The first highly stereoselective approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its analogues

Tetrahedron: Asymmetry 21 (2010) 226–231

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The first highly stereoselective approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its analogues Sen Xiao, Xiao-Xin Shi * Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, PO Box 363, 130 Mei-Long Road, Shanghai 200237, PR China

a r t i c l e

i n f o

Article history: Received 7 December 2009 Accepted 22 December 2009 Available online 26 February 2010

a b s t r a c t A general method for the synthesis of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues based on protecting group (PG)-modulated highly diastereoselective Pictet–Spengler reaction of L-tryptophan methyl ester hydrochloride with meta-(RO)-benzaldehyde is described. By using the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-b-carboline trans-4c as a common chiral synthon, HR22C16 1 and its analogues 2 and 3 were synthesized in 90.1%, 90.2%, and 86.5% overall yields, respectively. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction Cancer is one of the most fatal diseases, especially in the modern industrialized countries; hence the development of new drugs for the treatment of cancer is very important for human health. Traditional successful anticancer drugs such as vinca alkaloids, taxol, and epothilone perturb mitosis and disrupt proper cell division by targeting tubulin (the subunit of microtubules), thus leading ultimately to apoptosis of cancer cells. However, these drugs have undesired mechanism-based side effects,1 because microtubles are also involved in many other cellular processes.2–4 The mitotic kinesin Eg5, also known as kinesin spindle protein (KSP), plays an important role in the early stage of mitosis, it mediates separation of centrosome and formation of the bipolar mitotic spindle.5,6 Inhibition of Eg5 provides a new strategy for cancer treatment, drugs which target Eg5 might have less side effects, since Eg5 is exclusively involved in the formation and function of the mitotic spindle.7,8 Since the discovery of the first Eg5 inhibitor (monastrol in Scheme 1),9 increasing interest has been shown, leading to other types of Eg5 inhibitors being found.10–23 Recently, HR22C16 1 and it analogues 2 and 3 (Scheme 1) have been proven to be effective Eg5 inhibitors with smaller IC50 values.10,24,25 All these compounds contain a tetracyclic tetrahydro-b-carboline-fused hydantoin scaffold, which bears a meta-hydroxy group on the aromatic ring at C-5 and possesses two stereogenic centers at C-5 and C-11a with (S)- and (R)-configurations, respectively. Obviously, the Pictet–Spengler reaction of L-tryptophan with meta-hydroxy benzaldehyde is the key step for the synthesis of Eg5 inhibitor HR22C16 and its analogues, therefore the stereoselectivity of this particular

* Corresponding author. E-mail address: [email protected] (X.-X. Shi). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2009.12.029

reaction should be investigated and fully understood. Herein we report our recent study on this important reaction and a general approach to HR22C16 and its analogues.

H N

O

10

S 9

O

NH

6

8 7

O OH Monastrol (IC50 = 10 µM)

N H

11a 2 11 1 N 5 N 3 4

O

OH HR22C16 1 (IC50 = 0.80 µM)

O

N H

N

N O

OH HR22C16 analogue 2 (IC50 = 0.65 µM)

O Ph N H

N

N ( )4

NH2

O

OH HR22C16 analogue 3 (IC50 = 0.09 µM)

Scheme 1. Kinesin spindle protein (KSP) inhibitors.

2. Results and discussion At first, the high stereoselectivity of Pictet–Spengler reaction of methyl ester hydrochloride with meta-hydroxy benzaldehyde was obtained via a two-step procedure (Scheme 2), in which refluxing in isopropanol produced a mixture mix-4a–HCl (R = H) of almost equal molar hydrochloride salts of cis- and trans-1,3-disubstituted tetrahydro-b-carboline 4a, and then a L-tryptophan

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CHO

COOMe NH3Cl

N H

3 COOMe

a

+

N H

OR 3 COOMe 1 NH2Cl

N H

b CIAT

H 1 NH H

NOE

3 COOMe N H

H 1 NH H

OH

cis-4a-HCl (R=H) cis-4b-HCl (R=Ac)

OAc

cis-4a

trans-4c-HCl (R=Bz) trans-4d-HCl (R=Allyl)

OR

mix-4-HCl Scheme 2. The highly stereoselective Pictet–Spengler reaction of L-tryptophan methyl ester hydrochloride with meta-(RO)-benzaldehyde via a CIAT process. Reagents and conditions: (a) refluxing in isopropanol for 5 h; (b) refluxing in a mixed solvent of toluene and nitromethane (see also Table 1).

cis-4b 3 COOMe

3 COOMe N H H

H 1 NH NOE NOE H

N H H

H 1 NH NOE NOE H O

OBz

trans-4c

NOE

trans-4d

Figure 1. NOEs of compounds 4a–4d.

process via crystal-induced asymmetric transformation (CIAT)26–38 in a mixed solvent of toluene and nitromethane afforded cis-4a–HCl in 93% yield and with 98% de. However, high trans-stereoselectivity rather than cis-stereoselectivity is required to satisfy the absolute configurations of the two stereogenic centers of the title compounds HR22C16 and its analogues. Fortunately, after trial and error, we finally obtained the desired high trans-stereoselectivity. It was found that a protecting group of the meta-hydroxy group of the aromatic aldehyde could modulate the stereoselectivity of the above-mentioned Pictet–Spengler reaction. As can be seen from Table 1, the stereoselectivities of the reaction dramatically varied depending on the protecting groups. When R is either H or Ac, the reaction produced cis-4a–HCl or cis-4b–HCl in high yield and with high stereoselectivity (Table 1, entries 1 and 2) after the CIAT process; when R is either Bz or allyl, the reaction produced trans-4c–HCl or trans-4d–HCl in high yield and with high stereoselectivity (Table 1, entries 3 and 4). The high diastereoselectivity of this CIAT process could be attributed to the large solubility difference between both hydrochloride salts (cis-4–HCl and trans-4–HCl) in the reaction solvent.26 Table 1 Modulation of protecting groups on the stereoselectivities of Pictet–Spengler reactions (see also Scheme 2) via CIAT process

a b c

Entry

R

Tol/CH3NO2

Time (h)a

Product 4 (cis:trans)b

Yieldc (%)

1 2 3 4

H Ac Bz Allyl

1:1 2:1 2:1 6:1

12 18 18 20

4a (99:1) 4b (99:1) 4c (1:99) 4d (1:99)

93 95 95 96

Under reflux. Determined by both 1H NMR (500 MHz) and HPLC. Isolated yield based on two steps.

The stereochemistry of all four compounds cis-4a, cis-4b, trans4c, and trans-4d was unequivocally assigned according to correlation spots (NOEs in Figure 1) in the 1H–1H NOESY spectra of these compounds. In the 1H–1H NOESY spectra of cis-4a, there are correlation spots between H-1 (5.22 ppm) and H-3 (3.93 ppm), which means that H-1 and H-3 have a cis-relationship; in the 1H–1H NOESY spectra of cis-4b, there are correlation spots between H-1 (5.26 ppm) and H-3 (3.97 ppm), which also means that H-1 and H-3 have a cis-relationship; in the 1H–1H NOESY spectra of trans4c, H-3 (3.99 ppm) does not correlate with H-1 (5.43 ppm), but it correlates with two neighboring ortho-protons (7.10–7.24 ppm) on the aromatic ring at C-1, meaning that H-1 and H-3 have a trans-relationship; in the 1H–1H NOESY spectra of trans-4d, H-3 (4.00 ppm) does not correlate with H-1 (5.38 ppm), but it correlates with the two neighboring ortho-protons (6.84–6.89 ppm) on the aromatic ring at C-1, also meaning that H-1 and H-3 have a trans-relationship.

With the desired compounds trans-4c and trans-4d in hand, we attempted to develop a general approach to the three title compounds 1–3. Considering the fact that the Bz-protecting group can be more easily removed than an allyl group, compound trans-4c was chosen as the starting material for the following syntheses. As depicted in Scheme 3, HR22C16 1, compound 2, and compound 3 can be readily synthesized from the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-b-carboline trans-4c. Compound trans-4c was treated successively with 0.5 equiv of triphosgene and 5.0 equiv of butylamine or benzylamine at 0 °C in the presence of 5.0 equiv of triethylamine, after acidifying with excessive aqueous 2 M HCl and continuous stirring at room temperature for 25 h, the one-pot reaction produced tetracyclic compound 5a or 5b in 91% or 92% yield without isolation of intermediates as shown in the square parenthesis of Scheme 3. When butylamine or benzylamine was replaced by 5-azido-pentyl amine which was prepared from the bistosylate of 1,5-pentandiol according to a known method,39 compound 5c was obtained in 93% yield. Compounds 5a and 5b were then transformed into the title compounds HR22C16 1 and its analogue 2 in almost quantitative yields via alcoholysis in methanol at reflux in the presence of catalytic amounts of potassium carbonate. Compound 6 was also obtained in nearly quantitative yield after removal of the protecting group of compound 5c via methanolysis under the same conditions. Reduction of the azido group of compound 6 was finally performed via Pd/C-catalyzed hydrogenation at room temperature in methanol to afford compound 3 in 94% yield, while Staudinger reduction40,41 of the azido group of compound 6 with triphenylphosphine only gave compound 3 in 85% yield.

3. Conclusion In conclusion, a dramatic modulation of protecting groups (R = H, Ac, Bz or allyl) over the stereoselectivities of the Pictet– Spengler reactions of L-tryptophan methyl ester hydrochloride with meta-(RO)-PhCHO was observed, the desired high trans diastereoselectivities were obtained by using benzoyl or allyl as a protecting group. A highly stereoselective approach for the syntheses of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues 2 and 3 from enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-b-carboline trans-4c has been developed. It is noteworthy that the primary amine R’NH2 used in the formation of the hydantoin ring is not limited to butylamine, benzylamine, and 5-azidopentylamine, so the synthetic approach outlined in Scheme 3 is a general one, and may be quite useful for the construction of HR22C16-like tetracyclic scaffold.

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a

NH

N H

COOMe N

N H

91% for 5a 92% for 5b 93% for 5c

O

OBz

b

NHR'

N

N H

N R' O

OBz

OBz

trans-4c

5a (R'=Bu) 5b (R'=Bn) 5c (R'=5-azido-pentyl) O

c

N H

99% for 1 98% for 2 99% for 6

N

N R' O

1 (R'=Bu) 2 (R'=Bn) 6 (R'=5-azido-pentyl)

OH O

N

N H

N O

O N3

d 94%

N

N H

NH2

O

OH

6

N

OH

3

Scheme 3. Syntheses of HR22C16 1 and its analogues 2 and 3 from compound trans-4c. Reagents and conditions: (a) 0.5 equiv of triphosgene and 5.0 equiv of triethylamine, in toluene, 0 °C for 15 min; then 5.0 equiv of R0 NH2, 0 °C for 15 min; (b) excess aqueous 2 M HCl, at room temperature for 25 h; (c) catalytic amount of K2CO3, refluxing in methanol for 2 h; (d) catalytic amounts of Pd/C, 1 atm of H2, in methanol, at room temperature for 10 h.

The title compound HR22C16 1 was synthesized from trans-4c in 90.1% yield or from L-tryptophan methyl ester hydrochloride in 85.6% overall yield; compound 2 was synthesized from trans4c in 90.2% yield or from L-tryptophan methyl ester hydrochloride in 85.7% overall yield; compound 3 was synthesized from trans-4c in 86.5% yield or from L-tryptophan methyl ester hydrochloride in 82.2% overall yield. 4. Experimental

continued at reflux for 12 h, the mixture was cooled down to room temperature. A pale yellow solid was collected in a Buchner funnel by suction and was rinsed with a small amount of fresh mixed solvent of nitromethane and toluene (1:1). The solid was then partitioned between ethyl acetate (40 mL) and saturated aqueous solution of sodium bicarbonate (30 mL). The organic layer was separated and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave a crude product which was purified by flash chromatography to afford compound 4a (3.37 g, 9.39 mmol) in 93% yield.

4.1. General methods Melting points are uncorrected. 1H and 13C NMR spectra were acquired on a Bruker AM-500, chemical shifts were given on the delta scale as parts per million (ppm) with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on a Nicolet Magna IR-550. Mass spectra were recorded on HP5989A. Optical rotations were measured on a WZZ-1S automatic polarimeter at room temperature. Column chromatography was performed on silica gel (Qingdao Ocean Chemical Corp.). All chemicals were analytically pure. The L-tryptophan methyl ester hydrochloride was prepared according to a known procedure.42 4.2. Typical two-step procedure for the Pictet–Spengler reaction of L-tryptophan methyl ester hydrochloride with meta(RO)-benzaldehyde To a solution of meta-hydroxy benzaldehyde (1.36 g, 11.14 mmol) in isopropanol (25 mL) was added powdered D-tryptophan methyl ester hydrochloride (2.57 g, 10.09 mmol). The mixture was heated to reflux while being stirred, and then stirring was continued for around 5 h under refluxing. The reaction solution was then concentrated to dryness under vacuum to give a crude solid product. The above-mentioned crude solid product was then suspended in a mixed solvent of nitromethane (12 mL) and toluene (12 mL), and the suspension was heated to reflux, and then stirring was

4.2.1. (1S,3S)-Methyl 1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro1H-pyrido[3,4-b] indole-3-carboxylate 4a 1 Mp 267–268 °C. ½a20 D ¼ 45:1 (c 1.5, DMF). H NMR (acetoned6) d 2.54 (br s, 1H), 2.89 (ddd, J1 = 14.6 Hz, J2 = 11.1 Hz, J3 = 2.4 Hz, 1H), 3.12 (ddd, J1 = 14.8 Hz, J2 = 4.1 Hz, J3 = 1.8 Hz, 1H), 3.77 (s, 3H), 3.93 (dd, J1 = 11.1 Hz, J2 = 4.1 Hz, 1H), 5.22 (s, 1H), 6.78 (ddd, J1 = 8.3 Hz, J2 = 2.2 Hz, J3 = 0.7 Hz, 1H), 6.85 (dd, J1 = 2.1 Hz, J2 = 1.7 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.98–7.06 (m, 2H), 7.17 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 8.19 (s, 1H), 9.18 (s, 1H). 13C NMR (DMSO-d6) d 172.99, 157.49, 143.52, 136.42, 135.44, 129.32, 126.59, 120.72, 119.40, 118.43, 117.54, 115.33, 114.84, 111.29, 106.88, 57.76, 56.24, 51.77, 25.54. MS m/z (relative intensity) 323 (M++1, 20), 322 (M+, 100), 321 (23), 307 (8), 273 (4), 263 (47), 248 (9), 246 (10), 235 (61), 234 (65), 229 (17), 220 (9), 218 (23), 206 (11), 204 (10), 191 (4), 169 (20), 144 (19), 131 (4), 120 (5), 115 (6), 102 (3), 89 (2). IR (KBr) 3404, 2975, 1751, 1731, 1600, 1455, 1288, 1276, 1242, 1000, 760 cm1. HRMS (EI) calcd for C19H18N2O3: 322.1317; found: 322.1314. 4.2.2. (1S,3S)-Methyl 1-(3-acetoxyphenyl)-2,3,4,9-tetrahydro1H-pyrido[3,4-b] indole-3-carboxylate 4b 1 Mp 220–221 °C. ½a20 D ¼ 7:2 (c 3.3, CHCl3). H NMR (cDCl3) d 2.26 (s, 3H), 3.00 (ddd, J1 = 15.0 Hz, J2 = 11.1 Hz, J3 = 2.4 Hz, 1H), 3.22 (ddd, J1 = 15.1 Hz, J2 = 4.2 Hz, J3 = 1.8 Hz, 1H), 3.81 (s, 3H), 3.97 (dd, J1 = 11.0 Hz, J2 = 4.2 Hz, 1H), 5.26 (s, 1H), 7.07–7.16 (m,

S. Xiao, X.-X. Shi / Tetrahedron: Asymmetry 21 (2010) 226–231

4H), 7.22 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.39 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.55 (br s, NH on the indole ring, 1H). 13C NMR (CDCl3) d 173.60, 170.12, 151.40, 143.09, 136.78, 134.59, 130.30, 127.40, 126.60, 122.40, 122.38, 122.25, 119.98, 118.61, 111.62, 109.20, 58.63, 57.26, 52.74, 26.14, 21.48. MS m/z (relative intensity) 365 (M++1, 21), 364 (M+, 100), 363 (23), 349 (7), 321 (8), 305 (55), 290 (6), 277 (32), 261 (25), 235 (64), 229 (27), 218 (28), 206 (14), 204 (15), 191 (5), 169 (29), 144 (28), 130 (4), 115 (6), 102 (2), 77 (2), 43 (6). IR (KBr) 3390, 2975, 1745, 1739, 1600, 1452, 1370, 1268, 1211, 744 cm1. HRMS (EI) calcd for C21H20N2O4: 364.1423; found: 364.1424. 4.2.3. (1R,3S)-Methyl 1-(3-benzoyloxyphenyl)-2,3,4,9-tetra hydro-1H-pyrido[3,4-b] indole-3-carboxylate 4c 1 Mp 185–186 °C. ½a20 D ¼ 33:5 (c 0.9, CHCl3). H NMR (CDCl3) d 2.37 (br s, 1H), 3.14 (ddd, J1 = 15.4 Hz, J2 = 6.8 Hz, J3 = 1.2 Hz, 1H), 3.28 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H), 3.72 (s, 3H), 3.99 (dd, J1 = 6.3 Hz, J2 = 5.9 Hz, 1H), 5.43 (s, 1H), 7.10–7.24 (m, 6H), 7.39 (dd, J1 = 7.9 Hz, J2 = 7.9 Hz, 1H), 7.48 (dd, J1 = 7.9 Hz, J2 = 7.7 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.62 (dd, J1= 7.5 Hz, J2 = 7.5 Hz, 1H), 7.77 (br s, NH on the indole ring, 1H), 8.15 (d, J = 7.8 Hz, 2H). 13C NMR (CDCl3) d 174.64, 165.92, 151.76, 144.65, 136.92, 134.31, 133.31, 130.79, 130.23, 129.87, 129.19, 127.41, 126.51, 122.54, 122.34, 122.04, 120.01, 118.77, 111.87, 108.99, 55.06, 52.73, 52.72, 25.51. MS m/z (relative intensity) 427 (M++1, 23), 426 (M+, 100), 425 (15), 411 (10), 367 (32), 352(9), 350 (10), 340 (6), 321 (12), 304 (4), 261 (7), 234 (19), 229 (15), 217 (12), 206 (9), 204 (7), 169 (18), 144 (13), 130 (4), 105 (78), 77 (17). IR (KBr) 3395, 2980, 1735, 1605, 1454, 1271, 1225, 1065, 750, 705 cm1. HRMS (EI) calcd for C26H22N2O4: 426.1580; found: 426.1581. 4.2.4. (1R,3S)-Methyl 1-(3-allyloxyphenyl)-2,3,4,9-tetrahydro1H-pyrido[3,4-b] indole-3-carboxylate 4d 1 Mp 166–167 °C. ½a20 D ¼ 34:5 (c 1.2, CHCl3). H NMR (CDCl3) d 3.13 (ddd, J1 = 15.3 Hz, J2 = 6.6 Hz, J3 = 1.2 Hz, 1H), 3.26 (dd, J1 = 15.2 Hz, J2 = 5.2 Hz, 1H), 3.72 (s, 3H), 4.00 (dd, J1 = 6.1 Hz, J2 = 5.9 Hz, 1H), 4.48 (d, J = 5.3 Hz, 2H), 5.25 (dd, J1 = 10.5 Hz, J2 =1.2 Hz, 1H), 5.36 (dd, J1 = 15.4 Hz, J2 = 1.4 Hz, 1H), 5.38 (s, 1H), 5.97–6.04 (m, 1H), 6.84–6.89 (m, 3H), 7.10–7.18 (m, 2H), 7.21– 7.25 (m, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.61(br s, NH on the indole ring, 1H). 13C NMR (CDCl3) d 174.69, 159.51, 144.20, 136.82, 133.69, 133.63, 130.29, 127.53, 122.49, 121.46, 120.01, 118.78, 118.40, 115.49, 114.69, 111.58, 108.89, 69.36, 55.46, 53.03, 52.70, 25.30. MS m/z (relative intensity) 363 (M++1, 22), 362 (M+, 100), 361 (14), 347 (10), 345 (8), 321 (33), 303 (28), 286 (12), 276 (5), 261 (16), 247 (7), 234 (56), 229 (19), 218 (6), 206 (21), 204 (17), 191 (5), 169 (26), 160 (4), 144 (17), 130 (4), 115 (4), 89 (2). IR (KBr) 3391, 2980, 1736, 1599, 1488, 1454, 1323, 1268, 1176, 1005, 743 cm1. HRMS (EI) calcd for C22H22N2O3: 362.1630; found: 362.1631. 4.3. Typical procedure for the preparation of compounds 5a, 5b, and 5c A solution of compound trans-4c (1.10 g, 2.58 mmol) and triethylamine (1.31 g, 12.95 mmol) in toluene (20 mL) was cooled to around 0 °C with an ice-bath. A freshly prepared solution of triphosgene (382 mg, 1.28 mmol) in dichloromethane (2 mL) was added dropwise over 1 min, and the reaction mixture was then stirred at 0 °C for around 15 min. Butylamine (0.94 g, 12.85 mmol) was added, and the mixture was then stirred at 0 °C for around 15 min. After a dilute aqueous HCl solution (2 M, 15 mL) was added, the ice-bath was removed, and the two-phase reaction mixture was allowed to warm to room temperature and was stirred at 25 °C for around 25 h. After the mixture was transferred into a

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separatory funnel, the organic phase was separated and washed twice with brine (2  10 mL). The organic solution was dried over anhydrous sodium sulfate and was then concentrated in vacuo to give a crude product which was purified by flash chromatography to afford compound 5a (1.16 g, 2.35 mmol) in 91% yield. 4.3.1. (5R,11aS)-2-Butyl-5-(3-benzoyloxyphenyl)-6H-1,2,3,5,11, 11a-hexahydro- imidazo[1,5-b]-b-carboline-1,3-dione 5a 20 Mp 130–131 °C. ½aD ¼ 199:0 (c 0.9, CHCl3). 1H NMR (CDCl3) d 0.93 (t, J = 7.4 Hz, 3H), 1.30–1.36 (m, 2H), 1.58–1.64 (m, 2H), 2.89 (ddd, J1 = 15.2 Hz, J2 = 11.0 Hz, J3 = 1.6 Hz, 1H), 3.47–3.54 (m, 3H), 4.30 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 6.31 (s, 1H), 7.12–7.30 (m, 6H), 7.39 (dd, J1 = 7.9 Hz, J2 = 7.9 Hz, 1H), 7.47 (dd, J1 = 7.9 Hz, J2 = 7.7 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 8.11 (d, J = 8.2 Hz, 2H), 8.15 (br s, NH on the indole ring, 1H). 13C NMR (CDCl3) d 173.44, 165.77, 155.59, 151.89, 141.66, 137.34, 134.38, 130.78, 130.76, 130.68, 129.59, 129.16, 126.62, 126.39, 123.40, 122.90, 122.15, 120.61, 118.99, 112.01, 108.53, 53.69, 52.15, 39.25, 30.80, 24.00, 20.60, 14.22. MS m/z (relative intensity) 494 (M++1, 27), 493 (M+, 100), 492 (7), 442 (1), 388 (66), 372 (15), 360 (3), 339 (4), 296 (13), 294 (3), 261 (9), 234 (8), 233 (6), 217 (5), 206 (4), 204 (5), 169 (6), 105 (33), 77(7). IR (KBr) 3388, 2959, 2873, 1767, 1738, 1707, 1600, 1453, 1425, 1270, 1245, 1082, 1064, 745, 711 cm1. HRMS (EI) calcd for C30H27N3O4: 493.2002; found: 493.1995. 4.3.2. (5R,11aS)-2-Benzyl-5-(3-benzoyloxyphenyl)-6H1,2,3,5,11,11a-hexahydro- imidazo[1,5-b]-b-carboline-1,3-dione 5b 1 Mp 125–126 °C. ½a20 D ¼ 146:8 (c 1.7, CHCl3). H NMR (CDCl3) d 2.83 (ddd, J1 = 15.2 Hz, J2 = 11.1 Hz, J3 = 1.6 Hz, 1H), 3.49 (dd, J1 = 15.3 Hz, J2 = 5.5 Hz, 1H), 4.35 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 4.64 (d, J = 14.6 Hz, 1H), 4.74 (d, J = 14.6 Hz, 1H), 6.32 (s, 1H), 7.16 (td, J1 = 7.7 Hz, J2 = 0.8 Hz, 2H), 7.21 (td, J1 = 7.1 Hz, J2 = 0.9 Hz, 2H), 7.23–7.34 (m, 5H), 7.37–7.43 (m, 3H), 7.49 (dd, J1 = 7.9 Hz, J2 = 7.7 Hz, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.97 (br s, NH on the indole ring, 1H), 8.13 (d, J = 7.8 Hz, 2H). 13C NMR (CDCl3) d 173.04, 165.75, 155.22, 151.92, 141.54, 137.27, 136.63, 134.38, 130.78, 130.71, 130.44, 129.62, 129.36, 129.26, 129.23, 129.17, 128.59, 127.88, 126.56, 126.44, 123.42, 122.96, 122.20, 120.59, 118.99, 53.81, 52.18, 43.00, 23.80. MS m/z (relative intensity) 528 (M++1, 31), 527 (M+, 100), 449 (3), 436 (16), 422 (52), 406 (12), 405 (7), 365 (5), 339 (3), 330 (10), 261 (7), 234 (7), 217 (4), 204 (4), 169 (3), 105 (31), 91 (10), 77 (7). IR (KBr) 3409, 2950, 1768, 1740, 1711, 1450, 1270, 1244, 1078, 749, 706 cm1. HRMS (EI) calcd for C33H25N3O4: 527.1845; found: 527.1849. 4.3.3. (5R,11aS)-2-(5-Azido-pentyl)-5-(3-benzoyloxyphenyl)6H-1,2,3,5,11,11a- hexahydro-imidazo[1,5-b]-b-carboline-1,3dione 5c 1 Mp 87–88 °C. ½a20 D ¼ 168:4 (c 0.9, CHCl3). H NMR (CDCl3) d 1.35–1.42 (m, 2H), 1.58–1.70 (m, 4H), 2.89 (ddd, J1 = 15.2 Hz, J2 = 11.1 Hz, J3 = 1.4 Hz, 1H), 3.24 (t, J = 6.9 Hz, 2H), 3.47–3.59 (m, 3H), 4.32 (dd, J1 = 11.0 Hz, J2 = 5.5 Hz, 1H), 6.30 (s, 1H), 7.15–7.25 (m, 4H), 7.27–7.31 (m, 2H), 7.40 (dd, J1 = 7.9 Hz, J2 = 7.9 Hz, 1H), 7.48 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.62 (dd, J1 = 7.4 Hz, J2 = 7.5 Hz, 1H), 8.11 (d, J = 7.3 Hz, 2H), 8.16 (br s, NH on the indole ring, 1H). 13C NMR (CDCl3) d 173.39, 165.75, 155.43, 151.87, 141.60, 137.30, 134.38, 130.71, 130.67, 130.58, 129.52, 129.15, 126.58, 126.33, 123.39, 122.90, 122.15, 120.60, 118.98, 111.97, 108.46, 53.69, 52.15, 51.70, 39.09, 28.88, 28.24, 24.43, 23.93. MS m/z (relative intensity) 549 (M++1, 6), 548 (M+, 16), 520 (59), 490 (10), 476 (8), 462 (14), 444 (6), 436 (7), 416 (9), 391 (6), 365 (39), 332 (6), 294 (22), 261 (36), 234 (21), 204 (18), 169 (14), 115 (4), 105 (100), 84 (9), 77 (29), 70 (9). IR (KBr)

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3321, 3059, 2936, 2858, 2095, 1766, 1731, 1704, 1589, 1452, 1424, 1269, 1243, 1139, 1061, 746, 709, 433 cm1. HRMS (EI) calcd for C31H28N6O4: 548.2172; found: 548.2180. 4.4. Preparation of HR22C16 1 and its analogue 2 To a solution of compound 5a (1.10 g, 2.23 mmol) in methanol (10 mL) was added powdered potassium carbonate (28 mg, 0.20 mmol). The solution was then heated at reflux, and stirring was continued at reflux for 2 h. When the reaction was complete (TLC), the solvent was removed under a reduced pressure. The residue was then partitioned between ethyl acetate (25 mL) and water (20 mL). The organic phase was separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave crude product which was purified by flash chromatography to furnish compound 1 (0.86 g, 2.21 mmol) in 99% yield. For compound 2, the same procedure as described above was followed. 4.4.1. (5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11, 11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 1 20 Off-white solid, mp 107–108 °C (lit.24 107 °C). ½aD ¼ 162:2 (c 1 0.2, CHCl3). H NMR (DMSO-d6) d 0.86 (t, J = 7.3 Hz, 3H), 1.20–1.28 (m, 2H), 1.45–1.52 (m, 2H), 2.78 (dd, J1 = 13.9 Hz, J2 = 11.2 Hz, 1H), 3.32–3.42 (m, 3H), 4.48 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s, 1H), 6.70 (d, J = 7.7 Hz, 1H), 6.71 (s, 1H), 6.76 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.3 Hz, J2 = 7.2 Hz, 1H), 7.08 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 7.15 (dd, J1 = 7.9 Hz, J2 = 8.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 9.46 (s, 1H), 10.93 (s, 1H). 13 C NMR (DMSO-d6) d 172.63, 157.68, 154.31, 141.43, 136.73, 131.24, 129.79, 125.83, 121.69, 118.85, 118.48, 118.20, 115.13, 114.81, 111.43, 106.04, 52.75, 51.40, 37.73, 29.72, 22.82, 19.44, 13.50. MS m/z (relative intensity) 390 (M++1, 24), 389 (M+, 100), 388 (16), 372 (4), 360 (2), 332 (2), 296 (35), 261 (18), 234 (41), 220 (7), 218 (14), 206 (6), 196 (3), 169 (9), 115 (2), 105 (2), 91 (1). IR (KBr) 3340, 2954, 2929, 2870, 1757, 1701, 1591, 1458, 1426, 1328, 1240, 1140, 749 cm1. HRMS (EI) calcd for C23H23N3O3: 389.1739; found: 389.1734. 4.4.2. (5R,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11, 11a-hexahydro-imidazo[1,5-b]-b-carboline-1,3-dione 2 Off-white solid, mp 150–151 °C (lit.24 148 °C). ½a20 D ¼ 162:6 (c 0.9, CHCl3). 1H NMR (DMSO-d6) d 2.82 (dd, J1 = 14.1 Hz, J2 = 11.3 Hz, 1H), 3.40 (dd, J1 = 15.1 Hz, J2 = 5.7 Hz, 1H), 4.55–4.63 (m, 3H), 6.14 (s, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 7.09 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1H), 7.15 (dd, J1 = 7.7 Hz, J2 = 7.7 Hz, 1H), 7.22–7.34 (m, 6H), 7.54 (d, J = 7.8 Hz, 1H), 9.46 (s, 1H), 10.94 (s, 1H). 13C NMR (DMSO-d6) d 172.52, 157.69, 154.11, 141.35, 136.73, 136.62, 131.18, 129.84, 128.61, 127.48, 127.42, 125.82, 121.74, 118.89, 118.52, 118.24, 115.20, 114.86, 111.45, 105.99, 52.98, 51.55, 41.46, 22.82. MS m/z (relative intensity) 424 (M++1, 24), 423 (M+, 100), 422 (10), 406 (2), 345 (2), 332 (28), 330(20), 289 (2), 261 (29), 235 (20), 234 (25), 220 (4), 218 (9), 206 (4), 169 (4), 115 (2), 91 (7). IR (KBr) 3411, 2980, 1765, 1703, 1602, 1453, 1240, 1142, 749, 702 cm1. HRMS (EI) calcd for C26H21N3O3: 423.1583; found: 423.1579. 4.5. (5R,11aS)-2-(5-Azido-pentyl)-5-(3-hydroxyphenyl)-6H1,2,3,5,11,11a-hexa-hydro-imidazo[1,5-b]-b-carboline-1,3dione 6

idue was then partitioned between ethyl acetate (30 mL) and water (20 mL). The organic phase was separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave a pale yellow solid, which was washed several times with a mixed solvent of ethyl acetate and hexane (1:1) to furnish compound 6 (1.04 g, 2.34 mmol) in 99% yield, mp 127–128 °C. ½a20 D ¼ 204:8 (c 0.2, CHCl3). 1H NMR (DMSO-d6) d 1.23–1.31 (m, 2H), 1.49– 1.59 (m, 4H), 2.80 (dd, J1 = 14.0 Hz, J2 = 11.2 Hz, 1H), 3.28 (t, J = 6.9 Hz, 2H), 3.34–3.43 (m, 3H), 4.48 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s, 1H), 6.71 (d, J = 7.0 Hz, 1H), 6.72 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.5 Hz, J2 = 7.3 Hz, 1H), 7.09 (dd, J1 = 7.2 Hz, J2 = 7.4 Hz, 1H), 7.15 (dd, J1 = 8.0 Hz, J2 = 8.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 9.46 (br s, 1H), 10.93 (br s, 1H). 13C NMR (DMSO-d6) d 172.64, 157.66, 154.28, 141.40, 136.71, 131.22, 129.79, 125.81, 121.70, 118.86, 118.46, 118.20, 115.12, 114.78, 111.43, 106.03, 52.77, 51.40, 50.46, 37.82, 27.78, 27.13, 23.33, 22.78. MS m/z (relative intensity) 445 (M++1, 8), 444 (M+, 31), 416 (41), 386 (13), 372 (11), 358 (22), 345 (5), 332 (12), 304 (4), 294 (22), 287 (11), 274 (3), 261 (100), 246 (5), 234 (41), 218 (15), 206 (12), 195 (3), 169 (13), 115 (4), 105 (4), 84 (5), 70 (7). IR (KBr) 3328, 2936, 2861, 2096, 1766, 1702, 1589, 1459, 1356, 1327, 1239, 1141, 749 cm1. HRMS (EI) calcd for C24H24N6O3: 444.1910; found: 444.1913.

4.6. (5R,11aS)-2-(5-Amino-pentyl)-5-(3-hydroxyphenyl)-6H-1,2, 3,5,11,11a-hexa- hydro-imidazo[1,5-b]-b-carboline-1,3-dione 3 A solution of compound 6 (1.55 g, 3.49 mmol) in methanol (20 mL) was placed into a three-necked round-bottomed flask, which was equipped with a stirrer bar, a gas inlet, and an outlet. The catalyst Pd/C (10%, 160 mg) was added, and the flask was then purged several times with hydrogen gas. The reaction mixture was stirred under an atmosphere of hydrogen gas at room temperature for 10 h. After the reaction was complete, the mixture was allowed to pass through a thin layer of Celite to remove the catalyst. Evaporation of solvent under vacuum gave a pale yellow solid which was washed several times with a mixed solvent of ethyl acetate and hexane (1:1) to afford compound 3 (1.37 g, 3.27 mmol) in 94% yield as an off-white solid, mp 112– 1 H NMR (DMSO-d6) d 113 °C. ½a20 D ¼ 151:5 (c 0.4, CHCl3). 1.20–1.26 (m, 2H), 1.27–1.36 (m, 2H), 1.46–1.54 (m, 2H), 2.48 (t, J = 6.9 Hz, 2H), 2.79 (dd, J1 = 13.9 Hz, J2 = 11.3 Hz, 1H), 3.32– 3.43 (m, 4H), 4.49 (dd, J1 = 10.8 Hz, J2 = 5.7 Hz, 1H), 6.12 (s, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.72 (s, 1H), 6.76 (d, J = 7.7 Hz, 1H), 7.01 (dd, J1 = 7.4 Hz, J2 = 7.4 Hz, 1H), 7.09 (dd, J1 = 7.2 Hz, J2 = 7.7 Hz, 1H), 7.15 (dd, J1 = 7.7 Hz, J2 = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 10.94 (br s, 1H). 13C NMR (DMSOd6) d 172.64, 157.88, 154.30, 141.38, 136.72, 131.27, 129.75, 125.82, 121.68, 118.85, 118.28, 118.19, 115.19, 114.81, 111.44, 106.00, 52.80, 51.42, 40.85, 38.01, 31.62, 27.45, 23.49, 22.79. MS m/z (relative intensity) 419 (M++1, 26), 418 (M+, 100), 400 (4), 389 (5), 372 (4), 358 (5), 345 (5), 332 (4), 308 (6), 289 (3), 273 (7), 261 (45), 246 (4), 234 (34), 218 (11), 206 (9), 191(4), 169 (10), 140 (4), 115 (4), 44 (4). IR (KBr) 3338, 2936, 2857, 1764, 1700, 1591, 1456, 1425, 1371, 1238, 1045, 745, 712 cm1. HRMS (EI) calcd for C24H26N4O3: 418.2005; found: 418.1997. Acknowledgments

To a solution of compound 5c (1.30 g, 2.37 mmol) in methanol (15 mL) was added powdered potassium carbonate (30 mg, 0.22 mmol). The solution was then heated at reflux, and stirring was continued at reflux for 2 h. When the reaction was complete (TLC), the solvent was removed under reduced pressure. The res-

We thank the National Natural Science Foundation of China (No. 20972048) and Shanghai Educational Development Foundation (The Dawn Program: No. 03SG27) for the financial support of this work.

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