Studies towards the total synthesis of Sch 56036; isoquinolinone synthesis and the synthesis of phenanthrenes

Article abstract of DOI:10.1016/j.tetlet.2005.07.084

The isoquinolinone hemisphere of Sch 56036 has been prepared using a modified Pomeranz-Fritsch reaction and the synthesis of the phenanthrene core has been modelled via a Suzuki coupling and subsequent ring closing metathesis.

Full text of DOI:10.1016/j.tetlet.2005.07.084

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6537–6540
Studies towards the total synthesis of Sch 56036;
isoquinolinone synthesis and the synthesis of phenanthrenes
Edward R. Walker, Shing Y. Leung and Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, London SW7 2AZ, England, UK
Received 15 June 2005; accepted 15 July 2005
Available online 2 August 2005
Abstract—The isoquinolinone hemisphere of Sch 56036 has been prepared using a modified Pomeranz–Fritsch reaction and the
synthesis of the phenanthrene core has been modelled via a Suzuki coupling and subsequent ring closing metathesis.
Ó 2005 Elsevier Ltd. All rights reserved.
There is continuing interest in the discovery of novel
antifungal agents for the treatment of opportunistic fun-
gal infections in patients, immuno-compromised either
through AIDS infection or the use of immuno-suppres-
sant drugs.1 In the course of the work to discover novel
antifungal agents, a polycyclic xanthone, Sch 56036 (1,
Fig. 1),2 was isolated from a culture of Actinoplanes
sp. (SCC 2314) collected on Tarlac in the Philippines.
Standard antifungal testing has shown this member of
the albofungin family to exhibit high activity against a
number of fungal pathogens.
high antibacterial, antifungal or anticancer activity.
Two members of the albofungin family have been sub-
jected to total synthetic studies: cervinomycin A1 (2)3–5
and lysolipin I (3, Fig. 2).6 However, no total syntheses
of Sch 56036 have been reported. The common feature
of the two most concise and successful cervinomycin
A1 syntheses was the strategy of retrosynthetically dis-
secting the molecule across the central phenanthrene
(ring C, see 1) system to provide two equivalent sized
precursor fragments. The synthesis then either used a
Natural products belonging to the albofungin family
have attracted considerable interest over the last
30 years and at least 28 variants on the common polycy-
clic xanthone core have been discovered, all exhibiting
OMe
OMe
O
HO
OH
O
O
HO
N
OH
H
F
O
C
O
OH
H
Me
E
2
HO
OH
O
O
A
D
Me
N
OMe
Cl
B
O
OMe
1
HO
OH
O
O
Figure 1.
Me
N
O
MeO
O
Keywords: Sch 56036; Albofungin; Antifungal natural product; Pom-
eranz–Fritsch reaction; Palladium(0) coupling; Ring closing metathe-
sis; Phenanthrene.
OH
OMe
3
*
Corresponding author. Tel.: +44 207 594 5766; fax: +44 207 594
5805; e-mail: agmb@imperial.ac.uk
Figure 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.084

6538
E. R. Walker et al. / Tetrahedron Letters 46 (2005) 6537–6540
7 (Scheme 1), was synthesized in five steps from com-
O
OMe
mercially available L-isoleucine (5)7 via Boc protection,
Weinreb amide formation, N-methylation, lithium alu-
minium hydride reduction of the Weinreb amide to the
aldehyde and a one-pot deprotection and ethyl acetal
formation to give 7 in an overall yield of 72%. The aro-
matic acid fragment, 8, was synthesized over three steps8
via mono-tosylation of 6, double methylation and selec-
tive saponification to give carboxylic acid 8 in an overall
yield of 78%. With the two fragments in hand the
required amide was prepared using thionyl chloride
and benzotriazole9 to form the acid chloride from 8,
which was subsequently allowed to condense with amine
hydrochloride 7. Detosylation with potassium hydr-
oxide in aqueous ethanol at reflux gave phenol 9 in a
67% yield from amine hydrochloride 7.10
Me
OTf
N
4
Figure 3.
Wittig reaction4 or a Heck coupling3 followed by a low
yielding photocyclization reaction to form the central
phenanthrene core. This strategy has the advantage of
convergence but the low yielding photocyclization seri-
ously constrains the approach. Recognizing the overall
utility of these compounds and the underlying strength
of late phenanthrene construction, we decided to apply
more modern, catalytic methods to the synthesis, with
the use of a Suzuki coupling reaction to form the aryl–
aryl bond and subsequent ring closing metathesis
(RCM) to close the phenanthrene ring.
With the required substrate 9 for the Pomeranz–Fritsch
reaction available, attempts were made to close the het-
erocyclic ring system using Brønsted11 or Lewis12 acid
catalysis. In the optimum cyclization, acetal 9 was
heated at 130 °C with 4 equiv of camphorsulfonic acid
in toluene to provide the isoquinolone 10. The necessary
high temperature acidic cyclization reaction conditions
also brought about O-demethylation. The overall yield
of 10 from L-isoleucine (5) was 34% over eight steps.13
Initial work was concentrated on the synthesis of the
required isoquinoline 4 (Fig. 3) that forms the western
hemisphere of Sch 56036. Retrosynthetic analysis of 4
leads, via a modified Pomeranz–Fritsch reaction and
amide formation, to a derivative of L-isoleucine and
the central aromatic ring. The required isoleucine acetal,
In parallel with the isoquinolinone 10 synthesis, model
studies were carried out on the elaboration of phenanthr-
enes relevant to the construction of the central ring C.
Recently, Iuliano et al. have reported14 an equivalent
process for the elaboration of phenanthrenes using tan-
dem palladium(0) coupling and RCM. In our hands and
prior to publication of the Iuliani paper, we examined
the model coupling of 2-vinylphenylboronic acid (12)
with 2-bromostyrene (13) under the Fu ꢀuniversalꢁ Suzu-
ki coupling conditions.15 This gave biphenyl 14 in mod-
erate yield (40%). Subsequent RCM using the second
generation Grubbs catalyst 11 (Fig. 4) cleanly gave
phenanthrene 15, again in moderate yield (Scheme 2)
(50%).16
NH2
CO2H
5
a - e
Me
NH.HCl
OH
OEt
OEt
OMe
i, j
Me
7
+
N
O
In further studies, a series of ortho-substituted triflates
1817 were synthesized in reasonable yields (Scheme 3).
Attempts at coupling these triflates18 with boronic acid
12 using the Fu conditions (Pd(OAc)2, PCy3) were
unsuccessful. In contrast, the use of Pd(PPh3)4 furnished
the corresponding biphenyls in good yields.19,20 Subse-
quent reaction with catalyst 11 at room temperature
proceeded with poor conversion. However, RCM in
dichloromethane at reflux gave the phenanthrenes 19
in excellent yields (P95%).21
OMe
OEt
HO2C
OTs
OEt
9
k
8
f - h
OH
O
OH
Me
OH
N
HO2C
OH
10
6
Scheme 1. Reagents and conditions: (a) Boc2O, NaOH, dioxane, H2O,
20 °C, 1 d (100%); (b) MeONHMe, EDCI, N-methylmorpholine,
CH2Cl2, À15 °C, 1 h (100%); (c) MeI, NaH, DMF, 0–20 °C, 2 d
(92%); (d) LiAlH4, THF, 0 °C, 35 min (82%); (e) HCl, EtOH, 20 °C,
3.75 h (96%); (f) TsCl, NaOH, Me2CO, H2O, 40 °C (100%); (g) MeI,
K2CO3, Me2CO, D, 15 h (88%); (h) NaOH, Me2CO, H2O, D, 19.5 h
(89%); (i) SOCl2, benzotriazole, Et3N, CH2Cl2, 2.5 h (68%); (j) KOH,
EtOH, H2O, D, 17 h (98%); (k) CSA, PhMe, D, 22 h (71%).
MesN
Cl
NMes
Ph
Ru
Cl
PCy3
11
Figure 4.

E. R. Walker et al. / Tetrahedron Letters 46 (2005) 6537–6540
6539
(to A.G.M.B.), the Royal Society and the Wolfson
Foundation for a Royal Society—Wolfson Research
Merit Award (to A.G.M.B.), and the Wolfson Founda-
tion for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College
London.
B(OH)2
Br
12
13
a
References and notes
1. Greene, S. I. Antifungal Drug Ther. 1990, 23, 237.
2. Chu, M.; Truumees, I.; Mierzwa, R.; Terracciano, J.;
Patel, M.; Das, P. R.; Puar, M. S.; Chan, T. M.
Tetrahedron Lett. 1998, 39, 7649.
14
3. Kelly, T. R.; Jagoe, C. T.; Li, Q. J. Am. Chem. Soc. 1989,
111, 4522.
b
4. Mehta, G.; Shah, S. R.; Venkateswarlu, Y. Tetrahedron
1994, 50, 11729.
5. Rao, A. V. R.; Yadav, J. S.; Reddy, K. K.; Upender, V.
Tetrahedron Lett. 1991, 32, 5199.
6. Duthaler, R. O.; Heuberger, C.; Wegmann, U. H.;
Scherrer, V. Chimia 1985, 39, 174.
7. Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K.
Synthesis 1998, 1707.
8. King, F. E.; Gilks, J. H.; Partridge, M. W. J. Chem. Soc.
1955, 4206.
15
Scheme 2. Reagents and conditions: (a) Pd2(dba)3, t-Bu3PHÆBF4, KF,
THF, 20 °C, 18 h (40%); (b) 11 (10 mol %), CH2Cl2, 20 °C, 24 h (50%).
9. Chaudhari, S. S.; Akamanchi, K. G. Synlett 1999, 1763.
10. Spectroscopic data: Compound 9: [a]D À3.09 (c 0.905,
CH3OH); IR (CHCl3 film) 3285, 1613, 1469 cmÀ1 1H
;
R2
R1
a - c
NMR (d8-toluene, 500 MHz, 80 °C): d 0.88 (t, J = 7.5 Hz,
3H), 0.98 (d, J = 6.7 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H),
1.07 (t, J = 7.0 Hz, 3H), 1.19 (m, 1H), 1.51 (m, 1H), 1.94
(m, 1H), 2.64 (s, 3H), 3.46 (diastereotopic m, 4H), 3.63 (s,
3H), 4.46 (d, J = 4.1 Hz, 1H), 4.74 (dd, J = 10.2, 4.1 Hz,
1H), 5.63 (s, 1H), 6.66 (dd, J = 7.5, 1.9 Hz, 1H), 6.69 (t,
J = 7.6 Hz, 1H), 6.77 (dd, J = 7.7, 1.9 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d 10.7, 15.2, 15.4, 15.6, 25.4, 32.3, 33.3,
57.3, 61.6, 63.6, 63.8, 103.0, 116.4, 118.3, 120.0, 124.8,
142.8, 149.4, 170.6; MS (ammonia, CI+) m/z 354, 308,
103; HRMS calcd for C19H32NO5: 354.2280 (M+H),
found: 354.2265 (M+H). Anal. Calcd for C19H31NO5: C,
64.56; H, 8.84; N, 3.96. Found: C, 64.49; H, 8.74; N,
3.82.
OH
OH
16
17
R1 = Me, NO2, CO2Me, OH; R2 = Me, NO2, CO2Me, OMe
R2
R2
d, e
f, g
OTf
R = Me, NO2, CO2Me, OMe
18
19
11. Kaufman, T. S. J. Chem. Soc., Perkin Trans. 1 1993, 403.
12. Perchonock, C. D.; Lantos, I.; Finkelstein, J. A.; Holden,
K. G. J. Org. Chem. 1980, 45, 1950.
Scheme 3. Reagents and conditions: (a) allyl bromide, K2CO3,
Me2CO, D, 16 h [R1 = NO2 (85%), CO2Me (78%), OH (60%)]; (b)
(R1 = OH only) MeI, K2CO3, Me2CO, D, 16 h (77%); (c) neat, 210 °C,
3 h, (R2 = NO2 170 °C, 45 h) [R2 = NO2 (76%), CO2Me (73%), OMe
(73%)]; (d) Tf2O, EtN-i-Pr2, CH2Cl2, À78 to 20 °C, 16 h [R2 = Me
(95%), NO2 (75%), CO2Me (91%), OMe (93%)]; (e) RhCl3, EtOH, D,
3.5 h [R2 = Me (46%), NO2 (45%), CO2Me (52%), OMe (48%)]; (f) 12,
Pd(PPh3)4, t-BuOK, DME, H2O, D, 17 h [R2 = Me (59%), NO2 (20%),
CO2Me (54%), OMe (55%)]; (g) 11 (10 mol %), CH2Cl2, D, 18 h
(P95%).
13. Spectroscopic data: Compound 10: [a]D +4.61 (c 1.09,
CH3OH); IR (neat) 3441, 2966, 1745, 1655, 1593,
1453 cmÀ1
;
1H NMR (CDCl3, 400 MHz): 0.97 (t,
J = 7.4 Hz, 3H), 1.27 (d, J = 6.7 Hz, 3H), 1.56 (m, 1H),
1.74 (m, 1H), 2.80 (m, 1H), 3.59 (s, 3H), 5.63 (s, 1H), 6.35
(s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H),
13.07 (s, 1H); 13C NMR (CDCl3, 100 MHz): d 11.8, 19.9,
29.3, 29.6, 36.4, 104.5, 110.6, 115.0, 122.7, 130.0, 141.1,
145.0, 146.2, 166.5; MS (ammonia, CI+) m/z 276 (impu-
rity), 262 (impurity), 248, 232, 218; HRMS calcd for
C14H18NO3: 248.1287 (M+H), found: 248.1282. Anal.
Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 67.91; H, 7.02; N, 5.59.
In summary, we have developed methods for the synthe-
sis of substituted isoquinolinones and ortho-substituted
phenanthrenes in good yields. Further studies on the
synthesis of Sch 56036 (1) will be reported in due course.
14. Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6,
3711.
15. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020.
16. The samples of 14 and 15 showed spectroscopic charac-
teristics in agreement with published data; see Acheson, R.
M.; Lee, G. C. M. J. Chem. Soc., Perkin Trans. 1 1987,
2321; Ibrahim, Y. A.; Al-Awadi, N. A.; Kaul, K.
Tetrahedron 2001, 57, 7377.
Acknowledgements
We thank the EPSRC for their generous support of this
project, GlaxoSmithKline for the generous endowment

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E. R. Walker et al. / Tetrahedron Letters 46 (2005) 6537–6540
17. For previous syntheses of the intermediates 17, see:
Houry, S.; Geresh, S.; Shani, A. Israel J. Chem. 1973,
11, 805; Geresh, S.; Levy, O.; Markovits, Y.; Shani, A.
Tetrahedron 1975, 31, 2803.
20. Competition between SNAr attack of hydroxide and
palladium catalyzed insertion resulted in low Suzuki
coupling yields where R = NO2.
21. For previous syntheses of the phenanthrenes 19, see:
Bachmann, W. E.; Edgerton, R. O. J. Am. Chem. Soc.
1940, 62, 2219; Dewar, M. J. S.; Warford, E. W. T. J.
Chem. Soc., Abstr. 1956, 3570; Dixon, J. A.; Neiswender,
D. D., Jr. J. Org. Chem. 1960, 25, 499; Barnes, R. A.;
Hirschler, H. P.; Bluestein, B. R. J. Am. Chem. Soc. 1952,
74, 32.
18. For
a previous synthesis of 2-allyl-6-methoxyphenyl
triflate, see: Ohe, T.; Miyaura, N.; Suzuki, A. J. Org.
Chem. 1993, 58, 2201.
19. Bringmann, G.; Wenzel, M.; Kelly, T. R.; Boyd, M. R.;
Gulakowski, R. J.; Kaminsky, R. Tetrahedron 1999, 55,
1731.