
ylating agents for this purpose have been reported, but their
use presents severe limitations that hinder up-scaling, such
as their low stabilities and/or reactivities and the harsh con-
ditions required to deprotect the amine moieties.[9] We re-
cently reported our preliminary results on the homologa-
tion of α-amino acids to β2-amino acids by means of Re-
formatsky-type reactions using highly reactive preformed
iminium ions as aminomethylating agents.[10] Here we dis-
close the scope and limitations of this approach, together
with its extension to the aminomethylation of silyl enol
ethers, which has allowed the development of a highly ef-
ficient and scalable synthesis of a wide range of optically
pure β2-amino acids.
Introduction
The development of scalable syntheses of β-amino acids
has constituted an important challenge since oligomers of
these compounds were reported to be excellent peptidomi-
metics.[1,2] This goal has been reached in the case of β3-
amino acids; indeed, the Arndt–Eistert homologation of
natural amino acids allows the large-scale synthesis of all
the β3-amino acids, which are now commercially available.[3]
This has permitted an extensive study of oligomers of these
compounds and their use for the development of interesting
peptidomimetics.
On the other hand, it is known that different β-peptide
secondary structures,[4] especially the design of β-turn-type
structures,[5] require the introduction of β2-amino acid iso-
mers. Use of these compounds, however, is still highly lim-
ited for practical reasons, as no general methodology for
the multigram preparation of these compounds has yet been
reported (especially those bearing suitably protected func-
tionalities on their side chains), even though it is a prerequi-
site for peptide synthesis. Although Seebach et al. succeeded
in preparing all of the β2-amino acids bearing proteinogenic
side chains, the syntheses of some are not straightforward,
and are limited to laboratory scales.[6] Many other methods
Results and Discussion
The classical Reformatsky reaction involves nucleophilic
species produced through zinc insertion into the carbon–
halogen bonds in α-haloacetate esters.[11] This reaction is
usually conducted under very mild conditions, the major
proviso being that highly reactive electrophiles are usually
needed. The addition of Reformatsky reagents to reactive
imine derivatives has been widely used for the preparation
of β3- or disubstituted β2,3-amino acids (Gilman–Speeter
reaction),[12] but the aminomethylation of such reagents is
limited by the inaccessibility of stable and reactive for-
mylimine equivalents. Interestingly, Mannich-type iminium
ions are very reactive aminomethylating agents: Knochel et
al. have reported the aminomethylation of organozinc and
[a] Chemistry, Université Pierre et Marie Curie-Paris 6, FR 2769,
CNRS/UMR 7613, Synthèse, Structure et Fonction de Molé-
cules Bioactives, Université P. et M. Curie,
Case courrier 45, 4 Place Jussieu, 75252 Paris Cedex 05, France
Fax: +33-1-44273843
E-mail: karoyan@ccr.jussieu.fr
[b] Senn Chemicals AG
Industriestrasse 12, P. O. Box 267, 8157 Dielsdorf, Switzerland
[c] Chemistry, Université Pierre et Marie Curie-Paris 6, FR 2769,
CNRS/UMR 7611, Laboratoire de Synthèse Organique, Uni-
versité P. et M. Curie,
4 Place Jussieu, 75252 Paris Cedex 05, France
[†] Deceased November 6, 2005; this article is dedicated to his
memory.
1912
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1912–1920

Asymmetric Aminomethylation for the Synthesis of β2-Amino Acids
FULL PAPER
Grignard reagents through the use of iminium trifluoroace- (derived from menthol, oxazolidines or oxazinanes) to halo
tates generated in situ.[13] We have thus explored the scope precursors had previously given rise to some diastereoselec-
of these iminium trifluoroacetate salts with regard to the tivity and enantiofacial differentiation.[11] We chose Oppol-
Reformatsky reaction.
zer’s sultam, easily obtained on multigram scales for labora-
Aminal 1 was generated by heating dibenzylamine and tory needs and used on kilogram scales for industrial pur-
aqueous formaldehyde at reflux, as reported by Knochel et poses (Scheme 3).[18] Good to excellent diastereoselectivities
al.,[13] and isolated by crystallization as a stable solid com- are usually observed with this chiral auxiliary. Sulfonamide
pound (Scheme 1). Treatment of this aminal with trifluoro- 6a was thus obtained by coupling 2-bromo-3-methylbut-
acetic anhydride produced the corresponding trifluoroacet- anoic acid with (+)-camphorsultam as shown in Scheme 3.
ate iminium salt, which was directly used in the Reformat-
sky reaction without further purification.
Scheme 1. Synthesis of the iminium trifluoroacetate salt.
α-Bromo esters 4a–e, bearing proteinogenic side chains,
if not commercially available, were easily obtained from the
corresponding α-amino acids by diazotization,[14] and sub-
sequent esterification under conditions compatible with
classical protective groups for peptide synthesis.[15] The zinc
Scheme 3. Synthesis of optically pure β2-homoleucine through a
Reformatsky reaction using the iminium trifluoroacetate salt. S* =
(+)-camphorsultam.
intermediate was generated, as reported by Dardoize et
al.,[16] in formaldehyde dimethylacetal at room temperature
and then treated with dibenzylideneiminium trifluoroacet-
ate, providing compounds 5a–e in good yields (Scheme 2
Treatment of sulfonamide 6a under the conditions de-
scribed above resulted in the corresponding β2-amino acid
derivative 7a as a single diastereoisomer. The stereochemis-
try of compound 7a was deduced by comparison of the
optical rotation of the N-Boc-β2-homoleucine (obtained
through deprotection/reprotection steps) with that of an au-
thentic sample.[19] The optical purity was confirmed by
NMR analysis by the methodology reported by Seebach et
al. (Scheme 4).[20] It should be noted that the stereochemical
course of this aminomethylation reaction is identical to that
usually observed with Oppolzer’s sultam for glycinate-de-
rived enolates.[21]
and Table 1). Subsequent debenzylation with ammonium
formate in the presence of palladium on charcoal,[17] fol-
lowed by ester saponification and N-Boc protection, pro-
vided racemic β2-amino acids suitably protected for peptide
synthesis.
Scheme 2. Synthesis of racemic β2-amino acids through Reformat-
sky reactions with the iminium trifluoroacetate salt.
Table 1. Yields for the Reformatsky reactions with iminium trifluo-
roacetate.
Entry
R
rac-5 (%)
Scheme 4. Enantiomeric excess.
a
b
c
d
e
CH3 (4a)
iBu (4b)
5a (43)
5b (66)
5c (74)
5d (73)
5e (72)
We then studied the scope of this aminomethylation reac-
tion with different α-bromosulfonamides (Scheme 5 and
Table 2). The mild conditions required for the Reformatsky
reaction are compatible with many of the sensitive protect-
CH2Ph (4c)
CH2-(3-indolyl-N-Boc) (4d)
CH2CO2-tBu (4e)
The ease of this reaction prompted us to explore its ing groups typically used in peptide synthesis. This could
asymmetric version for the synthesis of β2-homoleucine, allow for the direct synthesis of β2-amino acids bearing
which was needed for our structure/activity relationship functional groups on their side chains, avoiding many de-
studies of biologically active peptides. In classical Re- protection/reprotection steps usually required for their
formatsky reactions, the attachment of chiral auxiliaries preparation.
Eur. J. Org. Chem. 2007, 1912–1920
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1913

R. Moumné, B. Denise, K. Guitot, H. Rudler, S. Lavielle, P. Karoyan
Table 2. Levels of conversion and dr values for asymmetric Reformatsky reactions with the iminium trifluoroacetate salt.
FULL PAPER
Entry
R
Product
Conversion (yield)[a]
dr[a]
a
b
c
d
e
iBu (6a)
CH3 (6b)
7a
7b
7c
7d
7e
69% (64%)
71% (nd)
71% (57%)
nd[b]
Ͼ98:2
72:28
87:13
nd[c]
CH2Ph (6c)
CH2(N-Boc-indolyl) (6d)
(CH2)4NHBoc (6e)
69% (47%)
nd[c]
[a] Calculated from the NMR spectrum of the crude mixture. [b] A complex mixture that contained the product was obtained. [c] Complex
mixture of diastereoisomers with cis/trans-N-Boc isomerism.
Scheme 5. Asymmetric synthesis of β2-amino acids through Re-
formatsky reactions using the iminium trifluoroacetate salt. S* =
Scheme 6. Aminomethylation of chiral silyl ketene N,O-acetal with
(+)-camphorsultam.
the iminium trifluoroacetate salt. S* = (+)-camphorsultam.
In a first attempt the silyl ketene acetal was generated
from the corresponding alkanoylsultam sulfonamide[24] by
Unfortunately, use of α-bromo sulfonamides bearing less treatment with tert-butyldimethylsilyl triflate and triethyl-
hindered side chains gave disappointing results. Indeed, amine at room temperature.[25] After addition of the imin-
with all the compounds tested, inseparable mixtures of dia- ium trifluoroacetate salt, the protected β2-homoalanine de-
stereoisomers were obtained. Screening of different reaction rivative 11a was obtained in moderate yield (60%) and with
conditions (solvents, temperature, reagent loading) and use virtually complete diastereoselectivity. In the case of deriva-
of other chiral auxiliaries (Evans oxazolidinone, menthol) tives bearing hindered side chains (11b–d, 11f–g), the for-
did not improve the diastereoselectivities of the aminometh- mation of the corresponding ketene acetal was not ob-
ylations.[22]
served. Replacement of tert-butyldimethylsilyl triflate with
We anticipated that the use of classical enolate chemistry the cheaper trimethylsilyl triflate allowed the formation of
with this aminomethylating reagent should solve the prob- the silylenol intermediates of all other alkanoylsultam sul-
lem, but all the attempts to achieve reactions with ester fonamides. Indeed, tert-butyldimethylsilyl triflate was inef-
enolates generated from various bases with the iminium tri- ficient, probably because of the steric hindrance developed
fluoroacetate ion failed. Silyl enol ethers have been reported in the transition state, preventing the formation of the (Z)-
as an alternative to ester enolates,[23] so we examined the silylenol ether. These intermediates reacted with the imin-
reactivity of the chiral silyl ketene N,O-acetals, generated in ium salt to give the corresponding protected β2-amino acids
situ from Oppolzer’s sultam derivatives, toward the iminium as single diastereoisomers, with all compounds being ob-
trifluoroacetate salt (Scheme 6 and Table 3).
tained in excellent yields as solids. The stereochemical
Table 3. Yields of the asymmetric aminomethylations of silyl ketene N,O-acetals.
Entry
R
RЈMe2SiOTf
Product (yield)
dr[b]
a
b
c
d
e
f
g
h
i
CH3 (9a)
TBDMSOTf
TMSOTf
TBDMSOTf
TMSOTf
TBDMSOTf
TMSOTf
TBDMSOTf
TMSOTf
11a (60%)
(91%)
11b (0%)
(81%)
11c (0%)
(82%)
11d (0%)
(72%)
11e (61%)
(74%)
11f (76%)
11g (88%)
Ͼ98:2
Ͼ98:2
iPr (9b)
iBu (9c)
Bn (9d)
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
hexyl (9e)
TBDMSOTf
TMSOTf
TMSOTf
j
k
l
Br-(CH2)4 (9f)
N-benzylindolyl-3-methylene (9g)[a]
TMSOTf
[a] Use of 2 equiv. of TMSOTf. [b] Calculated from NMR data of the crude mixture.
1914
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Eur. J. Org. Chem. 2007, 1912–1920

Asymmetric Aminomethylation for the Synthesis of β2-Amino Acids
FULL PAPER
electron Corporation, Bremen, Germany). Cy = cyclohexane; EA
= ethyl acetate.
course of this aminomethylation reaction is identical to that
observed in the Reformatsky strategy,[10] and also to that
usually observed with glycine enolates derived from Oppol- General Procedure for the Conversion of α-Amino Acids with Non-
zer’s sultam.[21]
The obtained derivatives were then debenzylated with
ammonium formate in the presence of palladium on char-
coal, with the chiral auxiliary being removed by saponifica-
tion. All compounds were isolated by simple crystallization
functionalized Side Chains into α-Bromo Acids: Sodium nitrite
(1.25 equiv.) in H2O was added dropwise at 0 °C to a stirred solu-
tion of -amino acid and sodium bromide (3.5 equiv.) in H2SO4
(2.5 , 1.3 mL per mmol). After stirring at 0 °C for 1 h, the reaction
mixture was brought to room temperature and stirred for 6 h. The
mixture was extracted with ethyl acetate, and the combined organic
after Boc protection of their amine moieties (Scheme 7).
solutions were washed with brine, dried (MgSO4) and concentrated
The optical purities were confirmed by measurement of the
optical rotations and comparison with the literature data.
in vacuo.
General Procedure for the Conversion of Amino Acids with Function-
alized Side Chains into the Corresponding α-Bromo Acids: NaBr
(3.7 equiv.) was dissolved in an aqueous solution of HBr (0.75 )
in a three-necked flask with an overhead stirrer. The solution was
cooled to –15 °C and sodium nitrite (1.3 equiv.) was added in one
portion. The amino acid (1 equiv.) was then added and the reaction
mixture was kept between –15 °C and –10 °C for 1.5 h. The mixture
was extracted twice with precooled EtOAc (0 °C) and the combined
organic layers were washed with saturated aqueous solution of
NH4Cl, dried (MgSO4) and concentrated in vacuo.
Scheme 7. Deprotection and Boc protection.
Protection of the Acid Function for Compounds with Nonfunction-
alized Side Chains: The α-bromo acid was treated with a solution
of concentrated sulfuric acid (30 µL per mmol) in methanol (2 mL
per mmol) and the mixture was heated at reflux for 1 h. The solu-
Conclusions
We have developed a straightforward synthesis of β2-
amino acids, which has been easily scaled up for the prepa- tion was allowed to cool to room temperature and concentrated in
ration of the β2-homophenylalanine derivative in 100 g
quantities in the laboratory by use of the same procedure
as described for smaller scales. All reactions may be per-
vacuo, Et2O was added, and the organic layer was washed with
aqueous NaHCO3 (5%) followed by brine, dried with MgSO4 and
concentrated in vacuo.
Protection of the Acid Function for Compounds with Functionalized
Side Chains: The α-bromo acid was treated with a solution of acetyl
chloride (30 µL per mmol) in methanol (2 mL per mmol) for 1 h.
The solution was allowed to cool to room temperature and concen-
trated in vacuo.
formed at room temperature and the compounds can be
isolated by simple precipitation or crystallization. With the
strategy described here we have shown that β2-amino acids
with various side chains can be obtained, establishing the
versatility of this aminomethylation reaction. This route op-
ens a new avenue to explore the potential of β2-amino acids
in various fields.
General Procedure for the Acylation of Oppolzer’s Sultam Starting
from Acid Chloride Derivatives: A solution of 10,2-camphorsultam
(1 equiv.) in dimethoxyethane (3 mL per mmol) was added slowly
at room temperature to a stirred suspension of NaH (1.1 equiv.)
in the same solvent. After the mixture had been stirred at room
temperature for 1 h, the acid chloride derivative (1.1 equiv.) was
added. The mixture was stirred at room temperature for an ad-
ditional 1 h, and was then quenched with water and concentrated.
After addition of ethyl acetate, the solution was washed with satu-
rated aqueous NH4Cl, and the organic layer was dried with anhy-
drous MgSO4 and concentrated. The acylsultam derivatives were
obtained by precipitation from diethyl ether/pentane.
Experimental Section
General Considerations: Tetrahydrofuran (THF) was distilled from
sodium/benzophenone and kept over molecular sieves (4 Å).
Dichloromethane (CH2Cl2) and triethylamine (NEt3) were distilled
from CaH2. Anhydrous methylal, anhydrous DMF and other rea-
gents were obtained from commercial suppliers and used without
further purification. Compound 4a is commercially available. Op-
polzer’s sultams were a gift from Senn Chemicals. Anhydrous reac-
tions were performed under argon, and glassware was dried in an
oven prior to use. Prior to preparation of the HBr solution, the
commercial concentrated HBr was washed with a solution of tri-
butyl phosphate in CHCl3 (5%) to remove contaminating Br2. Re-
action progress was monitored by TLC on precoated silica plates
(Merck 60 F254 0.25 µm). Spots were detected by UV, molybdo-
phosphoric acid oxidation or ninhydrin reagent. Flash column
chromatography was carried out with Merck 60 F254 0.040–
General Procedure for the Acylation of Oppolzer’s Sultam Starting
from Carboxylic Acid Derivatives: A solution of 10,2-camphorsul-
tam (1 equiv.) in dimethoxyethane (3 mL per mmol) was added
slowly at room temperature to a stirred suspension of NaH
(1.1 equiv.) in the same solvent. The solution was stirred for 1 h.
In parallel, isobutyl chloroformate (1.1 equiv.) and N-methyl-
morpholine (1.1 equiv.) were added at –15 °C to a solution of the
carboxylic acid (1 equiv.) in dimethoxyethane (3 mL per mmol).
After 15 min of stirring at –15 °C, this preformed mixed anhydride
was rapidly introduced, after filtration through a Celite pad, into
the sultam sodium salt solution. After 1 h of stirring at –15 °C and
1 h at room temperature, the crude mixture was quenched with
water and concentrated. Ethyl acetate was added and the organic
layer was washed with saturated aqueous NH4Cl, dried with anhy-
drous MgSO4 and concentrated. Acylsultam derivatives were ob-
tained by precipitation from diethyl ether/pentane.
1
0.063 µm silica gel. H and 13C NMR spectra were recorded with
Bruker Avance 250 or 400 MHz spectrometers. Chemical shifts (δ)
are reported in ppm relative to internal TMS. Optical rotations
were determined at 20 °C with a Perkin–Elmer Model 141 polari-
meter with a 10 cm path-length cell. Microanalyses were obtained
from CNRS central service. HR mass spectra were recorded at the
Université Pierre et Marie Curie with an LTQ Orbitrap (Thermo-
Eur. J. Org. Chem. 2007, 1912–1920
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1915

R. Moumné, B. Denise, K. Guitot, H. Rudler, S. Lavielle, P. Karoyan
FULL PAPER
General Procedure for the Reformatsky Reaction: Dibromoethane
(20 µL per mmol) was added to a suspension of zinc dust
(1.5 equiv.) in methylal (0.5 mL per mmol) and the mixture was
heated at reflux for a few minutes. A solution of the α-bromo acid
(1 equiv.) in methylal (1 mL per mmol) was added dropwise, the
uct being purified by flash column chromatography (Cy/EA/AcOH,
99:1) to give an oil (19 g, 68%), Rf = 0.33 (CH2Cl2/EtOH/AcOH,
9:1:0.1). [α]2D0 = –11.4 (c = 2, MeOH). 1H NMR (400 MHz, CDCl3):
δ = 7.18–7.36 (m, 5 H), 4.42 (t, J = 7.7 Hz, 1 H), 3.47 (dd, J =
8 Hz, 14.2 Hz, 1 H), 3.24 (dd, J = 7.2 Hz, 14.2 Hz, 1 H) ppm. 13C
reaction mixture was stirred at room temperature for 15 min, and NMR (100 MHz, CDCl3): δ = 175.5, 136.3, 129.4, 129.0, 128.5,
a solution of the iminium trifluoroacetate, freshly prepared from
N,N,NЈ,NЈ-tetrabenzylmethanediamine,[13] was added. The reaction
mixture was stirred at room temperature for 1.5 h, and was then
quenched with a saturated solution of NH4Cl and extracted with
Et2O. The combined organic layers were washed with saturated
aqueous NaHCO3, aqueous Na2S2O3 (5%) and saturated aqueous
NH4Cl, and were then dried (MgSO4) and concentrated.
127.5, 44.8, 40.7 ppm. C9H9BrO2 (229.07): calcd. C 47.19, H 3.96;
found C 47.21, H 3.60.
(S)-2-Bromo-3-[N-(tert-butoxycarbonyl)indol-3-yl]propionic
Acid
(3d):[14b] This compound was prepared from H-Trp(Boc)-OH (5 g,
16.4 mmol), the crude product being purified by flash column
chromatography (Cy/EA/AcOH, 7:3:0.1) to give compound 3d as
an oil (4 g, 67%); Rf = 0.21 (Cy/EA/AcOH, 7:3:0.1). [α]2D0 = –13.2
(c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.87 (br. s, 1 H),
8.10 (br. s, 1 H), 7.51–7.53 (m, 2 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.24
(t, J = 6.8 Hz, 1 H), 4.52 (t, J = 7.6 Hz, 1 H), 3.58 (dd, J = 8.1 Hz,
14.9 Hz, 1 H), 2.93 (dd, J = 6.8 Hz, 14.9 Hz, 1 H), 1.65 (s, 9 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 174.5, 149.6, 135.3, 129.7,
124.7, 124.5, 122.7, 118.5, 115.5, 115.4, 84.0, 43.3, 30.5, 28.2 ppm.
General Procedure for the Aminomethylation: Trimethylsilyl triflate
(1.5 equiv.) and triethylamine (1.1 equiv.) were added successively
to a stirred solution of the sulfonamide derivative (1 equiv.) in
CH2Cl2 (1 mL per mmol) and the mixture was stirred at room tem-
perature for 6 h. A solution of N,N-dibenzyliminium trifluoroacet-
ate salt (1.1 equiv.) in CH2Cl2 (1 mL per mmol) freshly prepared
from N,N,NЈ,NЈ-tetrabenzylmethanediamine[13] was added and the
mixture was stirred for 15 min. TBAF in THF (1 , 1 equiv.) was
added, the reaction was quenched with water, and CH2Cl2 was re-
moved in vacuo. The aqueous layer was extracted with diethyl ether
and the combined organic solutions were washed with a saturated
solution of NH4Cl, dried (MgSO4) and concentrated in vacuo.
(S)-2-Bromo-3-(tert-butoxycarbonyl)propionic Acid (3e):[14b] This
compound was prepared from H-Asp(OtBu)-OH (5 g, 26.4 mmol),
the crude product being purified by flash column chromatography
(Cy/EA/AcOH, 7:3:0.1) to give compound 3e as an oil (11.5 g,
86%); Rf = 0.48 (Cy/EA/AcOH, 6:4:0.1). [α]2D0 = –45.4 (c = 2,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 10.60 (br. s, 1 H), 4.55
General Procedure for the Deprotection and Boc Protection: Pd/C
(10%, 100 mg per mmol) and ammonium formate (5 equiv.) were
added to a solution of the amine in a THF/MeOH mixture (1:4,
5 mL per mmol) and the reaction mixture was stirred at room tem-
perature. The solution was filtered through Celite and concentrated
to give the corresponding amine, which was dissolved in a THF/
water mixture (1:1, 5 mL per mmol). After addition of LiOH
(2 equiv.), the reaction mixture was stirred at room temperature
overnight, the THF was then evaporated, and dioxane (2 mL per
mmol) was added. After addition of Boc2O (1.1 equiv.) and K2CO3
(1.1 equiv.), the solution was stirred for 5 h and then concentrated
to remove organic solvents. After addition of water and extraction
with Et2O, the aqueous layer was cooled to 0 °C, acidified to pH
= 2 with HCl (1 ), and extracted with ethyl acetate. The combined
organic layers were dried and concentrated in vacuo to afford the
Boc-protected amino acid, which was purified by recrystallization
from diethyl ether/pentane.
(S)-2-Bromopropionic Acid (3a):[26] This compound was prepared
from -alanine (50 g, 562 mmol), the crude product being purified
by distillation under reduced pressure (P = 0.06 Torr, T = 63–
64 °C) to give an oil (58.7 g, 68%); Rf = 0.24 (Cy/EA/AcOH,
8:2:0.1). [α]2D0 = –28.5 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 11.54 (br. s, 1 H), 4.42 (q, J = 6.8 Hz, 1 H), 1.85 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.6, 39.4,
21.4 ppm. C3H5BrO2 (152.97): calcd. C 23.55, H 3.29; found C
23.60, H 3.55.
(dd, J = 9.1 Hz, 6.1 Hz, 1 H), 3.18 (dd, J = 9.1 Hz, 16.9 Hz, 1 H),
2.93 (dd, J = 6.1 Hz, 16.9 Hz, 1 H), 1.40 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.8, 168.7, 82.5, 40.7, 38.1, 27.9 ppm.
C9H13BrO2 (233.10): calcd. C 37.96, H 5.18; found C 37.70, H 5.33.
Methyl (S)-2-Bromo-4-methylpentanoate (4b): Ester 4b was purified
by flash column chromatography (Cy/EA, 99:1) to give an oil
(2.5 g, 79%), Rf = 0.67 (Cy/EA, 8:2). [α]2D0 = –49.6 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 4.29 (t, J = 7.6 Hz, 1 H), 3.78
(s, 3 H), 1.86–2.05 (m, 2 H), 1.71–1.81 (m, 1 H), 0.96 (d, J = 6.8 Hz,
3 H), 0.91 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.6, 52.9, 44.3, 43.5, 26.3, 22.3, 21.5 ppm.
Methyl (S)-2-Bromo-3-phenylpropanoate (4c):[29] Ester 4c was puri-
fied by flash column chromatography (Cy/EA, 99:1) to give an oil
(6.8 g, 94%); Rf = 0.33 (Cy/EA, 95:5). [α]2D0 = –11.1 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.17–7.29 (m, 5 H), 4.39 (t, J =
8.3 Hz, 1 H), 3.36 (s, 3 H), 3.45 (dd, J = 8.3 Hz, 14.1 Hz, 1 H),
3.22 (dd, J = 7.1 Hz, 13.9 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.8, 136.7, 129.1, 128.6, 127.3, 52.8, 45.1, 41.0 ppm.
Methyl (S)-2-Bromo-3-[N-(tert-butoxycarbonyl)indol-3-yl]propion-
ate (4d): The crude product was purified by flash column
chromatography (Cy/EA, 97:3) to give compound 4d as an oil (1 g,
59%); Rf = 0.58 (Cy/EA, 8:2). [α]2D0 = –18.6 (c = 1, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 8.12–8.13 (m, 1 H), 7.47–7.53 (m, 2
H), 7.31–7.34 (m, 2 H), 4.50 (dd, J = 8.6 Hz, 6.6 Hz, 1 H), 3.73 (s,
3 H), 3.58 (dd, J = 8.6 Hz, 14.9 Hz, 1 H), 3.35 (dd, J = 6.6 Hz,
14.9 Hz, 1 H), 1.66 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 170.0, 150.0, 135.5, 129.7, 124.7, 124.5, 122.7, 118.6, 115.8, 115.4,
83.8, 53.0, 43.5, 30.8, 20.2 ppm. C17H20BrNO4 (382.25): calcd. C
53.42, H 5.27, N 3.66; found C 53.00, H 5.43, N 3.27.
(S)-2-Bromo-4-methylpentanoic Acid (3b):[27] This compound was
prepared from -leucine (20 g, 153 mmol), the crude product being
purified by distillation under reduced pressure (P = 0.03 Torr, T =
96 °C) to give an oil (20.8 g, 70%); Rf = 0.60 (CH2Cl2/EtOH, 9:1).
[α]2D0 = –39.9 (c = 2, MeOH). 1H NMR (400 MHz, CDCl3): δ =
9.80–10.50 (br. s, 1 H), 4.30 (t, J = 7.5 Hz, 1 H), 1.93 (t, J = 7.5 Hz,
2 H), 1.76–1.90 (m, 1 H), 0.98 (d, J = 6.5 Hz, 3 H), 0.94 (d, J =
6.25 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.4, 44.0,
43.2, 26.3, 22.3, 21.5 ppm.
Methyl (S)-2-Bromo-4-(tert-butoxycarbonyl)propionate (4e): The
crude product was purified by flash column chromatography (Cy/
EA, 97:3) to give compound 4e as an oil (2.9 g, 51%); Rf = 0.53
1
(Cy/EA, 8:2). [α]2D0 = –53.5 (c = 1, CHCl3). H NMR (400 MHz,
CDCl3): δ = 4.53 (dd, J = 9.1 Hz, 6.1 Hz, 1 H), 3.80 (s, 3 H), 3.19
(dd, J = 9.1 Hz, 16.9 Hz, 1 H), 2.91 (dd, J = 6.1 Hz, 16.9 Hz, 1 H),
1.44 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7, 168.6,
(S)-2-Bromo-3-phenylpropionic Acid (3c):[28] This compound was
prepared from -phenylalanine (20 g, 121.2 mmol), the crude prod-
1916
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1912–1920

Asymmetric Aminomethylation for the Synthesis of β2-Amino Acids
FULL PAPER
82.0, 53.1, 40.9, 38.3, 27.9 ppm. C9H15BrO4 (267.12): calcd. C
40.47, H 5.66; found C 40.89, H 5.68.
H), 0.97 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.3, 64.9, 53.0, 48.7, 47.9, 44.5,
43.7, 42.4, 37.5, 32.7, 26.5, 26.4, 22.4, 22.0, 20.7 19.9 ppm.
C16H26BrNO3S (392.35): calcd. C 48.98, H 6.68, N 3.57; found C
48.60, H 6.72, N 3.53.
Methyl 2-[(Dibenzylamino)methyl]propionate (5a): The crude prod-
uct was treated with a solution of TFA in EA (1%) and purified
by flash column chromatography (Cy/EA, 8:2; then Cy/EA/NEt3,
1
(2S)-N-(2-Bromopropionyl)camphorsultam 6b: 68% yield (12.3 g);
Rf = 0.26 (Cy/EA, 9:1); m.p. 132 °C. [α]2D0 = 81.0 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 4.98 (q, J = 6.6 Hz, 1 H), 3.93
(dd, J = 5.3 Hz, 7.3 Hz, 1 H), 3.44 (d, J = 13.9 Hz, 1 H), 3.56 (d,
J = 13.9 Hz, 1 H), 1.98–2.11 (m, 2 H), 1.86–1.95 (m, 3 H), 1.82 (d,
J = 6.8 Hz, 3 H), 1.34–1.46 (m, 2 H), 1.20 (s, 3 H), 0.99 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 168.7, 64.9, 52.9, 48.8,
47.8, 44.5, 39.4, 37.5, 32.8, 26.5, 20.7, 20.5, 19.9 ppm.
C13H20BrNO3S (350.27): calcd. C 44.58, H 5.76, N 4.00; found C
44.59, H 5.83, N 3.95.
8:2:0.1) to give 5a as an oil (3 g, 43%); Rf = 0.61 (Cy/EA, 8:2). H
NMR (400 MHz, CDCl3): δ = 7.19–7.30 (m, 10 H), 3.62 (d, J =
13.4 Hz, 2 H), 3.61 (s, 3 H), 3.46 (d, J = 13.4 Hz, 2 H), 2.73–2.70
(m, 2 H), 2.37–2.44 (m, 1 H), 1.07 (d, J = 6.3 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 176.1, 139.2, 128.9, 128.1, 126.9,
58.4, 57.3, 51.4, 38.6, 15.3 ppm. C19H23NO2 (297.39): calcd. C
76.73, H 7.80, N 4.71; found C 76.87, H 7.99, N 4.65.
Methyl 2-[(Dibenzylamino)methyl]-4-methylpentanoate (5b): The
crude product was treated with a solution of TFA in EA (1%) and
purified by flash column chromatography (Cy/EA, 8:2; then Cy/
EA/NEt3, 8:2:0.1) to give 5b as an oil (4.8 g, 66%); Rf = 0.69 (Cy/
(2S)-N-(2-Bromo-3-phenylpropionyl)camphorsultam 6c:[30] 82%
yield (6.7 g); Rf = 0.23 (Cy/EA, 9:1); m.p. 156–157 °C. [α]2D0 = 84.1
1
EA, 8:2). H NMR (400 MHz, CDCl3): δ = 7.20–7.30 (m, 10 H),
1
(c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 5
3.72 (d, J = 13.6 Hz, 2 H), 3.63 (s, 3 H), 3.36 (d, J = 13.6 Hz, 2
H), 2.73–2.80 (m, 2 H), 2.36–2.39 (m, 1 H), 1.39–1.49 (m, 2 H),
1.15–1.22 (m, 1 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.82 (d, J = 6.6 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.9, 139.2, 128.9,
128.1, 126.9, 58.4, 56.8, 51.3, 42.9, 39.6, 26.3, 23.0, 22.0 ppm.
C22H29NO2 (339.47): calcd. C 77.84, H 8.61, N 4.13; found C
77.61, H 8.73, N 4.04.
H), 5.07 (t, J = 7.1 Hz, 1 H), 3.88 (dd, J = 7.6 Hz, 5 Hz, 1 H), 3.53
(dd, J = 14.2 Hz, 7.0 Hz, 1 H), 3.39 (d, J = 13.9 Hz, 1 H), 3.49 (d,
J = 13.9 Hz, 1 H), 3.25 (dd, J = 7.3 Hz, 14.2 Hz, 1 H), 2.01–2.09
(m, 2 H), 1.89–1.94 (m, 3 H), 1.30–1.41 (m, 2 H), 1.18 (s, 3 H),
0.96 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.7, 136.5,
129.6, 128.5, 127.2, 64.8, 52.9, 48.7, 47.8, 44.8, 44.5, 39.8, 37.5,
32.7, 26.4, 20.7, 19.9 ppm. C19H24BrNO3S (426.37): calcd. C 53.52,
H 5.67, N 3.29; found C 53.31, H 5.80, N 3.35.
Methyl 2-[(Dibenzylamino)methyl]-3-phenylpropionate (5c): Com-
pound 5c was obtained after precipitation in MeOH/CHCl3 as a
white powder (14.6 g, 74%); Rf = 0.65 (Cy/EA, 8:2); m.p. 83 °C.
1H NMR (400 MHz, CDCl3): δ = 7.1–7.3 (m, 15 H), 3.66 (d, J =
13.6 Hz, 2 H), 3.42 (d, J = 13.6 Hz, 2 H), 3.55 (s, 3 H), 2.95–3.00
(m, 3 H), 2.79–2.85 (m, 1 H), 2.75–2.76 (m, 2 H), 2.50–2.54 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.9, 139.2, 139.0,
129.0, 128.7, 128.4, 128.2, 127.0, 126.3, 58.5, 55.9, 51.3, 46.9,
36.4 ppm. C25H27NO2 (373.49): calcd. C 80.40, H 7.29, N 3.75;
found C 80.16, H 7.34, N 3.67.
(2S)-N-{2-Bromo-3-[N-(tert-butoxycarbonyl)indol-3-yl]propionyl}-
camphorsultam 6d: Compound 6d was obtained after purification
by flash column chromatography (Cy/EA, 85:15) as a white powder
(2.3 g, 44%); Rf = 0.18 (Cy/EA, 9:1); m.p. 79 °C. [α]2D0 = 53.8 (c =
1
1, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.1 (m, 1 H), 7.54–
7.60 (m, 2 H), 7.24–7.33 (m, 2 H), 5.15–5.20 (m, 1 H), 3.91 (dd, J
= 5.3 Hz, 7.1 Hz, 1 H), 3.63 (dd, J = 15.2 Hz, 7.1 Hz, 1 H), 3.50
(d, J = 13.6 Hz, 1 H), 3.44 (d, J = 13.6 Hz, 1 H), δ = 3.35 (dd, J
= 15.4 Hz, 7.6 Hz, 1 H), 2.01–2.10 (m, 2 H), 1.82–1.94 (m, 3 H),
1.66 (s, 9 H), 1.30–1.42 (m, 2 H), 1.18 (s, 3 H), 0.96 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 167.7, 149.6, 135.3, 129.9, 124.7,
124.4, 122.6, 118.9, 115.6, 115.2, 83.6, 64.9, 52.9, 48.8, 47.8, 44.5,
43.2, 37.5, 32.7, 29.6, 28.2, 26.4, 20.7, 19.8 ppm.
Methyl
3-[N-(tert-Butoxycarbonyl)indol-3-yl]-2-[(dibenzylamino)-
methyl]propionate (5d): Compound 5d was obtained after flash col-
umn chromatography (Cy/EA, 98:2) as an oil (14.6 g, 73%); Rf =
1
0.53 (Cy/EA, 8:2). H NMR (400 MHz, CDCl3): δ = 8.1 (br. s, 1
H), 7.43 (d, J = 7.6 Hz, 1 H), 7.19–7.31 (m, 14 H), 3.67 (d, J =
13.6 Hz, 2 H), 3.45 (d, J = 13.6 Hz, 2 H), 3.59 (s, 3 H), 3.07–3.13
(m, 1 H), 2.80–2.90 (m, 1 H), 2.59 (dd, 1 H, 5.8 Hz, 12.6 Hz), 1.65
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.1, 149.7,
138.0, 130.3, 128.9, 128.1, 127.0, 124.3, 123.1, 122.4, 118.8, 115.2,
83.4, 58.4, 56.0, 51.5, 44.8, 28.2, 25.7 ppm. MS (CI; NH3): m/z =
513 [M + H]+, 413 [M – Boc]+.
(2S)-N-{2-Bromo-6-[(tert-butoxycarbonyl)amino]hexanoyl}-
camphorsultam 6e: Compound 6e was obtained after purification
by flash column chromatography (Cy/EA, 9:1) as a powder
(430 mg, 70%); Rf = 0.37 (Cy/EA, 8:2); m.p. 110–112 °C. [α]2D0
=
1
42.2 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 4.79 (t, J
= 7.1 Hz, 1 H), 3.93 (dd, J = 5.3 Hz, 7.3 Hz, 1 H), 3.69 (t, J =
7.3 Hz, 2 H), 3.53 (d, J = 13.6 Hz, 1 H), 3.43 (d, J = 13.6 Hz, 1
H), 2.04–2.09 (m, 3 H), 1.90–1.99 (m, 4 H), 1.65 (s, 9 H), 1.19–1.44
(m, 6 H), 1.19 (s, 3 H), 0.98 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.1, 152.1, 85.2, 64.9, 53.0, 48.8, 47.9, 44.5, 44.3,
40.2, 37.6, 33.2, 32.8, 28.1, 26.4, 24.6, 20.7, 19.9 ppm.
Methyl
3-(tert-Butoxycarbonyl)-2-[(dibenzylamino)methyl]propi-
onate (5e): Compound 5e was obtained after flash column
chromatography (Cy/EA, 97:3) as an oil (1.3 g, 72%); Rf = 0.49
(Cy/EA, 8:2). 1H NMR (400 MHz, CDCl3): δ = 7.2–7.4 (m, 10 H),
3.59 (d, J = 13.6 Hz, 2 H), 3.51 (d, J = 13.6 Hz, 2 H), 3.3 (s, 3 H),
3.0–3.1 (m, 1 H), 2.7 (dd, J = 7.3 Hz, 10.2 Hz, 1 H), 2.4–2.6 (m, 3
H), 1.4 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.4,
171.2, 138.9, 128.9, 128.2, 127.0, 126.3, 80.7, 58.3, 55.1, 51.7, 40.5,
35.6, 28.0 ppm. C24H31NO4 (397.51): calcd. C 72.52, H 7.86, N
3.52; found C 72.72, H 7.89, N 3.46.
(2S)-N-{(2R)-2-[(Dibenzylamino)methyl]-4-methylpentanoyl}-
camphorsultam 7a: Compound 7a was obtained by precipitation
from methanol/chloroform as a single diastereoisomer (7.2 g, 64%);
Rf = 0.21 (Cy/EA, 9:1); m.p. 108 °C. [α]2D0 = 69.9 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.18–7.33 (m, 10 H), 3.87 (dd, J
= 5 Hz, 7.6 Hz, 1 H), 3.68 (d, J = 13.9 Hz, 2 H), 3.41–3.52 (m, 5
H), 2.76 (dd, J = 6.3 Hz, 12.4 Hz, 1 H), 2.50 (dd, J = 12.4 Hz,
7.3 Hz, 1 H), 2.00–2.11 (m, 2 H), 1.86–1.92 (m, 4 H), 1.46–1.56 (m,
(2S)-N-(2-Bromo-4-methylpentanoyl)camphorsultam 6a:[30] 61%
yield (8 g); Rf = 0.23 (Cy/EA, 9:1); m.p. 132 °C. [α]2D0 = 59.5 (c =
1
1, CHCl3). H NMR (400 MHz, CDCl3): δ = 4.91 (t, J = 7.3 Hz, 3 H), 1.31–1.42 (m, 2 H), 1.22 (s, 3 H), 0.97 (s, 3 H), 0.87 (d, J =
1 H), 3.93 (dd, J = 4.8 Hz, 7.3 Hz, 1 H), 3.49 (d, J = 13.9 Hz, 2
5.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.9, 139.1,
H), 3.39 (d, J = 13.9 Hz, 2 H), 1.94–2.09 (m, 3 H), 1.88–1.94 (m, 129.1, 128.0, 126.8, 65.5, 58.1, 56.5, 53.2, 48.2, 47.8, 44.6, 42.6,
4 H), 1.74 (m, 1 H), 1.36–1.45 (m, 2 H), 1.20 (s, 3 H), 0.98 (s, 3 38.8, 38.6, 32.9, 26.5, 26.0, 23.0, 22.7, 21.0, 19.9 ppm.
Eur. J. Org. Chem. 2007, 1912–1920
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1917

R. Moumné, B. Denise, K. Guitot, H. Rudler, S. Lavielle, P. Karoyan
FULL PAPER
C31H42N2O3S (522.74): calcd. C 71.23, H 8.10, N 5.36; found C
71.05, H 8.30, N 5.11.
H), 2.04–2.13 (m, 2 H), 1.86–1.96 (m, 3 H), 1.54–1.63 (m, 2 H),
1.16 (s, 3 H), 0.97 (s, 3 H), 0.90 (d, J = 6.3 Hz, 3 H), 0.89 (d, J =
6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3, 65.2,
53.0, 48.4, 47.7, 44.6, 38.5, 33.6, 33.2, 32.8, 27.6, 26.5, 22.3, 22.2,
20.8, 19.9 ppm. C16H27NO3S (313.46): calcd. C 61.31, H 8.68, N
4.47; found C 61.15, H 8.85, N 4.41.
(2S)-N-{2-[(Dibenzylamino)methyl]propionyl}camphorsultam 7b:
Compound 7b was obtained as a mixture of diastereoisomers
1
(72:28); Rf = 0.39 (Cy/EA, 8:2); major diastereoisomer. H NMR
(400 MHz, CDCl3): δ = 7.2–7.3 (m, 10 H), 3.9 (dd, J = 7.6 Hz,
5.1 Hz, 1 H), 3.6 (s, 4 H), 3.4–3.5 (m, 3 H), 2.9 (dd, J = 7.6 Hz,
(2S)-N-(3-Phenylpropanoyl)camphorsultam 9d:[ 3 1 ] 92 %
12.6 Hz, 1 H), 2.4 (dd, J = 6.3 Hz, 12.6 Hz, 1 H), 2.0–2.1 (m, 1 H), yield (11.9 g); Rf = 0.37; (Cy/EA, 8:2); m.p. 149 °C. [α]2D0 = 82.2 (c
1
2.0 (dd, J = 7.6 Hz, 13.9 Hz, 1 H), 2.02–2.11 (m, 2 H), 1.86–1.91 = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.2–7.3 (m, 5 H),
(m, 3 H), 1.3–1.4 (m, 2 H), 1.2 (s, 3 H), 1.1 (s, 3 H), 1.0 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 175.3, 138.9, 128.0, 126.8,
65.4, 57.9, 57.8, 53.1, 48.2, 47.7, 44.7, 38.6, 38.4, 32.9, 26.4, 21.0,
19.9, 15.5 ppm.
3.86 (t, J = 6.3 Hz, 1 H), 3.48 (d, J = 13.6 Hz, 1 H), 3.41 (d, J =
13.6 Hz, 1 H), 3.0–3.1 (m, 4 H), 2.0–2.1 (m, 2 H), 1.8–1.9 (m, 3
H), 1.3–1.4 (m, 2 H), 1.08 (s, 3 H), 0.95 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.1, 140.1, 128.5, 128.4, 126.2, 65.2, 52.9,
48.4, 47.7, 44.6, 38.4, 36.9, 32.8, 30.4, 26.4, 20.8, 19.9 ppm.
C19H25NO3S (347.47) calcd. C 65.68, H 7.25, N 4.03; found C
65.40, H 7.35, N 3.99.
(2S)-N-{2-[(Dibenzylamino)methyl]-3-phenylpropionyl}camphor-
sultam 7c: Compound 7c was obtained after purification by flash
column chromatography (Cy/EA, 9:1) as a mixture of diastereoiso-
mers (87:13, 5.1 g, 57 %), Rf = 0.41 (Cy/EA, 8:2). 1H NMR
(400 MHz, CDCl3): δ = 7.16–7.26 (m, 15 H), 3.86 (dd, J = 7.6 Hz,
5.1 Hz, 1 H), 3.73 (m, 1 H), 3.41–3.54 (m, 6 H), 3.04 (dd, J =
13.6 Hz, 5.6 Hz, 1 H), 2.92 (dd, J = 12.6 Hz, 8.1 Hz, 1 H), 2.65
(dd, J = 13.6 Hz, 8.6 Hz, 1 H), 2.49 (dd, J = 12.6 Hz, 5.3 Hz, 1 H),
2.02–2.11 (m, 2 H), 1.87–1.91 (m, 3 H), 1.31–1.38 (m, 2 H), 1.24
(s, 3 H), 0.98 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.1, 139.3, 138.7, 129.4, 129.1, 128.3, 128.0, 126.8, 126.2, 65.4,
57.7, 55.7, 53.2, 48.3, 47.8, 44.9, 44.8, 38.6, 36.0, 32.9, 26.5, 20.1,
19.9 ppm.
(2S)-N-Octanoylcamphorsultam 9e: This compound, obtained as an
oil, was purified by flash column chromatography (Cy/EA, 95:5),
92% yield (7.32 g); Rf = 0.61 (Cy/EA, 8:2). [α]2D0 = 88.4 (c = 1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.86 (dd, J = 7.3 Hz,
5.3 Hz, 1 H), 3.49 (d, J = 13.9 Hz, 1 H), 3.43 (d, J = 13.9 Hz, 1
H), 2.68–2.73 (m, 2 H), 2.08–2.12 (m, 2 H), 1.86–1.91 (m, 2 H),
1.63–1.69 (m, 2 H), 1.21–1.41 (m, 12 H), 1.16 (s, 3 H), 0.97 (s, 3
H), 0.87 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 65.2, 52.9, 48.3, 47.7, 44.6, 38.5, 35.4, 32.8, 31.6, 28.97, 28.92,
26.9, 26.4, 24.4, 22.5, 20.8, 19.8, 14.0 ppm. C18H31NO3S (341.51):
calcd. C 63.31, H 9.15, N 4.10; found C 63.40, H 9.28, N 4.07.
(2S)-N-{6-[(tert-Butoxycarbonyl)amino]-2-[(dibenzylamino)-
methyl]hexanoyl}camphorsultam 7e: Compound 7e was obtained af-
ter purification by flash column chromatography (Cy/EA, 9:1) as a
mixture of diastereoisomers (251 mg, 47%); Rf = 0.41 (Cy/EA, 8:2).
1H NMR (400 MHz, CDCl3): δ = 7.18–7.34 (m, 10 H), 3.86 (t, J
= 7.2 Hz, 1 H), 3.54–3.80 (m, 4 H), 3.45–3.53 (m, 3 H), 2.29–3.34
(m, 2 H), 2.75 and 2.69 (dd, J = 12.2 Hz, 6.2 Hz and dd, J =
13.5 Hz, 4.7 Hz, 1 H), 2.57 and 2.48 (dd, J = 13 Hz, 8.7 Hz and
dd, J = 12.5 Hz, 7.2 Hz, 1 H), 2.03–2.06 (m, 2 H), 1.86–1.89 (m, 3
H), 1.52–1.64 (m, 13 H), 1.13–1.37 (m, 7 H), 0.96 and 0.98 (s and
s, 3 H) ppm.
(2S)-N-(6-Bromohexanoyl)camphorsultam 9f: Compound 9f was
obtained by crystallization from ethanol, 82% yield (7.56 g); Rf =
1
0.49 (Cy/EA, 8:2); m.p. 54–55 °C. [α]2D0 = 87.8 (c = 1, CHCl3). H
NMR (400 MHz, CDCl3): δ = 3.86 (dd, J = 7.4 Hz, 5.3 Hz, 1 H),
3.50 (d, J = 13.6 Hz, 1 H), 3.43 (d, J = 13.6 Hz, 1 H), 3.40 (t, J =
6.8 Hz, 2 H), 2.71–2.75 (m, 2 H), 2.04–2.12 (m, 2 H), 1.85–1.92 (m,
5 H), 1.65–1.74 (m, 2 H), 1.33–1.53 (m, 4 H), 1.15 (s, 3 H), 0.97 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.6, 65.2, 52.9,
48.4, 47.7, 44.6, 38.5, 35.1, 33.5, 32.8, 32.4, 27.5, 26.4, 23.5, 20.8,
19.9 ppm. C16H26NO4SBr (408.35): calcd. C 48.98, H 6.68, N 3.57;
found C 48.93, H 6.75, N 3.57.
(2S)-N-Propionylcamphorsultam 9a:[31] 91% yield (5.7 g); Rf = 0.43
(Cy/EA, 8:2); m.p. 145 °C. [α]2D0 = 116.5 (c = 1, CHCl3). H NMR
1
(2S)-N-[3-(N-Benzylindol-3-yl)propanoyl]camphorsultam 9g: Com-
pound 9g was obtained from 3-(N-benzylindol-3-yl)propionic acid.
A stirred solution of 3-(indol-3-yl)propionic acid (10 g, 52.9 mmol)
in DMF (55 mL) was cooled to 0 °C and NaH (4.66 g, 116.4 mmol)
was added in small portions. The mixture was stirred at 0 °C for
30 min and benzyl bromide (6.6 mL, 55.54 mmol) was added. After
the mixture had been stirred for 1 h, the reaction was quenched
with water, the mixture acidified to pH = 2, and extracted with
diethyl ether. The combined organic layers were washed with satu-
rated aqueous NH4Cl, dried and concentrated in vacuo. Purifica-
tion by flash column chromatography (Cy/EA/AcOH, 7:3:0.1) gave
3-(N-benzylindol-3-yl)propionic acid as a white solid, 75% yield
(400 MHz, CDCl3): δ = 3.86 (dd, J = 7.6 Hz, 5.1 Hz, 1 H), 3.49 (d,
J = 13.9 Hz, 1 H), 3.43 (d, J = 13.9 Hz, 1 H), 2.69–2.81 (m, 2 H),
2.04–2.16 (m, 1 H), 2.07 (dd, J = 13.6 Hz, 7.6 Hz, 1 H), 1.85–1.96
(m, 3 H), 1.32–1.44 (m, 2 H), 1.16 (t, 3 H, 7.3 Hz), 1.16 (s, 3 H),
0.97 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.6, 65.2,
52.9, 48.5, 47.7, 44.6, 38.5, 32.8, 28.9, 26.4, 20.8, 19.9, 8.39 ppm.
C13H21NO3S (271.38): calcd. C 57.54, H 7.80, N 5.16; found C
57.60, H 7.83, N 5.07.
(2R)-N-(3-Methylbutanoyl)camphorsultam 9b:[31] 93% yield (6.4 g),
Rf = 0.45 (Cy/EA, 8:2), m.p. 114 °C. [α]2D0 = –88.4 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 3.88 (t, J = 6.3 Hz, 1 H), 3.50
(d, J = 13.6 Hz, 1 H), 3.43 (d, J = 13.6 Hz, 1 H), 2.66 (dd, J =
15.6 Hz, 7.0 Hz, 1 H), 2.51 (dd, J = 15.6 Hz, 6.8 Hz, 1 H), 2.18–
2.28 (m, 1 H), 2.08–2.1 (m, 2 H), 1.87–1.96 (m, 3 H), 1.32–1.44 (m,
2 H), 1.16 (s, 3 H), 0.97 (s and t, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.5, 65.2, 53.0, 48.2, 47.7, 44.6, 44.2, 38.6, 32.8,
26.4, 25.5, 22.3, 22.2, 20.8, 19.8 ppm. C15H25NO3S (299.43): calcd.
C 60.17, H 8.42, N 4.68; found C 60.15, H 8.48, N 4.61.
1
(11 g); Rf = 0.25 (Cy/EA, 8:2); m.p. 117 °C. H NMR (400 MHz,
CDCl3): δ = 7.60 (d, J = 7.6 Hz, 1 H), 7.22–7.29 (m, 5 H), 7.17 (t,
J = 7.1 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.1 Hz, 1
H), 6.93 (s, 1 H), 5.24 (s, 2 H), 3.71 (t, J = 7.6 Hz, 2 H), 2.76 (t, J
= 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.5,
137.6, 136.7, 128.7, 127.7, 127.5, 126.7, 125.6, 121.9, 119.1, 118.8,
113.8, 109.7, 49.9, 34.8, 20.4 ppm. C18H17NO2: calcd. C 77.40, H
6.13, N 5.01; found C 77.12, H 6.37, N 4.89. Compound 9g was
obtained from this compound according to the general procedure
and purified by flash column chromatography (Cy/EA, 8:2), white
solid, 70% yield (4.7 g), Rf = 0.42 (Cy/EA/NEt3, 8:2:0.1), m.p.
(2S)-N-(4-Methylpentanoyl)camphorsultam 9c:[31] 81 % yield
(5.84 g); Rf = 0.44 (Cy/EA, 8:2); m.p. 44 °C. [α]2D0 = 97.6 (c = 1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.85–3.88 (m, 1 H), 3.50
(d, J = 13.9 Hz, 1 H), 3.43 (d, J = 13.9 Hz, 1 H), 2.66–2.76 (m, 2
1
123 °C. [α]2D0 = 57.4 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
1918
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1912–1920

Asymmetric Aminomethylation for the Synthesis of β2-Amino Acids
δ = 7.63–7.65 (m, 1 H), 7.20–7.28 (m, 4 H), 7.07–7.16 (m, 4 H), 11 H), 0.97 (s, 3 H), 0.86 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
FULL PAPER
6.97 (s, 1 H), 5.23 (s, 2 H), 3.85 (t, J = 6.3 Hz, 1 H), 3.45 (d, J =
13.9 Hz, 1 H), 3.42 (d, J = 13.9 Hz, 1 H), 3.06–3.19 (m, 4 H), 2.03–
2.05 (m, 2 H), 1.81–1.87 (m, 3 H), 1.29–1.39 (m, 2 H), 1.05 (s, 3
H), 0.92 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.5,
137.7, 136.6, 128.7, 127.9, 127.4, 126.7, 125.8, 121.7, 119.1, 119.0,
113.8, 109.5, 65.2, 52.9, 49.8, 48.4, 47.7, 44.6, 38.5, 36.1, 32.8, 26.4,
20.7, 20.2, 19.8 ppm. C28H32N2O3S (476.63): calcd. C 70.56, H
6.77, N 5.88; found C 70.31, H 6.98, N, 5.67.
(100 MHz, CDCl3): δ = 174.8, 139.0, 129.1, 128.0, 126.8, 65.4, 58.0,
56.4, 53.3, 48.2, 47.8, 44.7, 44.2, 38.6, 38.6, 32.9, 31.6, 30.1, 29.4,
27.2, 26.5, 21.0, 19.9, 14.1 ppm. C33H46N2O3S (550.79): calcd. C
71.96, H 8.42, N 5.09; found C 71.67, H 8.62, N 4.94.
(2S)-N-{(2R)-6-Bromo-2-[(dibenzylamino)methyl]hexanoyl}-
camphorsultam 11f: Purification by flash column chromatography
(Cy/EA, 9:1), 76 % yield (14.6 g); Rf = 0.47 (Cy/EA, 8:2); m.p.
1
90 °C. [α]2D0 = 57.3 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
(2S)-N-{(2R)-2-[(Dibenzylamino)methyl]propanoyl}camphorsultam
11a: Crystallization from CHCl3/MeOH, 91% yield (16.7 g); Rf =
0.39 (Cy/EA, 8:2); m.p. 143 °C. [α]2D0 = 50.2 (c = 1, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.2–7.3 (m, 10 H), 3.9 (dd, J =
7.6 Hz, 5.1 Hz, 1 H), 3.6 (s, 4 H), 3.4–3.5 (m, 3 H), 2.9 (dd, J =
7.6 Hz, 12.6 Hz, 1 H), 2.4 (dd, J = 6.3 Hz, 12.6 Hz, 1 H), 2.0–2.1
(m, 1 H), 2.0 (dd, J = 7.6 Hz, 13.9 Hz, 1 H), 2.02–2.11 (m, 2 H),
1.86–1.91 (m, 3 H), 1.3–1.4 (m, 2 H), 1.2 (s, 3 H), 1.1 (s, 3 H), 1.0
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.3, 138.9,
128.0, 126.8, 65.4, 57.9, 57.8, 53.1, 48.2, 47.7, 44.7, 38.6, 38.4, 32.9,
26.4, 21.0, 19.9, 15.5 ppm. C28H36N2O3S (480.66): calcd. C 69.96,
H 7.55, N 5.83; found C 69.85, H 7.67, N 5.92.
δ = 7.20–7.40 (m, 10 H), 3.87 (dd, J = 7.3 Hz, 5.3 Hz, 1 H), 3.68
(d, J = 13.6 Hz, 2 H), 3.51 (d, J = 13.9 Hz, 1 H), 3.47 (d, J =
13.6 Hz, 2 H), 3.43 (d, J = 13.9 Hz, 1 H), 3.31–3.37 (m, 3 H), 2.77
(dd, J = 12.6 Hz, 6.6 Hz, 1 H), 2.52 (dd, J = 12.6 Hz, 7.3 Hz, 1 H),
2.03–2.07 (m, 2 H), 1.86–1.90 (m, 3 H), 1.77–1.81 (m, 2 H), 1.56–
1.60 (m, 2 H), 1.33–1.42 (m, 4 H), 1.21 (s, 3 H), 0.97 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 174.4, 139.0, 129.0, 128.1, 126.9,
65.4, 58.2, 56.3, 53.2, 48.2, 47.7, 44.6, 44.0, 38.5, 33.5, 32.9, 32.8,
28.9, 26.4, 25.7, 21.0, 19.9 ppm. MS (ESI+): m/z = 603 [M + H]+.
(2S)-N-{(2R)-3-(N-Benzylindol-3-yl)-2-[(dibenzylamino)methyl]-
propanoyl}camphorsultam 11g: Purification by flash column
chromatography (Cy/EA, 9:1), 88% yield (5.8 g); Rf = 0.35 (Cy/
EA, 8:2); m.p. 80–81 °C. [α]2D0 = 25.0 (c = 1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.78–7.80 (m, 1 H), 7.09–7.34 (m, 16 H),
6.99–7.01 (m, 2 H), 6.85 (s, 1 H), 5.20 (s, 2 H), 3.88 (m, 2 H), 3.42–
3.52 (m, 6 H), 3.21 (dd, J = 14.4 Hz, 3.8 Hz, 1 H), 2.94 (dd, J =
12.4 Hz, 10.3 Hz, 1 H), 2.86 (dd, J = 14.4 Hz, 9.1 Hz, 1 H), 2.56
(dd, J = 12.6 Hz, 4.5 Hz, 1 H), 2.06–2.15 (m, 2 H), 1.85–1.87 (m,
3 H), 1.30–1.37 (m, 2 H), 1.23 (s, 3 H), 0.96 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 174.7, 138.7, 137.9, 136.6, 129.1,
128.6, 128.4, 127.9, 127.0, 126.7, 126.6, 121.6, 119.6, 112.4, 109.4,
65.4, 57.5, 55.8, 53.2, 49.8, 48.3, 47.7, 44.7, 38.6, 32.8, 26.5, 25.8,
21.0, 19.9 ppm. C43H47N3O3S (685.92): calcd. C 75.29, H 6.91, N
6.13; found C 75.45, H 7.20, N 5.81.
(2R)-N-{(2S)-2-[(Dibenzylamino)methyl]-3-methylbutanoyl}-
camphorsultam 11b: Purification by flash column chromatography
(Cy/EA, 92:8), 81 % yield (8.3 g); Rf = 0.45 (Cy/EA, 8:2); m.p.
1
96 °C. [α]2D0 = –41.4 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
δ = 7.19–7.31 (m, 10 H), 3.88 (dd, J = 5.0 Hz, 7.6 Hz, 1 H), 3.64
(d, J = 13.6 Hz, 1 H), 3.51 (d, J = 13.6 Hz, 1 H), 3.49 (d, J =
13.9 Hz, 1 H), 3.43 (d, J = 13.6 Hz, 1 H), 3.27–3.29 (m, 1 H), 2.93
(dd, J = 9.1 Hz, 12.6 Hz, 1 H), 2.59 (dd, J = 3.8 Hz, 12.9 Hz, 1 H),
2.16–2.20 (m, 1 H), 1.98–2.08 (m, 2 H), 1.87–1.94 (m, 3 H), 1.31–
1.41 (m, 2 H), 1.25 (s, 3 H), 0.97 (s, 3 H), 0.91 (d, J = 7.1 Hz, 3
H), 0.88 (d, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 174.3, 138.9, 129.3, 128.0, 126.8, 65.7, 57.8, 53.4, 53.3, 48.5,
48.0, 47.7, 44.7, 38.7, 32.9, 29.1, 26.5, 21.1, 20.9, 19.9, 18.5 ppm.
C30H40N2O3S (508.72): calcd. C 70.83, H 7.93, N 5.51; found C
70.22, H 7.99, N 5.45. MS (ESI+): m/z = 509 [MH+].
(R)-2-{[(tert-Butoxycarbonyl)amino]methyl}propionic Acid (12a):
68% yield (4.6 g), Rf = 0.20 (CH2Cl2/MeOH/AcOH, 99:1:0.1); m.p.
89–90 °C. [α]2D0 = –17.7 (c = 1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 10.6 (br. s, 1 H), 6.43 and 5.08 (br. s, 1 H), 3.21–3.39
(m, 2 H), 2.65–2.74 (m, 1 H), 1.47 and 1.44 (s, 9 H), 1.2 (d, J =
7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.9, 179.6,
157.8, 156.1, 81.1, 79.6, 44.1, 42.7, 40.3, 40.0, 28.4, 14.6 ppm.
C9H17NO4 (203.24): calcd. C 53.19, H 8.43, N 6.89; found C 53.41,
H 8.42, N 6.85.
(2S)-N-{(2R)-2-[(Dibenzylamino)methyl]-4-methylpentanoyl}-
camphorsultam 11c: Purification by flash column chromatography
(Cy/EA, 9:1), 82% yield (2.7 g); analytical data are identical to
those of compound 7a obtained by the Reformatsky reaction.
(2S)-N-{(2R)-2-[(Dibenzylamino)methyl]-3-phenylpropanoyl}-
camphorsultam 11d: Purification by flash column chromatography
(Cy/EA, 9:1), 76% yield (9.3 g); Rf = 0.41 (Cy/EA, 8:2); m.p. 59 °C.
[α]2D0 = 45.6 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.16–
7.26 (m, 15 H), 3.86 (dd, J = 7.6 Hz, 5.1 Hz, 1 H), 3.73 (m, 1 H),
3.41–3.54 (m, 6 H), 3.04 (dd, J = 13.6 Hz, 5.6 Hz, 1 H), 2.92 (dd,
J = 12.6 Hz, 8.1 Hz, 1 H), 2.65 (dd, J = 13.6 Hz, 8.6 Hz, 1 H), 2.49
(dd, J = 12.6 Hz, 5.3 Hz, 1 H), 2.02–2.11 (m, 2 H), 1.87–1.91 (m,
3 H), 1.31–1.38 (m, 2 H), 1.24 (s, 3 H), 0.98 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 174.1, 139.3, 138.7, 129.4, 129.1,
128.3, 128.0, 126.8, 126.2, 65.4, 57.7, 55.7, 53.2, 48.3, 47.8, 44.9,
44.8, 38.6, 36.0, 32.9, 26.5, 20.1, 19.9 ppm. C34H40N2O3S (556.76):
calcd. C 73.35, H 7.24, N 5.03; found C 73.01, H 7.31, N 4.90.
(S)-2-{[(tert-Butoxycarbonyl)amino]methyl}-4-methylbutanoic Acid
(12b): 59% yield (1.7 g), Rf = 0.30 (Cy/EA/AcOH, 7:3:0.1); m.p.
78 °C. [α]2D0 = 6.9 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ
1
= 6.89 and 5.05 (br. s, 1 H), 3.37–3.47 (m, 1 H), 3.20–3.27 (m, 0.3
H), 3.06–3.17 (m, 0.6 H), 2.42–2.49 (m, 1 H), 1.87–2.03 (m, 1 H),
1.48 and 1.44 (s, 9 H), 0.97 and 0.99 (d, J = 6.6 Hz, 6 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 178.2, 158.3, 81.1, 52.7, 52.0, 40.6,
39.5, 28.9, 28.4, 26.4, 20.4, 20.3, 19.8 ppm. C10H19NO4 (217.26):
calcd. C 57.12, H 9.15, N 6.06; found C 56.98, H 9.29, N 5.98.
(R)-2-{[(tert-Butoxycarbonyl)amino]methyl}-4-methylpentanoic Acid
(2S)-N-{(2R)-2-[(Dibenzylamino)methyl]octanoyl}camphorsultam (12c): 80% yield (2.3 g), Rf = 0.21 (Cy/EA/AcOH, 8:2:0.1); m.p.
1
11e: Purification by flash column chromatography (Cy/EA, 95:5),
74% yield (12.98 g); Rf = 0.5 (Cy/EA, 8:2); m.p. 60 °C. [α]2D0 = 13.7
(c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.21–7.32 (m,
74 °C. [α]2D0 = –3.1 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
δ = 6.76 and 5.02 (br. s, 1 H), 3.32–3.41 (m, 1 H), 3.19–3.26 and
3.00–3.07 (m, 1 H), 2.68–2.70 (m, 1 H), 1.64–1.72 (m, 1 H), 1.52–
10 H), 3.88 (dd, J = 7.6 Hz, 5.3 Hz, 1 H), 3.65 (d, J = 13.6 Hz, 1 1.60 (m, 1 H), 1.44–1.48 (s, 9 H), 1.19–1.35 (m, 3 H), 0.93 (d, J =
H), 3.51 (d, J = 13.6 Hz, 1 H), 3.50 (d, J = 13.9 Hz, 1 H), 3.43 (d,
6.1 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
J = 13.9 Hz, 1 H), 3.34–3.38 (m, 1 H), 2.80 (dd, J = 12.6 Hz, CDCl3): δ = 180.8, 179.4, 155.9, 158.1, 79.6, 81.1, 43.7, 44.1, 41.7,
7.1 Hz, 1 H), 2.52 (dd, J = 12.6 Hz, 6.8 Hz, 1 H), 2.01–2.12 (m, 2 43.0, 38.6, 39.0, 28.4, 25.8, 22.4 ppm. C12H23NO4 (245.32): calcd.
H), 1.86–1.93 (m, 3 H), 1.55 (m, 2 H), 1.27–1.42 (m, 2 H), 1.22 (m, C 58.75, H 9.45, N 5.71; found C 58.84, H 9.59, N 5.61.
Eur. J. Org. Chem. 2007, 1912–1920
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1919

R. Moumné, B. Denise, K. Guitot, H. Rudler, S. Lavielle, P. Karoyan
FULL PAPER
Daura, K. Gademann, H. Schäfer, B. Jaun, D. Seebach, W. F.
Van Gunsteren, J. Am. Chem. Soc. 2001, 123, 2393.
[6] T. Hintermann, D. Seebach, Helv. Chim. Acta 1998, 81, 2093;
R. Sebesta, D. Seebach, Helv. Chim. Acta 2003, 86, 4061; D.
Seebach, K. Namoto, Y. R. Mahajan, P. Bindschädler, Chem.
Biodiversity 2004, 1, 65 and references cited therein.
[7] E. Juaristi, V. A. Soloshonok in Enantioselective Synthesis of
Beta-Amino Acids, 2nd ed., John Wiley & Sons, New York,
2005; G. Lelais, D. Seebach, Biopolymers (Peptides Science)
2004, 76, 206.
[8] Y. Chi, S. H. Gellman, J. Am. Chem. Soc. 2006, 128, 6804.
[9] a) N-(Chloromethyl)benzamide, see: D. A. Evans, F. Urpi, T. C.
Somers, J. S. Clark, M. T. Bilodeau, J. Am. Chem. Soc. 1990,
112, 8215; b) 1-[(benzoylamino)methyl]benzotriazole, see A. R.
Katritzky, X. Lan, W.-Q. Fan, Synthesis 1994, 445; c) N-(bro-
momethyl)phthalimide, see: M. Calmes, F. Escale, C. Glot, M.
Rolland, J. Martinez, Eur. J. Org. Chem. 2000, 2459.
[10] P. Karoyan, S. Lavielle, R. Moumne, H. Rudler, B. Denise,
Patent No. 0508890, August 30th, 2005; R. Moumne, S. Lavi-
elle, P. Karoyan, J. Org. Chem. 2006, 71, 3332.
[11] A. Fürstner, Synthesis 1989, 571; R. Ocampo, W. R. Dolbier Jr,
Tetrahedron 2004, 60, 9325.
(R)-2-{[(tert-Butoxycarbonyl)amino]methyl}-3-phenylpropionic acid
(12d): 73% yield (1.6 g); Rf = 0.21 (Cy/EA/AcOH, 8:2:0.1); m.p.
1
74 °C. [α]2D0 = 16.9 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
δ = 9.65 (br. s, 1 H), 7.18–7.30 (m, 5 H), 6.67 and 5.01 (br. s, 1 H),
3.37–3.41 (m, 0.5 H), 3.22–3.27 (m, 1 H), 2.80–3.11 (m, 3 H), 2.63–
2.72 (m, 0.5 H), 1.37–1.42 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 179.01, 179.28, 155.91, 157.98, 138.19, 138.06, 128.91,
128.77, 126.62, 79.73, 81.19, 47.17, 47.53, 41.25, 42.01, 35.66,
35.82 ppm. C15H21NO4 (279.33): calcd. C 64.50, H 7.58, N 5.01;
found C 64.19, H 7.62, N 4.90.
(R)-2-{[N-(tert-Butoxycarbonyl)amino]methyl}octanoic Acid (12e):
Purification by flash column chromatography (Cy/EA/AcOH,
85:15:1), 44% yield (0.87 g). 1H NMR (400 MHz, CDCl3): δ = 6.63
and 5.01 (br. s, 1 H), 3.34–3.40 (m, 2 H), 3.23–3.28 (m, 2 H), 3.10–
3.12 (m, 2 H), 2.61 (m, 1 H), 1.27–1.64 (m, 19 H), 0.88 (t, J =
6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 180.7, 180.0,
158.2, 156.1, 81.3, 79.7, 45.8, 42.8, 41.5, 31.7, 29.8, 29.3, 28.5, 27.1,
22.7, 14.2 ppm. The amino acid was crystallized as its dicyclohex-
ylamine (DCHA) salt from diethyl ether (700 mg, 24 %); m.p.
103 °C. [α]2D0 = –3.73 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 8.10 (br. s, 2 H), 5.51 and 5.20 (br. s, 1 H), 3.29–3.35 (m, 1 H),
3.11–3.18 (m, 1 H), 2.89–2.96 (m, 2 H), 2.62–2.31 (m, 1 H), 1.99–
2.02 (m, 4 H), 1.78–1.81 (m, 4 H), 1.58–1.66 (m, 3 H), 1.12–1.42
(m, 28 H), 0.86 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 180.02, 156.1, 78.5, 52.5, 47.6, 42.5, 31.8, 30.8, 29.6,
28.5, 27.7, 25.3, 24.8, 22.6, 14.1 ppm. C26H50N2O4 (454.69): calcd.
C 68.68, H 11.48, N 6.13; found C 68.44, H 11.63, N 6.05.)
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Acknowledgments
This work is part of the PhD Thesis of R. M., who is grateful to
Senn Chemicals for the financial support.
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Received: October 23, 2006
Published Online: February 27, 2007
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