Diversity-oriented synthesis of enantiopure N-protected β,β-dialkylserines

Article abstract of DOI:10.1139/v03-193

A series of enantiomerically pure N-Boc-protected β,β- dialkylserines was synthesized by addition of the appropriate Grignard reagent to N-(Boc)serine methyl ester, followed by TEMPO-catalysed oxidation of the primary alcohol with sodium chlorite and sodi

Full text of DOI:10.1139/v03-193

3
18
Diversity-oriented synthesis of enantiopure N-
1
protected ␤,␤-dialkylserines
James E. Dettwiler and William D. Lubell
Abstract: A series of enantiomerically pure N-Boc-protected β,β-dialkylserines was synthesized by addition of the ap-
propriate Grignard reagent to N-(Boc)serine methyl ester, followed by TEMPO-catalysed oxidation of the primary alco-
hol with sodium chlorite and sodium hypochlorite.
Key words: amino acid, serine, β,β-dialkylserines, ring-closing metathesis.
Résumé : Une série énantiomériquement pure de β,β-dialkylserines N-Boc protégées est synthétisée par addition du
réactif de Grignard correspondant sur l’ester méthylique de la N-(Boc)serine suivie d’une oxydation catalysée de
l’alcool primaire avec TEMPO, du chlorite de sodium et de l’hypochlorite de sodium.
Mots clés : acide aminé, sérine, β,β-dialkylserines, cyclisation par métathèse.
Dettwiler and Lubell 324
Introduction
methyl ester with methyl Grignard reagent followed by a
selective oxidation of the resulting diol (14). When N-Boc-
D-serine methyl ester was employed in this sequence, the
corresponding N-Boc-L-β-hydroxyvaline (97% enantiomeric
purity) was produced in 80% overall yield on a multi-gram
scale. In light of this efficiency, we have investigated alter-
native Grignard reagents in this process and have now devel-
oped an effective diversity oriented synthesis of enantiopure
N-Boc-β,β-dialkyl serines.
β-Alkylserines are constituents of biologically active pep-
tides, as well as starting materials for the synthesis of un-
usual amino acids and heterocycles (1–14). In peptides, the
alkyl groups of β-substituted amino acids may exhibit steric
interactions that can restrain χ-dihedral angle geometry and
orient side-chains in particular conformations (1). They may
also play roles that influence the interactions of the peptide
with its environment and with its biological receptor.
Alcohol activation and displacement may be used to convert
β-alkylserines into aziridine-2-carboxylates (2–8), β-
alkylcysteines (2, 3), and β-alkyltryptophans (4, 5), as well
as amino acids possessing unnatural β-substituents like fluo-
rine (6–8). Although many methods have been developed for
the preparation of β-alkylserines, few approaches have been
explored for the synthesis of the related, more substituted
β,β-dialkylserines (10–14). The protection of serine as its
OBO (2,6,7-trioxabicyclo[2.2.2]octyl) ester, followed by
oxidation and addition of nucleophiles, such as Grignard re-
agents, at the β-carbon represents a notable means for stereo-
selectively synthesizing β,β-dialkylserines (10). Although
diastereoselective condensations of aldehydes onto chiral
glycine enolates have furnished a series of β-alkylserine
analogs, the lower reactivity of ketones in this aldol ap-
proach limits its application for making β,β-dialkylserines
Results and discussion
For our investigation, a series of Grignard reagents were
chosen, possessing primary and secondary alkyl, allyl, vinyl,
benzyl, and aryl substitution. All of the Grignard reagents
were obtained from commercial sources and used without
further purification. Using conditions optimized with methyl
magnesium bromide (14), the Grignard reagent was added to
a solution of N-Boc-D-serine methyl ester at –78 °C in di-
ethyl ether (THF in the case of vinyl magnesium bromide,
Scheme 1). The desired diol 2 was typically obtained as the
major product, contaminated with minor amounts of the cor-
responding ketone 3. For example, diols 2a–2e were isolated
in 68%–83% yields after purification by silica gel column
chromatography (Table 1). On the other hand, iso-propyl
magnesium chloride reacted on N-Boc-D-serine methyl ester
to provide diol 2g in 38% yield along with the less substi-
tuted diol 4 (4:1 diastereomeric mixture) from reduction of
the ketone intermediate 3g (15). Reversing the addition of N-
Boc-D-serine methyl ester by adding it to a solution of the
iso-propyl Grignard reagent afforded the same result. Vinyl-
magnesium bromide reacted with the N-Boc-D-serine methyl
ester to provide a 1:1 mixture of diol 2f and homoallylic
(
11–13). Recently, we have reported a two-step approach for
synthesizing N-protected β-hydroxyvaline (β,β-dimethyl-
serine), which involved treatment of N-protected serine
Received 8 October 2003. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 13 February 2004.
2
J.E. Dettwiler and W.D. Lubell. Département de chimie,
Université de Montréal, C.P. 6128, Succursale Centre Ville,
Montréal, QC H3C 3J7, Canada.
ketone 3h, as measured by integration of the vinyl protons at
1
6
.01 and 5.80 parts per million (ppm), respectively, in the H
1This article is part of a Special Issue dedicated to Professor
Ed Piers.
NMR spectrum of the crude product in CDCl . Silica gel
3
column chromatography was used to isolate diol 2f and
ketone 3h in 25% and 35% respective yields, as well as a
2
Corresponding author (e-mail: Lubell@chimie.umontreal.ca).
Can. J. Chem. 82: 318–324 (2004)
doi: 10.1139/V03-193
© 2004 NRC Canada

Dettwiler and Lubell
319
Scheme 1. Synthesis of β,β-dialkyl-N-(Boc)serines 1a–1g.
Table 1. Results of Grignard addition on N-(Boc)-L-serine methyl ester and oxidation of the re-
sulting amino diol 2.
Yields (%)a
Entry
RMgX
Amino diol 2
Amino ketone 3
Amino acid 1
a
b
c
d
e
f
CH MgBr
83
2
96
92
76
74
78
81
72
3
CH CH MgBr
81
4
3
2
C H MgBr
79
4
6
5
C H CH MgBr
74
11
6
5
2
CH =CHCHMgBr
68
16b
2
CH =CHMgBr
25
35c
2
g
(CH ) CHMgCl
38 (41)
19 (10)d
3
2
a
Results obtained from inverse addition of N-Boc- -serine methyl ester to iso-propyl Grignard reagent are re-
L
ported in parentheses.
b
trans-α,β-Unsaturated enone (2R)-2-[N-(Boc)amino]-1-hydroxy-hex-4-en-3-one 3i.
c
(
2R)-2-[N-(Boc)Amino]-1-hydroxy-hept-6-en-3-one 3h; in addition, a 1:4 mixture of 3h and (2R)-2-[N-
(
Boc)amino]-3-vinyl-pent-4-en-1,3-diol 2f was isolated in 22% yield.
d
(
2R)-2-[N-(Boc)Amino]-4-methyl-pentane-1,3-diol 4, resulting from ketone reduction, was also isolated as a
4
:1 diastereomeric mixture in 32% (41%) yield.
2
2% yield of a mixed fraction containing a 1:4 ratio of 3h
Cycloalkyl β-hydroxy α-amino acids, such as 7 in racemic
form, have served as intermediates for preparation of novel
β-lactam antibiotics (19–21). (S)-Cleonin, a component of
the antitumor antibiotic cleorycin, is a cyclopropyl β-
hydroxy α-amino acid that has recently been made by a
route featuring the titanium(VI)-isopropoxide-catalysed ad-
dition of ethyl magnesium bromide to a fully protected
serine methyl ester (22, 23). Cyclopentyl β-hydroxy α-amino
acid has been introduced into the antimicrobial agent R-106
aureobasidin (24) by a route featuring a retro-aldol–aldol
reaction, in which the β-hydroxy-N-methyl valine residue
loses acetone and incorporates cyclopentanone into the na-
tive peptide (25, 26). The new aureobasidin analogue
showed activity comparable with the native peptide R-106
(26). In light of such interest in cycloalkyl β-hydroxy α-
amino acids, cyclopentenyl amino diol 5 was synthesized by
ring-closure metathesis on bis-allyl amino diol 2e (27–29).
Exposure of amino diol 2e to benzylidene[1,3-
bis(mesitylene)-2-imidazolidinylidene]tricyclohexylphosphine
ruthenium(IV) dichloride (10 mol%) in CH Cl for 24 h at
and 2f. Addition of N-Boc-D-serine methyl ester to vinyl-
magnesium bromide gave a similar result. Homoallylic
ketone 3h was identified based on the presence of its car-
bonyl carbon at 207 ppm, as well as its COSY spectrum in
CDCl , in which the vinyl protons (5.01 and 5.79 ppm) were
3
shown to be coupled to allylic protons at 2.37 ppm. Appar-
ently, attack of the ester followed by loss of methoxide ion
provided the α,β-unsaturated ketone 3f, which underwent
conjugate addition to furnish the corresponding enolate and
delivered 3h after work-up (Scheme 2). Homoallylic ketone
has been previously reported as the side product from addi-
tion of vinylmagnesium bromide to β-hydroxy ester deriva-
tives in ether (16, 17). The addition of allyl magnesium
chloride on N-Boc-D-serine methyl ester provided diol 2e in
6
8% yield, as well as trans-α,β-unsaturated enone 3i in 16%
yield. Enone 3i was likely formed from β,γ-unsubstituted
ketone during quenching of the reaction with aqueous satu-
rated NH Cl, which has previously been reported to effect
conjugation (18).
4
2
2
©
2004 NRC Canada

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20
Can. J. Chem. Vol. 82, 2004
Scheme 2. Mechanism for the formation of (2R)-2-[N-(Boc)amino]-1-hydroxy-hept-6-en-3-one 3h.
Scheme 3. Synthesis and enantiomeric purity of cyclopentane amino acid 7.
4
0 °C provided a dark brown, crude reaction product that
7 were obtained in 72%–96% yields after purification by sil-
ica gel column chromatography (Table 1).
was first passed through a silica gel column and then treated
with activated carbon for 12 h at room temperature to yield
5
ble bond in the five-membered ring of 5 was accomplished
using Wilkinson’s catalyst, which provided, after a similar
chromatography – activated carbon purification, saturated
product 6 in 98% yield (31, 32).
To ascertain if racemization had occured during the synthesis
of the various β,β-dialkylserines 1a–1f and 7 from N-Boc-D-
serine methyl ester, the enantiomeric purity of cyclopentane
amino acid 7 was evaluated after conversion to diastereo-
meric dipeptide 8 (Scheme 3). Both (S)- and (R)-phenylalanine
methyl ester hydrochloride were independently coupled with
acid 7, using benzotriazol-1-yl-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole
as a colorless oil in 81% yield (30). Reduction of the dou-
As in our synthesis of β-hydroxyvaline (14), selective pri-
mary alcohol oxidation was accomplished by treating diols
2
a–2g and 6 with TEMPO (2,2,6,6-tetramethyl-1-piperi-
(
HOBt) in acetonitrile. Observation of the signals for the
dinyloxy) free radical, sodium chlorite, and sodium
hypochlorite in a sodium-phosphate-buffered acetonitrile so-
lution (Scheme 1) (33). N-Boc-β,β-Dialkylserines 1a–1g and
diastereotopic α-protons at 3.91 and 3.84 ppm in the
4
1
00 MHz H NMR spectra of 8 (obtained after aqueous
workup) during incremental additions of (S)-8 in (R)-8 in
©
2004 NRC Canada

Dettwiler and Lubell
321
CDCl , demonstrated dipeptide (R)-8 to be of >98% diaste-
Second to elute was (2R)-2-[N-(Boc)amino]-1-hydroxy-
3
reomeric purity. Protected diastereomer (S)-8 and N-Boc-
β,β-dialkylserines 1a–1g and 7 are thus all presumed to be of
similarly high enantiomeric purity.
pentan-3-one (3b), an oil (22 mg, 4%): TLC R = 0.14 (50%
f
1
EtOAc in hexanes). H NMR (400 MHz, CDCl ) δ: 0.97 (q,
3H, J = 7.6), 1.44 (s, 9H), 3.48–3.68 (m, 4H). MS (TIC)
3
+
m/z: 219.8 ([M + 2H] ).
Conclusion
(
2R)-2-[N-(Boc)Amino]-1,1-diphenyl-propane-1,3-diol
(2c)
Product from addition of phenyl magnesium bromide
The diversity oriented synthesis of enantiopure L-N-Boc-β,
β-dialkylserines has been achieved in two practical steps
from N-(Boc)-D-serine methyl ester as chiral educt. In light
of applications of alkyl-branched serines in the study of bio-
logically active peptides and the synthesis of other amino ac-
ids and heterocycles, this route provides a useful set of tools
for peptide science and novel building blocks for diversity
oriented synthesis.
–
1
(3.0 mol L in Et O) was purified on a silica gel column us-
ing a gradient of 10%–15% EtOAc in hexanes as eluant.
First to elute was diol 2c, a white solid (678 mg, 79%): TLC
2
2
0
R = 0.48 (50% EtOAc in hexanes); mp 68 to 69 °C. [α]
f
D
1
65.6° (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ: 1.32
3
3
(s, 9H), 2.91 (s, 1H), 3.67 (d, 1H, J = 11.0), 3.77 (d, 1H, J =
1
8
0.7), 4.65 (d, 1H, J = 7.7), 4.86 (s, 1H), 5.53 (d, 1H, J =
.4), 7.13–7.31 (m, 6H), 7.45–7.51 (m, 4H). 13C NMR
Experimental section
(
100 MHz, CDCl ) δ: 28.4, 55.5, 63.9, 79.9, 81.8, 125.2
3
General
(2C), 125.5 (2C), 126.9, 127.0, 128.3 (2C), 128.6 (2C),
+
Reagent and solvent purification, spectroscopic and spec-
trometric analyses, and chromatography — all were
performed as described in the general section of the experi-
mental that was presented in a previous work (14). The spec-
144.7, 145.5, 156.2. HR-MS calcd. for C20H26NO4 ([MH] ):
344.1862; found: 344.1851.
Second to elute was (2R)-2-[N-(Boc)amino]-3-hydroxy-1-
phenyl-propan-1-one (3c), an oil (27 mg, 4%): TLC Rf =
0.37 (50% EtOAc in hexanes). H NMR (400 MHz,
1
tra for 1b, 1f, and 1g were measured in D O with added
2
NaOD, using dioxane (3.75 ppm, 67.19 ppm) as internal ref-
CD3OD) δ: 1.45 (s, 9H), 3.80 (dd, 1H, J = 5.0, J = 11.4),
3.91 (dd, 1H, J1 = 4.7, J2 = 11.4), 5.23 (s, 1H), 7.00–7.53
(m, 2H), 7.54–7.66 (m, 1H), 8.01 (m, 2H). MS (TIC) m/z:
erence; in CDCl , the compounds were observed as
3
conformational isomers. The synthesis and the analysis of
+
(
S)-β-hydroxy-N-(Boc)valine 1a was performed as described
266.8 ([MH] ).
previously (14). Minor reaction components were character-
ized by LC-MS using total ion chromatography (TIC).
(2R)-2-[N-(Boc)Amino]-3-benzyl-4-phenyl-butane-1,3-
diol (2d)
General procedure for preparation of diol derivatives
Product from addition of benzyl magnesium bromide
–
1
A solution of N-(Boc)-L-serine methyl ester (548 mg,
(3.0 mol L in Et O) was purified on a silica gel column us-
2
2
.5 mmol) in Et O at –78 °C was treated dropwise with a so-
ing a gradient of 10%–15% EtOAc in hexanes as eluant.
2
lution of the Grignard reagent (600 mol%, 15 mmol). The
First to elute was diol 2d, a white solid (687 mg, 74%): TLC
–
1
20
initial volume of Et O was adjusted to afford a 0.1 mol L
R = 0.49 (50% EtOAc in hexanes); mp 86 to 87 °C. [α]
2
f
D
1
concentration of N-(Boc)-L-serine methyl ester after Grig-
nard reagent addition. The dry ice bath was removed, and
the reaction mixture was stirred for 2 h at room temperature,
cooled to 0 °C, and treated dropwise with a solution of aque-
–13.6° (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ: 1.44
3 3
(s, 9H), 2.68–3.00 (m, 6H), 3.64 (br s, 1H), 3.92 (br s, 2H),
5.19 (br s, 1H), 7.19–7.33 (m, 10H). C NMR (100 MHz,
1
3
CDCl ) δ: 28.1, 28.5, 42.6, 42.8, 57.0, 63.6, 80.0, 126.9
3
ous saturated NH Cl (20 mL). The phases were separated,
(2C), 128.5 (4C), 130.9 (4C), 136.4 136.6, 156.7. HR-MS
calcd. for C H NO (TOF EI): 372.2175; found: 372.2174.
4
and the aqueous layer was extracted with EtOAc (3 ×
2
2
30
4
2
0 mL). The organic phases were combined, washed with
Anal. calcd. for C H NO +H O: C 67.84, H 8.02, N 3.60;
22 29 4 2
brine, dried with MgSO , filtered, and evaporated to an oily
found: C 67.91, H 8.11, N 3.65.
4
residue, which was purified on silica gel.
Second to elute was (2R)-3-[N-(Boc)amino]-4-hydroxy-1-
phenyl-butan-2-one (3d), an oil (77 mg, 11%): TLC R =
f
1
(
2R)-2-[N-(Boc)Amino]-3-ethyl-pentane-1,3-diol (2b)
0.39 (50% EtOAc in hexanes). H NMR (400 MHz,
Product from addition of ethyl magnesium bromide
CD3OD) δ: 1.45 (s, 9H), 3.79 (d, 1H, J = 10.9), 3.89 (s, 2H),
–
1
(
3.0 mol L in Et O) was purified on a silica gel column us-
3.90 (d, 1H, J = 10.9), 4.29 (s, 1H), 7.20–7.19 (m, 5H). MS
2
+
ing a gradient of 5%–10% EtOAc in hexanes as eluant. First
(TIC) m/z: 280.8 ([MH] ).
to elute was diol 2b, a white solid (501 mg, 81%). TLC R =
f
2
0
0
.30 (50% EtOAc in hexanes); mp 97 to 98 °C. [α] –29.0°
(2R)-2-[N-(Boc)Amino])-3-allyl-hex-5-ene-1,3-diol (2e)
D
1
(
c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ: 0.84 (t, 3H,
Product from addition of allyl magnesium bromide
3
3
–
1
J = 7.31), 0.90 (t, 3H, J = 7.38), 1.45 (s, 9H), 1.50–1.61 (m,
(1.0 mol L in Et O) was purified on a silica gel column us-
2
3
1
5
7
H), 1.66–1.75 (m, 1H), 3.05 (s, 1H), 3.32 (s, 1H), 3.57 (d,
ing a gradient of 20%–25% EtOAc in hexanes as eluant.
H, J = 9.0), 3.78 (d, 1H, J = 4.7), 4.00 (d, 1H, J = 11.2),
First to elute was diol 2e, a white solid (485 mg, 68%): TLC
.50 (d, 1H, J = 8.9). 13C NMR (100 MHz, CDCl ) δ: 7.6,
R = 0.48 (50% EtOAc in hexanes); mp 69 to 70 °C. [α]
20
3
f
D
1
.9, 27.2, 28.2, 28.5, 54.4, 63.6, 78.2, 79.6, 156.5. HR-MS
–21.0° (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ: 1.45
3 3
(s, 9H), 2.30–2.36 (m, 3H), 2.45 (dd, 1H, J = 6.4, J =
+
calcd. for C H NO ([MH] ): 248.1862; found: 248.1871.
1
2
26
4
1 2
Anal. calcd. for C H NO : C 58.27, H 10.19, N 5.66;
found: C 58.44, H 10.50, N 5.65.
14.0), 3.30–3.37 (m, 2H), 3.59 (d, 1H, J = 8.9), 3.80 (d, 1H,
J = 10.5), 4.00 (d, 1H, J = 10.8), 5.10–5.18 (m, 4H), 5.51 (d,
1
2
25
4
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2004 NRC Canada

3
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Can. J. Chem. Vol. 82, 2004
1
H, J = 9.0), 5.78–5.90 (m, 2H). 13C NMR (100 MHz,
Second to elute was (2R)-2-[N-(Boc)amino]-1-hydroxy-4-
CDCl ) δ: 28.5, 40.47, 41.3, 54.9, 63.3, 77.0, 79.8, 119.2,
methyl-pentan-3-one (3g), an oil (110 mg, 19%): R = 0.38
3
f
1
1
19,3, 132.8, 132.9, 156.3. HR-MS calcd. for C H NO
(50% EtOAc in hexanes). H NMR (400 MHz, CD OD) δ:
1
4
26
4
3
+
([MH] ): 272.1862; found: 272.1874. Anal. calcd. for
C H NO : C 61.97, H 9.29, N 5.16; found: C 61.71, H
1.07 (d, 3H, J = 6.8), 1.11 (d, 3H, J = 6.8), 1.45 (s, 9H),
2.96 (sept, 1H, J = 6.9), 3.75–3.86 (m, 2H), 1.45 (s, 9H),
1
4
25
4
+
9
.52, N 5.08.
4.79 (s, 1H). MS (TIC) m/z: 232.8 ([MH] ).
Second to elute was (2R)-2-[N-(Boc)amino]-1-hydroxy-
Third to elute was (2R)-2-[N-(Boc)amino]-4-methyl-pentane-
1,3-diol (4), a white solid (186 mg, 32%) containing a 4:1
diastereomeric mixture, as ascertained on measurement of
hex-4-en-3-one (3i), an oil (109 mg, 16%): TLC R = 0.44
f
1
(
50% EtOAc in hexanes). H NMR (400 MHz, CDCl ) δ:
.44 (s, 9H), 1.94 (d, 3H, J = 6.3), 3.76 (s, 1H), 3.88 (m,
H), 6.31 (d, 1H, J = 15.6), 7.07 (m, 1H). MS (TIC) m/z:
3
1
2
2
the diastereotopic multiplets for the C proton at 1.80 and
4
1.68 ppm. TLC R = 0.15 (50% EtOAc in hexanes). Signals
f
+
1
30.8 ([MH] ).
for the major diastereomer: H NMR (400 MHz, CD OD) δ:
.92 (d, 3H, J = 6.6), 0.97 (d, 3H, J = 6.9), 1.78 (s, 9H),
3
0
(
2R)-2-[N-(Boc)Amino]-3-vinyl-pent-4-en-1,3-diol (2f)
A solution of N-Boc-L-serine methyl ester (1.1 g,
1.80 (m, 1H), 3.31–3.53 (m, 1H), 3.53- 3.76 (m, 3H), 6.26
(d, 1H, J = 8.4).
Distinct signals for the minor isomer: 1H NMR
(400 MHz, CD3OD) δ: 1.68 (m, 1H), 5.82 (d, 1H, J = 8.4).
5
.0 mmol) in THF (20 mL) at –78 °C was treated with a so-
–
1
lution of vinyl magnesium bromide in THF (1.0 mol L ,
00 mol%, 30 mmol, 30 mL), and the reaction mixture was
+
6
MS (TIC) m/z: 234.9 ([MH] ).
stirred, quenched, and purified as described in the general
procedure. Chromatography was performed using a gradient
of 25%–30% EtOAc in hexanes as eluant. First to elute was
homoallylic ketone (2R)-2-[N-(Boc)amino]-1-hydroxy-hept-
General procedure for preparation of N-protected β,β-
dialkyl-L-serines (1a–1g) and (7)
A mixture of diol 2b–2g (1.5 mmol), sodium phosphate
–
1
6
-en-3-one 3h, a white solid (429 mg), TLC R = 0.53 (50%
buffer (6.0 mL, 0.67 mol L , pH = 6.7), and TEMPO
(10 mol%, 0.15 mmol, 24 mg) in acetonitrile (7.5 mL) was
heated to 35 °C and treated simultaneneously over 2 h (Cau-
tion! Do not mix bleach and sodium chlorite before adding
to the reaction mixture) (33) with sodium chlorite
(200 mol%, 3 mmol, 1.5 mL of solution: 5.71 g 80% mass
fraction, 50.5 mmol in 25 mL of water) and diluted sodium
hypochlorite (2 mol%, 0.03 mmol, 790 µL of solution:
0.66 mL commercial bleach 10.8% mass fraction in 25 mL
of water). The mixture was stirred at 35 °C overnight,
cooled to room temperature, treated with solid citric acid
(pH = 3), and extracted with EtOAc (3 × 10 mL). The or-
f
20
EtOAc in hexanes); mp 57 to 58 °C. [α] –30.0° (c 1.0,
CHCl ). H NMR (400 MHz, CDCl ) δ: 1.45 (s, 9H), 2.36–
D
1
3
3
2
1
1
6
.39 (m, 2H), 2.65–2.75 (m, 3H), 3.90 (m, 1H), 3.96 (m,
H), 4.33 (s, 1H), 5.01 (m, 2H), 5.76–5.81 (s, 1H), 5.79 (m,
1
3
H). C NMR (100 MHz, CDCl ) δ: 28.1, 29.0, 39.8, 62.4,
3
3.8, 81.1, 116.3, 137.4, 158.0, 207.9. HR-MS calcd. for
+
C H NO ([MH] ): 244.1549; found: 244.1551. Anal.
1
2
22
4
calcd. for C H NO : C 59.24, H 8.70, N 5.76; found: C
1
2
21
4
5
9.29, H 8.80, N 5.59.
Then a 1:4 mixture of 3h and diol 2f was recovered
264 mg, 22%).
(
ganic phases were combined, dried with MgSO , filtered,
Last to elute was diol 2f, a white solid (306 mg, 25%):
4
and evaporated. The solid residue, containing 1b–1g and 7,
was purified by filtration through a pad of silica gel using,
initially, 5% EtOAc in hexanes, followed by a solution of
TLC R = 0.48 (50% EtOAc in hexanes); mp 68 to 69 °C.
f
2
0
1
[
α] 35.7° (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ:
D
3
3
1
1
5
(
7
.44 (s, 9H), 3.66 (br s, 1H), 3.75 (d, 1H, J = 3.1), 3.78 (d,
H, J = 3.2), 3.96 (d, 1H, J = 16.9), 5.17 (d, 1H, J = 10.7),
.25–5.34 (br m, 3H), 5.44 (d, 1H, J = 17.2), 5.89–6.02
1
% AcOH in AcOEt. Evaporation of the collected filtrate
gave N-protected β,β-dialkyl-L-serines 1b–1g and 7.
1
3
br m, 2H). C NMR (100 MHz, CDCl ) δ: 28.5, 56.1, 63.2,
9.7, 79.8, 114.2, 114.4, 139.9, 140.2, 156.5. HR-MS calcd.
3
(2R)-2-[N-(Boc)Amino]-3-ethyl-3-hydroxy-pentanoic acid
(1b)
+
for C H NO ([MH] ): 244.1549; found: 244.1551. Anal.
1
2
22
4
calcd. for C H NO : C 59.24, H 8.70, N 5.76; found: C
Product was isolated as a white solid (361 mg, 92%): TLC
Rf = 0.35 (89% CHCl3, 10% MeOH, 1% CH3CO2H); mp
1
2
21
4
5
9.20, H 9.06, N 5.70.
2
0
1
1
(
1
13 to 114 °C. [α] –9.5° (c 1.0, CHCl3). H NMR
D
300 MHz, D O, NaOD) δ: 0.80–0.91 (m, 6H), 1.43 (s, 9H),
.46–1.66 (m, 4H), 3.98 (s, 1H). C NMR (75 MHz, D O,
(
1
2R)-2-[N-(Boc)Amino]-3-isopropyl-4-methyl-pentane-
2
1
3
,3-diol (2g)
2
NaOD) δ: 7.5, 7.7, 27.5, 28.3, 28.5, 60.6, 76.6, 81.8, 158.2,
Product from addition of iso-propyl magnesium chloride
+
–
1
178.9. HR-MS calcd. for C H NO ([MH] ): 262.1654;
(
2.0 mol L in Et O) was purified on a silica gel column us-
12 24
5
2
found: 262.1659. Anal. calcd. for C H NO : C 55.16, H
ing a gradient of 10%–15% EtOAc in hexanes as eluant.
12 23
5
8
.87, N 5.36; found: C 55.31, H 9.09, N 5.36.
First to elute was diol 2g, a white solid (262 mg, 38%): TLC
2
0
R = 0.55 (50% EtOAc in hexanes); mp 84 to 85 °C. [α]
f
D
1
(
2R)-2-[N-(Boc)Amino]-3-hydroxy-3,3-diphenyl-
–
24.4° (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ: 1.01
3 3
m, 12H), 1.45 (s, 9H), 2.06 (br s, 2H), 2.94 (s, 1H), 3.26
br s, 1H), 3.83 (br s, 1H), 3.94 (br d, 2H, J = 7.7), 5.41
br s, 1H). C NMR (100 MHz, CDCl ) δ: 17.9, 18.6, 18.7,
9.1, 28.5, 32.4, 34.9, 53.5, 64.8, 79.7, 80.0, 156.1. HR-MS
calcd. for C H NO ([MH] ) 276.2175; found: 276.2179.
propionic acid (1c)
(
(
(
Product was isolated as a white solid (407 mg, 76%): TLC
R = 0.55 (89% CHCl , 10% MeOH, 1% CH CO H); mp
1
3
f
3
3
2
3
2
0
1
1
75 to 176 °C. [α] 29.9° (c 1.0, CHCl3). H NMR
1
D
+
(400 MHz, CD OD) δ: 1.32 (s, 9H), 5.27 (s, 1H), 7.17 (m,
3
13
1
4
30
4
2
H), 7.28 (m, 4H), 7.53 (m, 4H). C NMR (100 MHz,
Anal. calcd. for C H NO : C 61.06, H 10.61, N 5.09;
1
4
29
4
CDCl ) δ: 28.6, 60.6, 80.5, 80.8, 126.9 (2C), 127.2 (2C),
found: C 61.48, H 10.78, N 5.08.
3
©
2004 NRC Canada

Dettwiler and Lubell
323
1
27.9, 128.0, 129.0 (4C), 145.7, 146.0, 157.5, 174.6. HR-
(1′R)-1-[1′-N-(Boc)Amino-2′-hydroxy-ethyl]-cyclopent-3-
enol (5)
A solution of amino diol 2e (68 mg, 0.25 mmol) in de-
gassed CH Cl (1 mL) was treated with benzylidene[1,3-
+
MS calcd. for C H NO ([MH] ): 358.1654; found:
3
3
2
0
24
5
58.1645. Anal. calcd. for C H NO : C 67.21, H 6.49, N
20 23 5
.92; found: C 67.05, H 6.66, N 4.00.
2
2
bis(mesitylene)-2-imidazolidinylidene]tricyclohexylphosphine
ruthenium(IV) dichloride (21 mg, 0.025 mmol) under an ar-
gon atmosphere, stirred overnight at 40 °C, and evaporated
to a dark brown, oily residue, which was passed through a
(
2R)-2-[N-(Boc)Amino]-3-benzyl-3-hydroxy-4-phenyl-
butyric acid (1d)
Product was isolated as a white solid (428 mg, 74%): TLC
R = 0.48 (89% CHCl , 10% MeOH, 1% CH CO H); mp 76
silica gel column using a 1:1 mixture of EtOAc in CHCl as
3
f
3
3
2
2
0
1
eluant. The colored product was stirred overnight with acti-
vated charcoal (50 mass equiv., 3.4 g) in CH Cl (25 mL) to
to 77 °C. [α] –20.0° (c 1.0, MeOH). H NMR (400 MHz,
D
CD OD) δ: 1.46 (s, 9H), 2.66 (d, 1H, J = 14.1), 2.85–2.92
2
2
3
1
3
give, after filtration, cyclopentene 5 as a colorless oil
(
(
m, 3H), 4.0 (s, 1H), 7.19–7.32 (m, 10H). C NMR
(
49 mg, 81%): TLC R = 0.39 (70% EtOAc in hexanes).
100 MHz, CD OD) δ: 28.7, 43.2, 43.3, 60.4, 76.7, 80.8,
f
3
2
0
1
[
α] –10.5° (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ:
1
1
27.4, 127.5, 128.9, 129.0, 132.1 (2C), 138.0 (2C), 157.8,
75.4. HR-MS calcd. for C H NO (TOF EI): 385.1877;
D
3
3
1
1
5
.46 (s, 9H), 2.34–2.68 (m, 6H), 3.67 (m, 1H), 3.84 (dd,
H, J = 3.2, J = 11.4), 3.99 (dd, 1H, J = 3.0, J = 11.4),
2
2
27
5
found: 385.1889. Anal. calcd. for C H NO : C 68.55, H
1
2
1
2
2
2
27
5
1
3
.49 (d, 1H, J = 8.5), 5.73 (s, 2H). C NMR (75 MHz,
7
.06, N 3.63; found: C 68.10, H 7.17, N 3.68.
CDCl ) δ: 28.5, 45.4, 46.1, 57.4, 64.4, 79.8, 84.8, 128.1,
3
+
1
2
28.8, 156.4. HR-MS calcd. for C H NO ([MH] ):
12 22 4
(
2R)-2-[N-(Boc)Amino]-3-allyl-3-hydroxy-hex-5-enoic
acid (1e)
Product was isolated as a yellow oil (334 mg, 78%): TLC
44.1549; found: 244.1552.
2
0
(1′R)-1-[1′-N-(Boc)Amino-2′-hydroxy-ethyl]-cyclopentanol
(6)
A solution of cyclopentene 5 (60 mg, 0.25 mmol) in de-
gassed benzene (3.1 mL) was treated with tris(triphenyl-
phosphine)chlororhodium(I) (9.34 mol%, 0.01 mmol,
R = 0.45 (89% CHCl , 10% MeOH, 1% CH COOH). [α]
1
(
5
4
1
2
f
3
3
D
1
4.4° (c 1.0, CH OH). H NMR (400 MHz, CD OD) δ: 1.45
3
3
s, 9H), 2.27–2.39 (m, 4H), 4.84 (s, 1H), 5.08–5.16 (m, 4H),
.80–5.96 (m, 2H). 1 C NMR (100 MHz, CD OD) δ: 28.7,
3
3
1.4, 41.7, 60.4, 75.9, 80.8, 119.1, 119.3, 134.2, 134.4,
57.8, 174.3. HR-MS calcd. for C H NO (TOF EI):
9
.3 mg), heated at 60 °C under a hydrogen atmosphere
1
4
24
5
(
4 atm (1 atm = 101.325 kPa)) for 24 h, and evaporated to a
86.1654; found: 286.1660.
dark brown residue, which was passed through a pad of sil-
ica gel using a 1:1 mixture of EtOAc in CHCl as eluant.
The colored product was stirred overnight with activated
3
(
2R)-2-[N-(Boc)Amino]-3-hydroxy-3-vinyl-pent-4-enoic
acid (1f)
Product was isolated as yellow oil 1f (313 mg, 81%): TLC
charcoal (50 mass equiv., 3.0 g) in CHCl (25 mL) and fil-
3
tered to give cyclopentane 6 as a white solid (59 mg, 98%):
2
0
R = 0.40 (89% CHCl , 10% MeOH, 1% CH CO H). [α]
f
3
3
2
D
TLC R = 0.39 (70% EtOAc in hexanes); mp 88 to 89 °C.
1
f
1
1
2
8
7.9° (c 1.0, CHCl ). H NMR (300 MHz, D O, NaOD) δ:
.42 (s, 9H), 4.02 (s, 1H), 5.23–5.36 (m, 4H), 5.96–6.08 (m,
H). C NMR (75 MHz, D O, NaOD) δ: 28.3, 62.8, 77.3,
1.9, 115.9, 116.0, 138.7, 139.2, 158.1, 177.0. HR-MS
20
1
3
2
[
α] –14.1° (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ:
.45 (s, 9H), 1.52–1.95 (m, 8H), 3.27 (br s, 1H), 3.37 (br s,
H), 3.49 (d, 1H, J = 8.9), 3.83 (d, 1H, J = 10.1), 3.97 (dd,
H, J = 2.8, J = 11.2), 5.61 (d, 1H, J = 8.8). C NMR
D
3
3
1
1
1
1
3
2
13
+
1
2
calcd. for C H NO ([MH] ): 258.1342; found: 258.1344.
1
2
20
5
(
7
2
75 MHz, CDCl ) δ: 23.5, 24.1, 28.5, 38.4, 38.5, 57.6, 64.5,
3
+
9.6, 85.6, 156.4. HR-MS calcd. for C H NO ([MH] ):
12 24 4
(
2R)-2-[N-(Boc)Amino]-3-hydroxy-3-isopropyl-4-methyl-
46.1705; found: 246.1712.
pentanoic acid (1g)
Product was isolated as a white solid 1g (313 mg, 72%):
Enantiomeric purity of (2R)-2-[1-N-(Boc)amino-2-(1′-
TLC R = 0.57 (89% CHCl , 10% MeOH, 1% CH CO H);
f
3
3
2
hydroxy-cyclopentyl)]-acetic acid (7)
2
0
1
mp 55 to 56 °C. [α] 18.0° (c 1.0, CHCl3). H NMR
D
A solution of 7 (15 mg, 0.058 mmol) in CH CN (0.5 mL)
3
(
300 MHz, D O, NaOD) δ: 0.84–1.01 (m, 12H), 1.44 (s,
2
at 0 °C was treated with HOBt (100 mol%, 11 mg,
9
H), 1.88–1.98 (m, 1H), 2.03–2.14 (m, 1H), 4.19 (s, 1H).
0
.058 mmol) and TBTU (150 mol%, 28 mg, 0.087 mmol),
stirred for 30 min, and treated with a premixed solution of
S)- or (R)-phenylalanine methyl ester hydrochloride (300
mol%, 37.5 mg, 0.174 mmol) and diisopropylethylamine
1
3
C NMR (75 MHz, D O, NaOD) δ: 16.8, 17.6, 17.8, 31.5,
2
3
5.1, 55.1, 67.2, 79.5, 81.7, 158.1, 180.8. HR-MS calcd. for
(
C H NO (TOF EI): 290.1967; found: 290.1966.
1
4
28
5
(
DIEA) (400 mol%, 30 mg, 0.232 mmol, 41 µL) in CH CN
3
(
2R)-2-[1-N-(Boc)Amino-2-(1′-hydroxy-cyclopentyl]-
(0.5 mL) at 0 °C. The reaction mixture was stirred for 48 h
at room temperature when TLC (EtOAc) showed complete
disappearance of the starting acid 7. The solvent was evapo-
acetic acid (7)
Product was isolated from TEMPO oxidation of diol 6
(
39.6 mg, 0.161 mmol) as a yellow oil 7 (37 mg, 88%): TLC
rated, and the solid residue was resuspended in CH Cl2
2
2
0
R = 0.40 (89% CHCl , 10% MeOH, 1% CH COOH). [α]
–
(
(10 mL). The organic phase was washed with an aqueous
saturated solution of NaHCO (2 × 3 mL), 1 N NaH PO
4
f
3
3
D
1
86.5° (c 1.5, CHCl ). H NMR (400 MHz, CDCl ) δ: 1.45
s, 9H), 1.61–1.85 (m, 8H), 4.25 (d, 1H, J = 8.5), 5.74 (d,
H, J = 8.1). C NMR (100 MHz, CDCl ) δ: 23.3, 24.1,
8.4, 37.4, 38.0, 60.5, 80.7, 83.6, 156.5, 174.8. HR-MS
3
3
3
2
(2 × 3 mL), and brine (3 mL); dried with MgSO ; filtered;
4
1
3
1
2
and evaporated to give a residue that was directly examined
3
1
by 400 MHz H NMR spectroscopy in CDCl . Observation
3
+
1
calcd. for C H NO ([MH] ): 260.1498; found: 260.1510.
of the 400 MHz H NMR spectra during incremental addi-
1
2
22
5
©
2004 NRC Canada

3
24
Can. J. Chem. Vol. 82, 2004
tions of (S)-8 in (R)-8 in CDCl and respective measurement
8. J.E. Baldwin, R.M. Adlington, and N.G. Robinson. J. Chem.
Soc. Chem. Commun. 153 (1987).
3
of the signals for the diastereotopic α-protons at 3.91 and
9
. Recent synthesis of $-alkyl branched α-amino acids: M.J.
O’Donnell, J.T. Cooper, and M.M. Mader. J. Am. Chem. Soc.
3
.84 ppm demonstrated dipeptide (R)-8 to be of >98% dia-
stereomeric purity.
1
25, 2370 (2003), and ref. 3 therein.
1
1
0. M.A. Blaskovich, G. Evindar, N.G.W. Rose, S. Wilkinson, Y.
(
2R, 2′S)-N-2-[1-N-(Boc)Amino-2-(1′-hydroxy-
Luo, and G.A. Lajoie. J. Org. Chem. 63, 3631 (1998), and ref.
cyclopentyl)]-acetyl phenylalanine methyl ester (8)
1
1 therein.
1. U. Schöllkopf, W. Hartwig, K.-H. Pospischil, and H. Kehne.
Synthesis, 966 (1981).
2. U. Schöllkopf, J. Nozulak, and U. Groth. Synthesis, 868 (1982).
3. Y.N. Belokon, K.A. Kochetkov, N.S. Ikonnikov, T.V. Strelkova,
S.R. Harutyunyan, and A.S. Saghiyan. Tetrahedron Asymmetry,
(
S)-8
1
H NMR (400 MHz, CDCl ) δ: 1.45 (s, 9H), 1.50–1.95
m, 8H), 3.05 (dd, 1H, J = 6.8, J = 14.0), 3.14 (dd, 1H,
3
1
1
(
1
2
J = 5.5, J = 13.8), 3.71 (s, 3H), 3.91 (d, 1H, J = 8.6), 4.83
1
2
(
1
q, 1H, J = 6.5, J = 13.0), 5.55 (d, 1H, J = 8.3), 6.85 (d,
1 2
1
2, 481 (2001).
14. J.E. Dettwiler and W.D. Lubell. J. Org. Chem. 68, 177 (2003).
5. E.P. Kohler and D. Thompson. J. Am. Chem. Soc. 55, 3822
1933).
16. B. Schmidt and H. Wildemann. Synlett, 10, 1591 (1999).
H, J = 7.4), 7.14 (d, 2H, J = 7.4), 7.20–7.35 (m, 3H). MS
+
(
(
(
TIC) m/z: 421.1 ([MH] ).
1
(
R)-8
1
H NMR (400 MHz, CDCl ) δ: 1.43 (s, 9H), 1.48–1.90
m, 8H), 3.03 (dd, 1H, J = 7.9, J = 14.0), 3.17 (dd, 1H,
3
1
7. B. Schmidt and H. Wildemann. J. Chem. Soc. Perkin Trans. 1,
1
2
2
916 (2000).
J = 5.4, J = 13.9), 3.72 (s, 3H), 3.84 (d, 1H, J = 8.6), 4.83
1
2
1
1
8. C.G. Knudsen and H. Rapoport. J. Org. Chem. 48, 2260 (1983).
9. V.F. Martynov and N.P. Sukhinin. Zh. Obshch. Khim. 28, 2075
(
1
(
q, 1H, J = 7.7, J = 13.5), 5.53 (d, 1H, J = 8.4), 6.85 (d,
1 2
H, J = 8.0), 7.14 (d, 2H, J = 7.2), 7.20–7.35 (m, 3H). MS
(
1958).
+
TIC) m/z: 421.1 ([MH] ).
2
0. K.A. Kochetkov, K.K. Babievskii, N.S. Garbalinskaya, and V.M.
Belikov. Izv. Akad. Nauk Arm. SSR Ser. Khim. 11, 2515 (1982).
Acknowledgements
21. J.E. Sundeen, W.H. Koster, and R. Zahler. U.S. Patent 4 638
0
60. 1987.
This research was supported in part by the Natural Sci-
ences and Engineering Research Council of Canada
2
2. A. Esposito, P.P. Piras, D. Ramazzotti, and M. Taddei. Org.
Lett. 3, 3273 (2001).
23. L. Wessjohann, N. Krass, D. Yu, and A. de Meijere. Chem.
(
NSERC), the Ministère de l’Éducation du Québec, and
Valorisation-Recherche Québec.
Ber. 125, 867 (1992).
2
2
4. Y. Yoshikawa, K. Ikai, Y. Umeda, A. Ogawa, K. Takesako, I.
Kato, and H. Naganawa. J. Antibiot. 46, 1347 (1993).
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©
2004 NRC Canada