Improved synthesis of L,L-cycloisodityrosine subunit of antitumor agents deoxybouvardin and RA-VII

Article abstract of DOI:10.1080/00397910903245166

A facile synthesis of the core cycloisodityrosine 14-membered ring system is detailed from commercially available L-tyrosine through a novel synthetic approach to aryl boronic acid 12 via intramolecular cyclization. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903245166

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Improved Synthesis of L,L-
Cycloisodityrosine Subunit of Antitumor
Agents Deoxybouvardin and RA-VII
Samir Ghosh a , A. Sanjeev Kumar a , G. N. Mehta b & R.
Soundararajan a
a Chemical Research and Development Department , Pfizer Ltd. ,
Mumbai, India
b Applied Chemistry Department , S.V. National Institute of
Technology , Surat, India
Published online: 26 Jul 2010.
To cite this article: Samir Ghosh , A. Sanjeev Kumar , G. N. Mehta & R. Soundararajan (2010)
Improved Synthesis of L,L-Cycloisodityrosine Subunit of Antitumor Agents Deoxybouvardin and RA-VII,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:16, 2389-2396, DOI: 10.1080/00397910903245166
To link to this article: http://dx.doi.org/10.1080/00397910903245166
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Synthetic Communications1, 40: 2389–2396, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903245166
IMPROVED SYNTHESIS OF L,L-CYCLOISODITYROSINE
SUBUNIT OF ANTITUMOR AGENTS
DEOXYBOUVARDIN AND RA-VII
Samir Ghosh,1 A. Sanjeev Kumar,1 G. N. Mehta,2
and R. Soundararajan1
1Chemical Research and Development Department, Pfizer Ltd.,
Mumbai, India
2Applied Chemistry Department, S.V. National Institute of Technology,
Surat, India
A facile synthesis of the core cycloisodityrosine 14-membered ring system is detailed from
commercially available L-tyrosine through a novel synthetic approach to aryl boronic acid
12 via intramolecular cyclization.
Keywords: Aryl boronate; cycloisodityrosin; deoxybouvardin; palladium catalyst; ring closure
INTRODUCTION
Deoxybouvardin1 and RA-VII 2 constitute representative members of a
growing class of naturally occurring antitumor agents (Chart 1).[1,2] The molecular
architecture and interesting biological activity make these compounds attractive
synthetic targets.[3] Although several synthetic strategies could be envisaged, only
three primary routes have been exploited, namely (1) transannulation,[4] (2)
bottom-up route, and (3) top-down route.[4–6] Although the first two strategies
failed to give the target molecules, the top-down approach was more rewarding.
Because ring closure of the bottom 18-membered macrocycle from secoacid 3 (bond
disconnection a) is relatively easy,[7] all synthetic efforts have thus far concentrated
on synthesis of the key subunit, L,L-cycloisodityrosine 4. Several synthetic routes
to cycloisodityrosines are known. Total synthesis of cycloisodityrosines involves
construction of a strained 14-membered macrocycle, which requires elaborate work
for the preparation of chiral phenylalanine or tyrosine derivatives and subsequent
transformations,[8,9] whereas preparation of cycloisodityrosines via degradation of
natural RA-VII 2 into cycloisodityrosine requires a large quantity of 2 as the starting
material.[10] Such difficulty in the formation of the cycloisodityrosine unit has
hampered the synthesis of the analogs of those important peptides.
Received May 19, 2009.
Address correspondence to R. Soundararajan, Chemical Research and Development Department,
Pfizer Ltd., Mumbai, India. E-mail: soundara1959@yahoo.com
2389

2390
S. GHOSH ET AL.
Chart 1. Preparation of the cycloisodityrosine subunit.
DISCUSSION
In the present article, we describe a practical and short synthetic route to
L,L-cycloisodityrosines from commercially available L-tyrosine by a coupling
reaction of arylboronic acids with phenols originally developed by Chan et al.,[11]
Evans et al.,[12] and Lam et al.[13]
Commercially available L-tyrosine 5 was brominated at the 3-position with
bromine in acetic acid and hydrobromic acid in acetic acid at 25 ꢀC to afford
3-bromo-L-tyrosine hydrobromide 6 in 95% yield from 5. Compound 6 was
N-protected with a Boc group and methylated with dimethyl sulfate in the presence
of potassium carbonate in acetone to afford protected bromotyrosine 7 in 96%
yield from 6. The methylation step was initially conducted using methyl iodide
and potassium carbonate as a base, but the reaction ended with the formation of
many impurities. The reaction was optimized with dimethyl sulfate (2.5 equiv) and
potassium carbonate (3 equiv) in acetone at 25 ꢀC in 96% yield. Compound 7 was
N-deprotected using 2 N HCl in ethyl acetate at 25 ꢀC for 30 min to afford
compound 8 in 96% yield (Scheme 1).
Compound 8 was coupled with compound 9 using EDCI and HOBt in the
presence of diisopropyl ethyl amine in CH2Cl2 at 25 ꢀC to afford dipeptide 10 in
90% yield (Scheme 2).
When compound 10 was treated with bis(pinacolato)diboron (1.3 equiv)
and potassium acetate (3 equiv) in dimethylsulfoxide (DMSO) using Pd(PPh3)4
as a catalyst for 18 h at 90 ꢀC, no desired product 11 observed (Table 1, entry 1). When
the same reaction was performed using dimethylformamide (DMF) as a solvent under
the same condition, only 5% of product 11 was observed (entry 2). More reactions were
performed under the same conditions with different bases such as sodium acetate and
sodium carbonate, but no product 11 was observed (entries 3 and 4). We thought that
perhaps the catalyst was the culprit, and we conducted a few more reactions using
PdCl2[1,10-bis(diphenylphosphino)ferrocene](dppf) as a catalyst. When compound 10

IMPROVED SYNTHESIS OF L,L-CYCLOISODITYROSINE
2391
Scheme 1. Reagents and conditions: (a) Br2=AcOH, HBr=AcOH, 25 ꢀC, 6 h, 95%; (b) (Boc)2O, NaHCO3,
MeOH, EtOAc, 25 ꢀC, 4 h; (c) Me2SO4, K2CO3, acetone, 25 ꢀC, 12 h, 96% (from 6 to 7); and (d) 2 N HCl,
EtOAc, 25 ꢀC, 30 min, 96%.
Scheme 2. Reagents and conditions: (a) EDCI, HOBt, DIPEA, CH2Cl2, 25 ꢀC, 1 h, 90%.
was treated with bis(pinacolato)diboron (1.3 equiv) and potassium acetate (3 equiv) in
DMSO using PdCl2(dppf) as a catalyst for 18h at 90ꢀC, only 20% of desired product
11 was observed (entry 5). When the same reaction was performed using DMF as a sol-
vent under the same condition, only 30% of product 11 was observed (entry 6). The most
favorable yield was obtained using potassium acetate as a base (3 equiv) and PdCl2(dppf)
as a catalyst (0.05 equiv) in 1,2-dimethoxyethane (DME) as a solvent at 110ꢀC for 16h.
The yield was 90% (entry 7).
Table 1. Reaction conditions for conversion of 10 to 11
Entry
Base
Solvent
Catalyst
Temp. (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
KOAc
KOAc
NaOAc
Na2C03
KOAc
KOAc
KOAc
DMSO
DMF
DMF
DMF
DMSO
DMF
DME
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(dppf)
PdCI2(dppf)
PdCI2(dppf)
90
90
18
18
18
18
18
18
18
Nil
<5
Nil
Nil
20
90
90
90
90
30
90
110

2392
S. GHOSH ET AL.
Scheme 3. Reagents and conditions: (a) bis(pinacolato)diboron, KOAc, PdCl2(dppf), DME, 110 ꢀC, 18 h,
90%; (b) NaIO4, acetone, 0.1 N aq. NH4OAc, 25 ꢀC, 16 h, 90%; (c) Cu(OAc)2, DMAP, CH2Cl2, powdered
0
˚
4-A molecular sieves, 48 h, 60%.
This aryl boronate 11 was converted into aryl boronic acid 12 using NaIO4 in
acetone in the presence of 0.1 N NH4OAc aq. solutions at 25 ꢀC for 16 h in 90% yield.
The key ring closure of 12 to 4[14] via the intramolecular O-arylation of phenols with
aryl boronic acid 12 reaction smoothly proceeded using Cu(OAc)2 (1.3 equiv) and
dimethylaminopyridine (DMAP; 5ꢀequiv) in CH2Cl2 in the presence of powered
˚
4-A molecular sieves for 48 h at 25 C in 60% yield (Scheme 3).
In conclusion, we have developed a practical method for the synthesis of
L,L-cycloisodityrosine from commercially available L-tyrosine. Thus, it is possible
to get sufficient quantities of cycloisodityrosine to facilitate the analog synthesis of
deoxybouvardin 1 and RA-VII 2 for structure–activity relationship studies and
design of more promising antitumor peptide analogs.
EXPERIMENTAL
Materials and Instruments
All solvents and reagents were purchased from the suppliers and used without
further purification. All nonaqueous reactions were performed in dry glassware
under a dry nitrogen atmosphere. Organic solutions were concentrated under
reduced pressure. Thin-layer chromatography (TLC) was performed on Merck pre-
coated silica-gel 60 F254 plates. 1H and 13C NMR spectra were recorded on a Varian
Gemini 400-MHz Fourier transform (FT) NMR spectrometer using DMSO-d6
and CDCl3 as a solvent. The chemical shifts were reported in d ppm relative to
tetramethylsilane (TMS). The mass spectra (MS) were recorded on Shimadzu

IMPROVED SYNTHESIS OF L,L-CYCLOISODITYROSINE
2393
LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS=MS instruments. Melting
points were obtained using the open capillary method and are uncorrected.
(S)-2-Amino-3-(3-bromo-4-hydroxyphenyl) propanoic acid
hydrobromide (6)
A solution of HBr in glacial acetic acid (33% w=v) (15 ml, 61 mmol) was added
to a vigorously stirred suspension of (S)-tyrosine (5.54 g, 30.6 mmol) in glacial acetic
acid (25 ml). A solution of bromine (1.7 ml, 33.2 mmol) in glacial acetic acid (11.3 ml)
was added dropwise over 3 h, and the resulting mixture was stirred at rt for 24 h. The
precipitate was filtered and washed with glacial acetic acid (3 ꢁ 5 ml) and Et2O
1
(5 ꢁ 5 ml) to furnish 6 as a white solid (10.03 g, 95%); mp 210–215 ꢀC. H NMR
(400 MHz, DMSO-d6): d 12.10 (br s, 1H), 10.16 (s, 1H), 8.13 (br s, 2H), 7.33
(s, 1H), 7.01 (m, 1H), 6.86 (d, J ¼ 8 Hz, 1H), 4.10 (t, 1H), 2.99 (m, 2H), 1.86
(s, 1H); ESIMS: m=z calcd. [M þ ]: 260; found: 261.94 [MþHþ].
(S)-Methyl 3-(3-bromo-4-methoxyphenyl)-2-(tert-butoxycarbonyl)
propanoate (7)
NaHCO3 (2.45 g, 29.32 mmol) and H2O (20 mL) were added, followed by
(Boc)2O (4.8 g, 22 mmol), to a solution of compound 6 (5.0 g, 14.66 mmol) in MeOH
(30 mL) and EtOAc (30 mL) at 25 ꢀC. The reaction mixture was stirred at the same
temperature for 4 h. Heptane (50 mL) was added to the reaction mixture, and it was
diluted with water (20 mL). The organic layer was separated, and aqueous layer was
washed with heptane (40 mL) one more time. Then the aqueous layer was acidified
with 10% aqueous citric acid solution (20 mL) to make the pH ꢂ 4–5. The aqueous
layer was extracted with EtOAc (2 ꢁ 50 mL) and concentrated under vacuum to
afford the corresponding Boc-protected compound (5.2 g). K2CO3 (6 g, 43.33 mmol)
and Me2SO4 (4.5 g, 36.11 mmol) were added to a solution of Boc-protected
compound (5.2 g, 14.44 mmol) in acetone (50 mL) at 25 ꢀC. The reaction mixture
was stirred at the same temperature for 12 h. The reaction mixture was filtered
through a pad of Celite and washed with acetone (50 mL). The acetone layer was
concentrated under vacuum. Purification by column chromatography (silica, 7:3
hexane=EtOAc) provided arylbromide 7 as an off-white solid (on storage at rt, it
slowly became solid) (5.5 g, 96% yield), Rf ¼ 0.6 (7:3; heptanes=EtOAc), mp
66–70 ꢀC. 1H NMR (400 MHz, DMSO-d6): d 7.40 (s, 1H), 7.25 (d, J ¼ 8.4 Hz,
1H), 7.18 (dd, 1H), 6.99 (d, J ¼ 8.4 Hz, 1H), 4.08 (m, 1H), 3.76 (s, 3H), 3.57 (s,
3H), 2.89 (m, 1H), 2.75 (m, 1H), 1.28 (s, 9H); 13C NMR (400 MHz, DMSO-d6): d
170.9, 158.9, 155.1, 134.2, 131.0, 130.6, 114.5, 113.1, 79.9, 56.7, 53.5, 53.3, 35.4,
34.8; ESIMS: m=z calcd [Mþ]: 388; found: 287.94 [Mþ].
(S)-Methyl 3-(3-bromo-4-methoxyphenyl)-2-((S)-
2-(tert-butoxycarbonyl)-3-(4-hydroxyphenyl)propanamido)
propanoate (10)
Compound 9 (2.60 g, 9.25 mmol), EDCI (2.65 g, 13.87 mmol), HOBt (1.25 g,
9.25 mmol), and DIPEA (3.57 g 27.75 mmol) were added to a suspension of 8

2394
S. GHOSH ET AL.
(3.0 g, 9.25 mmol) in dry CH2Cl2 (50 mL) at 25 ꢀC. The resulting mixture was stirred
at 25 ꢀC for 2 h. The reaction mixture was quenched with water and neutralized with
10% aq. citric acid solution, and CH2Cl2 layer was separated and concentrated to get
a residue. The residue was purified by column chromatography (silica, 5:5; heptanes=
EtOAc) to afford compound 10 as an off-white solid (4.6 g, 90% yield), Rf ¼ 0.2 (5:5;
heptane=EtOAc), mp 90–95 ꢀC. 1H NMR (400 MHz, DMSO-d6): d 9.25 (s, 1H), 8.20
(d, J ¼ 8 Hz, 1H), 7.39 (s, 1H), 7.16 (d, J ¼ 8.4 Hz, 1H), 6.97 (m, 3H), 6.67 (m, 3H),
4.40 (m, 1H), 4.09 (m, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 2.94–2.83 (m, 4H), 1.28 (s, 9H);
13C NMR (400 MHz, DMSO-d6): d 172.5, 172.1, 156.0, 155.5, 155.0, 154.5 133.9,
131.0, 130.4, 130.1, 128.3, 115.2, 112.8, 110.6, 78.6, 56.5, 55.5, 53.8, 52.4, 39.0,
37.1, 28.5; ESIMS: m=z calcd [Mþ]: 551; found: 452.77 [MþHþ].
(S)-Methyl 2-((S)-2-(tert-butoxycarbonyl)-3-(4-hydroxyphenyl)-
propanamido)-3-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl) propanoate (11)
Aryl bromide 10 (5.0 g, 9.06 mmol), bis(pinacolato)diboron (2.95 g,
11.78 mmol), KOAc (2.66 g, 27.2 mmol), and PdCl2(dppf) (0.369 g, 0.453 mmol) were
suspended in dry 1,2-dimethoxyethane (50 mL, degassed by sparging with N2) and
heated to 110 ꢀC for 18 h. Water (30 ml) and EtOAc (30 ml) were added. The layers
were separated, and the aqueous layer was extracted with EtOAc (2 ꢁ 50). The
combined organic layers were dried (MgSO4), filtered, and concentrated in vacuum.
Purification by column chromatography (silica, 5:5 hexane=EtOAc) provided aryl
boronate 11 as an off-white solid (4.8 g, 90% yield), mp 80–83 ꢀC. 1H NMR
(400 MHz, DMSO-d6): d 9.13 (s, 1H), 8.22 (d, J ¼ 7.44 Hz, 1H), 7.36–6.61 (m,
8H), 4.40 (q, 1H), 4.05 (q, 1H), 3.69 (s, 3H), 3.58 (s, 3H), 2.94–2.75 (m, 4H), 1.33
(s,12H), 1.26 (s, 9H); 13C NMR (400 MHz, DMSO-d6): d 171.9, 171.8, 162.7,
155.7, 155.0, 137.0, 133.3, 130.0, 129.6, 128.5, 128.0, 114.7, 110.7, 82.9, 77.9, 56.0,
55.3, 53.8, 51.7, 36.7, 35.8, 28.0, 24.9, 24.5. ESIMS: m=z calcd. [Mþ]: 598; found:
598.93 [M þHþ], 621.86 [Mþ þNa]. HRMS (ESI): m=z calcd. [Mþ]: 598.4921;
found: 598.4935 [Mþ].
5-((S)-2-((S)-2-(tert-Butoxycarbonyl)-3-(4-hydroxyphenyl)-
propanamido)-3-methoxy-3-oxopropyl)-2-methoxyphenylboronic
acid (12)
NH4OAc (aq) (50 mL, 0.l N) and NaIO4 (3.21 g, 15.04 mmol) were added to a
stirred solution of the boronate ester 11 (3.0 g, 5.01 mmol) in acetone (60 mL). The
mixture was stirred at 25 ꢀC for 24 h. The reaction was monitored by TLC, and
no starting material was left. Ethyl acetate (50 ml) was added to the reaction mixture,
and the ethyl acetate layer was separated and concentrated to afford the product 12.
This was purified by column chromatography using silica (5:5 hexane=EtOAc) to
provide aryl boronate 12 as an off-white solid (2.32 g, 90% yield), mp 98–102 ꢀC.
1H NMR (400 MHz, DMSO-d6): d 9.13 (s, 1H), 8.23 (d, J ¼ 7.48 Hz, 1H), 7.65
(m, 10H), 4.41 (q, 1H), 4.04 (q, 1H), 3.69 (s, 3H), 3.57 (s, 3H), 2.96–2.75 (m, 4H),
1.25 (s, 9H); 13C NMR (400 MHz, DMSO-d6): d 171.7, 171.6, 162.6, 155.6, 154.9,
136.2, 132.0, 129.9, 128.4, 128.0, 127.8, 114.9, 110.2, 77.9, 55.7, 55.2, 53.7, 51.6,

IMPROVED SYNTHESIS OF L,L-CYCLOISODITYROSINE
2395
36.6, 36.0, 28.8. ESIMS: m=z calcd. [Mþ]: 516; found: 516.90 [MþHþ], 538.89 [Mþ
þNa]. HRMS (ESI): m=z calcd. [Mþ]: 516.3485; found: 516.3935 [Mþ].
12-tert-Butoxycarbonylamino-4-methoxy-11-oxo-2-oxa-10-aza-
tricyclo[12.2.2.1ꢃ3,7ꢃ]nonadecA-1(17),3(19),4,6,14(18),15-hexaene-9-
carboxylic acid methyl ester (4)
˚
DMAP (2.36 g, 19.36 mmol) and powdered 4-A molecular sieves (4 g) were
added to a solution of compound 12 (2.0 g, 3.87 mmol) in CH2Cl2 (200 mL), and the
mixture was stirred at 25 ꢀC for 30 min. Copper(II) acetate (0.91 g, 5.034 mmol) was
added to the mixture, and the mixture was stirred at 25 ꢀC for 48 h. The mixture
was filtered, washed successively with 5% aqueous KHSO4(50 mL) and brine
(50 mL), and dried over MgSO4. The solvent was removed in vacco, and the residue
was purified by column chromatography using silica (7:3 hexane=EtOAc) to provide
25
compound 4[14] as an off-white solid (1.00 g, 60% yield); ½aꢄ D þ 57 (c 0.6, CHCl3),
1
mp 84–88 ꢀC. H NMR (400 MHz, DMSO-d6): d 9.14 (s, 1H), 7.77 (s, 1H), 7.10 (m,
J ¼ 8.8 Hz, 8.4 Hz, 2H), 6.96 (m, J ¼ 8.8 Hz, 9.6 Hz, 2H), 6.82 (d, J ¼ 6.8 Hz, 1H),
6.60 (d, J ¼ 8 Hz, 1H), 4.94 (s, 1H), 4.40 (m, 1H), 4.21 (m, 1H), 3.77 (m, 3H), 3.49
(m, 3H), 3.07 (m, 4H), 1.25 (s, 9H); 13C NMR (400 MHz, DMSO-d6): d 174.4,
173.7, 160.6, 158.3, 154.3, 136.8, 134.7, 133.0, 132.7, 129.6, 123.9, 116.3, 114.4, 80.6,
57.5, 56.9, 56.3, 54.4, 35.7, 33.9, 30.9. ESIMS: m=z calcd. [Mþ]: 470; found: 471.12
[MþHþ]. HRMS (ESI): m=z calcd [Mþ]: 470.5149; found: 470.5135 [Mþ].
ACKNOWLEDGMENTS
We are grateful to the Indian Association for Cultivation Sciences, Jadavpur,
for analytical support, Pfizer Ltd., and SVNIT, Surat, India.
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