Formal total synthesis of (-)-balanol: a potent PKC inhibitor

Article abstract of DOI:10.1016/j.tetlet.2009.10.120

An efficient formal total synthesis of the PKC inhibitor balanol 1 is described, starting from the commercially available pentane1,5-diol. A Shi epoxidation and Pd(0)-mediated nitrogen substitution with double inversion established the correct configuration of the balanol precursor 3.

Full text of DOI:10.1016/j.tetlet.2009.10.120

Tetrahedron Letters 51 (2010) 467–470
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Tetrahedron Letters
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Formal total synthesis of (ꢀ)-balanol: a potent PKC inhibitor
*
Srinivasarao Yaragorla, Ramaiah Muthyala
Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient formal total synthesis of the PKC inhibitor balanol 1 is described, starting from the commer-
cially available pentane1,5-diol. A Shi epoxidation and Pd(0)-mediated nitrogen substitution with double
inversion established the correct configuration of the balanol precursor 3.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 October 2009
Accepted 26 October 2009
Available online 13 November 2009
Keywords:
Balanol
PKC inhibitors
Triphenyl phosphine mediated
rearrangement
Shi epoxidation
Pd(PPh3)4-mediated epoxide opening
Balanol 1 is a fungal metabolite, isolated at Sphynx Pharmaceu-
ticals from Verticillium balanolides1 and Fusarium merismoides.2 Ini-
tially, Balanol was reported as a PKC inhibitor,1,3 and later it was
found to be a competitive inhibitor of ATP and to potently inhibit
PKA and other kinases as well.4 Some balanol analogues inhibit
PKA more specifically than PKC (some 2000-fold more potent than
the parent molecule).5 The selectivity of balanol itself is different
among different PKC isoenzymes; the nanomolar IC50 values for
PKA made it a promising lead structure for drug development. This
high selectivity and potency indicates the focused attention of syn-
thetic and medicinal chemists for synthesizing novel analogues for
the development of therapeutic drugs. The first total synthesis of
balanol was published by Nicolaou et al.6a Later, various research
groups throughout the world published additional total6 and for-
mal syntheses7 of balanol and its analogues.
Generally, the formal syntheses are focused on making the two
segments namely, hexahydroazepine segment with 4-hydroxy
benzamide (3) and benzophenone moiety (2) with suitable protec-
tions on oxygen and nitrogen atoms (Scheme 1).6f,7f,p,u
As part of our ongoing program directed toward the develop-
ment of therapeutic agents for the treatment of PKC- and PKA-
mediated disorders, we planned a procedure amenable to the
synthesis of 3, a key intermediate frequently employed in total
syntheses of balanol. This compound contains a hexahydroazepine
core and a protected 4-hydroxy benzamide segment of balanol.
This would enable the discovery of more analogues for enhanced
enzyme selectivity and improved pharmacokinetic properties.
Herein we report the synthesis of this common intermediate 3.7
The structure of balanol 1 consists of four rings, linked by amide
and ester bonds. A commonly used retrosynthesis of 1 is shown in
Scheme 1.
As shown in Scheme 2, we envisaged a practical synthesis that
the hexahydroazepine 3 could be synthesized from hydroxyl azide
5, which in turn could be constructed from the Pd (0)-catalyzed
azide substitution on epoxy ester 6.
The synthesis of azepine compound 3 commenced with the
commercially available 1,5-pentanediol (see Scheme 3). This was
selectively silylated as its mono tert-butyldimethylsilyl ether un-
der standard conditions (TBDMSCl, imidazole, DMF, rt, 6 h) in
90% yield. PDC oxidation of the resultant alcohol in dichlorometh-
ane at rt furnished aldehyde 7 in 88% yield. Aldehyde 7 was treated
with lithiated ethyl propiolate at ꢀ78 °C to furnish the hydroxyl
alkynoate 8 in 83% yield. Triphenylphosphine-mediated deoxyge-
native rearrangement (via allene formation)8 of 8 in benzene at
rt yielded the (E,E)-a,b,c,d-unsaturated ester 9 in 76% yield. Treat-
ment of this diene ester 9 under Shi epoxidation9 conditions with
ketone 12 as a catalyst provided the desired epoxide 6 in moderate
yield (46%, 60% conversion) along with ꢁ5% of bis-epoxide. How-
ever, enantioselectivity of the epoxidation was excellent (96.2%
ee).10 The resultant
a,b-unsaturated c,d-epoxy ester 6 was sub-
jected to Pd(0)-catalyzed stereospecific azide substitution (TMSN3,
Pd(PPh3)4, THF, rt, 5 h) to furnish syn-azido alcohol 5 in 91% yield
with double inversion of configuration.11 The secondary hydroxyl
of 5 was silylated quantitatively with tert-butyldimethylsilyl tri-
fluoromethanesulfonate and 2,6-lutidine (CH2Cl2, rt, 12 h) to yield
the corresponding disilyl compound. We initially tried the depro-
tection of the primary silyl ether with oxone in aqueous methanol
(1:1).12 Unfortunately after stirring for 24 h, we observed that both
the silyl groups were deprotected (30%) along with the required
* Corresponding author. Tel.: +1 612 624 7120; fax: +1 612 626 2595.
E-mail address: muthy003@umn.edu (R. Muthyala).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.120

468
S. Yaragorla, R. Muthyala / Tetrahedron Letters 51 (2010) 467–470
COOH
OR1
O
OH
RO
O
ROOC
OH
H
N
HO
OH
HO
O
H
N
O
O
OH
N
OR OR
O
O
R1
NH
3
2
Balanol
1
Scheme 1. Retrosynthetic analysis of balanol 1; R, R1 are some suitable protecting groups (R1 = Bn).
TBSO
N3
HO
N3
O
TBSO
COOEt
3
N
COOEt
6
TBSO
5
4
1,5-Pentane diol
Scheme 2.
COOEt
a.TBDMSCl, imidazole,
DMF, r.t., 6 h, 90%.
LHMDS, THF,
Ethylpropiolate,
-78 oC, 3 h, 83%
TBSO
O
HO
OH
TBSO
b.PDC, CH2Cl2,
r.t., 3 h, 88%
OH
8
7
TMSN3, Pd(PPh3)4,
THF, r.t., 5 h, 91%
Shi epoxidation,
Ph3P, C6H6,
r.t., 5 h, 76%
12, Oxone, 0 oC,
O
TBSO
COOEt
TBSO
COOEt
double inversion
6 h, 46%
6
9
TBSO
TBSO
a.O3, CH2Cl2,
N3
a.TBSOTf, 2,6 lutidine,
CH2Cl2, r.t., 12 h, 99%
N3
OH
-78 oC, 15 min.,
TBSO
COOEt
OH
OH
b.NaBH4, MeOH,
0 oC, 30 min.,
80% for two steps.
b.TsOH, MeOH,
OH
10
N3
COOEt
-10 oC, 15 min., 80%
5
11
O
TBSO
HO
N3
HN
N
(CF3SO2)2O,
2,6 lutidine,
a.LiAlH4, THF,
reflux, 1h.
reference
CH2Cl2, BnNH2,
1
N
-78 oC to r.t.,
24 h., 65%
b.NEt3, CH2Cl2,
OBn
13,
3 h, 55%
O
Cl
O
for two steps.
O
O
O
O
4
O
3
OBn
Shi epoxidation catalyst
13
12
Scheme 3. Synthesis of azepine 3 of (ꢀ)-balanol.
compound 10 (ꢁ80% conversion of the starting material). This
deprotection was successfully achieved instead with a catalytic
amount of para-toluenesulfonic acid in methanol at ꢀ10 °C, for
15 min,13 which provided monoalcohol 10 in 80% yields. In one-
pot, ozonolysis of compound 5 at ꢀ78 °C followed by the reduction
(NaBH4, MeOH, 0 °C, 30 min) of the resultant aldehyde to alcohol
yielded diol 11 in 80% yield. Diol 11 was treated with trifluoro-
methanesulfonic anhydride in the presence of 2,6-lutidine (CH2Cl2,

S. Yaragorla, R. Muthyala / Tetrahedron Letters 51 (2010) 467–470
469
Chem. 2000, 3903–3907; (m) Riber, D.; Hazell, R.; Skrystrup, T. J. Org. Chem.
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ꢀ78 °C, 30 min) to form the ditriflate of 11. This was treated in situ
with excess benzylamine (ꢀ78 °C to rt) for 24 h to provide the aze-
pine 4 in 65% yield. Lithium aluminum hydride reduction (LiAlH4,
THF, 0 °C to reflux, 1 h) of azepine 4 followed by treatment of the
resultant hydroxy amine with 4-benzyloxy benzoyl chloride
(NEt3, CH2Cl2, 0 °C, 3 h) provided the key intermediate hexa-
hydroazepine 3 (55% yield for two steps), the spectral data for
which are in agreement with the literature data.7v,u
In conclusion, an efficient formal total synthesis of protein
kinase inhibitor balanol is described, starting from the known alde-
hyde (7) in eight steps in high overall yields (6%). Triphenylphos-
phine-mediated deoxygenative rearrangement of hydroxy
8. (a) Guo, C.; Lu, X. J. Chem. Soc., Chem. Commum. 1993, 394–395; (b)
Chandrasekhar, S.; Sultana, S. S. Tetrahedron Lett. 2006, 47, 7255–7258.
9. (a) Wang, Z.-X.; Tu, Y.; Fronh, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 118,
11224; (b) Fronh, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem.
1998, 63, 2948.
10. HPLC was determined by Chiralcel OD-H 98/2 hexanes/iPrOH, 254 nm.
11. (a) Miyashita, M.; Mizutani, T.; Tadano, G.; Iwata, Y.; Miyazawa, M.; Tanino, K.
Angew. Chem., Int. Ed. 2005, 44, 5094–5097; (b) Chandrasekhar, S.; Parida, B. B.;
Rambabu, C. J. Org. Chem. 2008, 73, 7826–7828.
alkynoate to the corresponding (E,E)-a,b.c,d-unsaturated diene es-
ter and its Shi epoxidation followed by Pd(0)-mediated nitrogen
substitution with double inversion of configuration were key steps
in the construction of the hexahydroazepine 3.14
12. Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 1, 1701–1703.
13. Crouch, R. D. Tetrahedron. 2004, 60, 5833–5871. and references cited therein.
14. Experimental section and spectral data for some key intermediates: (E)-Ethyl 3-
((2R,3R)-3-(3-(tert-butyldimethylsilyloxy) propyl)oxiran-2-yl)acrylate (6):
A
Acknowledgments
mixture of 5 mL acetonitrile, 10 mL buffer (0.05 M, Na2B2O4ꢂ10H2O in EDTA
4 ꢃ 10ꢀ4 M), 10 mL dimethoxymethane, diene ester
9 (0.8 g, 2.8 mmol),
tetrabutylammonium hydrogen sulfate (38 mg, 0.1 mmol), and Shi
epoxidation catalyst9b 12 (218 mg, 0.9 mmol) was stirred at 0 °C. A solution
of Oxone (1.5 g, 3.0 mmol) in 10 mL of 4 ꢃ 10ꢀ4 M EDTA and a solution of
potassium carbonate (1.9 g, 14.0 mmol) in 10 mL of water were added
separately and simultaneously, via a syringe pump over a 6h period. The
reaction was then immediately quenched by the addition of hexanes (30 mL)
and the aqueous layer was further extracted with hexanes (3 ꢃ 20 mL). The
combined organic layers were washed with brine (20 mL), dried over Na2SO4,
and concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (hexanes/ethyl acetate = 25/1, buffered with
1% NEt3) to afford the compound 6 as a light yellow oil (390 mg, 46% yield)
with 96.2% ee (determined by HPLC: Chiralcel OD-H, 98/2 hexanes/iPrOH,
This work was supported by Bob Allison Ataxia Research Center.
Professor Harry Orr is thanked for guiding us to identify drug lead
compound. Sandyasri Yaragorla is thanked for her technical sup-
port. Institute for Therapeutics Discovery & Development, the Uni-
versity of Minnesota is acknowledged for NMR and mass spectral
data.
Supplementary data
254 nm). ½a 2D1
ꢄ
+20.8 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz): d 6.62 (dd,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.120.
J = 7.1, 15.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.65–3.54 (m, 2H), 3.15 (dd, J = 1.8,
7.08 Hz, 1H), 2.89–2.86 (m, 1H), 1.69–1.59 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H), 0.84
(s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3, 100 MHz): d 165.6, 144.7, 123.6, 62.3,
61.2, 60.5, 56.3, 28.9, 28.5, 25.9 (3C), 18.2, 14.2,ꢀ5.3 (2C); IR (film)
2985, 1733, 1374, 1265, 1249, 1216, 1046 cmꢀ1
Mass (ESI, m/z): 315.4
(M+H)+; HRMS (ESI, m/z): calcd for C16H30O4Si: 315.1992. found: 315.1995.;
(4R,5R,E)-Ethyl 4-azido-8-(tert-butyldimethylsilyloxy)-5-hydroxyoct-2-enoate
(5): To a stirred solution of (E)- ,b-unsaturated - ,d -epoxy ester 6 (300 mg,
mmax: 3021,
References and notes
;
1. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen, W. P.; Ballas,
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1993, 115, 6452.
a
c
1.0 mmol) in THF (15 mL) were added TMSN3 (0.25 mL, 2.0 mmol) and
Pd(PPh3)4 (126 mg, 0.10 mmol) under nitrogen atmosphere at room
temperature and the mixture was stirred for 5 h. Then 2 mL of 10% citric
acid in methanol was added to the reaction mixture and stirred for 2 h at room
temperature; the solvent was removed under reduced pressure and the crude
solid was triturated with diethyl ether (3 ꢃ 10 mL). The combined organic
layers were dried over Na2SO4, concentrated, and purified by column
chromatography (hexanes/ethyl acetate = 1/5) to afford syn azido alcohol 5
2. Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujji, T.; Sano, T.; Matsukuma, S.;
Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.; Arisawa, M.; Okuda, T. J.
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Taylor, S. S. Biochemistry 2004, 43, 85–96.
as a colorless oil (318 mg, 91% yield). ½a D21
ꢄ
ꢀ3.2 (c 0.5, CHCl3); 1H NMR (CDCl3,
400 MHz): d 6.80 (dd, J = 7.1, 15.6 Hz, 1H), 6.02 (dd, J = 1.2, 15.6 Hz, 1H), 4.14
(q, J = 7.2 Hz, 2H), 3.95–3.91 (m, 1H), 3.67–3.51 (m, 2H), 3.40 (d, J = 4.0 Hz, 1H),
1.69–1.57 (m, 3H), 1.48–1.39 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), 0.82 (s, 9H), 0.00
(s, 6H); 13C NMR CDCl3, 100 MHz): d 165.5, 141.5, 124.8, 73.1, 67.3, 63.2, 60.7,
6. (a) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402–
8403; (b) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J. Org.
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Eur. J. 1995, 1, 454–466; (d) Adams, C. P.; Fairway, S. M.; Hardy, C. J.; Hibbs, D.
E.; Hursthouse, M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I. J. Chem.
Soc., Perkin Trans. 1 1995, 2355–2362; (e) Tanner, D.; Almario, A.; Högberg, T.
Tetrahedron 1995, 51, 6061–6070; (f) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.;
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30.9, 28.8, 25.9 (3C), 18.3, 14.2, ꢀ5.4 (2C); IR (neat)
mmax: 3430, 2980, 2932,
2108, 1733, 1685, 1450, 1250, 1180 cmꢀ1; Mass (ESI, m/z): 358.2 (M+H)+;
HRMS (ESI, m/z): calcd for C16H32N3O4Si: 358.2162. found: 358.2151.; N-
((3R,4R)-1-Benzyl-4-hydroxyazepan-3-yl)-4-(benzyloxy) benzamide (3): To a
stirred solution of LiAlH4 (31 mg, 0.8 mmol) in 6 mL dry THF at 0 °C was slowly
added azepine 4 (100 mg, 0.28 mmol, in 2 mL THF) and stirred at reflux for 1 h
under nitrogen atmosphere. The reaction was cooled to 0 °C and Glaubler’s salt
(sodium sulfate decahydrate) was slowly added to precipitate the aluminum
salts and then filtered on a Celite pad. Celite cake was washed with ethyl
acetate (2 ꢃ 5 mL) and the filtrate was dried over anhyd Na2SO4, concentrated
under reduced pressure to provide the crude azepine core with free hydroxyl
and amine functionalities. This crude azepine was used for the amide bond
formation without further purification. Azepine amine (50 mg, 0.02 mmol) was
dissolved in CH2Cl2 (5 mL) and was added to triethylamine (0.12 mmol,
0.12 mL) and 4-benzyloxybenzoylchloride (56 mg, 0.02 mmol) at 0 °C under
nitrogen atmosphere and stirred for 3 h. Water (5 mL) was added to the
reaction mixture and the organic layer was separated. The aqueous layer was
extracted (2 ꢃ 10 mL) with dichloromethane and the combined organic layers
were washed with brine (10 mL), dried over sodium sulfate, and concentrated
under reduced pressure to give the crude product. This crude mixture was
purified by silica gel column chromatography (hexanes/ethyl acetate = 1/2) to
yield compound 3 as a yellow viscous liquid (67 mg, 55% for two steps). ½a D23
ꢄ
ꢀ5.6 (c 0.2, CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.47–7.38 (m, 4H), 7.37–7.23
(m, 8H), 6.93 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 6.8 Hz, 1H), 5.12 (s, 2H), 3.90–3084
(m, 1H), 3.77–3.74 (m, 1H), 3.71 (d, J = 12.8 Hz, 1H), 3.42 (d, J = 12.8 Hz, 1H),
3.04–2.98 (m, 1H), 2.95 (dd, J = 2.8, 14.4 Hz, 1H), 2.72 (dd, J = 2.9, 14.4 Hz, 1H),
2.53-2.44 (m, 1H), 1.94-1.85 (m, 2H), 1.71–1.69 (m, 1H), 1.68–1.57 (m, 1H); 13C

470
S. Yaragorla, R. Muthyala / Tetrahedron Letters 51 (2010) 467–470
NMR (CDCl3, 100 MHz): d 167.6, 161.3, 139.6, 136.3, 129.4 (2C), 128.9, 128.8
(2C), 128.7 (2C), 128.2 (2C), 127.5 (2C), 127.4 (2C), 126.5, 114.5 (2C), 77.4, 76.5,
64.1, 59.4, 57.5, 53.8, 31.2, 24.6. IR (film) max: 3407, 3376, 2955, 1638, 1611,
1296, 1140 cmꢀ1; Mass (ESI, m/z): 431.2 (M+H)+; HRMS (ESI, m/z): calcd for
C27H31N2O3: 431.2335, found: 431.2328.
m