Benzyl N-[(benzyloxy)methyl]carbamate: An improved aminomethylation electrophile for the synthesis of (benzyloxy)carbonyl (Cbz)-protected chiral β2-amino acids

Article abstract of DOI:10.1002/hlca.200900401

α-Aminomethylation of (R)-DIOZ-alkylated (DIOZ=4-isopropyl-5,5- diphenyloxazolidin-2-one) substrates is a key step in the asymmetric synthesis of β²-amino acids, but it is unfortunately often accompanied by formation of transcarbamation by-prod

Full text of DOI:10.1002/hlca.200900401

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Benzyl N-[(Benzyloxy)methyl]carbamate: An Improved Aminomethylation
Electrophile for the Synthesis of (Benzyloxy)carbonyl (Cbz)-Protected Chiral
b2-Amino Acids
by Cara E. Brocklehurst*, Markus Furegati*, J. Constanze D. Mꢀller-Hartwieg, Flavio Ossola, and
Luigi La Vecchia
Preparation Laboratories, Global Discovery Chemistry, Novartis Institutes for Biomedical Research,
Klybeckstrasse 141, CH-4057 Basel
(phone: þ 41616964576; fax: þ 41616968016; e-mail: markus.furegati@novartis.com)
a-Aminomethylation of (R)-DIOZ-alkylated (DIOZ ¼ 4-isopropyl-5,5-diphenyloxazolidin-2-one)
substrates is a key step in the asymmetric synthesis of b2-amino acids, but it is unfortunately often
accompanied by formation of transcarbamation by-products. Aminomethylation was tested using a range
of electrophiles, and the amount of by-product formation was assessed in each case. Benzyl N-
[(benzyloxy)methyl]carbamate electrophile 3d is unable to form this by-product due to its inherent
benzyl substitution. Use of electrophile 3d showed an improved impurity profile in aminomethylation,
thus leading to easier intermediate purification.
Introduction. – b-Peptides are well-known to form highly stable secondary
structures such as helices, turns, and sheets [1 – 8], which can be designed so as to
mimic the activity-related structural features of natural peptides or proteins [9 – 14].
Peptides constructed from b-amino acids exhibit increased stability towards degrading
and metabolizing enzymes in living organisms [15][16], compared to their natural
counterparts, the a-peptides. For example, b-peptide-based antibiotics are being
explored as ways of evading antibiotic resistance [17].
Work on the synthesis of b-amino acids, in which an additional CH2 group is
inserted either between the C¼O group and the C(a)-atom (b3), or between the C(a)-
and N-atom (b2) was pioneered by Seebach et al. [18], and Gellman and co-workers
[19]. Given the diversity of functional groups attached to the C(b)-atom and the
difficulties in maintaining chirality, the chemical synthesis of b-amino acids is especially
challenging. Since many b3-amino acids are already commercially available, we turned
our attention to the synthesis of b2-amino acids as highly interesting building blocks for
the synthesis of drug candidates.
Results and Discussion. – Several diastereoselective methods to give b2-amino acids
are described in the literature [20][21]. One strategy for the synthesis of such building
blocks is the highly diastereoselective aminoalkylation of N-acyloxazolidinone-derived
titanium enolates with suitable electrophiles [22 – 24]. An example is the asymmetric
synthesis of Cbz-(S)-b2-hPhe-OH (5), outlined in Scheme 1, using chiral auxiliary, (R)-
4-isopropyl-5,5-diphenyloxazolidin-2-one ((R)-DIOZ; 1) [25][26]. The synthesis was
performed according to a method developed by Seebach and co-workers [27 – 31] and
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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carried out on large scale (100 g of 5) in our laboratories. Attachment and removal of
the auxiliary occurred smoothly (steps 1 and 3; Scheme 1). The key aminomethylation
step delivers a (benzyloxy)carbonyl (Cbz)-protected amine side chain. Recently,
Hartman et al. described the synthesis and use of the corresponding 9H-fluoren-9-yl N-
(acetoxymethyl)carbamate (Fmoc variant) as an electrophile under Lewis acid
catalysis (ZnCl2 or BF3) with achiral C-atom nucleophiles [32]. When we performed
the Ti-catalyzed aminomethylation (or Mannich) step (step 2; Scheme 1), utilizing
benzyl N-(methoxymethyl)carbamate (3a) as the electrophile, the reaction was
accompanied by formation of the by-product 6a (Fig.). The impurity forms, in up to
15% yield (HPLC), via nucleophilic substitution of the productꢂs benzyloxy group of
Cbz, by the MeO leaving group formed, when the reactive electrophile
(CbzþNH¼CH2) is created in situ.
Scheme 1. Synthesis of Cbz-(S)-b2-hPhe-OH (5), Starting from (R)-DIOZ (1) and Using Methyl
Electrophile 3a for the Aminomethylation Step
Figure. Structure of the main by-product 6a isolated after aminomethylation
with methyl electrophile 3a
Formation of this by-product led to difficulties in purifying this material on large
scale. The material was purified by column chromatography on kilograms of silica,
which was made more complicated by the presence of the close-running by-product 6a.
However, observation of this by-product is not unknown, and a recent publication of
Seebach and co-workers, in collaboration with our group, outlines the use of benzyl N-
(isopropoxymethyl)carbamate (3b; Scheme 2) in aminomethylation reactions [33]. If
i
electrophile 3b is used, the increased steric bulk of the PrO leaving group leads to
reduced by-product formation, higher yields, and easier purification.

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Scheme 2. Synthesis of Electrophiles 3a – 3d for Aminomethylation
We set out to prepare a series of benzyl N-(alkoxymethyl)carbamates 3a – 3d
(Scheme 2) with the aim of comparing by-product formation in aminomethylation
reactions. Benzyl N-(methoxymethyl)carbamate (3a) [34] and benzyl N-(isopropoxy-
methyl)carbamate (3b) [35] were included in our screen for completeness. As our third
generation electrophiles, we chose benzyl N-[(2,2,2-trifluoroethoxy)methyl]carbamate
(3c; because we envisaged that the 2,2,2-trifluoroethoxy leaving group would be less
likely to act as a nucleophile) and benzyl N-[(benzyloxy)methyl]carbamate (3d;
containing a BnO leaving group). When using 3d, any nucleophilic attack would give a
product still containing the required Cbz protecting group.
The synthesis of electrophiles 3a – 3d is outlined in Scheme 2. The key intermediate,
benzyl N-(hydroxymethyl)carbamate (7), was prepared by mono-condensation with
HCHO in 64% yield [35]. This intermediate was condensed with MeOH, iPrOH, 2,2,2-
trifluoroethanol, or BnOH to give benzyl N-(alkoxymethyl)carbamates 3a – 3d,
respectively, in high-to-moderate yields. Benzyl N-[(2,2,2-trifluoroethoxy)methyl]car-
bamate (3c) required column chromatography to remove some by-products, but
removal of BnOH from benzyl N-[(benzyloxy)methyl]carbamate (3d) was easily
achieved by steam distillation.
Taking the aminomethylation of (R)-4-isopropyl-5,5-diphenyl-3-(3-phenyl-propa-
noyl)oxazolidin-2-one (2a) as our standard reaction, aminomethylation was performed
with the four electrophiles 3a – 3d. The results of these experiments are collected in the
Table. The yield of each impurity, the diastereomeric ratio (dr) of products, and the
percentages of the desired product and remaining starting material were calculated for
each reaction, using either UPLC/MS or standard HPLC calibration curves.
We observed that, as expected, the yield of the by-products 6a – 6d decreased with
reducing nucleophilicity of the leaving group (i.e., in the order MeO > iPrO >
CF3CH2O). Also, as predicted, the yield of the product was highest, when benzyl N-
[(benzyloxy)methyl]carbamate (3d) was used, as material was not lost in forming an
impurity. The diastereoselectivity remained similar for all four electrophiles (ca.
90 :10), being only slightly higher when 3d was applied. Overall, the yield of desired
diastereoisomer increased with reducing nucleophilicity of the leaving group.
We then applied 3d in the larger-scale synthesis (8 – 9 g; Scheme 3) of three key
intermediates 4a – 4c with different side chains. Compounds 4a – 4c would give Cbz-(S)-
b2-hPhe-OH (5; Scheme 1) [33], Cbz-(S)-b2-hLeu-OH, and Cbz-(S)-b2-hLys-OH,
respectively, on removal of the auxiliary, the latter requiring further side-chain
manipulation to introduce the lysine side chain.
All of the aminomethylation reactions (step 2, Scheme 3) proceeded to give good
yields and required less, or simplified, purification due to the fact that no by-product
was formed. Products 4a and 4c were crystalline and, therefore, were purified by simple

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317
Table. Aminomethylation Using Electrophiles 3a – 3d
Entry Electrophile R Key impurity R’ % Impuritya) dra)
% Yield of % of remaining
desired
diastereo-
isomerb)
starting
materialc)
1
2
3
4
Me
Me
8.3
6.5
3.9
0
88.1 : 11.9 65.0
88.4 : 11.6 68.9
89.0 : 11.0 64.1
11.3
8.6
15.7
9.1
iPr
iPr
CH2CF3
Bn
CH2CF3
Bn (¼ 4a)
90.3 : 9.7
73.1
a) Determined by UPLC/MS. b) Maximum yield of desired diastereoisomer as determined by HPLC
using standard calibration curves. c) Maximum yield of recoverable starting material as determined by
HPLC using standard calibration curves.
Scheme 3. Larger-Scale Synthesis of Key Intermediates 4a – 4c Using Benzyl Electrophile 3d
crystallization, whereas the product 4b was an oil which required purification via
column chromatography.
Conclusions. – In summary, we have demonstrated how a third-generation
electrophile, benzyl N-[(benzyloxy)methyl]carbamate (3d), can be used in amino-
methylation reactions for b2-amino acid synthesis, resulting in an improved purity
profile and thus easier isolation of pure products.
The authors would like to thank Heiner Schꢀtz, Dominique Ducret, and Sandro Nocito for their
synthesis support, and Eric Francotte and Gabrielle Lecis for analytical UPLC-MS. The authors also
acknowledge their continuing collaboration with Dieter Seebach, Hartmut Meyer, and Karl Beck.

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Experimental Part
General. All chemicals were purchased from Fluka or Sigma-Aldrich unless otherwise mentioned.
Intermediates 7 and 3b were prepared according to an Organic Synthesis procedure [35], electrophile 3a
was prepared according to a literature procedure [34], and Cbz-protected b2-amino acid 5 according to an
Organic Synthesis procedure [33]. TLC: Merck silica-gel plates 60 F-254, Art. Nr. 5729, detection with
UV (254 nm). Reversed-phase (RP) HPLC: Agilent-1100 apparatus, with a Zorbax Eclipse XDB-C18,
4.6 ꢀ 50 mm, 1.8-m column, MeCN and H2O as eluent (both containing 0.1% TFA); column temp., 358;
flow rate, 1.0 ml/min; measurement at 216 nm, the standard gradient, 5 – 100% MeCN over 6 min, 100%
MeCN for 1.5 min, followed by 100 – 5% MeCN over 0.5 min. For separation of diastereoisomers formed
on aminomethylation, an alternative HPLC method was utilised in order to achieve a better separation.
The second standard gradient used was 40 – 75% MeCN over 12.5 min, then 75 – 100% MeCN over
0.5 min, followed by 100% MeCN over 1.5 min, with a flow rate of 2 ml/min. M.p.: Bꢀchi B-545
1
apparatus. NMR: 400-MHz Varian, AS 400 Oxford spectrometer, H and 13C shifts were referenced to
1
(D6)DMSO at 2.49 ppm for H- and 39.52 ppm for 13C-NMR. MS: VG Platform (Fisons Instruments),
Spectraflow 783 detector, HP 1100 series HPLC.
Benzyl N-[(2,2,2-Trifluoroethoxy)methyl]carbamate (3c). To a soln. of benzyl N-(hydroxymethyl)-
carbamate (7; 10.0 g, 55.2 mmol) dissolved in 2,2,2-trifluoroethanol (22.1 g, 221 mmol, 4 equiv.) and
CH2Cl2 (100 ml) was added TsOH · H2O (105 mg, 0.6 mmol, 1 mol-%), and the clear soln. was stirred at
258 for 3 h. Then, NaHCO3 (232 mg, 2.8 mmol, 5 mol%) was added, and the suspension was stirred at r.t.
for 1.5 h. The volatiles were removed in vacuo at < 408, and the crude product was purified by column
chromatography (CC) on 50 g of silica gel (SiO2) eluting with hexane/AcOEt 8 :2 to give 3c (9.07 g,
64.5%). Colorless clear oil. HPLC (Macherey-Nagel CC 70/4 Nucleosil 100-3 C18 HD, 5 – 100% MeCN
(6 min), 100% MeCN (4 min), flow rate 1 ml/min): tR 7.40 min (not stable on column); purity 85%
(215 nm). 1H-NMR (400 MHz, (D6)DMSO): 4.01 (q, J ¼ 9.4, CF3CH2); 4.61 (d, J ¼ 7.0, CH2N); 5.06 (s,
CH2O); 7.38 – 7.28 (m, 5 arom. H); 8.09 (t, J ¼ 5.9, NH, minor rotamer); 8.36 (t, J ¼ 6.6, NH, major
rotamer). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 65.0 (q, J ¼ 33.2, CF3CH2); 66.5 (CH2); 73.4 (CH2);
125.1 (q, J ¼ 279, CF3); 128.5 (arom. C); 128.6 (arom. C); 129.0 (arom. C); 137.3 (arom. C); 157.0 (C¼O).
ES-MS (pos.): 281 ([M þ NH4]þ). ES-MS (neg.): 262 ([M ꢁ H]ꢁ).
Benzyl N-[(Benzyloxy)methyl]carbamate (3d). To a soln. of 7 (126.8 g, 700 mmol) in BnOH
(360 ml, 5 equiv.) was added TsOH · H2O (2.66 g, 14 mmol, 2 mol-%), and the clear soln. was stirred at
258 for 3 h. HPLC Analysis after 30 min showed < 1% of starting material present in the mixture.
Na2CO3 (7.42 g, 70.0 mmol, 0.1 equiv.) was added, and the suspension was stirred at r.t. overnight. The
mixture was heated (jacket temp. 1308), and for several hours hot steam was introduced, while the H2O/
BnOH azeotrope was removed by distillation. In the beginning, the distillate was muddy, then became
clear, and a total of 16 l was distilled off. The mixture was cooled to 208, and the liquid product started to
crystallize (BnOH effectively inhibits the crystallization). The crude product was filtered, washed with
H2O, dissolved in 500 ml of t-BuOMe, and washed with H2O (400 ml). The org. phase was dried (Na2SO4)
and concentrated in vacuo including high vacuum to give 3d (126 g, 64.6%). Colorless solid. HPLC
(Macherey-Nagel CC 70/4 Nucleosil 100-3 C18 HD, 5 – 100% MeCN (6 min), 100% MeCN (4 min), flow
rate 1 ml/min): tR 7.58 min (not stable on column); purity 98% (215 nm). M.p. 36.4 – 36.58. 1H-NMR
(400 MHz, (D6)DMSO): 4.45 (s, CH2O); 4.55 (d, J ¼ 6.7, CH2N); 5.06 (s, CH2O); 7.38 – 7.24 (m, 10 arom.
H); 8.27 (t, J ¼ 6.7, NH). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 66.3 (CH2); 69.4 (CH2); 72.0 (CH2);
128.0 (arom. C); 128.2 (arom. C); 128.5 (arom. C); 128.6 (arom. C); 128.9 (arom. C); 129.1 (arom. C);
137.5 (arom. C); 139.0 (arom. C); 157.0 (C¼O). ES-MS (pos.): 289 ([M þ NH4]þ). ES-MS (neg.): 270
([M ꢁ H]ꢁ).
(R)-4-(1-Methylethyl)-5,5-diphenyl-3-(3-phenylpropanoyl)oxazolidin-2-one (2a). (R)-4-Isopropyl-
5,5-diphenyloxazolidin-2-one (DIOZ; 50 g, 177.7 mmol) was dissolved in THF (700 ml) under Ar, and
the soln. was cooled to ꢁ 308 in a dry ice/acetone bath under Ar. BuLi (1.6m in hexanes; 120 ml,
191.9 mmol) was transferred via cannula to the dropping funnel using N2 pressure and was added
dropwise to the suspension, keeping the temp. between ꢁ 30 and ꢁ 408, to give a cream cloudy soln. The
mixture was stirred at ꢁ 308 for 10 min to give a clearer soln. Hydrocinnamoyl chloride (¼ 3-
phenylpropanoyl chloride; 36.4 g/32 ml, 211.5 mmol) was dissolved in THF (100 ml) and added dropwise

Helvetica Chimica Acta – Vol. 93 (2010)
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to the mixture, again keeping the temp. below ꢁ 308 to give a clear colorless soln. The mixture was
allowed to warm to 08 over 40 min at which time HPLC showed no remaining starting material. The
mixture was cooled to ꢁ 108 and carefully diluted with sat. NH4Cl soln. (200 ml). The mixture was stirred
at this temp. for 10 min, and then further 500 ml sat. NH4Cl soln. were added. The soln. was allowed to
warm to r.t. and poured into AcOEt (600 ml), and the org. phase was separated. The org. phase was
washed with 1m HCl (500 ml), NaHCO3 soln. (500 ml), and brine (500 ml). The combined aq. phases
were washed once more with t-BuOMe (500 ml). The combined org. phases were dried over (Na2SO4)
and concentrated in vacuo including the high vacuum to give a brown solid (82.0 g, 112%). The crude
product was purified by CC (SiO2; CH2Cl2/hexane 7:3) to give 2a (63.7 g, 86.7%). White solid. HPLC
(Macherey-Nagel CC 70/4 Nucleosil 100-3 C18 HD, 40 – 75% MeCN (12.5 min), 75 – 100% MeCN
(0.5 min), 100% MeCN (1.5 min), flow rate 2 ml/min): tR 9.61 min; purity > 99% (215 nm). M.p. 98 –
1
1008. [a]D ¼ þ17.5 (c ¼ 1.0, CHCl3). H-NMR (400 MHz, (D6)DMSO): 0.57 (d, J ¼ 6.64, 3 H, Me2CH);
0.81 (d, J ¼ 7.00, 3 H, Me2CH); 2.01 (dsept., J ¼ 6.64, 2.36, Me2CH); 2.73 (t, J ¼ 7.40, PhCH2); 2.92 – 2.98
(m, 1 H, PhCH2CH2); 3.09 – 3.15 (m, 1 H, Ph); 5.56 (d, J ¼ 2.32, Me2CHCH); 7.04 (d, J ¼ 6.64, 2 arom.
H); 7.12 – 7.20 (m, 3 arom. H); 7.28 (q, J ¼ 7.40, 2 arom. H); 7.36 (t, J ¼ 7.80, 4 arom. H); 7.54 (d, J ¼ 7.44, 2
arom. H); 7.63 (d, J ¼ 7.40, 2 arom. H). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 16.1 (Me2CH); 21.9
(Me2CH); 30.2 (Me2CH); 30.5 (CH2); 36.9 (CH2); 65.1 (Me2CHCH); 89.3 (Ph2C); 125.6 (arom. C);
126.0 (arom. C); 126.7 (arom. C); 128.4 (arom. C); 128.8 (arom. C); 128.9 (arom. C); 129.0 (arom. C);
129.1 (arom. C); 129.5 (arom. C); 138.8 (arom. C(ipso)); 140.9 (arom. C(ipso)); 143.8 (arom. C(ipso));
153.3 (C¼O); 172.0 (C¼O). Anal. calc. for C27H27NO3: C 78.42, H 6.58, N 3.39; found: C 78.38, H 6.60, N
3.46. ES-MS (pos.): 414 ([M þ H]þ).
General Procedure: Alkylation to Test Electrophiles. Compound 2a (2.3 g, 5.56 mmol) was dissolved
in CH2Cl2 (25 ml) under N2 to give a clear colorless soln. The mixture was cooled to ꢁ 508 in a dry ice/
acetone bath. TiCl4 (6.1 ml, 1m in CH2Cl2, 6.11 mmol) was added dropwise to give an orange colored soln.
Et3N (0.62 g/0.75 ml, 6.11 mmol) was added dropwise (taking care for any exothermic reaction) to give a
dark red soln. (a persistent red color developed after one drop of Et3N). The soln. was then stirred at
ꢁ 508 for further 30 min. The electrophile (6.11 mmol) was dissolved in CH2Cl2 (12 ml) in a separate flask
and added slowly to the original flask maintaining the internal temp. below ꢁ 408. TiCl4 (6.1 ml, 1m in
CH2Cl2, 6.11 mmol) was added dropwise, and the mixture was transferred to an ice/brine bath at 08. The
soln. was stirred for 6 h between 0 and 58, warming slowly for the first 3 h. Towards the end of the
reaction, the soln. began to decolorize to give a yellow soln. The reaction was monitored using TLC (30%
AcOEt/hexanes, UV) and HPLC, until there was minimal remaining starting material. The reaction was
quenched with sat. aq. NH4Cl soln. (25 ml) and H2O (50 ml). The pale yellow suspension was extracted
with AcOEt (2 ꢀ 150 ml; the aq. phase was yellow and org. phase colorless) and the combined org. phases
washed with sat. aq. NaHCO3 (100 ml) and brine (100 ml). The org. phase was dried (Na2SO4) and
concentrated in vacuo to give a pale yellow oil, which foamed on rotorvap and was stored in the fridge to
prevent decomposition. The exact composition of the crude product was calculated using standard
calibration curves to determine the amounts of the starting material and required product.
Benzyl {[(S)-2-Benzyl-3-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxazolidin-3-yl]-3-oxopropyl}-
carbamate (4a). Scale-Up Using Benzyl N-[(Benzyloxy)methyl]carbamate. Compound 2a (9.0 g,
21.8 mmol) was dissolved in CH2Cl2 (99 ml) under N2 to give a clear colorless soln. The mixture was
cooled to ꢁ 508 in an dry ice/acetone bath. TiCl4 (24 ml, 1m in CH2Cl2, 24.0 mmol) was added dropwise to
give an orange colored soln. Et3N (2.43 g/3.34 ml, 24.0 mmol) was added dropwise (taking care for any
exothermic reaction) to give a dark red soln. (a persistent red color developed after five drops of Et3N).
The soln. was then stirred at ꢁ 508 for a further 30 min. Benzyl N-[(benzyloxy)methyl]carbamate
(6.51 g, 24.0 mmol) was dissolved in CH2Cl2 (47 ml) in a separate flask, and added slowly to the original
flask, maintaining the internal temp. below ꢁ 408. TiCl4 (24 ml, 1m in CH2Cl2, 24.0 mmol) was added
dropwise, and the mixture was transferred to an ice/brine bath at 08. The soln. was stirred for 6 h between
0 and 58; warming slowly for the first 3 h. Towards the end of the reaction, the soln. began to decolorize to
give a yellow soln. The reaction was monitored using TLC (30% AcOEt/hexanes, UV) and HPLC, until
there was minimal remaining starting material. The reaction was quenched with sat. aq. NH4Cl soln.
(125 ml) and H2O (250 ml). The pale yellow suspension was extracted with AcOEt (2 ꢀ 500 ml), and the
combined org. phases washed with sat. aq. NaHCO3 (500 ml) and brine (500 ml). The org. phase was

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Helvetica Chimica Acta – Vol. 93 (2010)
dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil (16.6 g, 132%) containing 1.1 equiv. of
BnOH (2.59 g; therefore maximum weight 12.6 þ 2.59 ¼ 15.2 g). The oil was left to stand in the fridge to
induce crystallization. The crystalline product formed was triturated with 10% Et2O in hexane (40 ml)
and washed with further 20 ml to give a pale yellow crystalline solid (12.3 g, 97.6%). The product was
triturated again with 20% Et2O in hexane (40 ml) and washed with further 10 ml to give a paler yellow
crystalline solid (10.1 g, 80.2%). The product was triturated a third time with 20% Et2O in hexane (40 ml)
and washed with further 10 ml to give an even paler yellow crystalline solid (9.03 g, 71.7%). HPLC
(Macherey-Nagel CC 70/4 Nucleosil 100-3 C18 HD, 40 – 75% MeCN (12.5 min), 75 – 100% MeCN
(0.5 min), 100% MeCN (1.5 min), flow rate 2 ml/min): tR (Eþ) 2.50 min, tR(starting material) 9.61 min,
tR(BnOH) at solvent front, tR(product) 10.13 min, tR(diastereoisomer) 10.75 min. Remaining starting
material 2.3%, dr 96.8 :3.2. M.p. 130 – 1318. [a]D ¼ þ97.2 (c ¼ 0.98, CHCl3). 1H-NMR (400 MHz,
(D6)DMSO): 0.58 (d, J ¼ 7.04, 3 H, Me2CH); 0.83 (d, J ¼ 7.00, 3 H, Me2CH); 2.01 (sept., J ¼ 6.64,
Me2CH); 2.37 – 2.42 (m, 1 H, PhCH2); 2.55 – 2.60 (m, 1 H, PhCH2); 3.18 – 3.22 (m, CH2NH); 4.10 (t, J ¼
6.28, PhCH2CH); 4.95 (q, J ¼ 6.24, 1 H, PhCH2O); 5.54 (d, J ¼ 1.96, Me2CHCH); 6.63 (d, J ¼ 7.00, 2 arom.
H); 6.98 – 7.06 (m, 3 arom. H); 7.25 – 7.39 (m, 11 arom. H); 7.55 (d, J ¼ 7.40, 2 arom. H); 7.60 (d, J ¼ 7.44, 2
arom. H). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 15.4 (Me2CH); 21.2 (Me2CH); 29.5 (Me2CH); 34.4
(CH2); 41.3 (CH2); 44.0 (PhCHCH); 64.7 (Me2CHCH); 65.0 (CH2); 88.3 (Ph2C); 124.4 (arom. C); 124.9
(arom. C); 125.7 (arom. C); 127.3 (arom. C); 127.3 (arom. C); 127.4 (arom. C); 127.7 (arom. C); 127.9
(arom. C); 128.0 (arom. C); 128.0 (arom. C); 128.1 (arom. C); 128.5 (arom. C); 136.7 (arom. C(ipso));
137.3 (arom. C(ipso)); 137.7 (arom. C(ipso)); 142.7 (arom. C(ipso)); 151.9 (C¼O); 155.6 (C¼O); 171.0
(C¼O). ES-MS (pos.): 577 ([M þ H]þ). Anal. calc. for C36H36N2O5: C 74.98, H 6.29, N 4.86; found: C
75.02, H 6.21, N 4.88.
Methyl {(S)-2-Benzyl-3-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxazolidin-3-yl]-3-oxopropyl}-
carbamate (by-product; 6a). Compound 6a was obtained from a large-scale reaction of the methyl
electrophile. The analytical data of this product are included for reference. HPLC (Macherey-Nagel CC
70/4 Nucleosil 100-3 C18 HD, 40 – 75% MeCN (12.5 min), 75 – 100% MeCN (0.5 min), 100% MeCN
(1.5 min), flow rate 2 ml/min): tR 7.22 min. M.p. 128 – 1348. [a]D ¼ þ94.0 (c ¼ 1, CHCl3). 1H-NMR
(400 MHz, (D6)DMSO): 0.75 (d, J ¼ 7.04, 3 H, Me2CH); 0.87 (d, J ¼ 7.04, 3 H, Me2CH); 1.97 (dsept., J ¼
6.64, 3.52, Me2CH); 2.51 (dd, J ¼ 13.68, 6.64, 1 H, PhCH2); 2.72 (dd, J ¼ 13.64, 6.64, 1 H, PhCH2); 3.38 –
3.51 (m, CH2NH); 3.62 (s, MeO); 4.19 (dt, J ¼ 7.44, 2.36, PhCH2CH); 4.83 (d, J ¼ 3.52, Me2CHCH); 6.91
(d, J ¼ 2.36, 2 arom. H); 7.08 – 7.09 (m, 3 arom. H); 7.24 – 7.39 (m, 10 arom. H). 13C-NMR (101 MHz,
DEPT, (D6)DMSO): 15.3 (Me2CH); 21.1 (Me2CH); 29.5 (Me2CH); 34.4 (CH2); 41.4 (CH2); 44.1
(PhCH2CH); 51.1 (MeO); 64.7 (Me2CHCH); 88.3 (Ph2C); 124.4 (arom. C); 124.9 (arom. C); 125.6
(arom. C); 127.4 (arom. C); 127.6 (arom. C); 127.8 (arom. C); 127.9 (arom. C); 128.0 (arom. C); 128.0
(arom. C); 128.4 (arom. C); 137.3 (arom. C(ipso)); 137.7 (arom. C(ipso)); 142.6 (arom. C(ipso)); 151.9
(C¼O); 155.2 (C¼O); 171.9 (C¼O). ES-MS (pos.): 501 ([M þ H]þ). Anal. calc. for C30H32N2O5: C
71.98, H 6.44, N 5.60; found: C 72.17, H 6.32, N 5.63.
(R)-3-(3-Methylbutanoyl)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (2b). DIOZ (100 g,
355.4 mmol) was dissolved in THF (1000 ml) under Ar and cooled to ꢁ 308 in a dry ice/acetone bath
under Ar. BuLi (1.6m in hexanes, 233 ml, 373.2 mmol) was transferred via cannula to the dropping funnel
using N2 pressure and was added dropwise to the suspension, keeping the temp. between ꢁ 30 and ꢁ 408,
to give a yellow soln. Isovaleryl chloride (47.1 g, 48.0 ml, 391.0 mmol) was added dropwise to the mixture,
again keeping the temp. under ꢁ 308. The mixture was allowed to warm to r.t. and left to stir overnight
after which time HPLC showed no more starting material. The reaction was carefully quenched with 10%
NH4Cl soln. (500 ml), the mixture was diluted with t-BuOMe (1000 ml), and the org. phase was
separated. The org. phase was washed with 10% HCl soln. (500 ml), 10% NaOH soln. (500 ml), and
brine (500 ml). The org. phase was dried (Na2SO4) and concentrated in vacuo to give a white crystalline
solid. The crude product was dissolved in hot iPrOH and then cooled to r.t. to give a white suspension,
which was filtered to give 2b (100 g, 77.0%). White solid. HPLC (Macherey-Nagel CC 70/4 Nucleosil 100-
3 C18 HD, 40 – 75% MeCN (12.5 min), 75 – 100% MeCN (0.5 min), 100% MeCN (1.5 min); flow rate
2 ml/min): tR 8.63 min; purity > 99% (215 nm). M.p. 118.8 – 118.98. [a]D ¼ þ180.5 (c ¼ 1.0, CH2Cl2).
1H-NMR (400 MHz, (D6)DMSO): 0.60 (d, J ¼ 6.64, 3 H, Me2CH); 0.66 (d, J ¼ 6.64, 3 H, Me2CH); 0.70
(d, J ¼ 6.64, 3 H, Me2CH); 0.87 (d, J ¼ 6.64, 3 H, Me2CH); 1.81 (sept., J ¼ 6.64, Me2CH); 2.03 (dsept.,

Helvetica Chimica Acta – Vol. 93 (2010)
321
J ¼ 6.64, 1.96, Me2CH); 2.52 – 2.66 (m, Me2CHCH2); 5.57 (d, J ¼ 2.72, Me2CHCH); 7.29 – 7.38 (m, 8 arom.
H); 7.55 (d, J ¼ 8.60, 2 arom. H); 7.64 (d, J ¼ 8.20, 2 arom. H). 13C-NMR (101 MHz, DEPT, (D6)DMSO):
16.3 (CHMe2); 21.9 (Me2CH); 22.5 (2 Me2CH); 25.7 (Me2CH); 30.1 (Me2CH); 43.5 (CH2); 65.2
(Me2CHCH); 89.3 (Ph2C); 125.5 (arom. C); 125.9 (arom. C); 128.4 (arom. C); 128.9 (arom. C); 129.1
(arom. C); 129.4 (arom. C); 138.8 (arom. C(ipso)); 143.8 (arom. C(ipso)); 153.4 (C¼O); 172.0 (C¼O).
ES-MS (pos.): 366 ([M þ H]þ). Anal. calc. for C23H27NO3: C 75.59, H 7.45, N 3.83; found: C 75.72, H 7.63,
N 3.83.
Benzyl {(S)-3-Methyl-2-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxazolidine-3-carbonyl]butyl}-
carbamate (4b). Compound 2b (10.0 g, 27.4 mmol) was dissolved in CH2Cl2 (120 ml) under N2 to give
a clear colorless soln. The mixture was cooled to ꢁ 508 in an dry ice/acetone bath. TiCl4 (28.7 ml, 1m in
CH2Cl2, 28.7 mmol) was added dropwise to give a yellow colored soln. Et3N (2.77 g/3.82 ml, 27.4 mmol)
was added dropwise (taking care for any exothermic reaction) to give a dark red soln. (a persistent red
color developed after five drops of Et3N). The soln. was then stirred at ꢁ 508 for further 30 min. Benzyl
N-[(benzyloxy)methyl]carbamate (8.17 g, 30.1 mmol) was dissolved in CH2Cl2 (60 ml) in a separate flask
and added slowly to the original flask maintaining the internal temp. below ꢁ 408. TiCl4 (28.7 ml, 1m in
CH2Cl2, 28.7 mmol) was added dropwise, and the mixture was transferred to an ice/brine bath at 08. The
soln. was stirred for 5 h between 0 and 58, warming slowly for the first 3 h. Towards the end of the
reaction, the soln. began to decolorize to give a yellow soln. The reaction was monitored using TLC (30%
AcOEt/hexanes, UV) and HPLC, until there was minimal remaining starting material. The reaction was
quenched with 10% aq. NH4Cl soln. (600 ml). The org. phases were separated and the aq. phase was
extracted with AcOEt (2 ꢀ 250 ml), and the combined org. phases were washed with sat. aq. NaHCO3
(250 ml) and brine (250 ml). The org. phase was dried (Na2SO4) and concentrated in vacuo to give a pale
yellow oil (16.0 g, 111%) containing 1.1 equiv. BnOH (3.25 g; therefore maximum weight 14.5 þ 3.25 ¼
17.75 g). The oil was left to stand in fridge to induce crystallization. The product could not be triturated
directly as it was too gummy. The crude material was purified by CC on SiO2 (100 g) eluting with 10%
AcOEt/hexanes (80 ꢀ 200 ml) to give 4b (10.3 g, 71.2%). Clear colorless oil. HPLC (Macherey-Nagel CC
70/4 Nucleosil 100 – 3 C18 HD, 40 – 75% MeCN (12.5 min), 75 – 100% MeCN (0.5 min), 100% MeCN
(1.5 min), flow rate 2 ml/min): tR(Eþ) 2.50 min, tR(starting material) 8.63 min, tR(BnOH) at solvent front,
tR(product) 8.90 min, tR(diastereoisomer) 9.61 min. No starting material, d.r. ¼ 96.8 :3.2. [a]D ¼ þ91.9
1
(c ¼ 1.0, CH2Cl2). H-NMR (400 MHz, (D6)DMSO): 0.31 (d, J ¼ 6.64, 3 H, Me2CH); 0.48 (d, J ¼ 6.64,
3 H, Me2CH); 0.58 (d, J ¼ 6.64, 3 H, Me2CH); 0.86 (d, J ¼ 7.04, 3 H, Me2CH); 1.42 (sept., J ¼ 6.64,
Me2CH); 1.99 (sept., J ¼ 7.04, Me2CH); 3.16 – 3.29 (m, CH2NH); 3.78 (t, J ¼ 9.96, Me2CHCH); 4.95 (q,
J ¼ 10.96, OCH2Ph); 5.58 (s, Me2CHCH); 7.24 – 7.38 (m, 11 arom. H); 7.56 (d, J ¼ 8.20, 2 arom. H); 7.66
(d, J ¼ 8.56, 2 arom. H). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 16.1 (CHMe2); 19.4 (Me2CH); 20.1
(Me2CH); 21.8 (Me2CH); 29.2 (Me2CH); 30.0 (Me2CH); 40.8 (CH2NH); 48.7 (NHCH2CH); 65.8
(PhCH2); 65.8 (Me2CHCH); 89.1 (Ph2C); 125.6 (arom. C); 125.9 (arom. C); 127.1 (arom. C); 127.3
(arom. C); 128.3 (arom. C); 128.7 (arom. C); 128.9 (arom. C); 129.1 (arom. C); 129.3 (arom. C); 138.7
(arom. C(ipso)); 143.2 (arom. C(ipso)); 144.0 (arom. C(ipso)); 153.3 (C¼O); 156.7 (C¼O); 174.1
(C¼O). ES-MS (pos.): 529 ([M þ H]þ).
(R)-3-(6-Bromohexanoyl)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (2c). DIOZ (25 g,
88.9 mmol) was dissolved in THF (400 ml) under Ar and cooled to ꢁ 308 in a dry ice/acetone bath
under Ar. BuLi (1.6m in hexanes; 60.0 ml, 96.0 mmol) was transferred via cannula to the dropping funnel
using N2 pressure and was added dropwise to the suspension, keeping the temp. between ꢁ 30 and ꢁ 408,
to give a cream cloudy soln. The soln. became too cold (ꢁ 508) and so was allowed to warm to ꢁ 308. The
mixture was then stirred at this temp. for 10 min to give a clearer soln. 6-Bromohexanoyl chloride (22.8 g/
16.3 ml, 106.6 mmol) was dissolved in THF (45 ml) and added dropwise to the mixture, again keeping the
temp. below ꢁ 308 to give a clear colorless soln. The mixture was allowed to warm to r.t. over 2 h, and
HPLC after 3 h showed no remaining starting material. The mixture was cooled to 08 in an ice bath and
carefully diluted with sat. NH4Cl soln. (200 ml). The mixture was stirred at r.t. for 10 min and poured into
t-BuOMe (500 ml), and the org. phase was separated. The org. phase was washed with 1m HCl (500 ml),
NaHCO3 soln. (500 ml), and brine (500 ml). The combined aq. phases were washed once more with t-
BuOMe (500 ml). The combined org. phases were dried (Na2SO4) and concentrated in vacuo including
the high vacuum to give a pale yellow oil (43.1 g, 106%). The oil was left to stand in the fridge over the

322
Helvetica Chimica Acta – Vol. 93 (2010)
weekend during which time crystals had formed and were triturated with hexane (200 ml), crushed, and
filtered to give 2c (36.2 g, 88.9%). White solid. HPLC (Macherey-Nagel CC 70/4 Nucleosil 100-3 C18 HD,
20 – 100% MeCN (6 min), 100% MeCN (1.5 min), 100 – 20% MeCN (0.5 min)): tR(starting material)
5.47 min, tR(acid chloride) 4.38 min, tR(product) 7.19 min; purity 96% (215 nm). M.p. 75.7 – 76.38. [a]D ¼
1
þ161 (c ¼ 1.0, CHCl3). H-NMR (400 MHz, (D6)DMSO): 0.76 (d, J ¼ 6.64, 3 H, Me2CH); 0.87 (d, J ¼
7.00, 3 H, Me2CH); 1.33 – 1.41 (m, CH2); 1.51 – 1.62 (m, CH2); 1.76 – 1.83 (m, CH2); 1.92 – 1.99 (m,
Me2CH); 2.75 – 2.81 (m, 1 H, CH2CO); 2.84 – 2.92 (m, 1 H, CH2CO); 3.34 (t, J ¼ 6.64, CH2Br); 5.36 (d,
J ¼ 3.12, Me2CHCH); 7.25 – 7.48 (m, 10 arom. H). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 16.2
(Me2CH); 22.0 (Me2CH); 24.0 (CH2); 27.4 (CH2); 30.2 (Me2CH); 32.5 (CH2); 34.9 (CH2); 35.4 (CH2);
65.1 (Me2CHCH); 89.3 (Ph2C); 125.6 (arom. C); 126.0 (arom. C); 126.4 (arom. C); 129.0 (arom. C);
129.1 (arom. C); 129.5 (arom. C); 138.8 (arom. C(ipso)); 143.8 (arom. C(ipso)); 153.3 (C¼O); 172.7
(C¼O). ES-MS (pos.): 458/460 ([M þ H]þ), 480/482 ([M þ Na]þ). Anal. calc. for C24H28BrNO3: C 62.89,
H 6.16, N 3.06, Br 17.43; found: C 63.07, H 6.25, N 3.10, Br 16.94.
Benzyl {(S)-6-Bromo-2-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxazolidine-3-carbonyl]hexyl}-
carbamate (4c). Compound 2c (10.0 g, 21.8 mmol) was dissolved in CH2Cl2 (99 ml) under N2 to give a
clear colorless soln. The mixture was cooled to ꢁ 508 in a dry ice/acetone bath. TiCl4 (24 ml, 1m in
CH2Cl2, 24.0 mmol) was added dropwise to give an orange colored soln. Et3N (2.43 g/3.34 ml, 24.0 mmol)
was added dropwise (taking care for any exothermic reaction) to give a dark red soln. (a persistent red
color developed after five drops of Et3N). The soln. was then stirred at ꢁ 508 for further 30 min. Benzyl
N-[(benzyloxy)methyl]carbamate (6.51 g, 24.0 mmol) was dissolved in CH2Cl2 (47 ml) in a separate flask
and added slowly to the original flask maintaining the internal temp. below ꢁ 408. TiCl4 (24 ml, 1m in
CH2Cl2, 24.0 mmol) was added dropwise, and the mixture was transferred to an ice/brine bath at 08. The
soln. was stirred for 7.5 h between 0 and 58, warming slowly for the first 3 h. Towards the end of the
reaction, the soln. began to decolorize to give a yellow soln. The reaction was monitored using TLC (30%
AcOEt/hexanes, UV) and HPLC, until there was minimal remaining starting material. The reaction was
quenched with sat. aq. NH4Cl soln. (125 ml) and H2O (250 ml). The pale yellow suspension was extracted
with AcOEt (2 ꢀ 500 ml), and the combined org. phases washed with sat. aq. NaHCO3 (500 ml) and
brine (500 ml). The org. phase was dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil
(16.4 g, 121%) containing 1.1 equiv. BnOH (2.59 g; therefore, maximum weight 13.6 þ 2.59 ¼ 16.2 g). The
oil was left to stand in the fridge to induce crystallization. The product could not be triturated directly as it
was too gummy. The crude material was purified by CC on SiO2 (500 g) eluting with 20% AcOEt/hexanes
(80 ꢀ 50 ml, Frs. 20 – 24 (starting material) and Frs. 46 – 80 (product)) to give the product as a clear
colorless oil which crystallized on standing (12.3 g, 75.9%). The diastereoisomers were not separated, and
the product still contained some BnOH. The product was triturated with 10% Et2O in hexane (20 ml) and
washed with further 10 ml to give a white crystalline solid (9.79, 72.0%). The product was triturated again
with 20% Et2O in hexane (30 ml) and washed with further 10 ml to give 4c (8.69 g, 63.9%). White
crystalline solid. HPLC (Macherey-Nagel CC 70/4 Nucleosil 100-3 C18 HD, 40 – 75% MeCN (12.5 min),
75 – 100% MeCN (0.5 min), 100% MeCN (1.5 min), flow rate 2 ml/min): tR(Eþ) 2.48 min, tR(starting
material) 9.91 min, tR(BnOH) at solvent front, tR(product) 10.31 min, tR(diastereoisomer) 10.79 min.
Remaining starting material 0.8%, dr 97.0 :3.0. M.p. 97.7 – 98.38. [a]D ¼ þ98.3 (c ¼ 1.0, CHCl3). 1H-NMR
(400 MHz, (D6)DMSO): 0.59 (d, J ¼ 6.64, 3 H, Me2CH); 0.85 (d, J ¼ 6.64, 3 H, Me2CH); 1.08 – 1.37 (m,
2 CH2); 2.00 (dsept., J ¼ 6.64, 3.72, Me2CH); 3.09 – 3.24 (m, 2 CH2); 3.79 – 3.85 (m, PhCH2CH); 4.96 (q,
J ¼ 11.32, OCH2Ph); 5.56 (d, J ¼ 2.32, Me2CHCH); 7.24 – 7.39 (m, 11 arom. H); 7.56 (d, J ¼ 7.44, 2 arom.
H); 7.65 (d, J ¼ 7.80, 2 arom. H). 13C-NMR (101 MHz, DEPT, (D6)DMSO): 16.1 (Me2CH); 21.8
(Me2CH); 24.6 (CH2); 29.1 (CH2); 30.0 (Me2CH); 32.7 (CH2); 34.8 (CH2); 42.7 (PhCH2CH, NHCH2);
65.7 (Me2CHCH); 65.8 (PhCH2O); 89.3 (Ph2C); 125.5 (arom. C); 125.9 (arom. C); 128.3 (arom. C);
128.4 (arom. C); 128.5 (arom. C); 129.0 (arom. C); 129.1 (arom. C); 129.4 (arom. C); 130.0 (arom. C);
137.8 (arom. C(ipso)); 138.6 (arom. C(ipso)); 143.9 (arom. C(ipso)); 153.2 (arom. C(ipso)); 158.8
(C¼O); 174.2 (C¼O). ES-MS (pos.): 621/623 ([M þ H]þ). Anal. calc. for C33H37BrN2O5: C 63.77, H 6.00,
N 4.51, Br 12.86; found: C 64.03, H 6.05, N 4.53, Br 12.48.
Cbz-(S)-b2-hPhe-OH (5). Cleavage of the auxiliary to give Cbz-(S)-b2-hPhe-OH (5) was performed
according to the procedure described in [33]. The conversion was carried out with a LiOH/H2O2 mixture,
otherwise racemization occurred.

Helvetica Chimica Acta – Vol. 93 (2010)
323
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Received November 11, 2009