Highly enantioselective synthesis of orthogonally protected (2S)-2,3-diaminopropanoates through catalytic phase-transfer aza-Henry reaction

Article abstract of DOI:10.1002/hlca.201100013

The syntheses of enantiomer-enriched orthogonally protected different (2S)-2,3-diaminopropanoates and unnatural furyl-substituted (tert-butoxy) carbonyl (Boc) as well as (benzyloxy)carbonyl (Cbz) protected amino acid esters are accomplished by means of an

Full text of DOI:10.1002/hlca.201100013

Helvetica Chimica Acta – Vol. 94 (2011)
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Highly Enantioselective Synthesis of Orthogonally Protected (2S)-2,3-
Diaminopropanoates through Catalytic Phase-Transfer Aza-Henry Reaction
by Gullapalli Kumaraswamy* and Arigala Pitchaiah
Organic Division III, Indian Institute of Chemical Technology, Hyderabad-500607, India
(phone: þ 91-40-27193154; fax: þ 91-40-27193275; e-mail: gkswamy_iict@yahoo.co.in)
The syntheses of enantiomer-enriched orthogonally protected different (2S)-2,3-diaminopropa-
noates and unnatural furyl-substituted (tert-butoxy)carbonyl (Boc) as well as (benzyloxy)carbonyl (Cbz)
protected amino acid esters are accomplished by means of an enantioselective aza-Henry reaction. A key
feature of this protocol is organocatalysis as a genesis of chirality to ensure high enantioselectivity.
Introduction. – The nonproteinogenic a,b-diamino acids (DAPS) have received
renewed attention due to their incorporation into peptides which are used to modulate
secondary and tertiary conformation [1]. Furthermore, such peptides resist proteolysis
[2]. In addition, the active ingredients derived from these a,b-diamino acids display a
wide range of pharmaceutical activities as insulinotropic, antidyslipidemic, and
antihyperglycemic agent [3] (see 1 – 4 in Fig. 1). Some a,b-diamino acid derivatives
are protein-tyrosine kinase inhibitors and glycoprotein IIb/IIIa receptor antagonists
[4a,b]. Furthermore, a,b-diamino acids are part of several b-lactam antibiotics [4c].
(2S)-2,3-Diaminopropanoic acid has been also used to surrogate natural amino
acids, i.e., lysine, to investigate the size effect of the side chain on the stability of a-helix
formation in simple polypeptides. Additionally, compounds derived from nonprotei-
nogenic a,b-diamino acids such as TAN-1057A (3) and TAN-1057B (4) were found to
be dipeptide antibiotics with potent activity against MRSA [5] (Fig. 1).
Fig. 1. Pharmaceutically active a,b-diamino acid derivatives
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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a,b-Diamino esters 5a, 5b, 6a, and 6b (Fig. 2) have been regarded as attractive
prominent synthetic targets in view of their various biological activities. The develop-
ment of simple and efficient methods for the synthesis of enantiomerically pure DAPS
from readily available starting materials is always a demanding task. A number of
enantioselective synthetic methods for the synthesis of diaminopropanoic acids have
been reported thus far [6]. They have been commonly prepared by the Hoffman and
Curtius rearrangement of protected asparagine by using trivalent iodine such as
bis(trifluoroacetoxy)iodobenzene (¼ bis(trifluoroacetato-k0)phenyliodine), the Mit-
sunobu reaction of serine, and the Schmidt reaction of aspartic acid [7].
Fig. 2. Target a,b-diamino acid esters
A variety of other prominent methods includes the conjugate addition of
homochiral lithium N-benzyl-N-(a-methylbenzyl)amide to a,b-unsaturated esters, in
situ amination with trisyl azide (¼2,4,6-triisopropylbenzenesulfonyl azide), hydro-
genation of diastereoisomeric enamides, Sharpless asymmetric aminohydroxylation of
a,b-unsaturated esters, and aziridine ring opening with azide [8]. The genesis of
chirality in the above synthetic strategies is either from the chiral pool or initiated
through catalytic asymmetric transformations. Herein, we report an alternative
synthetic strategy for the synthesis of a,b-diamino esters 5a, 5b, 6a, and 6b (Fig. 2)
by means of a catalytic aza-Henry reaction.
Results and Discussion. – The aza-Henry reaction is a powerful synthetic
transformation that allows creation of a CꢀC bond bearing vicinal NO2 and NH2
functional groups and considered to be a key protocol for the synthesis of N-containing
chiral natural products and pharmaceuticals [9]. The asymmetric aza-Henry reaction
under phase-transfer catalysis (PTC) is established to be the most consistent reaction to
induce chirality with high enantioselectivity. In principle, the stereogenic center in 5a,
5b, 6a, and 6b could be accessed through a catalytic asymmetric aza-Henry reaction
under PTC conditions by employing N-Boc-furylamines 7a and 7b [10] and MeNO2
(Boc ¼ (tert-butoxy)carbonyl). We chose the furyl moiety as a masked carboxylic acid
as well as to enhance its solubility and to induce high enantioselectivity of the desired
product. Consequently, the reaction of 7a with MeNO2 (10 equiv.), in the presence of
quininium catalyst A (12 mol-%) and 1.3 equiv. of CsOH · H2O at ꢀ 458 for 30 h led to
8a in 85% yield with 82% enantiomer excess (ee) [11]. For further enantiomer
enrichment of the product 8a, the reaction conditions were optimized by varying the
amount of catalyst and the temperature. After considerable experimentation, we
accomplished that increasing the catalyst loading from 12 to 15 mol-% and lowering the
temperature (ꢀ 558) and in the presence of CsOH · H2O (1.3 equiv.) for 40 h furnished
8a with 94% ee without compromising the yield (Scheme 1). The ee of the desired
product was confirmed by chiral HPLC.

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Scheme 1
It was anticipated that in the presence of diastereoisomeric quinidinium quaternary
salt A’ as catalyst, the antipode of 8a would be formed. With catalyst A’ in place of A
under otherwise identical conditions as above, ent-8a with 40% ee in 85% yield was
obtained. Surprisingly, cinchonine salt also did not improve the ee of ent-8a [11].
Having prepared the N-Boc-protected b-nitroamine 8a, we next proceeded to
synthesize 8b. To this end, the N-Cbz-aminosulfone 7b (Cbz ¼ (benzyloxy)carbonyl)
was subjected to the aza-Henry reaction in the presence of catalyst A, and under
identical conditions as for 8a, this led to the nitro compound 8b with 99% ee. The ee of
8b was ascertained by HPLC with respect to the racemic compound (Chiralpak OD-H,
hexane/EtOH 7:3, 220 nm).
With the optically active compounds 8a and 8b in hand, we advanced further. To this
end, the furan moiety of 8a was oxidatively cleaved (RuCl3/NaIO4) to afford the
carboxylic acid, which was subjected to esterification with CH2N2 to give 9a in 72%
yield (two steps) (Scheme 2). The NO2 functionality was converted to the primary
amine by NaBH4 in the presence of NiCl2 · 6 H2O, and subsequent protection with
CbzCl under basic conditions resulted in 5a in 82% yield. The optical yield of 5a was
established by comparing the magnitude of its optical rotation with that reported in
[6a]. The reaction of 10a with FmocCl (Fmoc ¼ (9H-fluoren-9-ylmethoxy)carbonyl) in
the presence of base furnished Fmoc-protected 5b in 62% yield (Scheme 2).
Similarly, the reduction of the NO2 group of 9b was achieved with NiCl2 · 6 H2O/
NaBH4, and protection of the resulting amino group of 10b with (Boc)2O led to 6a in
68% yield (Scheme 2). The crude amino derivative 10b was protected with FmocCl
under basic conditions to give 6b in good yield. The optical yields of the 6a and 6b were
established by comparing their magnitude of the optical rotation, respectively, with that
reported in [6a].

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 2
En route to the synthesis of unnatural protected heterocyclic amino acids for our
ongoing project, we envisioned to convert the optically pure intermediates 8a and 8b
into the desired amino acids [12]. Therefore, the nitro derivatives 8a and 8b were
subjected to oxidation under Nef conditions (NaNO2/DMF) leading to the corre-
sponding acids. Following esterification of the crude acids resulted in Boc-protected
furylglycine methyl ester 11a and the Cbz-protected analog 11b, respectively, in good
yields (Scheme 3).
Scheme 3
In the course of exploring the synthetic applications of furyl-substituted inter-
mediate 11b, together with our interest in stereoselective synthesis, prompted us to
explore supplementary utility. Hence, 11b was reduced with DIBAL-H (diisobutyl-
aluminium hydride) at ꢀ 308 in CH2Cl2 followed by protection of the primary alcohol
with (tert-butyl)dimethylsilyl chloride to give the silyl ether derivative 12. According to
[13b], aza-Achamotowicz reaction of 12 led to a key intermediate for the synthesis of
the alkaloid (þ)-prosopinine (Scheme 4). The same intermediate has also been
employed for the synthesis of d- and l-deoxymannojirimycin [13a], and (þ)-spectaline
[13c].

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Scheme 4
Conclusions. – In conclusion, we have synthesized different orthogonally protected
(2S)-2,3-diaminopropanoates in up to 55% overall yield via a modified aza-Henry
reaction. The present protocol was also employed for the preparation of enantiomer-
enriched unnatural furyl substituted Boc- and Cbz-protected amino acid esters,
respectively, which are considered to be key intermediates for the synthesis of
compounds exhibiting anticancer, anti-HIV, and glycosidase-inhibitory activity. Addi-
tionally, the application of this methodology is currently under progress for the
synthesis of bioactive natural and unnatural products.
We are grateful to Dr. J. S. Yadav, Director, IICT, for his constant encouragement. Financial support
was provided by the DST, New Delhi, India (Grant No: SR/SI/OC-12/2007), and UGC (New Delhi) is
gratefully acknowledged for awarding the fellowship to A. P. Thanks are also due to Dr. G. V. M. Sharma
for his support.
Experimental Part
General. CH2Cl2 was distilled from P2O5, THF from Na benzophenone ketyl. All other chemicals
used were commercially available. All reactions were conducted under N2 (IOLAR, grade I). Progress of
the reactions was monitored by TLC on pre-coated silica gel 60 F254 plates (SiO2, Merck). Column
chromatography (CC): SiO2 grade 60 – 120 and 100 – 200 mesh. Optical rotations: Horiba high-sensitive
polarimeter; 10 mm cell. IR Spectra: Thermo-Nicolet-FT/IR-5700 instrument; ˜n in cmꢀ1 1H- and
.
13C-NMR Spectra: Varian 200 and 500 or Bruker 300 and 400 at 300, 400, or 500 MHz (1H) and 75 or
100 MHz (13C); in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. ESI- and HR-MS:
quadrupole time-of-flight (QTOF) mass spectrometer QSTAR XL (Applied Biosystems MDSSciex,
Foster City, USA); in m/z.
tert-Butyl N-[(1S)-1-(Furan-2-yl)-2-nitroethyl]carbamate (8a). To N-Boc aminosulfone 7a (1.75 g,
5 mmol) and catalyst A (0.342 g, 0.75 mmol) in toluene (0.8m) were added MeNO2 (2.95 g, 50 mmol) and
CsOH · H2O (1.09 g, 6.5 mmol) successively under N2 at ꢀ 558. The mixture was stirred vigorously for
40 h at ꢀ 558. Then, the reaction was quenched with 0.1n HCl (20 ml), and the mixture was slowly
allowed to warm to r.t. The aq. layer was extracted with CHCl3 (3 ꢁ 20 ml), the combined org. layer
washed with brine (2 ꢁ 10 ml), the extract dried (Na2SO4) and concentrated, and the residue purified by
CC (SiO2, hexane/AcOEt 8 :2): 8a (1.08 g, 85%). Semi-solid. HPLC (chiral OD-H (lmax 220 nm),
hexanes/EtOH 85 :15, 1 ml/min): 94% ee; tR (major) 7.7 min, tR (minor) 10.27 min. [a]2D5 ¼ ꢀ23.95 (c ¼
2.10, CHCl3) ([11c]: [a]2D5 ¼ þ17.72 (c ¼ 1.50, CHCl3)). IR (neat): 3311, 1701, 1532, 1507, 1378, 1331, 1249,
1164. 1H-NMR (CDCl3, 500 MHz): 7.36 (s, 1 H); 6.32 (dd, J ¼ 1.6, 3.1, 1 H); 6.29 (d, J ¼ 3.1, 1 H); 5.44 –
5.38 (m, 1 H); 5.34 (br. s, 1 H); 4.87 (dd, J ¼ 4.5, 12.4, 1 H); 4.68 (dd, J ¼ 5.5, 12.8, 1 H); 1.45 (s, 9 H).
13C-NMR (CDCl3, 75 MHz): 154.2; 148.5; 142.8; 110.6; 107.7; 89.4; 80.8; 47.9; 28.2. ESI-MS: 279 ([M þ
Na]þ). HR-ESI-MS: 279.0963 ([M þ Na]þ, C11H16N2NaOþ5 ; calc. 279.0956).
Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-nitropropanoate (9a). To an ice-cold soln. of
NaIO4 (5.2 g, 24.1 mmol) in CCl4 (20 ml), MeCN (30 ml), and H2O (20 ml) was added RuCl3 · H2O
(20 mg, 0.07 mol), and stirring was continued for 15 min at 08. Then, 8a (0.896 g, 3.5 mmol) in MeCN
(10 ml) was added, and stirring was continued for additional 10 min at 08. The mixture was quenched with
H2O (10 ml), the aq. layer extracted with AcOEt (3 ꢁ 20 ml), and the combined org. extract washed with

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Helvetica Chimica Acta – Vol. 94 (2011)
brine (1 ꢁ 15 ml), dried (Na2SO4), and concentrated. The crude residue was dissolved in dry CH2Cl2
(15 ml) and benzene (5 ml) at 08. Then, CH2N2 in Et2O (30 mmol) was added. After 3 h of stirring at r.t.,
the mixture was concentrated and the resulting residue purified by CC (SiO2, hexane/acetone 85 :15): 9a
(0.63 g, 72%). Colorless solid. [a]2D5 ¼ ꢀ30.25 (c ¼ 1.5, MeOH) ([6f]: [a]2D5 ¼ ꢀ31.0 (c ¼ 1, MeOH)). IR
(neat): 3389, 2923, 1718, 1707, 1558, 1501, 1371, 1245, 1134. 1H-NMR (CDCl3, 500 MHz): 5.52 (d, J ¼ 6.5,
1 H); 4.86 (dd, J ¼ 3.4, 13.2, 1 H); 4.83 (dd, J ¼ 3.3, 13.4, 1 H); 4.73 – 4.61 (m, 1 H); 3.85 (s, 3 H); 1.46 (s,
9 H). 13C-NMR (CDCl3, 75 MHz): 168.7; 155.1; 81.0; 75.4; 53.3; 51.3; 28.1. ESI-MS: 271 ([M þ Na]þ).
HR-ESI-MS: 271.0919 ([M þ Na]þ, C9H16N2NaO6þ ; calc. 271.0906).
Methyl (2S)-3-{[(Benzyloxy)carbonyl]amino}-2-[(tert-butoxy)carbonyl]amino}propanoate (5a). To
9a (0.50 g, 2 mmol) and NiCl2 · 6 H2O (0.33 g, 2 mmol) in dry MeOH (15 ml) was gradually added NaBH4
(0.38 g, 10 mmol) under N2 within 10 min at ꢀ 58. The mixture was stirred for 15 min, quenched with sat.
NaHCO3 soln. (10 ml), and filtered through a Celite bed. The filtrate was concentrated, the biphasic
mixture extracted with AcOEt (3 ꢁ 10 ml), the org. layer washed with brine, dried (Na2SO4), and
concentrated, and the resulting crude 10a (0.37 g, 82%) subjected to the next reaction. To 10a (0.11 g,
0.5 mmol) in dry CH2Cl2 was added (Boc)2O (0.16 g, 0.75 mmol) and DMAP (¼ N,N-dimethylpyridin-4-
amine; 5 mg) sequentially at 08. The mixture was stirred for 5 h at r.t., then quenched with sat. NH4Cl
soln. (5 ml), and extracted with AcOEt (2 ꢁ 10 ml). The extract was washed with brine, dried (Na2SO4),
and concentrated and the residue purified by CC (SiO2, hexane/acetone 4 :1): 5a (0.13 g, 74%). Brown
1
oil. [a]2D5 ¼ ꢀ18.5 (c ¼ 2.0, CHCl3). IR (neat): 3324, 2922, 2853, 1707, 1501, 1457, 1319, 1211. H-NMR
(CDCl3, 300 MHz): 7.40 – 7.29 (m, 5 H); 5.48 (br. s, 1 H); 5.22 (br. s, 1 H); 5.09 (s, 2 H); 4.45 – 4.34 (m,
1 H); 3.73 (dd, J ¼ 3.7, 12.2, 1 H); 3.74 (s, 3 H); 3.60 (dd, J ¼ 4.3, 10.6, 1 H); 1.44 (s, 9 H). 13C-NMR
(CDCl3, 75 MHz): 171.5; 167.5; 156.7; 136.2; 128.5; 128.1; 127.8; 66.9; 53.9; 52.6; 42.8; 29.6. ESI-MS: 375
([M þ Na]þ). HR-ESI-MS: 375.1539 ([M þ Na]þ, C17H24N2NaO6þ ; calc. 375.1532).
Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}pro-
panoate (5b). To the crude 10a (0.11 g, 0.5 mmol) and NaHCO3 (0.11 g, 1.0 mmol) in MeOH was added
FmocCl (0.75 mmol) under Ar at 08. The mixture was stirred for 5 h at r.t. and then concentrated to
afford a grayish oil. The grayish oil was dissolved in AcOEt (10 ml), the soln. washed with sat. NaHCO3
soln. (1 ꢁ 5 ml), 1m HCl (1 ꢁ 5 ml), and brine (2 ꢁ 10 ml), dried (Na2SO4), and concentrated to afford a
white solid. This crude product was partially soluble in CH2Cl2. The white solid that did not dissolve in
CH2Cl2 was filtered off through a Celite pad, eluting with CH2Cl2. The crude that was obtained after
filtration and concentration was further purified by flash CC (SiO2, hexane/AcOEt 7:3): 5b (0.13 g,
62%). Semi-solid. [a]2D5 ¼ ꢀ12.5 (c ¼ 2.0, MeOH) ([6a]: [a]2D5 ¼ ꢀ13.2 (c ¼ 1.50, MeOH)). IR (neat):
3345, 2975, 1690, 1549, 1499, 1365, 1250, 1164. 1H-NMR (CDCl3, 300 MHz): 7.77 (d, J ¼ 7.6, 2 H); 7.61 (d,
J ¼ 7.6, 2 H); 7.42 – 7.26 (m, 6 H); 5.42 (br. s, 1 H); 5.19 (s, 1 H); 4.38 (m, 3 H); 4.21 (t, J ¼ 6.1, 1 H); 3.74
(s, 3 H); 3.62 (m, 2 H); 1.44 (s, 9 H). 13C-NMR (CDCl3, 75 MHz): 172.5; 144.4; 141.5; 137.9; 127.8; 127.6;
127.1; 124.7; 120.1; 73.5; 71.3; 69.6; 65.2; 50.4; 42.8; 31.9; 29.7. ESI-MS: 441 ([M þ H]þ). HR-ESI-MS:
441.4644 ([M þ H]þ, C24H28N2Oþ6 ; calc. 441.4632).
Benzyl N-[(1S)-1-(Furan-2-yl)-2-nitroethyl]carbamate (8b). As described for 8a, with 7b (1.92 g,
5 mmol), A, toluene, MeNO2, and CsOH · H2O. CC (SiO2, hexane/AcOEt 9 :1) afforded 8b (1.18 g,
82%). White solid. HPLC (chiral OD-H (lmax 220 nm), hexane/EtOH 7:3, 1 ml/min): 99% ee; tR (major)
11.83 min, tR (minor) 16.01 min. [a]D25 ¼ ꢀ19.5 (c ¼ 2.0, CHCl3) ([11c]: [a]D25 ¼ þ16.5 (c ¼ 1.50, CHCl3)).
IR (neat): 3311, 1701, 1552, 1507, 1378, 1331, 1429. 1H-NMR (CDCl3, 500 MHz): 7.36 – 7.26 (m, 6 H); 6.29
(dd, J ¼ 2.8, 9.6, 2 H); 6.21 (br. d, 1 H); 5.50 – 5.42 (m, 1 H); 5.19 (s, 2 H); 4.82 (dd, J ¼ 5.1, 12.8, 1 H); 4.64
(dd, J ¼ 5.4, 13.0, 1 H). 13C-NMR (CDCl3, 75 MHz): 155.2; 142.8; 142.8; 128.6; 128.4; 128.3; 110.8; 108.1;
96.2 76.2; 67.5; 47.8. ESI-MS: 313 ([M þ Na]þ). HR-ESI-MS: 313.0803 ([M þ Na]þ, C14H14N2NaOþ5 ; calc.
313.0800).
Methyl (2S)-2-{[(Benzyloxy)carbonyl]amino}-3-nitropropanoate (9b). As described for 9a, with
NaIO4, CCl4, MeCN, H2O, RuCl3 · H2O, 8b (1.02 g, 3.5 mmol), MeCN (10 ml), and CH2N2 in Et2O
(30 mmol): CC (SiO2, hexane/acetone 4 :1) gave 9b (0.64 g, 65%). White semi-solid. [a]2D5 ¼ ꢀ26.2 (c ¼
1
2.0, CHCl3). IR (neat): 3364, 2945, 1709, 1549, 1499, 1376, 1256, 1262. H-NMR (CDCl3, 300 MHz):
7.40 – 7.33 (m, 5 H); 5.79 (br. s, 1 H); 5.22 (br. s, 1 H); 5.14 (s, 2 H); 5.00 (dd, J ¼ 3.2, 14.7, 1 H); 4.82 (m,
2 H); 3.83 (s, 3 H); 3.60 (dd, J ¼ 4.3, 10.6, 1 H); 1.44 (s, 9 H). 13C-NMR (CDCl3, 75 MHz): 171.5; 167.5;

Helvetica Chimica Acta – Vol. 94 (2011)
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156.7; 136.2; 128.5; 128.1; 127.8; 66.9; 53.9; 52.6; 42.8; 29.6. ESI-MS: 375 ([M þ Na]þ). HR-ESI-MS:
305.6532 ([M þ Na]þ, C12H14N2NaOþ6 ; calc. 305.6524).
Methyl (2S)-2-{[(Benzyloxy)carbonyl]amino}-3-{[(tert-butoxy)carbonyl]amino}propanoate (6a).
As described for 5a, with 9b (0.564 g, 2 mmol), NiCl2 · 6 H2O, MeOH, and NaBH4: crude 10b (0.38 g,
75%). Then as described for 5a, with 10b (0.125 g, 0.5 mmol), CH2Cl2, (Boc)2O, and DMAP: 6a (0.11 g,
68%). Brown dense liquid. [a]2D5 ¼ ꢀ15.8 (c ¼ 2.0, CHCl3). IR (neat): 3334, 2978, 1726, 1677, 1619, 1536,
1
1495, 1449, 1370, 1272, 1159, 1094. H-NMR (CDCl3, 300 MHz): 7.42 – 7.37 (m, 5 H); 6.21 (br. d, 1 H);
5.28 (br. s, 1 H); 5.22 (s, 2 H); 4.24 – 4.11 (m, 1 H); 3.30 (dd, J ¼ 3.2, 10.6, 1 H); 3.18 (dd, J ¼ 3.4, 9.6, 1 H);
1.52 (s, 9 H). 13C-NMR (CDCl3, 75 MHz): 172.3; 168.1; 159.5; 135.01; 131.41; 128.9; 128.3; 128.1; 127.9;
75.6; 53.7; 42.6; 28.93; 24.40. ESI-MS: 375 ([M þ Na]þ). HR-ESI-MS: 375.6239 ([M þ Na]þ,
C12H14N2NaOþ6 ; calc. 375.6251).
Methyl (2S)-2-{[(Benzyloxy)carbonyl]amino}-3-{{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}pro-
panoate (6b). To the crude 10b (0.12 g, 0.5 mmol) and Et3N (0.11 g, 1.0 mmol) in CH2Cl2 was added
FmocCl (0.75 mmol) under Ar at 08. The mixture was stirred for 3 h at r.t. and then concentrated to
afford a semi-solid. The semi-solid was dissolved in AcOEt (10 ml), the org. layer washed with sat.
NaHCO3 soln. (1 ꢁ 5 ml), 1m HCl (1 ꢁ 5 ml), and sat. NaCl soln. (2 ꢁ 10 ml), dried (Na2SO4), and
concentrated to afford a white solid. This crude product was purified by CC (SiO2, hexane/acetone 7:3):
6b (0.13 g, 62%). Semi-solid. [a]2D5 ¼ ꢀ17.3 (c ¼ 2.0, CHCl3). IR (neat): 3345, 2975, 1690, 1549, 1499, 1365,
1250, 1164. 1H-NMR (CDCl3, 300 MHz): 7.79 (d, J ¼ 7.3, 2 H); 7.66 (d, J ¼ 7.3, 2 H); 7.42 – 7.26 (m, 11 H);
5.40 (br. s, 1 H); 5.10 (s, 2 H); 4.37 (m, 3 H); 4.18 (t, J ¼ 4.4, 1 H); 3.68 (s, 3 H); 3.64 (m, 2 H). 13C-NMR
(CDCl3, 75 MHz): 172.7; 157.3; 155.5; 143.6; 142.3; 135.4; 128.3; 127.6; 127.1; 126.3; 120.3; 67.3; 57.4; 51.8;
47.2; 42.8. ESI-MS: 475 ([M þ H]þ). HR-ESI-MS: 475.1539 ([M þ H]þ, C17H24N2NaOþ6 ; calc. 475.1532).
Methyl (2R)-2-{[(tert-Butoxy)carbonyl]amino}-2-(furan-2-yl)acetate (11a). To the stirred soln. of
8a (0.51 g, 2 mmol) in DMF/H2O 7:1 (0.4m) and AcOH (0.60 g, 10 mmol) was added solid NaNO2
(0.83 g, 12 mmol) at r.t. The mixture was heated to 458 for 12 h. Then, the reaction was quenched with
H2O (20 ml), the mixture extracted with CH2Cl2 (3 ꢁ 20 ml), and the org. extract washed with H2O (2 ꢁ
10 ml) and brine (2 ꢁ 10 ml), dried (Na2SO4), and concentrated. The crude residue was dissolved in dry
CH2Cl2 (10 ml) and benzene (2.5 ml) at 08. To this, CH2N2 in Et2O (20 mmol) was added. After 3 h of
stirring at r.t., the mixture was concentrated and the residue purified by CC (SiO2, hexane/AcOEt 9 :1):
11a (0.35g, 68%). Brown liquid. [a]2D5 ¼ ꢀ68.5 (c ¼ 2.0, CHCl3). IR (neat): 3362, 2973, 2924, 2855, 1748,
1
1499, 1158. H-NMR (CDCl3, 300 MHz): 7.33 (t, J ¼ 1.3, 1 H); 6.31 (dd, J ¼ 1.5, 2 H); 5.40 (br. s, 1 H);
3.76 (s, 3 H); 1.44 (s, 9 H). 13C-NMR (CDCl3, 75 MHz): 154.7; 136.9; 128.5; 126.3; 80.4; 78.8; 52.7; 28.1.
ESI-MS: 278 ([M þ H]þ). HR-ESI-MS: 278.1593 ([M þ H]þ, C12H17NNaO5þ ; calc. 278.1582).
Methyl (2R)-2-{[(Benzyloxy)carbonyl]amino}-2-(furan-2-yl)acetate (11b). As described for 11a,
with 8b (0.29 g, 1 mmol), DMF/H2O 7:1 (0.4m), AcOH (0.30 g, 5 mmol), and NaNO2 (0.42 g, 6 mmol).
Quenching with H2O (10 ml) and extraction with CH2Cl2 (3 ꢁ 10 ml). The crude residue in dry CH2Cl2
(8 ml) and benzene (1.5 ml) at 08 was treated with CH2N2 in Et2O (10 mmol) as described for 11a. CC
(SiO2, hexane/AcOEt 85 :15) gave 11b (0.17 g, 60%). Brown liquid. [a]2D5 ¼ ꢀ72.5 (c ¼ 2.0, CHCl3). IR
(neat): 2975, 1690, 1549, 1499, 1365, 1250, 1164. 1H-NMR (CDCl3, 300 MHz): 7.34 – 7.26 (m, 6 H); 6.34 –
6.30 (m, 2 H); 5.72 (d, J ¼ 7.3, 1 H); 5.46 (d, J ¼ 8.3, 1 H); 5.08 (s, 2 H); 4.64 (s, 1 H); 3.75 (s, 3 H).
13C-NMR (CDCl3, 75 MHz): 169.2; 155.4; 148.5; 142.8; 135.9; 128.5; 128.1; 126.9; 110.6; 108.6; 67.2; 53.0;
51.9. ESI-MS: 312 ([M þ Na]þ). HR-ESI-MS: 312.0847 ([M þ Na]þ, C15H15NNaOþ5 ; calc. 312.0847).
Benzyl N-{(1S)-2-{[(tert-Butyl)dimethylsilyl]oxy}-1-(furan-2-yl)ethyl}carbamate (12). To the stirred
soln. of 11b (0.14 g, 0.5 mmol) in dry CH2Cl2 was added 1m DIBAL-H in toluene (1.5 ml) at ꢀ 788 via
syringe. The mixture was stirred for 1 h at ꢀ 788 and for 2 h at ꢀ 308. Then, the reaction was quenched
with MeOH (1 ml), the mixture extracted with AcOEt (3 ꢁ 10 ml), and the org. extract washed with 0.1n
HCl (2 ꢁ 10 ml) and brine (2 ꢁ 10 ml), dried (Na2SO4), and concentrated to give crude primary alcohol
(80%). To the primary alcohol (0.10 g, 0.4 mmol) in dry CH2Cl2 was added Et3N (0.20 g, 0.8 mmol)
followed by tBuMe2SiCl (0.09 g, 0.6 mmol) at 08 successively. The mixture was stirred for 5 h at r.t. After
5 h, the solids were filtered through a Celite pad, and the resultant crude residue was purified by CC
(SiO2, hexane/AcOEt 8 :2): 12 (0.11 g, 76%). Colorless oil. [a]2D5 ¼ ꢀ14.1 (c ¼ 2.0, CH2Cl2) ([13c]:
1
[a]2D5 ¼ þ13.1 (c ¼ 1.15, CH2Cl2)). IR (neat): 3452, 3331, 2929, 2856, 1725, 1499, 1249, 1134. H-NMR
(CDCl3, 300 MHz): 7.38 – 7.28 (m, 6 H); 6.32 (dd, J ¼ 1.8, 3.5, 1 H); 6.23 (d, J ¼ 3.4, 1 H); 5.11 (s, 2 H);

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Helvetica Chimica Acta – Vol. 94 (2011)
5.04 (t, J ¼ 3.9, 1 H); 4.82 (t, J ¼ 6.0, 1 H); 3.51 (m, 1 H); 0.87 (s, 9 H); ꢀ 0.05 (s, 6 H). 13C-NMR (CDCl3,
75 MHz): 156.3; 154.4; 131.9; 136.5; 128.5; 128.1; 127.2; 110.1; 107.0; 67.3; 66.7; 46.1; 25.7; 18.1; ꢀ 5.4. ESI-
MS: 398 ([M þ Na]þ). HR-MS: 398.1777 ([M þ Na]þ, C20H29NNaO4Siþ; calc. 398.1763).
REFERENCES
[1] A. Viso, R. F. De la Pradilla, A. Garcꢂa, A. Flores, Chem. Rev. 2005, 105, 3167.
[2] R. Kuwano, S. Okuda, Y. Ito, Tetrahedron: Asymmetry 1998, 9, 2773; A. J. Robinson, P. Stanislawski,
˜
D. Mulholland, L. He, H.-Y. Li, J. Org. Chem. 2001, 66, 4148; K. Muniz, M. Nieger, Chem. Commun.
˜
2005, 2729; I. Almodovar, C. H. Hovelmann, J. Streuff, M. Nieger, K. Muniz, Eur. J. Org. Chem.
2006, 704; A. Guerrini, G. Varchi, C. Samori, A. Battaglia, Eur. J. Org. Chem. 2008, 3834; R. G.
´
Arrayas, J. C. Carretero, Chem. Soc. Rev. 2009, 38, 1940.
[3] C. Yuan, R. M. Williams, J. Am. Chem. Soc. 1997, 119, 11777; K. Groebke, P. Renold, K. Y. Tsang,
T. J. Allen, K. F. McClure, D. S. Kemp, Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 4025; S. Padmanabhan,
E. J. York, J. M. Stewart, R. L. Baldwin, J. Mol. Biol. 1996, 257, 726.
[4] a) I. H. Gilbert, D. C. Rees, A. K. Crockett, R. C. F. Jones, Tetrahedron 1995, 51, 6315; b) H. L.
van Maanen, H. Kleijn, J. T. B. H. Jastrzebski, J. Verweij, P. G. Kieboom, G. van Koten, J. Org.
Chem. 1995, 60, 4331; c) W. Dꢁrckheimer, J. Blumbach, R. Lattrell, K. H. Scheunemann, Angew.
Chem., Int. Ed. 1985, 24, 180.
[5] R. Cooper, A. C. Horan, F. Gentile, V. Gullo, D. Loebenberg, J. Marquez, M. Patel, M. S. Puar, I.
Truumees, J. Antibiot. 1988, 41, 13; J. A. Pesti, J. Yin, L.-H. Zhang, L. Anzalone, R. E. Waltermire, P.
Ma, E. Gorko, P. N. Confalone, J. Fortunak, C. Silverman, J. Blackwell, J. C. Chung, M. D. Hrytsak,
M. Cooke, L. Powell, C. Ray, Org. Proc. Res. Dev. 2004, 8, 22.
[6] a) E. A. Englund, H. N. Gopi, D. H. Appella, Org. Lett. 2004, 6, 213; b) R. Caputo, E. Cassano, L.
Longobardo, G. Palumbo, Tetrahedron 1995, 51, 12337; c) P. J. Colson, L. S. Hegedus, J. Org. Chem.
1993, 58, 5918; d) R. C. F. Jolles, A. K. Crockett, D. C. Rees, I. H. Gilbert, Tetrahedron: Asymmetry
´
1994, 5, 1661; e) C. Cativiela, M. D. Dꢂaz-de-Villegas, J. A. Galvez, Tetrahedron: Asymmetry 1994, 5,
´
1465; f) R. Badorrey, C. Cativiela, M. D. Diaz-de-Villegas, J. A. Galvez, Tetrahedron: Asymmetry
1995, 6, 2787; g) E. Castellanos, G. Reyes-Rangel, E. Juaristi, Helv. Chim. Acta 2004, 87, 1016;
h) S. S. Chauhan, H. J. Wilk, Tetrahedron Lett. 2010, 51, 3340.
[7] A. J. Robinson, C. Y. Lim, L. He, P. Ma, H.-Y. Li, J. Org. Chem. 2001, 66, 4141; D. Choi, H. Kohn,
Tetrahedron Lett. 1995, 36, 7371; F. Kelleher, K. Proinsias, Tetrahedron Lett. 2007, 48, 4879
[8] G. A. Cutting, N. E. Stainforth, M. P. John, G. Kociok-K”hn, M. C. Willis, J. Am. Chem. Soc. 2007,
129, 10632; Y. Ohfune, T. Shinada, Bull. Chem. Soc. Jpn. 2003, 76, 1115; Z. Chen, H. Morimoto, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 2170; Y. Kim, H.-J. Ha, K. Han, S. W. Ko, H.
Yun, H. J. Yoon, M. S. Kim, W. K. Lee, Tetrahedron Lett. 2005, 46, 4407; H. Teng, Z. Jing, L. Wu, J.
Su, X. Feng, G. Qiu, S. Liang, X. Hu, Synth. Commun. 2006, 3803; C. Zhao, C. Song, Y. Luo, Z. Yu,
M. Sun, FEBS Lett. 2008, 582, 3125.
[9] D. Enders, J. Wiedemann, Synthesis 1996, 1443; D. Lucet, L. Toupet, T. Le Gall, C. Mioskowski, J.
Org. Chem. 1997, 62, 2682.
[10] K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf, K. A. Jørgensen, J. Am. Chem. Soc. 2001,
123, 5843.
´
[11] a) C. Palomo, M. Oiarbide, A. Laso, R. Lopez, J. Am. Chem. Soc. 2005, 127, 17622; b) E. Gomez-
´
´
Bengoa, A. Linden, R. Lopez, I. Mugica-Mendiola, M. Oiarbide, C. Palomo, J. Am. Chem. Soc. 2008,
130, 7955; c) X. Xu, T. Furukawa, T. Okino, H. Miyabe, Y. Takemoto, Chem. – Eur. J. 2006, 12, 466.
[12] G. Kumaraswamy, N. Jayaprakash, B. Sridhar, J. Org. Chem. 2010, 75, 2745.
[13] a) M. H. Haukaas, G. A. OꢃDoherty, Org. Lett. 2001, 3, 401; b) S. D. Koulocheri, P. Magiatis, S. A.
Haroutounian, J. Org. Chem. 1984, 49, 4277; c) A. S. Radhakrishna, M. E. Parham, R. M. Riggs,
G. M. Loudon, J. Org. Chem. 1979, 44, 1746.
Received January 11, 2011