The first simple and efficient synthesis of the unusual dipeptide part of Phomopsin A

Article abstract of DOI:10.1016/j.tetasy.2005.05.023

A practical high yielding synthesis of the key halogenated dipeptide part of Phomopsin A 2 is reported. The key steps are a selective Heck coupling, a Sharpless asymmetric dihydroxylation in PEG and a benzoyl isocyanate mediated synthesis of dehydrovaline

Full text of DOI:10.1016/j.tetasy.2005.05.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2209–2214
The first simple and efficient synthesis of the unusual dipeptide
part of Phomopsin Aq
Srivari Chandrasekhar* and Gudise Chandrashekar
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 5 February 2005; accepted 12 May 2005
Abstract—A practical high yielding synthesis of the key halogenated dipeptide part of Phomopsin A 2 is reported. The key steps are
a selective Heck coupling, a Sharpless asymmetric dihydroxylation in PEG and a benzoyl isocyanate mediated synthesis of
dehydrovaline.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2-amino-3-methylbut-3-enoic acid [(S)-3,4-didehydrova-
line, H-L-3-DVal-OH], (2S,3S)-hydroxy isoleucine,
(2S,3S)-3-hydroxy-2-(N-methyl)-tyrosine, (E)-2,3-dide-
hydroaspartic acid, (E)-2,3-didehydroisoleucine (DIle)
and 3,4-didehydroproline (DPro).
The synthesis of unnatural amino acids especially those
that are part structures of bioactive molecules, continues
to attract the attention of synthetic organic chemists.
Phomopsin A 11 is one such 13-membered macrocycle
with six amino acid residues, which shows cytotoxic
activity by interfering with microtubule function
through binding to tubulin. This natural product is the
main cytotoxin isolated from cultures of Phomospsis
leptostromiformis. Biological studies2 have shown that
this natural product causes similar mycotoxicosis and
strongly inhibits polymerizatation of brain tubulin, sim-
ilar to the activity of spindle poisons such as colchicine,
podophyllotoxin, ustiloxin3 and maytansinoids.4 Pho-
mopsin A consists of the unusual amino acid moieties,
The presence of the ꢀunusual aminoacids ꢁ and its novel
biological properties,5 and relatively scarce availability
have prompted researchers to undertake its total synthe-
sis. Surprisingly, no total synthesis of 1 has been
achieved to date, although the synthesis of unusual
6
aminoacid parts has been described. The most recent
synthesis of the b-hydroxy phenyl alanine portion was
achieved by Joullie et al.,7 involving a Sharpless asym-
metric amino hydroxylation strategy which lacks regio-
control during the amino hydroxylation while the aryl
CO2H
Me
O
CO2H
N
H
H
N
H
O
MeHN
HO
N
Et
H
N
NH
Et
O
BocHN
HO
O
Me
COOMe
N
Me
O
O
O
1
2
Br
OBn
OH
Cl
Cl
q IICT Communication No. 041015.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512; e-mail: srivaric@iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.023

2210
S. Chandrasekhar, G. Chandrashekar / Tetrahedron: Asymmetry 16 (2005) 2209–2214
group is also not fully functionalized. The synthesis of
other unusual amino acid dehydrovaline8 is reasonably
well addressed albeit in a greater number of steps.
mate derivative 5 in over 90% yield. We anticipated that
the bromo group C-4 of the benzene ring was the least hin-
dered and would provide the required selectivity, which
turned out to be correct. To confirm the structure of 5,
the other possible regioisomer was prepared by a slightly
circuitous route11. The critical step of introducing chiral-
ity was achieved by using a modified Sharpless asymmet-
ric dihydroxylation condition12 [(DHQ)2PHAL, OSO4,
NMO, PEG (400), 3 h] torealize diol 6 in 95% yield and
over 98% ee (measured by chiral HPLC using chiralcel
10% isopropanol in hexane). Incidentally this substrate
gave poor results under the conventional protocol condi-
tions. The selective amination of the a-hydroxy group of 6
was effected in three steps via tosylation13 (TsCl, Et3N),
azidation (NaN3, DMF, 60 ꢁC) and reductive protection
carried out [TPP, EtOH, followed by exposure to
(Boc)2O] (Scheme 1, 42% overall yield).
Our studies have involved the total synthesis of bioac-
tive natural products9 especially compounds which have
an unusual aminoacid part structure. Herein, we report
a new and flexible strategy for the unusual dipeptide
part of Phomopsin A 2.
2. Results and discussion
The retrosynthetic analysis of b-hydroxy phenyl alanine
derivative revealed that cinnamate ester 5 would be an
ideal precursor, which in turn was realized from ortho-
chlorophenol 3 via dibromination and selective Heck
coupling with ethylacrylate. Accordingly, the commer-
cially available ortho-chlorophenol 3 was treated with
N-bromosuccinimide10 in THF at 0 ꢁC toyield the 2,4-
dibromo-6-chloro phenol in 95% yield, which was sub-
jected tobenzylation (BnBr, K 2CO3, acetone, reflux).
The resultant benzyl ether 4 was subjected toa selective
Heck reaction with ethyl acrylate in the presence of
Pd(OAc)2, PPh3 and Et3N at 100 ꢁC togive ethyl cinna-
The required dehydrovaline methyl ester 16 was synthe-
sized from prenol 10 via Sharpless asymmetric epoxida-
tion14 [(+)-DIPT, Ti(O-i-Pr)4, cumene hydroperoxide] to
obtain epoxide 11 in 95% ee and 90% yield. This, upon
treatment with benzoyl isocyanate15 in THF, K+tBuOꢀ,
furnished oxazolidinone 12. Oxazolidinone 12 in the
presence of 2 M KOH at 80 ꢁC followed by protection
EtOOC
EtOOC
HO
OH
Br
c
b
a
Br
OBn
Br
OBn
Br
OBn
Cl
OH
Cl
Cl
Cl
5
6
3
4
EtOOC
HO
BocHN
HO
N3
HO
COOEt
COOEt
OTs
e
d
f
Br
Br
OBn
Br
OBn
Cl
Cl
OBn
Cl
7
8
9
Scheme 1. Reagents and conditions: (a) (i) NBS, THF, 0 ꢁC, 0.5 h; (ii) BnBr, K2CO3, acetone, reflux, 92.2% (two steps); (b) CH2@CHCOOEt,
Pd(OAc)2, TPP, Et3N, 100 ꢁC, 90%; (c) (DHQ)2PHAL, OsO4, NMOÆH2O, PEG (400), 3 h, 95%; (d) TsCl, Et3N, CH2Cl2, 0 ꢁC, 12 h, 81%; (e) NaN3,
DMF, 60 ꢁC, 72%; (f) TPP, EtOH, (Boc)2O, 91%.
a
O
b
c
PhOCO
O
OH
NHBoc
HN
HO
OH
OH
11
10
13
12
O
e
f
d
HO
COOMe
NHBoc
O
O
BocN
BocN
16
14
15
˚
Scheme 2. Reagents and conditions: (a) (+)DIPT, Ti(O-i-Pr)4, cumene hydroperoxide, 4 A molecular sieves, CH2Cl2, ꢀ20 ꢁC, 90%; (b) PhCONCO,
THF, 0 ꢁC, 0.5 h then K+tBuOꢀ, 0 ꢁC, 1 h, 88%; (c) 2 M KOH(aq), 80 ꢁC, (Boc)2O, THF, 93%; (d) 2,2-DMP, Cat PTSA, CH2Cl2, 0 ꢁC, 86%; (e)
MsCl, Et3N, CH2Cl2, 76%; (f) (i) Jonesꢁ oxidation, (ii) CH2N2, dry other, 70% (two steps).

S. Chandrasekhar, G. Chandrashekar / Tetrahedron: Asymmetry 16 (2005) 2209–2214
2211
(2 · 100 mL). The combined organic layers were washed
with water and aqueous Na2S2O3, followed by brine and
dried over anhydrous Na2SO4. The solvent was removed
in vacuo to afford the dibromo compound as pale yellow
solid (10.51 g).
H
N
BocHN
HO
a
b
COOMe
9
O
c
Br
OBn
To a stirred solution of the above dibromo phenol
(10.51 g, 36 mmol) in dry acetone (100 mL) was added
K2CO3 (10.1 g, 73 mmol) followed by benzyl bromide
(6.9 g, 40 mmol). The reaction mixture was refluxed
for 3 h. After completion of the reaction, it was filtered
and washed with acetone. The filtrate was concentrated
under vacuo and purified by column chromatography to
afford compound 4 (13.4 g, 92.2%) as a white solid: mp:
2
16
Cl
Scheme 3. Reagents and conditions: (a) LiOHÆH2O, THF–H2O; (b)
60% TFA, CH2Cl2; (c) EDC, HOBt, CH2Cl2, 0 ꢁC tort, over 5 h, 83%.
with (Boc)2O in THF yielded the 1ꢁ and 3ꢁ diol 13. Ace-
tonation (DMP, Cat PTSA, CH2Cl2) and elimination of
the 3ꢁ alcohol (MsCl, Et3N, CH2Cl2) were rather
straightforward. The Jonesꢁ oxidation concomitantly
cleaved the isopropylidene group and also oxidized the
1ꢁ alcohol group to the acid, which was characterized
as its methyl ester 16 (Scheme 2, 33% overall yield).
1
52–53 ꢁC; IR (KBr): 1455, 1360, 1250, 1142 cmꢀ1; H
NMR (300 MHz, CDCl3): d 7.62 (d, J = 2.2 Hz, 1H),
7.51 (d, J = 2.3 Hz, 3H), 7.38–7.26 (m, 3H), 4.98 (s,
2H); MS (ESI): m/z 377 (M++1), 375.
4.1.2. Ethyl (2E)-3-[4-(benzyloxy)-3-bromo-5-chlorophen-
A mixture of compound 4 (2 g,
yl]acrylate 5.
After carrying out ester 9 hydrolysis and Boc deprotec-
tion of compound 16 to afford the corresponding free
amine, both the acid and amine were coupled using
EDC, HOBt to realize the dipeptide part of Phomopsin
A 2 in 83% yield (Scheme 3).
5.3 mmol), ethyl acrylate (0.8 g, 7.9 mmol), TPP
(0.056 g, 0.2 mmol), palladium acetate (0.024 g,
0.1 mmol) and triethyl amine (0.8 g, 7.9 mmol) in
DMF (20 mL) was heated at 100 ꢁC for 12 h under
nitrogen atmosphere. The reaction mixture was diluted
with ethyl acetate (100 mL), washed with water, brine,
dried over anhydrous Na2SO4 and concentrated in va-
cuo. The crude residue was purified by column chroma-
tography to afford the unsaturated ester 5 (1.9 g, 90%) as
a white solid: mp: 78–80 ꢁC; IR (KBr): 1710, 1645,
3. Conclusion
In conclusion, we have developed a novel procedure for
the synthesis of the fully functionalized dipeptide part of
Phomopsin A in high yields. Incidentally, this is the first
synthesis of the halogenated dipeptide portion of Pho-
mopsin A. The construction of a 13-membered macro-
cycle with various unnatural pharmacophores towards
understanding SAR is currently under progress.
1120 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.64 (d,
;
J = 2.26 Hz, 1H), 7.53–7.51 (m, 3H), 7.46 (d, J =
15.1 Hz, 1H), 7.44–7.30 (m, 3H), 6.36 (d, J = 15.8 Hz),
5.04 (s, 2H), 4.2 (q, J = 7.5 Hz, 2H), 1.34 (t, J =
7.5 Hz); MS (ESI): m/z 397 (M++1), 395, 351, 349 and
189.
4.1.3. Ethyl (2R,3S)-3-[4-(benzyloxy)-3-bromo-5-chloro-
phenyl]-2,3-dihydroxypropanoate 6. Tothe unsaturated
ester 5 (2 g, 5 mmol) in polyethylene glycol (400 MW,
5 g) was added OsO4 (6.5 mg, 0.025 mmol), NMOÆH2O
(0.89 g, 6.6 mmol) and (DHQ)2PHAL (79 mg,
0.1 mmol) under an inert atmosphere and stirred at
room temperature for 3 h. The reaction mixture was di-
luted with the ether (20 mL) and stirred for 5 min. The
ether layer was decanted and the procedure repeated
(4 · 20 mL). The combined ether layers were washed
with water and brine and dried over Na2SO4. The sol-
vent was removed and the crude product purified by col-
umn chromatography to afford diol 6 (2.0 g, 95%) as a
white solid. Diol 6 was formed in over 98% ee, measured
4. Experimental
4.1. General
All solvents and reagents were purified by standard
techniques. Crude products were purified by column
chromatography on silica gel of 60–120 mesh. IR spec-
tra were recorded on a Perkin–Elmer 683 spectrometer.
Optical rotations were obtained on Jasco Dip 360 digital
polarimeter. Melting points (uncorrected) were obtained
using a Buchi 535 melting point apparatus. H and 13C
1
NMR spectra were recorded in CDCl3 solution on a
Varian Gemini 200, Bruker Avance 300 or Varian Unity
400 NMR spectrometers. Chemical shifts were reported
in ppm with respect tointernal TMS. Cuopling
constants (J) are quoted in hertz. Mass spectra were
obtained on a Agilent Technologies LC/MSD Trap SL.
by chiral HPLC using chiralcel 10% isopropanol in hex-
25
D
ane: mp: 96 ꢁC; ½aŠ ¼ þ9.8 (c 1.0, MeOH); IR (KBr):
3411, 2929, 1718, 1462, 1259 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.54–7.50 (m, 3H), 7.41–7.29 (m,
4H), 5.0 (s, 2H), 4.84 (dd, J = 3.0, 7.5 Hz, 1H), 4.34–
4.23 (m, 3H), 3.13 (d, J = 7.5 Hz, OH), 2.74 (d,
J = 7.5 Hz, OH), 1.32 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 172.1, 151.2, 138.3, 135.9, 129.8,
129.2, 128.4 (2C), 128.3 (3C), 127.6, 118.6, 74.7, 74.2,
72.9, 62.3, 13.9; MS (ESI): m/z 453 (M++23), 451 and
269.
4.1.1. 2-(Benzyloxy)-1,5-dibromo-3-chlorobenzene 4. To
a stirred solution of 2-chlorophenol 3 (5 g, 40 mmol) in
THF (50 mL) was added a solution of NBS (15.2 g,
85 mmol) in THF (30 mL) over 30 min at 0 ꢁC. When
the addition was complete, the reaction mixture was
diluted with water and extracted with ethyl acetate

2212
S. Chandrasekhar, G. Chandrashekar / Tetrahedron: Asymmetry 16 (2005) 2209–2214
4.1.4. Ethyl (2R,3S)-3-[4-(benzyloxy)-3-bromo-5-chloro-
phenyl]-3-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}pro-
panoate 7. To a stirred solution of diol ester 6 (2.15 g,
5 mmol) in CH2Cl2 (25 mL) at 0 ꢁC under nitrogen was
added triethyl amine (1.3 g, 12.5 mmol), followed by p-
toluene sulfonyl chloride (1.15 g, 6 mmol). After stirring
for 12 h at room temperature, the reaction mixture was
diluted with water and extracted with CH2Cl2 (30 mL).
The combined organic extracts were washed with water
and brine and dried over anhydrous Na2SO4. The sol-
vent was removed under reduced pressure and the crude
product purified by column chromatography to give the
NMR (400 MHz, CDCl3): d 7.51–7.48 (m, 3H), 7.37–
7.31 (m, 4H), 5.21 (d, J = 9.5 Hz, BocNH), 5.16 (t,
J = 3.8 Hz, 1H), 5.00–4.94 (m, 2H), 4.42 (dd, J = 9.5,
3.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.03 (d,
J = 3.8 Hz, OH), 1.37 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 170.2, 155.6, 151.2,
138.5, 136.0, 129.6, 129.1, 128.4 (5C), 127.5, 118.5,
80.2, 74.8, 72.4, 61.8, 59.1, 28.0 (3C), 14.0; MS (ESI):
m/z 552 (M++23), 550, 455 and 412.
4.1.7. [(2S)-3,3-Dimethyloxiran-2-yl]methanol 11. In a
250 mL, round-bottomed two neck flask were flame-
˚
dried under vacuum 4 g of powdered 4 A molecular
tosylated product 7 (2.36 g, 81%) as a viscous liquid:
25
½aŠ ¼ þ36.8 (c 2.5, MeOH); IR (CHCl3): 3516, 1748,
sieves. Dry CH2Cl2 (100 mL), 3-methyl-2-butene-1-ol
10 (10 mL, 0.1 mol) and (+)-diisopropyl tartrate
(1.6 mL, 7.35 mmol) were added and the reaction mix-
ture cooled to ꢀ20 ꢁC. After the introduction of Ti(O-
i-Pr)4 (1.5 mL, 4.9 mmol), the mixture was stirred for
30 min. Cumene hydroperoxide (80%, 31 mL, 0.162
mol) was then added over 2 h and the mixture stirred
for an additional hour. Following the addition of citric
acid monohydrate (1.14 g, 5.4 mmol) and diethyl ether
(50 mL), the reaction mixture was warmed to room
temperature and stirred overnight. Filtration through a
pad of Celite and concentration in vacuo furnished
an oil, which was purified by column chromatography
D
1
1372, 1182, 1032 cmꢀ1; H NMR (300 MHz, CDCl3):
d 7.52–7.47 (m, 4H), 7.40–7.33 (m, 3H), 7.27 (d,
J = 2.3 Hz, 1H), 7.20–7.16 (m, 3H), 5.04 (d,
J = 3.8 Hz, 1H), 4.94 (s, 2H), 4.72 (d, J = 3.8 Hz, 1H),
4.25 (q, J = 7.3 Hz, 2H), 2.92 (d, J = 6.8 Hz, OH), 2.39
(s, 3H), 1.28 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 166.7, 151.7, 145.4, 136.1, 132.2, 129.6 (3C),
129.3, 128.4 (3C), 128.3 (3C), 127.5 (3C), 118.8, 80.6,
74.7, 72.0, 62.4, 21.6, 13.8; MS (ESI): m/z 607
(M++23), 605.
4.1.5. Ethyl (2S,3S)-2-azido-3-[4-(benzyloxy)-3-bromo-5-
chlorophenyl]-3-hydroxypropanoate 8. Toa stirred
solution of tosylate 7 (1 g, 1.72 mmol) in DMF
(10 mL) was added NaN3 (0.9 g, 13.8 mmol) as a solid
in one portion. The temperature was raised to 65 ꢁC
for 10 h, then cooled to room temperature and the reac-
tion mixture diluted with water and extracted with ethyl
acetate (2 · 20 mL). The combined organic layers were
washed with water and brine and dried over anhydrous
Na2SO4. The solvent was removed and the crude prod-
to afford epoxide 11 (9.1 g, 90%) as colorless oil:
25
D
½aŠ ¼ ꢀ18.0 (c 2.0, CHCl3); IR (neat): 3430, 3000,
2970, 2930, 1382, 1227, 1126, 1032 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 3.93 (br s 1H), 3.83–3.75 (m,
1H), 3.68–3.59 (m, 1H), 2.97 (dd, J = 4.2, 6.4 Hz), 1.34
(s, 3H), 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3): d
63.8, 60.9, 58.5, 24.4, 18.4; MS (ESI): m/z 125 (M++23).
4.1.8. 1-Methyl-1-[(4R)-2-oxo-1,3-oxazolidin-4-yl]ethyl
benzoate 12. To a stirred solution of epoxy alcohol 11
(1 g, 0.01 mol) in dry THF (10 mL) was added a solution
of benzoyl isocyanate (1.45 g, 0.01 mol) in THF (10 mL)
at 0 ꢁC under a nitrogen atmosphere. After stirring for
0.5 h at 0 ꢁC, the epoxy alcohol was converted into corre-
sponding carbamate. To this reaction mixture at 0 ꢁC was
added K+tBuOꢀ (2.2 g, 0.02 mol). After stirring for 1 h at
room temperature, the reaction mixture was diluted with
water and extracted with ethyl acetate (2 · 20 mL). The
combined organic layers were washed with brine and
dried over anhydrous Na2SO4. Concentration in vacuo
and purification by column chromatography led to oxa-
uct purified by column chromatography to yield azide 8
25
D
(0.56 g, 72%) as a highly viscous liquid: ½aŠ ¼ þ65.2 (c
1.0, MeOH); IR (CHCl3): 3486, 2115, 1737, 1259 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 7.52 (d, J = 7.4 Hz, 2H),
7.49 (d, J = 1.6 Hz, 1H), 7.40–7.32 (m, 4H), 5.07 (t,
J = 4.1 Hz, 1H), 5.02 (s, 2H), 4.27 (q, J = 7.5 Hz, 2H),
3.92 (d, J = 4.1 Hz, 1H), 2.92 (d, J = 4.2 Hz, OH), 1.31
(t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
168.1, 151.7, 137.6, 136.0, 129.8, 129.5, 128.5 (2C),
128.4 (3C), 127.6, 118.9, 74.9, 72.8, 67.1, 62.4, 14.0;
MS (ESI): m/z 477 (M++23), 475, 434, 282 and 191.
4.1.6. Ethyl (2S,3S)-3-[4-(benzyloxy)-3-bromo-5-chloro-
phenyl]-2-[(tert-butoxycarbonyl)amino]-3-hydroxypro-
panoate 9. To a stirred solution of azide compound 8
(0.6 g, 1.32 mmol) in ethanol (10 mL) was added TPP
(0.51 g, 1.98 mmol) as a solid in one portion at room
temperature. After stirring for 3 h, the azide was re-
duced into the corresponding amine. To this reaction
mixture was added (Boc)2O (0.34 g, 1.58 mmol) and stir-
red for 5 h. Ethanol was removed and extracted with
ethyl acetate (2 · 20 mL). The combined organic ex-
tracts were washed with water and brine and dried over
anhydrous Na2SO4. The solvent was removed under re-
duced pressure and the crude residue purified by column
zolidinone 12 (2.15 g, 88%) as a viscous liquid:
25
D
½aŠ ¼ þ12.3 (c 1.0, MeOH); IR (CHCl3): 2943, 1745,
1720, 1436, 1277, 1073 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d 7.85 (d, J = 7.4 Hz, 2H), 7.69 (br s, NH),
7.48 (t, J = 7.4 Hz, 1H), 7.35 (d, J = 7.4 Hz, 2H), 4.48–
4.39 (m, 2H), 4.06-4.03 (m, 1H), 1.56 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 165.3, 160.4, 133.0, 130.7, 129.44
(2C), 128.41 (2C), 82.0, 66.0, 60.3, 21.4 (2C); MS (ESI):
m/z M+ 250 (M++1), 206, 189, 128 and 105.
4.1.9. tert-Butyl [(1R)-2-hydroxy-1-(hydroxymethyl)-2-
methylpropyl]carbamate 13. Oxazolidinone 12 (1 g,
4 mmol) was taken in 2 M aqueous KOH (10 mL) and
the temperature raised to80 ꢁC for 3 h the reaction mix-
ture was cooled to room temperature and diluted with
THF (20 mL). Tothis reaction mixture was added a
chromatography to afford compound 9 (0.63 g, 91%) as
25
D
a viscous liquid: ½aŠ ¼ þ2.5 (c 1.0, MeOH); IR
1
(CHCl3): 3424, 2979, 1693, 1371, 1256, 1163 cmꢀ1; H

S. Chandrasekhar, G. Chandrashekar / Tetrahedron: Asymmetry 16 (2005) 2209–2214
2213
solution of (Boc)2O (1.0 g, 4.4 mmol) in THF (10 mL) at
0 ꢁC, and stirred for 6 h at room temperature. The reac-
tion mixture was diluted with water and extracted with
ethyl acetate (2 · 30 mL). The combined organic layers
were washed with water and brine and then dried over
anhydrous Na2SO4. The solvent was removed and the
residue was purified by column chromatography to af-
excess of Jonesꢁ reagent was quenched with isopropanol.
Acetone was removed and extracted with ethyl acetate
(2 · 10 mL). The combined organic extracts were
washed with water and brine, dried over anhydrous
Na2SO4 and concentrated to furnish the acid (0.24 g).
The above acid (0.24 g) was immediately dissolved in dry
ether at 0 ꢁC and treated with ethereal diazomethane.
After 0.5 h, the ether was removed and the residue on
ford 1ꢁ and 3ꢁ diol 13 (0.82 g, 93%) as a syrup:
25
½aŠ ¼ þ2.7 (c 1.0, MeOH); IR (neat): 3443, 2960,
D
2942, 1692, 1675, 1436 cmꢀ1
;
1H NMR (300 MHz,
purification by column chromatography afforded amino
25
D
CDCl3): d 5.37 (d, J = 8.3 Hz, NH), 3.97 (dd, J = 3.0,
11.3 Hz, 1H), 3.75 (dd, J = 2.2, 10.5 Hz, 1H), 3.40 (d,
J = 8.3 Hz, 1H), 2.93 (br s, OH), 1.45 (s, 9H), 1.34 (s,
3H), 1.22 (s, 3H); 13C NMR (75 MHz, CDCl3): d
156.4, 79.2, 73.6, 63.3, 57.9, 28.3 (3C), 27.5, 27.3; MS
(ESI): m/z 242 (M++23), 162 and 118.
acid ester 16 (0.2 g, 70%) as a syrup: ½aŠ ¼ þ37.5 (c 1.0,
MeOH); IR (neat): 3378, 2978, 1745, 1713 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 5.22 (br s, NH), 5.00 (d,
J = 15.8 Hz, 2H), 4.68 (d, J = 7.5 Hz, 1H), 3.75 (s, 3H),
1.78 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 171.1, 154.7, 140.3, 114.6, 79.8, 58.8, 52.3, 28.1 (3C),
19.2; MS (ESI): m/z 252 (M+ + 23), 195 and 151.
4.1.10. tert-Butyl (4R)-4-(1-hydroxy-1-methylethyl)-2,2-
dimethyl-1,3-oxazolidine-3-carboxylate 14. Toa stirred
solution of diol compound 13 (0.5 g, 2.3 mmol) in dry
CH2Cl2 (15 mL) was added p-toluenesulfonic acid
monohydrate (0.044 g, 0.23 mmol), 2,2-DMP (0.36 g,
3.4 mmol) at 0 ꢁC and the reaction mixture stirred for
2 h at 0 ꢁC. The reaction mixture was quenched with
aqueous saturated NaHCO3 solution and the organic
layer washed with water and brine and dried over anhy-
drous Na2SO4. After concentration and purification by
column chromatography 3ꢁ alcohol 14 (0.51 g, 86%)
4.1.13. Methyl (2S)-2-{[(2S,3S)-3-[4-(benzyloxy)-3-bromo-
5-chlorophenyl]-3-hydroxy-2-[(tert-butoxycarbonyl)amino]-
propanoyl]amino}-3-methylbut-3-enoate 2. A mixture
of ester 9 (0.15 g, 0.28 mmol) and LiOHÆH2O (36 mg,
0.86 mmol) in THF–H2O (8:2, 5 mL) were stirred at
room temperature for 2 h. The reaction mixture was
acidified with aqueous sodium bisulfite and extracted
with ethyl acetate. The organic layer was washed with
water and brine, dried over anhydrous Na2SO4 and
evaporated to furnish the acid (0.143 g), which was used
further without any purification.
was obtained as
a
white solid: mp 36–37 ꢁC;
25
D
½aŠ ¼ þ22.9 (c 1.0, MeOH); IR (KBr): 3412, 2970,
2925, 2878, 1696, 1670 cmꢀ1
;
1H NMR (300 MHz,
Compound 16 (70 mg, 0.31 mmol) was taken in 60%
TFA in CH2Cl2 (2 mL) at 0 ꢁC under an inert atmo-
sphere. The reaction mixture was stirred for 1 h and con-
centrated under reduced pressure. The reaction mixture
was basified by adding excess of Na2CO3 in CH2Cl2, the
reaction mixture was filtered and the filtrate concen-
trated under reduced pressure toaffrod the amine
(39 mg), which was used further without purification.
CDCl3): d 1.13 (s, 3H), 1.16 (s, 3H), 1.50 (s, 12H),
1.57 (s, 3H), 3.76 (m, 1H), 3.97 (m, 2H), 5.1 (br s,
OH); 13C NMR (75 MHz, CDCl3): d 155.5, 95.9, 81.1,
72.6, 66.2, 64.9, 28.1 (3C), 27.5, 27.1, 26.0, 24.4; MS
(ESI): m/z 282 (M++23), 213 and 182.
4.1.11. tert-Butyl (4S)-4-isopropenyl-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate 15. To a stirred solution of
3ꢁ alcohol compound 14 (0.98 g, 3.7 mmol) in CH2Cl2
(15 mL) was added methane sulfonyl chloride (1.4 mL,
18.3 mmol) and triethyl amine (5.1 mL, 36.6 mmol) at
ꢀ10 ꢁC. After stirring at room temperature for 1 h, the
reaction mixture was poured into ether (50 mL) and
water (30 mL). The organic layer was washed with aque-
ous 1 M 10% citric acid, aqueous saturated NaHCO3
solution, brine and then dried over anhydrous Na2SO4.
Concentration in vacuo gave a residue, which was puri-
To a stirred solution of the above acid (0.143 g,
0.29 mmol), amine (39 mg, 0.29 mmol) and HOBt
(40 mg, 0.29 mmol) in dry CH2Cl2 was added EDC
(55 mg, 0.29 mmol) at 0 ꢁC under an inert atmosphere
and stirred for 1 h at 0 ꢁC. The reaction mixture was
warmed to room temperature and stirred for 4 h the
reaction mixture was then diluted with water and
extracted intoCH Cl2. The organic layer was washed
2
with 5% aqueous citric acid, aqueous saturated NaH-
CO3 solution, brine and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure and
the crude product purified by column chromatography
fied by column chromatography to afford compound 15
25
D
MeOH); IR (CHCl3): 2982, 2928, 2875, 1703,
(0.68 g, 76%) as a colorless syrup: ½aŠ ¼ þ16.9 (c 1.2,
1
1663 cmꢀ1; H NMR (300 MHz, CDCl3): d 4.83 (br s,
toafford dipeptide 2 (0.14 g, 83%) as a highly viscous li-
25
2H), 4.02 (dd, J = 7.2, 8.2 Hz, 1H), 3.70 (dd, J = 2.4,
8.8 Hz, 1H), 1.72 (s, 3H), 1.64 (s, 3H), 1.49 (s, 9H),
1.39 (s, 3H); 13C NMR (75 MHz, CDCl3): d 151.8,
144.1, 110.9, 79.6, 67.2, 62.1, 59.9, 27.9 (3C), 27.5,
26.9, 18.1; MS (ESI): m/z 242 (M++1), 184, 140 and 102.
quid: ½aŠ ¼ þ16.9 (c 1.75, MeOH); IR (CHCl3): 3419,
D
1
1654 cmꢀ1; H NMR (400 MHz, CDCl3): d 7.54–7.52
(m, 3H), 7.39–7.30 (m, 4H and amideNH), 5.42 (d,
J = 8.1 Hz, BocNH), 5.29 (s, 1H), 5.07 (s, 2H), 4.99 (s,
2H), 4.93 (d, J = 7.4 Hz, 1H), 4.41 (d, J = 8.1 Hz, 1H),
4.11 (d, J = 7.4 Hz, OH), 3.78 (s,3H), 1.81 (s, 3H),
1.39 (s, 9H); 13C NMR (75 MHz, CDCl3): d 170.8,
170.0, 156.0, 151.2, 139.1, 138.1, 136.2, 129.6, 129.2,
128.4 (5C), 127.4, 118.6, 115.9, 80.9, 74.7, 70.8, 59.3,
57.9, 52.7, 28.0 (3C), 19.6; MS (ESI): m/z 635
(M++23), 633, 513 and 511.
4.1.12. Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-
methylbut-3-enoate 16. To a solution of compound 15
(0.3 g, 1.2 mmol) in dry acetone (10 mL) at 0 ꢁC, freshly
prepared Jonesꢁ reagent (1 mL, 2.5 mmol) was added
dropwise. After stirring for 12 h at room temperature,

2214
S. Chandrasekhar, G. Chandrashekar / Tetrahedron: Asymmetry 16 (2005) 2209–2214
Chem. Soc. Jpn. 1986, 59, 3573; (e) Stohlmeyer, M. M.;
Acknowledgements
Tanaka, H.; Wandless, T. J. J. Am. Chem. Soc. 1999, 121,
6100.
7. Park, H.; Cao, B.; Joullie, M. M. J. Org. Chem. 2001, 66,
7223.
G.C.S. thanks CSIR New Delhi for financial support
and DST, New Delhi for research grant.
8. (a) Nunomi, K.; Suzuki, M.; Yoneda, K. J. Chem. Soc.,
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