Synthesis of cribrostatin 6

Article abstract of DOI:10.1021/jo801694w

(Chemical Equation Presented) The synthesis of cribrostatin 6 (1) is described. A regioselective bromination, a biaryl coupling, and an intramolecular cyclization are the key steps in the synthesis.

Full text of DOI:10.1021/jo801694w

VOLUME 73, NUMBER 19
October 3, 2008
Copyright 2008 by the American Chemical Society
Synthesis of Cribrostatin 6
Michael D. Markey and T. Ross Kelly*
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
ross.kelly@bc.edu
ReceiVed July 30, 2008
The synthesis of cribrostatin 6 (1) is described. A regioselective bromination, a biaryl coupling, and an
intramolecular cyclization are the key steps in the synthesis.
Introduction
Results and Discussion
Shortly after our efforts had commenced, Nakahara et al.
confirmed4 the structure of 1 through total synthesis. Their
synthesis is summarized in eq 1. Herein, we report our synthesis
of cribrostatin 6 using an entirely different strategy.
In 2003, Pettit and colleagues reported the isolation and
structure determination of cribrostatin 6 (1) based on spectral
and X-ray crystallographic data.1 Cribrostatin 6, a constituent
of the Republic of Maldives’ marine sponge Cribrochalina sp.,
was found to be a cancer cell growth inhibitor (P388 ED50 0.3
µg/mL) and to inhibit the growth of a number of pathogenic
bacteria and fungi.2 Cribrostatin 6 is also the first known
naturally occurring example of the imidazo[5,1-a]isoquinoline
ring system. On the basis of its unique polycyclic framework
and biological activity, the synthesis of cribrostatin 6 was
undertaken.3
Retrosynthetic analysis (eq 2) suggested to us that 1 might
be derived from biaryl 2 through an intramolecular dehydrative
cyclization of the imidazole ring onto the neighboring aldehyde
followed by an oxidation. Biaryl 2 was envisioned to originate
from an appropriate cross-coupling reaction between monocycles
3 and 4, followed by functional group manipulation. Both 3
and 4 should be derivable from commerically available starting
materials.
(1) Pettit, G. R.; Collins, J. C.; Knight, J. C.; Herald, D. L.; Nieman, R. A.;
Williams, M. D.; Pettit, R. K. J. Nat. Prod. 2003, 66, 544–547.
(2) Pettit, R. K.; Fakoury, B. R.; Knight, J. C.; Weber, C. A.; Pettit, G. R.;
Cage, G. D.; Pon, S. J. Med. Microbiol. 2004, 53, 61–65.
(3) For a leading reference to some previous syntheses of the imidazo[5,1-
a]isoquinoline ring system, see: Hajos, G.; Riedl, Z. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Neier, R., Bellus, D., Eds.;
Category 2: Hetarenes and related ring systems; Georg Thieme Verlag: Stuttgart,
Germany, 2002; Vol. 12, pp 643-648.
(4) (a) Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 2355–2362. (b)
Nakahara, S.; Kubo, A.; Mikami, Y.; Ito, J. Heterocycles 2006, 68, 515–520.
10.1021/jo801694w CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7441–7443 7441

Markey and Kelly
SCHEME 1. Synthesis of Imidazole 7
SCHEME 2. Synthesis of Biaryl 13
SCHEME 3. Completion of the Synthesis of Cribrostatin 6
The synthesis began (Scheme 1) with the known protected
imidazole 6, available5 in one step from 2-methylimidazole (5)
and 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl). Directed
ortho-metalation of 6 with n-butyllithium and subsequent
quenching with tributyltin chloride gave the desired specific
embodiment (7) of 4.6
Preparation of the unit (12) corresponding to 3 commenced
(Scheme 2) with the known7 diethyl ether 9 of commercially
available 2-methylresorcinol (8). Hydroxylation8 of 9 with
hydrogen peroxide in acetic acid gave phenol 10 directly.9
Monobromination of phenol 10 with bromine-1,4-dioxane10,11
followed by protection of the hydroxyl group12 as its triisopro-
pylsilyl (TIPS) ether afforded bromide 12. Palladium-catalyzed
cross-coupling13 between bromide 12 and stannane 7 forged the
biaryl bond to give intermediate 13.
1,4-dioxane in a 1:1 (v:v) solvent mixture of diethyl ether (Et2O)
and trifluoroacetic acid (TFA) to give bromide 14. We speculate
that the TFA deactivates the imidazole ring toward electrophilic
bromination by protonation. If the bromination of 13 is carried
out in the absence of TFA, only bromination of the imidazole
ring is observed.
The side chain was introduced with another palladium-
catalyzed cross-coupling reaction between 14 and allyltributyltin
to give allyl biaryl 15. A two-step deprotection/reprotection of
15 was necessary to set the stage for the intramolecular
cyclization. Thus, 15 was first deprotected with TFA and then
regioisomerically reprotected with di-tert-butyl dicarbonate
(Boc2O) to afford carbamate 17. Thanks to the protecting group
shuffle, biaryl 17 underwent intramolecular cyclization upon
exposure to catalytic osmium tetroxide and excess sodium
periodate to generate aminal 18. Dehydration of 18 was
performed with methanesulfonyl chloride (MsCl) and triethy-
lamine to give imidazo[5,1-a]isoquinoline 19. Finally, removal
of the TIPS group from 19 with tetrabutylammonium fluoride
(TBAF) followed by the known4b oxidation of phenol 20 with
HNO3 delivered cribrostatin 6 (1). The spectra of synthetic 1
are in excellent agreement with those reported for the natural
product.1
Introduction of the final two carbons began (Scheme 3) with
a regioselective bromination of intermediate 13 with bromine-
(5) Clader, J. W.; Berger, J. G.; Burrier, R. E.; Davis, H. R.; Domalski, M.;
Dugar, S.; Kogan, T. P.; Salisbury, B.; Vaccaro, W. J. Med. Chem. 1995, 38,
1600–1607.
(6) Compare: (a) Keenan, R. M.; Weinstock, J.; Finkelstein, J. A.; Franz,
R. G.; Gaitanopoulos, D. E.; Girard, G. R.; Hill, D. T.; Morgan, T. M.; Samanen,
J. M.; Hempel, J.; Eggleston, D. S.; Aiyar, N.; Griffin, E.; Ohlstein, E. H.; Stack,
E. J.; Weidley, E. F.; Edwards, R. J. Med. Chem. 1992, 35, 3858–3872. For a
recent review of directed metalations, see: (b) Whisler, M. C.; MacNeil, S.;
Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206–2225.
(7) Doyle, F. P.; Hardy, K.; Nayler, J. H. C.; Soulal, M. J.; Stove, E. R.;
Waddington, H. R. J. J. Chem. Soc. 1962, 1453–1458.
In summary, we report a convergent synthesis of cribrostatin
6. The synthesis provides a new approach to both the imi-
dazo[5,1-a]isoquinoline ring system and cribrostatin 6.
(8) Gonza´lez, R. R.; Gambarotti, C.; Liguori, L.; Bjorsvik, H.-R. J. Org.
Chem. 2006, 71, 1703–1706.
(9) For a three-step conversion of 9 to 10, see ref 4.
(10) Finkelstein, B. L. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley: Chichester, UK, 1995; Vol. 1, p 686.
(11) The structure of 11 was confirmed by X-ray crystallography (see the
Supporting Information).
(12) Cursory attempts to achieve a palladium-catalyzed cross-coupling
reaction between 11 and 7 failed to give any of the desired biaryl product i.
Compounds 11 and 6 (protodestannylated 7) were recovered from the reaction
mixture.
Experimental Section
2,4-Diethoxy-3-methylphenol (10). To a 250 mL round-bot-
tomed flask, open to the air, were added 9 (5.00 g, 27.8 mmol),
acetic acid (125 mL, glacial), phosphoric acid (7.9 mL, g85 wt %
solution in water), hydrogen peroxide (5.8 mL, ca. 56 mmol, 30-32
wt % solution in water), and a stir bar. The resulting solution was
stirred open to the air at room temperature for 15 h and then
quenched with saturated NaHSO3 (75 mL). The homogeneous
solution was transferred to a 500 mL Erlenmeyer flask and stirred
until the peroxides (CAUTION: Explosion Hazard) were quenched
(ca. 15 min, checked with peroxide test paper, EM Science catalog
# 10011-1). The solution was transferred to a separatory funnel
(13) For a recent review, see: Espinet, P.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2004, 43, 4704–4734.
7442 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of Cribrostatin 6
containing saturated NaCl solution (230 mL). The resulting mixture
was extracted with CH2Cl2 (4 × 175 mL). The extracts were pooled,
washed with saturated NaCl solution (1 × 200 mL), dried with
MgSO4, and filtered. Removal of the solvent in vacuo gave a brown
oil. This oil was purified by flash column chromatography (24 cm
× 4 cm; silica gel) with 15% Et2O in hexanes (1 L) to afford 1.00 g
of 9 and 2.30 g (42%, or 53% based on unrecovered 9) of 1014 as
a white solid (Rf ) 0.3; 20% Et2O in hexanes; silica). An
analytically pure sample of 10 could be obtained by recrystallization
from cold (-25 °C) pentane to give a white solid: mp 42-43 °C;
1H NMR (400 MHz, CDCl3) δ 6.72 (d, J ) 8.8 Hz, 1H), 6.52 (d,
J ) 8.8 Hz, 1H), 5.25 (s, 1H), 3.98-3.91 (m, 4H), 2.17 (s, 3H),
1.42 (t, J ) 7.2 Hz, 3H), 1.39 (t, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 151.1, 144.8, 143.1, 120.4, 111.4, 108.0, 69.2, 64.5,
15.7, 15.0, 9.7; IR (neat) ν 3375, 2977, 1488 cm-1; HRMS (ESI)
calcd for C11H17O3 (MH+) 197.1178, found 197.1177. Anal. Calcd
for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.03; H, 8.15.
5-[2-Bromo-3,5-diethoxy-4-methyl-6-(triisopropylsiloxy)phe-
nyl]-2-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imid-
azole (14). To a 250 mL round-bottomed flask were added 13 (950
mg, 1.69 mmol), anhydrous Et2O (40 mL), and a stir bar. The flask
was stirred, placed in an ice bath (0 °C), and to it was added
trifluoroacetic acid (40 mL) over a period of 15 min. The resulting
solution was stirred at 0 °C for 10 min and then bromine-1,4-
dioxane (see preparation of 11 in Supporting Information, 831 mg,
3.35 mmol) was added in one portion. The orange solution was
stirred at 0 °C for 15 min and then slowly (ca. 15 min) quenched
with 6 M NaOH (100 mL). The flask was removed from the ice
bath and neutralized (ca. pH ) 7) with solid NaOH (ca. 2 g). The
mixture was transferred to a separatory funnel, the ether layer was
separated, and the aqueous layer was extracted with Et2O (3 × 40
mL). The ether layer and extracts were pooled, washed with 1 M
NaOH (1 × 50 mL), H2O (1 × 50 mL) and saturated NaCl solution
(1 × 50 mL), dried with MgSO4, and filtered. Removal of the
solvent in vacuo gave an orange oil. The oil was purified by flash
column chromatography (18 cm × 4 cm; silica) with 45% Et2O in
hexanes (1 L) to afford 788 mg (73%) of 14 (Rf ) 0.3; 50% Et2O
product Rf ) 0.2; 100% EtOAc; silica). Once the reaction was
complete (ca. 18 h), the solution was transferred to a separatory
funnel, diluted with H2O (20 mL), and extracted with Et2O (3 ×
20 mL). The organic extracts were pooled, washed with H2O (1 ×
25 mL) and saturated NaCl solution (1 × 25 mL), dried with
MgSO4, and filtered. Removal of the solvent in vacuo gave a crude
solid. The solid was purified by flash column chromatography (15
cm × 2 cm; silica) with 100% EtOAc (300 mL) to afford 121 mg
(66%) of 18 as a white solid: mp 190-192 °C; 1H NMR (400 MHz,
CDCl3) δ 7.48 (s, 1H), 5.81 (br s, 1H), 4.63 (br s, 1H), 4.10-4.03
(m, 1H), 3.84-3.70 (m, 3H), 3.55 (dd, J ) 16.0, 2.2 Hz, 1H), 2.88
(dd, J ) 16.0, 3.8 Hz, 1H), 2.35 (s, 3H), 2.20 (s, 3H), 1.43-1.34
(m, 9H), 1.05-0.99 (m, 18H); 13C NMR (100 MHz, CDCl3) δ
150.5, 148.5, 142.4, 142.3, 126.1, 124.5, 124.2, 118.0, 116.3, 72.6,
68.9, 68.8, 31.5, 18.1, 18.0, 15.6, 15.4, 14.1, 12.4, 10.3; IR (neat)
ν 3089, 2931, 2702, 2865, 1460, 1386, 1083 cm-1; HRMS (ESI)
calcd for C26H43N2O4Si (MH+) 475.2992, found 475.3001.
7,9-Diethoxy-3,8-dimethyl-10-(triisopropylsilyloxy)imidazo-
[5,1-a]isoquinoline (19). To a 25 mL round-bottomed flask were
added 18 (52 mg, 0.11 mmol), anhydrous CH2Cl2 (5 mL),
triethylamine (77 µL), and a stir bar. The solution was stirred, placed
in an ice bath (0 °C), and to it was added distilled (see general
procedures) methanesulfonyl chloride (9 µL, 0.1 mmol). The
solution was stirred at 0 °C, and the progress of the reaction was
monitored by TLC (desired product Rf ) 0.4; 75% EtOAc in
hexanes; silica). Once the reaction was complete (ca. 2.5 h), the
solution was transferred to a separatory funnel. To the separatory
funnel was added H2O (20 mL), the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
The organic layer and extracts were pooled, washed with H2O (1
× 25 mL) and saturated NaCl solution (1 × 25 mL), dried with
MgSO4, and filtered. Removal of the solvent in vacuo gave a crude
solid. The solid was purified by flash column chromatography (10
cm × 2 cm; silica) with 75% EtOAc in hexanes (300 mL) to afford
1
37 mg (74%) of 19 as a beige solid: mp 134-136 °C; H NMR
(400 MHz, CDCl3) δ 7.97 (s, 1H), 7.44 (d, J ) 7.6 Hz, 1H), 7.00
(d, J ) 7.6 Hz, 1H), 3.96-3.88 (m, 4H), 2.63 (s, 3H), 2.28 (s,
3H), 1.54-1.43 (m, 6H), 1.36 (t, J ) 7.2 Hz, 3H), 1.03 (d, J ) 7.2
Hz, 18H); 13C NMR (100 MHz, CDCl3) δ 148.9, 147.7, 141.7,
136.6, 125.6, 123.6, 122.9, 118.4, 117.7, 117.6, 107.8, 69.8, 69.1,
18.1, 15.6, 15.4, 14.1, 12.8, 10.4; IR (neat) ν 2865, 1459, 1367,
1255, 1015 cm-1; HRMS (ESI) calcd for C26H41N2O3Si (MH+)
457.2886, found 457.2888. Anal. Calcd for C26H40N2O3Si: C, 68.38;
H, 8.83; N, 6.13. Found: C, 68.40; H, 8.98; N, 5.89.
1
in hexanes; silica) as a white solid: mp 96-98 °C; H NMR (400
MHz, CDCl3) δ 6.88 (s, 1H), 5.18 (d, J ) 11.6 Hz, 1H), 4.82 (d,
J ) 11.6 Hz, 1H), 4.08-3.83 (m, 3H), 3.72-3.64 (m, 1H),
3.34-3.28 (m, 1H), 3.06-2.99 (m, 1H), 2.47 (s, 3H), 2.26 (s, 3H),
1.41 (t, J ) 6.8 Hz, 3H), 1.35 (t, J ) 6.8 Hz, 3H), 0.94-0.84 (m,
21 H), 0.71-0.66 (m, 2H), -0.11 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 149.5, 148.3, 145.3, 145.2, 128.3, 127.9, 127.8, 121.8,
115.7, 72.6, 68.3, 68.2, 65.2, 17.6, 17.4, 17.3, 15.1, 14.9, 13.3, 13.2,
10.7, -1.7; IR (neat) ν 2942, 2865, 1415, 1381 cm-1; HRMS (ESI)
calcd for C30H54BrN2O4Si2 (MH+) 641.2806, found 641.2810. Anal.
Calcd for C30H53BrN2O4Si2: C, 56.14; H, 8.32; N, 4.36. Found: C,
56.28; H, 8.31; N, 4.30.
7,9-Diethoxy-5,6-dihydro-3,8-dimethyl-10-(triisopropylsilyl-
oxy)imidazo[5,1-a]isoquinolin-5-ol (18). To a 25 mL round-
bottomed flask were added 17 (226 mg, 0.395 mmol), THF (7 mL),
tert-butanol (3.5 mL), H2O (3.5 mL), OsO4 (155 µL, ca. 0.024
mmol, 4 wt % in H2O), NaIO4 (279 mg, 1.30 mmol), and a stir
bar. The solution was stirred open to the air at room temperature,
and the progress of the reaction was monitored by TLC (desired
Acknowledgment. We thank the NSF for financial support
of the BC Mass Spectrometry Center (Grant # DBI-0619576).
We are also grateful to Dr. Bo Li (Boston College) for X-ray
crystallographic studies, and Dr. Alex Scopton for helpful
discussions.
Supporting Information Available: General experimental
procedures, experimental procedures for compounds 1, 6, 7, 9,
11-13, 15-17, and 20, copies of the 1H and 13C NMR spectra
for compounds 1, 6, 7, 9-15, and 17-20, and a CIF file giving
X-ray data for structure 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Phenol 10 is somewhat unstable to the reaction conditions. A better
yield of 10 is obtained if the reaction is not run to completion.
JO801694W
J. Org. Chem. Vol. 73, No. 19, 2008 7443