A concise synthesis of 5-demethyl-HKI 0231A and 5-demethyl-HKI 0231B

Article abstract of DOI:10.1016/j.tetlet.2006.08.065

The pentacyclic skeleton of HKI 0231A and HKI 0231B was synthesized by a novel radical cyclization/oxidation followed by DDQ oxidation to introduce the methoxyl groups. This is the first synthetic pathway to both the HKI 0231A and the HKI 0231B series.

Full text of DOI:10.1016/j.tetlet.2006.08.065

Tetrahedron Letters 47 (2006) 7801–7803
A concise synthesis of 5-demethyl-HKI 0231A
and 5-demethyl-HKI 0231B
George A. Kraus* and Tao Wu
Department of Chemistry, Iowa State University, Ames, IA 50011, United States
Received 1 March 2006; revised 17 August 2006; accepted 18 August 2006
Available online 15 September 2006
Abstract—The pentacyclic skeleton of HKI 0231A and HKI 0231B was synthesized by a novel radical cyclization/oxidation
followed by DDQ oxidation to introduce the methoxyl groups. This is the first synthetic pathway to both the HKI 0231A and
the HKI 0231B series.
Ó 2006 Elsevier Ltd. All rights reserved.
The structures of HKI 0231A (1) and HKI 0231B (2),
novel inhibitors of 3a-hydroxysteroid dehydrogenase,
were reported from Streptomyces sp. HKI0231.1 Com-
pounds that inhibit this enzyme may be useful leads
for new anti-inflammatory agents. In 2003, Nakatsuka
and co-workers reported a synthesis of 1 utilizing a
novel Friedel–Crafts alkylation reaction.2 In 2005,
Scopton and Kelly reported an innovative synthesis of
1 featuring an intramolecular aryl lithium cyclization.3
In 2005, we reported a formal synthesis of 1 wherein
the key tricyclic indole was synthesized by way of an
ethynyl aniline.4 We report herein, a very convenient
and flexible preparation of 5-demethyl HKI 0231A (3)
and HKI 0231 B (4) using an intramolecular radical
cyclization.
Both 3 and 4 were envisioned to come from indole 6,
readily available by an intramolecular aldol reaction
(t-BuOK, DMF, 23 °C, 96%) of 7 that in turn was pre-
pared from commercially available 4-formyl indole by a
Friedel–Crafts reaction (Ac2O, 0 °C, 61%). Indole 6
would be coupled with benzylic iodide 5, available from
iodoanisic acid5 by reduction (BH3, THF, reflux, 74%)
followed by iodide formation (Ph3P, I2; 65%). The reac-
tion of 6 with iodide 5 in the presence of potassium
hydroxide afforded indole 8 in 92% yield. Unfortunately,
despite several experiments, the conversion of 8 to 9
using organopalladium methodologies6 failed. At tem-
peratures below 50 °C, starting material was recovered.
At higher temperatures (80–120 °C), complex mixtures
were obtained. This intramolecular Heck reaction
O
O
O
CHO
OMe
Me
CH2I
I
t-BuOK
+
N
R'
N
H
N
H
R
MeO
5
OMe
7
6
1: R = OMe, R' = Me
2: R = H, R' = Me
3: R = OMe, R' = H
4: R = R' = H
*
Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294 0105; e-mail: gakraus@iastate.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.065

7802
G. A. Kraus, T. Wu / Tetrahedron Letters 47 (2006) 7801–7803
O
O
Pd(PPh3)4
KOAc
//
DMF
120 °C
5
6
I
KOH,
DMF
N
N
rt, 3 h
OMe
MeO
9
8
requires syn-addition and syn-elimination. The latter
process would be hard to achieve in this system.
logs. The novel radical cyclization/oxidation protocol
should prove useful in other systems where the organo-
palladium approach failed. This represents the first syn-
thetic pathway to both the HKI 0231A and the HKI
0231B series.
We then synthesized indole 10 in 93% yield by alkyl-
ation of keto aldehyde 7 with 5 and potassium hydr-
oxide. Although the use of organopalladium chemistry
to convert 10 into 11 failed, these conditions were suc-
cessful in the system lacking an acetyl group at C-3 of
the indole. Radical cyclization with tributyltin hydride
and AIBN7 in boiling benzene afforded 11 in 58% yield.
DDQ oxidation of 11 generated the corresponding
indole that failed to cyclize to 9 using potassium tert-
butoxide.
References and notes
1. Kleinwachter, P.; Schlegel, B.; Groth, I.; Hartl, A.; Grafe,
U. J. Antibiot. 2001, 54, 510.
2. (a) Komoda, T.; Shinoda, Y.; Nakatsuka, S. Biosci.
Biotechnol. Biochem. 2003, 67, 659; (b) Komoda, T.;
Nakatsuka, S. Heterocyclic Commun. 2003, 9, 119.
CHO
COCH3
Bu3SnH
CHO
COCH3
5
AIBN
7
DDQ
t-BuOK
//
THF rt
I
KOH,
DMF
rt, 3 h
9
N
benzene
80 °C
N
CH2Cl2
rt
11
OMe
10 MeO
3. Scopton, A.; Kelly, T. R. J. Org. Chem. 2005, 70, 10004.
4. Kraus, G. A.; Wu, T. Tetrahedron 2005, 61, 9502.
5. Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor,
R. J. K. Org. Biomol. Chem. 2003, 1, 104–116.
6. Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKil-
lop, A. Tetrahedron Lett. 1985, 26, 5963; Rudisill, D. E.;
Stille, J. K. J. Org. Chem. 1989, 54, 856; Cacchi, S.;
Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994,
475, 289.
7. Kraus, G. A.; Kim, H. Synth. Commun. 1993, 55; For
other studies featuring intramolecular cyclization on the 2
position of indoles, see: Campeau, L.; Thansandote, P.;
Fagnou, K. Org. Lett. 2005, 7, 1857; Itahara, T. Hetero-
cycles 1986, 24, 2557; Itahara, T. Synthesis 1979, 2,
151.
8. To a boiling solution of iodide 8 in toluene was added a
solution of n-Bu3SnH (0.48 mL, 1.8 mmol) and AIBN
(99 mg, 0.36 mmol) in 3 mL of toluene in 3 h via syringe
pump. The reaction mixture was kept in reflux for three
more hours. After removal of toluene, the residue was
stirred for 1 h with 10 mL of ether and 10 mL of saturated
KF solution. The mixture was extracted with ether. The
The reaction of 8 with tributyltin hydride and AIBN in
boiling toluene afforded indole 9 directly in 58% yield.8
We speculate that oxidation occurs via small amounts
of oxygen present in the system. The higher reaction
temperature could also be a factor. This reaction has
been reproduced three times with essentially the same
yields each time. Introduction of the methoxyl group,
a low yield transformation in the Nakatsuka synthesis,
was selectively achieved in high yield using DDQ9 in
methanol. At ambient temperature the reaction pro-
vided only 410 in 63% yield. However, 4 could be con-
verted into 311 in 58% yield with DDQ in boiling
methanol. This was unexpected, since 4 might be
expected to be more reactive to hydride abstraction than
9. We attribute the differential reactivity to allylic
strain12 between the two methoxyl groups in 4, forcing
the benzylic methoxyl group to an axial position. Com-
pound 9 could be converted to 3 in 62% yield in a
one-pot reaction using 2 equiv of DDQ in boiling
methanol.
O
O
Bu3SnH
AIBN
DDQ
DDQ
8
9
MeOH
rt 8 h
toluene
110 °C
3 h
MeOH
reflux
8 h
N
N
MeO
3
H
MeO
OMe
OMe
OMe
4
organic layer was dried and concentrated. The crude
product was purified by flash chromatography (ethyl
The synthetic approach to 3 and 4 is sufficiently direct
and flexible to permit the synthesis of a variety of ana-

G. A. Kraus, T. Wu / Tetrahedron Letters 47 (2006) 7801–7803
7803
acetate/hexane = 3:1) to give 9 as a yellow solid (100 mg,
58% yield), mp: 188–190 °C.
(s, 3H), 2.984 (s, 3H); 13C NMR (75 MHz, CDCl3): d
181.46, 156.31, 149.58, 137.93, 133.18, 132.89, 132.57,
131.15, 130.89, 128.03, 124.95, 124.65, 122.93, 118.31,
113.54, 113.21, 109.33, 87.08, 56.05, 51.31; MS (m/z): 318,
317, 316, 286, 285, 243, 242, 214; HRMS: calcd for
C20H15NO3: 317.1052. Found: 317.1059.
1H NMR (300 MHz, CDCl3): d 8.25 (d, J = 5.7 Hz, 1H),
7.66 (d, J = 7.2 Hz), 7.44–7.50 (m, 3H), 7.33 (t,
J = 5.7 Hz, 1H), 6.95 (d, J = 6.2 Hz, 1H), 6.73 (d,
J = 7.1 Hz, 1H), 5.12 (s, 2H), 3.93 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 180.7, 154.7, 152.6, 137.0, 133.0,
132.3, 131.2, 130.8, 130.6, 124.8, 123.6, 122.6, 118.1, 112.2,
112.2, 108.5, 55.7, 48.4; MS (m/z): 288, 287, 286, 273, 272,
271, 244, 243; HRMS: calcd for C19H13NO2: 287.0946.
Found: 287.0949.
11. To
a solution of demethyl HKI 0231B 4 (13 mg,
0.04 mmol) in 5 mL of methanol was added DDQ
(27 mg, 0.12 mmol) at rt. The reaction mixture was stirred
at reflux overnight. The solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (ethyl acetate/hexane = 2:1) to give 3 as
a yellow oil (8 mg, 58% yield).
9. Steenkamp, Jacobus A.; Mouton, C. Hendrik L.; Ferreira,
Daneel Tetrahedron 1991, 47, 6705.
10. To a solution of compound 9 (29 mg, 0.05 mmol) in 5 mL
of methanol was added DDQ (34 mg, 0.15 mmol) at
À78 °C. The reaction mixture was stirred at À78 °C to rt
overnight. The solvent was removed under reduced
pressure. The crude product was purified by flash chro-
matography (ethyl acetate/hexane = 2:1) to give 4 as a
yellow oil (10 mg, 63% yield).
Spectra for 3: 1H NMR (300 MHz, CDCl3): d 8.255 (d,
J = 7.5 Hz, 1H), 7.720 (d, J = 9.3 Hz, 2H), 7.622 (t,
J = 7.9 Hz, 1H), 7.516 (d, J = 7.3 Hz, 1H), 7.407 (t,
J = 7.6 Hz, 1H), 7.084 (d, J = 8.3 Hz, 1H), 6.742 (d,
J = 9.7 Hz), 4.001 (s, 3H), 3.020 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 181.78, 155.95, 146.97, 138.19,
134.10, 132.84, 132.55, 130.91, 130.20, 125.52, 125.14,
125.04, 123.08, 118.57, 114.53, 114.09, 109.75, 56.17,
52.88; MS (m/z): 348, 347, 346, 318, 317, 316, 315, 301,
300, 272; HRMS: calcd for C21H17NO4: 347.1158. Found:
347.1163.
Spectra for 4: 1H NMR (300 MHz, CDCl3): d 8.268 (d,
J = 7.4 Hz, 1H), 7.716 (d, J = 9.7 Hz, 1H), 7.664 (d,
J = 8.0 Hz, 1H), 7.599 (t, J = 7.9 Hz, 1H), 7.513
(d, J = 7.5 Hz, 1H), 7.398 (t, J = 7.7 Hz, 1H), 7.067 (d,
J = 8.3 Hz, 1H), 6.842 (s, 1H), 6.743 (d, J = 9.6 Hz), 4.004
12. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.