Heterocyclyl tetracyclines
C Sun et al
9
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-
methoxy-8-(1-methylpyrrolidin-2-yl)-1,11-dioxo-
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-8-[(2S)-1-ethylpyrrolidin-2-
yl]-3,10,12,12a-tetrahydroxy-7-methoxy-1,11-dioxo-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11b)
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11c)
General procedure B: Aqueous hydrogen fluoride (48–50%, 0.3 ml) was added Compound 10c was deprotected according to general procedure B. Purification
to a solution of the above intermediate 10b in THF (0.6 ml) in a polypropylene
reaction vessel at 23 °C. The mixture was stirred vigorously at 23 °C overnight
and poured into aqueous K2HPO4 (3.6 g dissolved in 30 ml water). The
mixture was extracted with EtOAc (30 ml, 15 ml). The combined organic phase
was dried over anhydrous sodium sulfate and concentrated. The residue was
used directly in the next step without further purification. MS (ESI) m/z
616.56 (M+H).
Pd-C (10 wt%, 3 mg) was added in one portion to a solution of the above
crude product in a mixture of HCl/CH3OH (0.5 N, 31 μl, 2 eq) and CH3OH
(1 ml) at 23 °C. The reaction vessel was sealed and purged with hydrogen by
briefly evacuating the flask followed by flushing with hydrogen gas (1 atm). The
reaction mixture was stirred under a hydrogen atmosphere (1 atm) at 23 °C for
1 h and filtered through a small Celite pad. The filtrate was concentrated. The
on a Si-Cyano column (35 g, eluting with 0.05 N aqueous HCl) yielded the
desired compound 11c as a yellow solid (1.33 g, HCl salt, 67% for two steps):
1H NMR (400 MHz, CD3OD, hydrochloride) δ 7.10 (s, 1 H), 4.10 (s, 1 H),
3.81–3.91 (m, 1 H), 3.68 (s, 3 H), 3.32–3.37 (m, 1 H), 3.25 (dd, J = 4.6,
15.6 Hz, 1 H), 2.96–3.21 (m, 11 H), 2.55–2.62 (m, 1 H), 2.40 (t, J = 14.6 Hz, 1
H), 2.23–2.34 (m, 4 H), 1.61–1.70 (m, 1 H), 1.25 (t, J = 7.3 Hz, 3 H); MS (ESI)
m/z 542.35 (M+H). A chiral synthesis of 11c (TP-2758) was later developed to
support preclinical and clinical development.16
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-8-[(2R)-1-ethylpyrrolidin-2-
yl]-3,10,12,12a-tetrahydroxy-7-methoxy-1,11-dioxo-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11d)
Prepared from 9B according to similar procedures used for 11c: 1H NMR
(400 MHz, CD3OD, hydrochloride) δ 7.20 (s, 1 H), 4.79 (m, 1 H), 4.18
(s, 1 H), 3.92 (m, 1 H), 3.77 (s, 3 H), 3.34–3.37 (m, 1 H), 2.99–3.23 (m, 11 H),
2.58 (m, 1 H), 2.30–2.40 (m, 4 H), 2.13–2.15 (m, 1 H), 1.64–1.66 (m, 1 H),
1.30 (br t, J = 7.3 Hz, 3 H); MS (ESI) m/z 542.48 (M+H).
residue was purified by preparative reverse-phase HPLC on
a Waters
Autopurification system using a Phenomenex Polymerx 10 μ RP-γ 100 A
column (10 μm, 150 × 21.20 mm; flow rate, 20 ml min− 1; Solvent A: 0.05 N
HCl/water; Solvent B: CH3CN; injection volume: 3.0 ml (0.05 N HCl/water);
gradient: 10 → 50% B over 15 min; mass-directed fraction collection). Fractions
containing the desired product, eluting at 6.5–9.0 min, were collected and
freeze-dried to yield compound 11b (2.7 mg, di-HCl salt, 57% for 3 steps): 1H
NMR (400 MHz, CD3OD, a mixture of diastereomers) δ 7.07 (s, 0.6 H), 7.02
(s, 0.4 H), 4.80–4.84 (m, 0.6 H), 4.71 (dd, J = 7.3, 10.5 Hz, 0.4 H), 4.10 (s, 1 H),
3.79–3.89 (m, 1 H), 3.76 (s, 1.2 H), 3.69 (s, 1.8 H), 3.32–3.36 (m, 1 H), 3.16–
3.26 (m, 1 H), 2.97–3.04 (m, 8 H), 2.83, 2.80 (s, 3 H), 2.57–2.63 (m, 1 H),
2.37–2.44 (m, 1 H), 2.14–2.35 (m, 4 H), 1.61–1.71 (m, 1 H); MS (ESI) m/z
528.51 (M+H).
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-
methoxy-1,11-dioxo-8-(1-propylpyrrolidin-2-yl)-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11e)
Prepared from 9 and propionaldehyde according to general procedures A and
B. 1H NMR (400 MHz, CD3OD, hydrochloride, a mixture of diastereomers) δ
7.12 (s, 0.67 H), 7.07 (s, 0.33 H), 4.75–4.80 (m, 0.33 H), 4.12 (s, 1 H),
3.82–3.93 (m, 1.67 H), 3.77 (s, 2 H), 3.69 (s, 1 H), 3.34–3.38 (m, 1 H), 2.97–
3.27 (m, 11 H), 2.55–2.63 (m, 1 H), 2.12–2.48 (m, 5 H), 1.62–1.74 (m, 3 H),
0.87–0.93 (m, 3 H); MS (ESI) m/z 556.55 (M+H).
The following compounds were prepared from 9 or 9A and the correspond-
ing aldehydes or ketones by following general procedures A and B.
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-
methoxy-1,11-dioxo-8-[(2S)-pyrrolidin-2-yl]-1,4,4a,5,5a,6,11,12a-
octahydrotetracene-2-carboxamide (11a)
Prepared by deprotection of 9A (34 mg, 0.042 mmol) according to general
procedure B (16.1 mg, 65% for 3 steps): 1H NMR (400 MHz, CD3OD,
hydrochloride) δ 6.95 (s, 1 H), 4.89–4.82 (m, 1 H), 4.10 (s, 1 H), 3.74 (s, 3
H), 3.49–3.43 (m, 1 H), 3.38–3.32 (m, 1 H), 3.24 (dd, J = 4.1, 15.1 Hz, 1 H),
3.04–2.97 (m, 8 H), 2.52-2.47 (m, 1 H), 2.41 (t, J = 14.4 Hz, 1 H), 2.29–2.16
(m, 4 H), 1.71–1.61 (m, 1 H); MS (ESI) m/z 514.29 (M+H).
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-
methoxy-1,11-dioxo-8-[1-(propan-2-yl)pyrrolidin-2-yl]-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11f)
Prepared from 9 and acetone according to general procedures A and B. 1H
NMR (400 MHz, CD3OD, hydrochloride, a mixture of diastereomers) δ 7.13 (s,
0.55 H), 7.08 (s, 0.45 H), 4.07 (s, 1 H), 3.75 (s, 1.35 H), 3.64 (s, 1.65 H), 3.58–
3.64 (m, 1 H), 3.38–3.46 (m, 2 H), 2.93–3.20 (m, 10 H), 2.54–2.55 (m, 1 H),
2.04–2.39 (m, 5 H), 1.58–1.68 (m, 1 H), 1.22–1.30 (m, 6 H); MS (ESI) m/z
556.59 (M+H).
(1R,3S,4S,11S)-8-(Benzyloxy)-11-[(tert-butyldimethylsilyl)oxy]-4-
(dimethylamino)-18-[(2S)-1-ethylpyrrolidin-2-yl]-12-hydroxy-19-
methoxy-10,14-dioxo-6-oxa-7-azapentacyclo[11.8.0.03,11.05,9.015,20]
henicosa-5(9),7,12,15(20),16,18-hexaen-16-yl tert-butyl carbonate
(10c)
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-
methoxy-8-[1-(2-methylpropyl)pyrrolidin-2-yl]-1,11-dioxo-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11g)
Prepared from 9 and isobutyraldehyde according to general procedures A and
B. 1H NMR (400 MHz, CD3OD, hydrochloride, a mixture of diastereomers)
δ 7.17 (s, 0.5 H), 7.10 (s, 0.5 H), 4.78-4.82 (m, 1 H), 4.12 (s, 1 H), 3.89-4.00
(m, 1 H), 3.78 (s, 1.5 H), 3.69 (s, 1.5 H), 3.34-3.41 (m, 1 H), 3.15-3.26
(m, 1 H), 2.84-3.09 (m, 9 H), 2.55-2.60 (m, 1 H), 2.40 (t, J = 14.6 Hz, 1 H),
2.12-2.34 (m, 4 H), 1.94-2.02 (m, 1 H), 1.61-1.70 (m, 1 H), 0.88-0.98 (m, 6 H);
MS (ESI) m/z 570.58 (M+H).
Compound 8A (7.81 g, 7.38 mmol, 1 eq) was treated with dilute HCl to remove
the trityl group. The resulting free amine 9A was dissolved in 1,2-dichlor-
oethane (120 ml) and cooled to 0 °C. Acetic acid (0.85 ml, 14.76 mmol, 2 eq)
and sodium triacetoxyborohydride (3.13 g, 14.76 mmol, 2 eq) were added
sequentially. Acetaldehyde (0.83 ml, 14.76 mmol, 2 eq) was added via a syringe
(pre-cooled with dry ice). The reaction mixture was stirred at 0 °C for 25 min.
Saturated aqueous NaHCO3 (300 ml) was added. The reaction mixture was
stirred for 20 min and extracted with dichloromethane (400 ml). The organic
extract was dried over anhydrous sodium sulfate and concentrated. The residue
was purified by flash column chromatography (8–66% ethyl acetate-hexanes) to
yield compound 10c as a pale yellow solid (3.45 g, 55% over two steps):
1H NMR (400 MHz, CDCl3) δ 15.73 (s, 1 H), 7.47–7.49 (m, 2 H), 7.30–7.38
(m, 4 H), 5.34 (s, 2 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.68 (s, 3 H), 3.63–3.74 (m,
1 H), 3.30–3.43 (m, 1 H), 3.25 (dd, J = 4.9, 15.9 Hz, 1 H), 2.94–3.02 (m, 1 H),
2.37–2.56 (m, 10 H), 2.10–2.20 (m, 3 H), 1.80–1.92 (m, 2 H), 1.48–1.62 (m, 2
H), 1.52 (s, 9 H), 0.98–1.02 (m, 3 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H);
MS (ESI) m/z 844.75 (M+H).
(4S,4aS,5aR,12aS)-8-[1-(Cyclopropylmethyl)pyrrolidin-2-yl]-4-
(dimethylamino)-3,10,12,12a-tetrahydroxy-7-methoxy-1,11-dioxo-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide (11h)
Prepared from 9 and 2-cyclopropylacetaldehyde according to general proce-
dures A and B. 1H NMR (400 MHz, CD3OD, hydrochloride, a mixture of
diastereomers) δ 7.11 (s, 0.5 H), 7.06 (s, 0.5 H), 4.76–4.83 (m, 1 H), 4.11
(s, 1 H), 3.91–4.02 (m, 1 H), 3.75 (s, 1.5 H), 3.68 (s, 1.5 H), 3.40–3.46 (m, 1
H), 3.14–3.27 (m, 1 H), 2.92–3.12 (m, 9 H), 2.57–2.61 (m, 1 H), 2.12–2.43 (m,
5 H), 1.60–1.70 (m, 1 H), 0.98–1.03 (m, 1 H), 0.60–0.66 (m, 2 H), 0.33–0.40
(m, 1 H), 0.20–0.27 (m, 1 H); MS (ESI) m/z 568.58 (M+H).
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