Stereoselective synthesis of MLN4924, an inhibitor of NEDD8-activating enzyme

Article abstract of DOI:10.1021/jo2001897

MLN4924 (1), which is in clinical trials as an anticancer agent, was stereoselectively synthesized from d-ribose via a route involving stereoselective reduction, regioselective cleavage of an isopropylidene moiety, and selective displacement of a cyclic s

Full text of DOI:10.1021/jo2001897

NOTE
pubs.acs.org/joc
Stereoselective Synthesis of MLN4924, an Inhibitor of
NEDD8-Activating Enzyme
Hyuk Woo Lee,† Soo Kyung Nam,† Won Jun Choi,†,‡ Hea Ok Kim,† and Lak Shin Jeong*,†
†Department of Bioinspired Science and Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea
‡College of Pharmacy, Dongguk University, Kyungki-do 410-774, Korea
S Supporting Information
b
ABSTRACT: MLN4924 (1), which is in clinical trials as an
anticancer agent, was stereoselectively synthesized from D-ribose
via a route involving stereoselective reduction, regioselective
cleavage of an isopropylidene moiety, and selective displacement
of a cyclic sulfate moiety as key steps.
he ubiquitin-proteasome system (UPS) plays an important
role in the conjugation pathway, which appends ubiquitin to
good overall yields is our immediate goal. Herein, we report a
new method for the stereoselective synthesis of MLN4924 from
D-ribose. In particular, the key steps in the synthesis include
stereoselective reduction, regioselective cleavage of an isopropy-
lidene moiety, and the selective displacement of a cyclic sulfate
moiety.
T
proteins targeted for regulated degradation.1 The ubiquitinyla-
tion pathway is composed of three enzymatic steps (i.e., E1:
ubiquitin-activating enzyme, E2: ubiquitin-conjugating enzyme
(UBC), and E3: ubiquitin-protein isopeptide ligase).2 A pathway
similar to ubiquitinylation that employs the ubiquitin-like protein
NEDD8 (neural precursor cell-expressed developmentally
down-regulated 8) has also been identified.3,4 In the first step,
NEDD8 is activated by an E1 enzyme (NEDD8 activating
enzyme, NAE). NEDD8 is then transferred to an E2 enzyme
(UBC12), and is subsequently conjugated to the protein targeted
for degradation. In this pathway, NAE plays an essential role in
regulating the activity of cullin-RING (really interesting new
gene) ubiquitin ligases, whose substrates play important roles in
cellular processes associated with cancer cell growth.5 Thus NAE
is a new target for the development of novel anticancer agents.
MLN4924 (1)6 is a potent and selective inhibitor of NAE and
is currently being investigated in phase I clinical trials as an
anticancer agent for both solid tumor and hematological malig-
nancies (Figure 1). MLN4924 mimics adenosine 50-monopho-
sphate (2, AMP), which is a tight binding product of the reaction
NAE catalyzes.7,8 MLN4924 inhibits the NAE pathway in cells,
which results in S-phase defects, DNA damage, and apoptosis.6
MLN4924 also damages DNA in mice bearing human HCT-116
tumor xenografts.6
Scheme 1 shows a retrosynthetic analysis of MLN4924 (1).
MLN 4924 (1) was envisioned to arise by condensing the glycosyl
donor, cyclic sulfate 3, with a purine base. Glycosyl donor 3 could
be produced from diol 4, which in turn could be obtained from
cyclopentanone 5 via a stereoselective reduction and a regioselec-
tive cleavage of the isopropylidene moiety. Cyclopentanone 5
could arise from cyclopentenone 6 via a stereoselective reduction,
and intermediate 6 can be easily obtained from D-ribose using our
previously published procedure.10
Our synthesis begins with cyclopentenone 6,10 which was
efficiently synthesized from D-ribose in 6 steps (Scheme 2).
Catalytic hydrogenation of cyclopentenone 6 with 10% Pd/C
gave cyclopentanone 5 in quantitative yield as a single stereoiso-
mer, due to the incorporation of hydrogen from the convex side
of the molecule. Luche reduction11 of ketone 5 with NaBH4 and
CeCl3 7H2O afforded alcohol 7 as a single diastereomer. The
3
configuration of the newly created asymmetric center in 7 was
easily confirmed by NOESY experiments (see the Supporting
Information). The NOE effect between H-1 and H-4 in com-
pound 7 was observed, indicating a cis relationship. Regioselec-
tive cleavage of the acetonide present in 7 was achieved by
treatment with trimethylaluminum,12 which gave diol 4. Diol 4
was converted to cyclic sulfate 3 by treatment with thionyl
chloride and subsequent oxidation with RuCl3 and NaIO4.13
Despite its potent anticancer activity, the synthesis of
MLN4924 has only been described in a single patent.9 The
aforementioned protocol (Scheme 1S in the Supporting In-
formation) started with cyclopentadiene, from which the synth-
esis of MLN4924 was achieved in 15 steps and 7.1% overall
yields.
Due to the importance of the compound, an efficient stereo-
selective synthesis of MLN4924 under mild conditions and in
Received: January 28, 2011
Published: March 21, 2011
r
2011 American Chemical Society
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|

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NOTE
To complete the synthesis of MLN4924 (1), glycosyl
donor 3 was reacted with the anion of N6-indanyl-7-deazaa-
denine in THF (Scheme 3). After hydrolyzing the resulting
sulfate, the desired N9-isomer 8 (65%) was obtained as a
single diastereomer.14 Treatment of 8 with phenyl chlor-
othionoformate and further reaction with n-Bu3SnH in the
presence of AIBN yielded the 20-deoxygenated derivative 9.
Compound 9 was treated with pyridine HF to give a 50-
3
hydroxyl compound 10, which was treated with chlorosulfo-
namide to produce the 50-sulfonamido derivative 11. The tert-
butyl group of 11 was removed with 70% TFA to afford
MLN4924 (1) in 90% yield.
In summary, we have completed an efficient stereoselective
synthesis of MLN4924, a compound in phase I clinical trials
as an anticancer agent. Starting from D-ribose, MLN4924 was
produced in 15 steps and 11% overall yields under mild
conditions. In particular, the key steps of the synthetic
sequence included a stereoselective reduction, the regiose-
lective cleavage of an isopropylidene moiety, and the posi-
tion-selective displacement of a cyclic sulfate moiety. All of
the reactions employed in the present synthesis are expected
to be very useful in the development of new carbocyclic
nucleosides. Structureꢀactivity relationship studies of
MLN4920 are currently in progress, and the results will be
reported in due course.
Figure 1. The structure of MLN4924 (1), a mimic of AMP.
Scheme 1. Retrosynthesis of the AMP Mimic MLN4924 (1)
Scheme 2. Synthesis of Glycosyl Donor 3
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NOTE
Scheme 3. Synthesis of MLN4924 (1)
’ EXPERIMENTAL SECTION
between ethyl acetate and water, and the organic layer was washed with
brine, dried with anhydrous MgSO4, filtered, and evaporated. The residue
was purified bysilica gel column chromatography(hexane/ethyl acetate =
5/1) to give 7 (20.86 g, 98%) as a colorless syrup: [R]20D þ34.55 (c 0.55,
MeOH); HR-MS (ESI) m/z calcd for C25H34NaO4Si [M þ Na]þ
449.2124, found 449.2110; 1H NMR (400 MHz, CDCl3)
δ 7.69 (m, 4H), 7.39 (m, 6H), 4.62 (t, J = 5.6 Hz, 1H), 4.44 (t, J = 5.6
Hz, 1H), 3.89 (dd, J = 6.0, 7.6 Hz, 1H), 3.84 (m, 1H), 3.68 (dd, J = 6.4,
10.0 Hz, 1H), 1.91 (m, 2H), 1.26 (m, 1H), 1.42 (s, 3H), 1.33 (s, 3H), 1.05
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.9, 135.8, 134.2, 134.1,
129.8, 129.7, 127.8, 127.7, 110.6, 79.4, 78.9, 77.6, 77.2, 76.9, 72.5, 62.9,
41.6, 33.4, 27.0, 25.9, 27.0, 25.9, 24.4, 19.5. Anal. Calcd for C25H34O4Si:
C, 70.38; H, 8.03. Found: C, 70.41; H, 8.08.
6-(tert-Butyldiphenylsilanyloxymethyl)-2,2-dimethyltetra-
hydrocyclopenta[1,3]dioxol-4-one (5). 10% Palladium on acti-
vated carbon (1.0 g) was added to a suspension of 6 (20.0 g, 47.1 mmol)
in methanol (400 mL), and the mixture was stirred overnight at room
temperature under an atmosphere of H2. After filtration, the solvent was
removed, and the residue wasdissolved in methylene chloride andfiltered
through a short pad of silica gel. The solvent was evaporated to give 5
(20.1 g, 100%) as a colorless syrup: [R]20D ꢀ28.32 (c 1.49, MeOH); HR-
MS (ESI) m/z calcd for C25H32NaO4Si [M þ Na]þ 447.1968, found
447.1956; 1H NMR (400 MHz, CDCl3) δ 7.69 (m, 4H), 7.40 (m, 6H),
4.84 (t, J = 4.4 Hz, 1H), 4.22 (dd, J = 1.2, 4.8 Hz, 1H), 3.96 (dd, J = 8.0,
10.0 Hz, 1H), 3.82 (dd, J = 6.8, 10.0 Hz, 1H), 2.37 (m, 1H), 2.30 (ddd, J =
1.2, 8.4, 18.4 Hz, 1H), 2.20 (ddd, J = 1.2, 12.0, 18.4 Hz, 1H), 1.37 (s, 3H),
1.35
3-tert-Butoxy-4-(tert-butyldiphenylsilanyloxymethyl)-
cyclopentane-1,2-diol (4). Trimethylaluminum (2.0 M in toluene,
132.1 mL) was added to a solution of 7 (20.86 g, 47.12 mmol) in
methylene chloride at 0 °C, and the mixture was stirred at room
temperature for 2 d. The mixture was cooled to 0 °C, slowly quenched
with saturated aqueous ammonium chloride, filtered, and evaporated.
The residue was partitioned between ethyl acetate and water, and the
organic layer was washed with brine, dried with anhydrous MgSO4,
filtered, and evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 2/1) to give 4 (13.42 g, 62%)
as a colorless syrup: [R]20D þ3.30 (c 0.55, MeOH); HR-MS (ESI) m/z
(s, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 112.6, 80.5, 77.6,
77.2, 76.9, 63.6, 38.1, 36.9, 27.1, 27.02, 27.01, 25.3, 19.5. Anal. Calcd for
C25H32O4Si: C, 70.72; H, 7.60. Found: C, 70.79; H, 7.75.
6-(tert-Butyldiphenylsilanyloxymethyl)-2,2-dimethyltetra-
hydrocyclopenta [1,3]dioxol-4-ol (7). Sodium borohydride (2.17
g, 57.4 mmol) and cerium(III) chloride heptahydrate (21.3 g, 57.2 mmol)
were added to a suspension of 5 (20.1 g, 47.1 mmol) in methanol
(500 mL) at 0 °C, and the mixture was stirred at room temperature for
30 min. After the solvent was removed, the residue was partitioned
1
calcd for C26H38NaO4Si [M þ Na]þ 465.2437, found 465.2423; H
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NOTE
NMR (400 MHz, CDCl3) δ 7.70 (m, 4H), 7.41 (m, 6H), 4.05 (dd, J =
4.4, 7.2 Hz, 1H), 3.93 (m, 1H), 3.72 (m, 2H), 3.59 (dd, J = 3.6, 12.0 Hz,
2H), 2.70 (d, J = 20.8 Hz, 1H), 2.10 (m, 2H), 1.60 (m, 1H), 1.20 (s, 9H),
1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.9, 133.5, 130.0, 129.9,
127.9, 127.9, 77.6, 77.2, 76.9, 74.9, 73.8, 72.7, 72.1, 63.3, 42.1, 34.0, 28.5,
27.0, 19.4. Anal. Calcd for C26H38O4Si: C, 70.55; H, 8.65. Found: C,
70.61; H, 8.70.
J = 5.2, 10.8 Hz, 1H), 3.84 (dd, J = 5.6, 10.4 Hz, 1H), 3.73 (dd, J = 8.4,
10.4 Hz, 1H), 3.37 (d, J = 5.6 Hz, 1H), 3.06 (m, 1H), 2.95 (m, 1H), 2.75
(m, 1H), 2.75 (m, 1H), 2.58 (m, 1H), 2.38 (m, 1H), 2.15 (m, 1H), 1.98
(m, 1H), 1.65 (s, 1H), 1.55 (s, 1H), 1.16 (s, 9H), 1.07 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 156.4, 151.8, 150.3, 144.1, 143.8, 135.9, 134.0,
129.9, 128.2, 127.9, 127.9, 127.0, 125.1, 124.4, 123.3, 103.8, 97.4, 77.8,
77.6, 77.2, 76.9, 74.9, 72.4, 63.5, 62.1, 56.3, 43.9, 34.9, 30.5, 30.5, 28.5,
27.2, 19.5. Anal. Calcd for C41H50N4O3Si: C, 72.96; H, 7.47; N, 8.30.
Found: C, 73.01; H, 7.45; N, 8.36.
(4-tert-Butoxy-2,2-dioxotetrahydro-2-yl-6-cyclopenta-
[1,3,2]dioxathiol-5-ylmethoxy)-tert-butyldiphenylsilane (3).
Triethyl amine (14.5 mL, 101.0 mmol) and thionyl chloride (3.7 mL,
47.4 mmol) were added to a solution of 4 (13.42 g, 30.3 mmol) in
methylene chloride at 0 °C, and the reaction mixture was stirred at 0 °C
for 10 min. The reaction mixture was partitioned between methylene
chloride and water, and the organic layer was washed with brine, dried
with anhydrous MgSO4, filtered, and evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate =
{7-[3-tert-Butoxy-4-(tert-butyldiphenylsilanyloxymethyl)-
cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}indan-1-yl-
amine (9). N,N-Dimethylaminopyridine (5.64 g, 51.6 mmol) and
phenyl chlorothionocarbonate (4.3 mL, 34.4 mmol) were added to a
solution of 8 (11.62 g, 17.2 mmol) in methylene chloride (300 mL), and
the reaction mixture was stirred overnight at room temperature. After
the solvent was removed, the residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 6/1) to give the thiocarbonate
6/1) to give the cyclic sulfite (14.37 g, 97%) as a white foam: [R]20
D
(13.82 g, 99%) as a white foam: UV (MeOH) λmax 271.50 nm; [R]20
þ20.00 (c 0.05, MeOH); HR-MS (ESI) m/z calcd for C26H36NaO5SSi
[M þ Na]þ 511.1950, found 511.1929; 1H NMR (400 MHz, CDCl3) δ
7.64 (m, 4H), 7.40 (m, 6H), 5.23 (m, 1H), 5.04 (dd, J = 4.4, 6.0 Hz, 1H),
4.01 (t, J = 4.8 Hz, 1H), 3.68 (dd, J = 3.6, 10.4 Hz, 1H), 3.56 (dd, J = 8.0,
10.4 Hz, 1H), 2.07 (m, 2H), 1.96 (m, 1H), 1.14 (s, 9H), 1.05 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 135.8, 135.7, 133.9, 133.8, 129.9, 129.9,
127.9, 127.8, 85.7, 83.2, 77.6, 77.2, 76.9, 75.0, 71.1, 62.7, 44.7, 31.4, 28.5,
27.1, 19.4. Anal. Calcd for C26H36O5SSi: C, 63.90; H, 7.42; S, 6.56.
Found: C, 63.94; H, 7.45; S, 6.61.
D
þ10.00 (c 0.15, MeOH); HR-MS (ESI) m/z calcd for C48H55N4O4SSi
[M þ H]þ 811.3713, found 811.3687; 1H NMR (400 MHz, CDCl3) δ
8.36 (s, 1H), 7.61 (dd, J = 1.6, 7.6 Hz, 4H), 7.34 (m, 5H), 7.26 (m, 4H),
7.18 (m, 6H), 6.86 (s, 1H), 6.25 (d, J = 3.2 Hz, 1H), 6.00 (dd, J = 3.2, 8.4
Hz, 1H), 5.83 (d, J = 6.8 Hz, 1H), 5.19 (m, 1H), 5.07 (br s, 1H), 4.48 (t, J
= 3.6 Hz, 1H), 3.82 (dd, J = 7.2, 10.4 Hz, 1H), 3.52 (dd, J = 7.2, 10.0 Hz,
1H), 2.99 (m, 1H), 2.88 (m, 2H), 2.69 (m, 2H), 2.18 (dd, J = 11.2, 13.6
Hz, 1H), 1.94 (m, 2H), 1.12 (s, 9H), 0.98 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 194.9, 153.5, 152.1, 143.9, 135.9, 135.8, 134.1, 129.9, 129.6,
128.3, 127.9, 127.0, 126.7, 125.1, 124.6, 123.2, 122.0, 87.9, 77.6, 77.2,
76.9, 74.6, 70.4, 63.5, 57.3, 42.8, 35.0, 30.7, 30.5, 29.9, 28.7, 27.1, 19.4.
Anal. Calcd for C48H54N4O4SSi: C, 71.08; H, 6.71; N, 6.91; S, 3.95.
Found: C, 71.14; H, 6.75; N, 6.95; S, 4.01.
Sodium metaperiodate (18.56 g, 56.4 mmol) and ruthenium chloride
(1.72 g, 8.25 mmol) were added to a solution of the cyclic sulfite (14.37
g, 29.4 mmol) in carbon tetrachloride, acetonitrile, and water (1:1:1.5,
210 mL), and the reaction mixture was stirred at room temperature for
10 min. The reaction mixture was partitioned between methylene
chloride and water, and the organic layer was washed with brine, dried
with anhydrous MgSO4, filtered, and evaporated. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate = 4/1) to give
Tri-n-butyltinhydride (9.4 mL, 34.1 mmol) and 2,20-azo-bis-isobu-
tyronitrile (4.32 g, 26.3 mmol) were added to a solution of the
thiocarbonate (13.82 g, 17.0 mmol) in toluene (200 mL), and the
reaction mixture was stirred at 110 °C for 1 h. After the mixture was
cooled, the solvent was removed, and the residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 3/1) to give
9 (9.21 g, 82%) as a white foam: UV (MeOH) λmax 272.50 nm;
3 (13.36 g, 90%) as a white solid: mp 101ꢀ104 °C; [R]20 ꢀ80.00
D
(c 0.05, MeOH); HR-MS (ESI) m/z calcd for C26H36NaO6SSi [M þ
Na]þ 527.1900, found 527.1881; 1H NMR (400 MHz, CDCl3) δ 7.64
(m, 4H), 7.41 (m, 6H), 5.13 (m, 1H), 4.83 (dd, J = 4.4, 6.8 Hz, 1H), 4.13
(t, J = 4.0 Hz, 1H), 3.92 (dd, J = 6.4, 10.4 Hz, 1H), 3.69 (dd, J = 5.2, 10.4
Hz, 1H), 2.11 (m, 2H), 2.02 (m, 1H), 1.15 (s, 9H), 1.05 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 135.7, 135.0, 133.8, 133.7, 130.0, 128.0,
127.9, 83.5, 82.2, 77.6, 77.2, 76.9, 75.4, 70.4, 70.4, 62.2, 43.9, 31.3, 28.2,
27.1, 26.8, 19.4. Anal. Calcd for C26H36O6SSi: C, 61.87; H, 7.19; S, 6.35.
Found: C, 61.91; H, 7.14; S, 6.30.
[R]20 ꢀ10.00 (c 0.20, MeOH); HR-MS (ESI) m/z calcd for
D
C41H51N4O2Si [M þ H]þ 659.3781, found 659.3757; 1H NMR
(400 MHz, CDCl3) δ 8.41 (s, 1H), 7.69 (m, 4H), 7.41 (m, 6H),
7.29 (m, 2H), 7.23 (m, 2H), 6.92 (d, J = 3.6 Hz, 1H), 6.31 (d, J = 3.6 Hz,
1H), 5.90 (dd, J = 7.2, 14.8 Hz, 1H), 5.38 (m, 1H), 5.15 (br s, 1H), 4.33
(dd, J = 5.2, 8.4 Hz, 1H), 3.88 (dd, J = 6.4, 10.0 Hz, 1H), 3.68 (dd, J =
7.2, 10.4 Hz, 1H), 3.05 (m, 1H), 2.96 (dd, J = 7.6, 15.6 Hz, 1H), 2.76
(m, 1H), 2.45 (d, J = 5.2 Hz, 1H), 2.29 (m, 2H), 2.06 (m, 1H), 1.95 (m,
2H), 1.55 (s, 1H), 1.13 (s, 9H), 1.06 (s, 9H); 13 C NMR (100 MHz,
CDCl3) δ 156.3, 151.9, 144.1, 143.9, 135.9, 135.8, 134.3, 129.8, 128.2,
127.8, 127.0, 125.1, 124.6, 121.8, 77.6, 77.2, 76.7, 73.5, 72.2, 63.6, 56.4,
52.8, 46.8, 42.8, 34.9, 34.5, 30.5, 28.6, 27.2, 28.7, 19.4. Anal. Calcd for
C41H50N4O2Si: C, 74.73; H, 7.65; N, 8.30. Found: C, 74.79; H, 7.61;
N, 8.25.
2-tert-Butoxy-3-(tert-butyldiphenylsilanyloxymethyl)-5-
[4-(indan-1-ylamino)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopen-
tanol (8). A suspension of N6-indanyl-7-deazaadenine (8.80 g, 35.2
mmol), sodium hydride (1.38 g, 45.7 mmol), and 18-crown-6 (9.11 g,
45.7 mmol) in THF (200 mL) was stirred at 80 °C. To this reaction
mixture was added a solution of 3 (13.36 g, 26.5 mmol) in THF
(150 mL), and stirring was continued at 80 °C overnight. The reaction
mixture was cooled to 0 °C, and concentrated HCl was added slowly
until a pH of 1ꢀ2 was attained. Subsequently, the reaction mixture was
stirred at 80 °C for an additional 2 h. After neutralization with saturated
aqueous NaHCO3, the reaction mixture was partitioned between ethyl
acetate and water, and the organic layer was washed with brine, dried
with anhydrous MgSO4, filtered, and evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate =
2/1) to give 8 (11.62 g, 65%) as a white foam: UV (CH2Cl2) λmax
272.5 nm; [R]20D ꢀ8.89 (c 0.45, MeOH); HR-MS (ESI) m/z calcd for
C41H51N4O3Si [M þ H]þ 675.3730, found 675.3717; 1H NMR (400
MHz, CDCl3) δ 8.38 (s, 1H), 7.70 (m, 4H), 7.41 (m, 6H), 6.92 (d, J =
3.6 Hz, 1H), 6.29 (d, J = 3.2 Hz, 1H), 5.91 (dd, J = 7.6, 14.8 Hz, 1H), 5.14
(br d, J = 6.8 Hz, 1H), 4.77 (m, 1H), 4.36 (t, J = 6.0 Hz, 1H), 4.22 (dd,
2-tert-Butoxy-4-[4-(indan-1-ylamino)pyrrolo[2,3-d]pyri-
midin-7-yl]cyclopentanol (10). Pyridine hydrofluoride (18.42 mL,
190.0 mmol) was added dropwise to a solution of 9 (9.21 g, 13.97 mmol)
in THF and pyridine (1:1, 160 mL) at 0 °C, and the reaction mixture was
stirred at room temperature for 1 h. The mixture was neutralized with
saturated aqueous NaHCO3, and partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried with anhydrous
MgSO4, filtered, and evaporated, and the residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 1/3) to give 10
(5.63 g, 99%) as a white foam: UV (MeOH) λmax 273.00 nm; [R]20
D
ꢀ6.36 (c 1.10, MeOH); HR-MS (ESI) m/z calcd for C25H33N4O2 [M þ
H]þ 421.2604, found 421.2599; 1H NMR (400 MHz, CDCl3) δ 8.34
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NOTE
(s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.15 (t, J = 6.8
Hz, 1H), 6.88 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.6 Hz, 1H), 5.83 (dd, J =
7.2, 15.2 Hz, 1H), 5.28 (m, 1H), 5.06 (m, 1H), 4.47 (dd, J = 5.6, 10.4 Hz,
1H), 3.78 (m, 1H), 3.70 (m, 1H), 3.24 (t, J = 5.2 Hz, 1H), 2.98 (m, 1H),
2.87 (m, 1H), 2.68 (m, 1H), 2.46 (m, 1H), 2.37 (m, 2H), 1.93 (m, 2H),
1.18(s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.2, 151.8, 147.9, 143.9,
143.9, 128.3, 126.9, 125.1, 124.5, 121.9, 97.7, 77.6, 77.2, 76.9, 75.5, 74.9,
63.4, 56.4, 53.8, 44.2, 42.2, 34.9, 33.2, 30.5, 28.6. Anal. Calcd for
C25H32N4O2: C, 71.40; H, 7.67; N, 13.32. Found: C, 71.46; H, 7.60;
N, 13.35.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: 82-2-3277-3466. Fax: 82-2-3277-2851. E-mail: lakjeon-
g@ewha.ac.kr.
’ ACKNOWLEDGMENT
H.W.L. acknowledges financial support from a Research
Professor Fellowship Grant (2010) of Ewha Womans University.
Sulfamic Acid 2-tert-Butoxy-4-[4-(indan-1-ylamino)pyrrolo-
[2,3-d]pyrimidin-7-yl]cyclopentylmethyl Ester (11)
Preparation of a 2.0 M Solution of Chlorosulfonamide in
Acetonitrile. Under an atmosphere of nitrogen at 0 °C, formic acid
(14.15 mL, 166.0 mmol) was added dropwise to chlorosulfonyl iso-
cyanate (32.0 mL, 162.5 mmol). When the addition was complete, the
mixture solidified. Acetonitrile (61.3 mL) was added, and the resulting
solution was allowed to stand under a vented source of nitrogen at room
temperature overnight.
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To a solution of 10 (5.63 g, 13.83 mmol) and triethylamine (9.7 mL,
0.74 mmol) in acetonitrile (278 mL) was added a 2.0 M solution of
chlorosulfonamide in acetonitrile (13.83 mL, 27.76 mmol) at 0 °C, and
the reaction mixture was stirred at room temperature for 45 min. An
additional portion of the 2.0 M solution of chlorosulfonamide in
acetonitrile (13.83 mL, 27.76 mmol) was added, and the mixture was
stirred at room temperature for 15 min. The reaction was quenched with
methanol, and the solvent was removed. The residue was purified by
silica gel column chromatography (methylene chloride/methanol = 20/
1) to give 11 (6.37 g, 92%) as a white foam: UV (MeOH) λmax
273.00 nm; [R]20D ꢀ18.00 (c 0.50, MeOH); HR-MS (ESI) m/z calcd
for C25H34N5O4S [M þ H]þ 500.2332, found 500.2331; 1H NMR (400
MHz, CDCl3) δ 8.38 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.2
Hz, 1H), 7.22 (m, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.31 (d, J = 3.2 Hz, 1H),
5.89 (d, J = 6.4 Hz, 1H), 5.10 (s, 2H), 4.41 (m, 2H), 4.26 (m, 1H), 3.05
(m, 1H), 2.94 (m, 1H), 2.76 (m, 2H), 2.27 (m, 3H), 2.06 (m, 1H), 1.97
(m, 1H), 1.76 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 156.4, 151.9,
149.9, 143.9, 143.8, 128.3, 126.9, 125.1, 124.5, 121.9, 121.9, 103.5, 97.9,
77.4, 77.2, 76.9, 74.3, 71.9, 71.3, 56.4, 53.1, 49.0, 42.3, 34.9, 34.3, 30.5,
28.6. Anal. Calcd for C25H33N5O4S: C, 60.10; H, 6.66; N, 14.02; S, 6.42.
Found: C, 60.15; H, 6.71; N, 13.98; S, 6.39.
Sulfamic Acid 2-Hydroxy-4-[4-(indan-1-ylamino)pyrrolo-
[2,3-d]pyrimidin-7-yl]cyclopentylmethyl Ester (1). A solution
of 11 (6.37 g, 12.72 mmol) in 70% trifluoroacetic acid (149.24 mL) was
stirred at room temperature for 2 h. The solvent was removed, and the
residue was purified by silica gel column chromatography (hexane/ethyl
acetate = 1/2) to give 1 (5.08 g, 90%) as a white foam: UV (MeOH) λmax
279.50 nm; [R]20D ꢀ6.41 (c 2.34, MeOH); HR-MS (ESI) m/z calcd for
(14) Lee, J. A.; Kim, H. O.; Tosh, D. K.; Moon, H. R.; Kim, S. H.;
Jeong, L. S. Org. Lett. 2006, 8, 5081–5083.
1
C21H26N5O4S [M þ H]þ 444.1705, found 444.1706; H NMR (400
MHz, CD3OD) δ 8.17 (d, J = 1.6 Hz, 1H), 7.25 (m, 2H), 7.18 (m, 2H),
6.64 (d, J = 3.6 Hz, 1H), 5.86 (t, J = 7.6 Hz, 1H), 5.46 (m, 1H), 4.49 (d,
J = 2.8 Hz, 1H), 3.07 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.64 (m, 1H),
2.35 (m, 1H), 2.25 (m, 2H), 2.03 (m, 2H); 13C NMR (100 MHz,
CD3OD) δ 152.1, 145.3, 144.6, 128.8, 127.6, 125.7, 125.2, 122.6, 100.5,
73.1, 70.9, 56.9, 54.0, 44.8, 43.6, 34.9, 34.6, 31.1. Anal. Calcd for
C21H25N5O4S: C, 56.87; H, 5.68; N, 15.79; S, 7.23. Found: C, 56.91;
H, 5.73; N, 15.82; S, 7.26.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of the NOESY spec-
b
trum of 7 and 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
3561
dx.doi.org/10.1021/jo2001897 |J. Org. Chem. 2011, 76, 3557–3561