Chemoenzymatic formal synthesis of (-)-balanol. Provision of optical data for an often-reported intermediate

Article abstract of DOI:10.1016/j.tetlet.2008.06.026

Formal total synthesis of (-)-balanol was accomplished from bromobenzene in 13 steps via the bis-benzyl derivative 3, whose optical rotation data have been provided.

Full text of DOI:10.1016/j.tetlet.2008.06.026

Tetrahedron Letters 49 (2008) 5211–5213
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Tetrahedron Letters
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Chemoenzymatic formal synthesis of (ꢀ)-balanol. Provision of
optical data for an often-reported intermediate
*
Bradford Sullivan, Tomas Hudlicky
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridhge Avenue, St. Catharines, Canada ON L2S 3A1
a r t i c l e i n f o
a b s t r a c t
Article history:
Formal total synthesis of (ꢀ)-balanol was accomplished from bromobenzene in 13 steps via the bis-
benzyl derivative 3, whose optical rotation data have been provided.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 28 April 2008
Revised 2 June 2008
Accepted 5 June 2008
Available online 12 June 2008
Balanol (1) is a fungal metabolite from Verticillium balanoides
whose isolation and structural elucidation was accomplished by
Sphinx Pharmaceticals in 1993.1 The first total synthesis was
accomplished by Nicolaou in 1994.2a The compound has become
a popular target of synthetic efforts in part because of its potent
inhibitory activity against protein kinase C3 and in part because
of the uniquely functionalized hexahydroazepine core. The focused
effort resulted in 10 total2 and 21 formal4 syntheses of balanol in
both enantiomeric series. The formal syntheses usually target the
hexahydroazepine core either as the free amino alcohol 24n or as
its partially protected forms such as the N-Cbz,4i,j N-Boc,4l,o or
N-benzyl2f,4f,p derivative of 3, Figure 1.
evaluated by the Mosher ester method and 19F NMR. The less than
absolute enantiomeric purity resulted from an incomplete separa-
tion of benzoate 6b from its diastereomer 6a. Thus, after the
removal of the menthyl auxiliary group, the minor diastereomer
led to the opposite enantiomer of the final product, contributing
to its lower optical purity.
As we failed to locate accurate optical reference data we
decided to prepare 3 in a manner that would provide unambigu-
ously the desired enantiomer with absolute optical purity. We
chose as the starting material the cis-bromo cyclohexadiene 7,
Figure 2, whose absolute stereochemistry as well as absolute enan-
tiomeric constitution is well established.5
Several syntheses of the latter compound were reported2f,4p,f in
recent years including our own approach published in early
2008.4u We prepared the bis-benzyl-protected derivative 3 from
vinyl oxirane 4 by the action of the chiral version of the Burgess
reagent, namely 5, as shown in abbreviated form in Scheme 1.
We were surprised to find no reference in the literature to the opti-
cal rotation or optical purity of compound 3 in spite of several
reported asymmetric syntheses of this material. Our own synthesis
produced alcohol 3 in approximately 95% enantiomeric excess as
The strategy of conversion of 7 to balanol intermediate 3, shown
in Figure 2, is based on the recognition that the vinyl bromide func-
tionality is easily saturated, and that the diol is a suitable precursor
for the dialdehyde required for reductive amination to the hexa-
hydroazepine core. The cis olefin can be converted to an aziridine,
which would serve as the means of introduction of the trans-amino
alcohol moiety.
To this end diol 7 available in multigram quantities from
the whole-cell fermentation of bromobenzene6 with E. coli JM109
HO
OH
O
O
O
O
OH
OH
HO
OH
H
H
N
NH2
N
OH
OBn
N
N
H
N
R
O
O
H
(-)-balanol
1
2
3
Figure 1. Balanol and intermediates frequently employed in formal syntheses.
* Corresponding author. Tel.: +1 905 688 5550.
E-mail address: thudlicky@brocku.ca (T. Hudlicky).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.026

5212
B. Sullivan, T. Hudlicky / Tetrahedron Letters 49 (2008) 5211–5213
(pDTG601)7 was protected as its acetonide and converted to the
syn aziridine 8 by adaptation of Corey’s protocol8 as shown in
Scheme 2. Opening of the acetyl aziridine with acetate provided
the protected trans amino alcohol 9b as a 4:1 mixture with the
cis product 9a. Column chromatography followed by crystalliza-
tion yielded only the trans product (GC–MS analysis), which was
O
O O
S
Et3N
N
O
O
O
O
O
5
1. THF, reflux
NH
NH
+
3
O
2. PhCO2NH4, DMF, 55 oC
3. H2SO4, THF, r.t.
OBz
OBz
4
6a
6b
Scheme 1. Formal synthesis of (ꢀ)-balanol.4u
OBn
Oxidative
Cleavage
Introduction of
Functionality
O
OH
HO
Br
NH
OH
BnN
Br
7
3
Saturation
Figure 2. Design of hexahydroazepine 3 from bromobenzene.
1. DMP, p-TsOH, r.t.
O
O
O
2. NBA, SnBr4
O
O
O
MeCN, -30 oC
NHAc
OAc
NHAc
OAc
AcOH, TMSOTf
DCM, r.t.
88%
+
:
7
N
O
3. KHMDS, nBu4NBr
DME, 0 oC
Br
Br
Br
8
9a
9b
68% over 3 steps
1
4
PtO2, NEt3
H2, 1 atm
EtOAc
84%
O
O
O
O
O
1. NaOMe, MeOH
reflux
H
O
O
O
NH
OH
NHAc
OAc
N
O
O
NaH, THF
reflux
83%
2. methylchloroformate
NEt3, DCM, DMAP, r.t
12
11
10
73% over 2 steps
4-benzyloxy-
benzoyl chloride
DCM, NEt3
DMAP, r.t.
82%
OBn
O
OBn
O
OBn
O
O
HO
BnN
HO
N
O
O
N
N
AcOH:THF:H2O
9:3:1
O
O
1. NaIO4, acetone, H2O
O
O
O
reflux
88%
2. Bn-NH2, NaCNBH3
15
13
14
1N NaOH
AcOH, 3 Å MS
THF, -20 oC
MeOH, -78 oC - r.t.
86%
64% over 2 steps
3
Scheme 2. Chemoenzymatic formal synthesis of (ꢀ)-balanol.

B. Sullivan, T. Hudlicky / Tetrahedron Letters 49 (2008) 5211–5213
5213
J. R.; Clardy, J. J. Am. Chem. Soc. 1993, 115, 6452; (b) Ohshima, S.; Yanagisawa,
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hydrogenated in the presence of PtO2 to 10 and converted further
to the cyclic carbamate 12 by basic hydrolysis, treatment with
methyl chloroformate, and sodium-hydride-mediated cyclization
of carbamate 11. The carbamate was acylated with p-benzyloxy
benzoyl chloride to yield 13 whose hydrolysis furnished diol 14.
Oxidative cleavage generated a dialdehyde species (not shown)
that was immediately subjected to reductive amination conditions
in the presence of benzylamine.9 Mild hydrolysis of the cyclic car-
bamate 15 furnished the N-benzyl derivative 310 exhibiting optical
4. For synthetic approaches to the hexahydroazepine unit see: (a) Mueller, A.;
Takyar, D. K.; Wit, S.; Konig, W. A. Liebigs Ann. Chem. 1993, 651; (b) Hughes, P.
F.; Smith, S. H.; Olson, J. T. J. Org. Chem. 1994, 59, 5799; (c) Hu, H.; Jagdmann, G.
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1996, 7, 2901; (f) Wu, M. H.; Jacobsen, E. N. Tetrahedron Lett. 1997, 38, 1693; (g)
Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V.
Tetrahedron 1997, 53, 17177; (h) Coulon, E.; Cano de Andrade, M. C.;
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B.; Schwabenländer, F.; Telser, J. Tetrahedron: Asymmetry 1999, 10, 4521; (l)
Phansavath, P.; Paule, S. D.; Ratovelomanana-Vidal, V.; Genêt, J. P. Eur. J. Org.
Chem. 2000, 3903; (m) Riber, D.; Hazell, R.; Skrystrup, T. J. Org. Chem. 2000, 65,
5382; (n) Masse, C. E.; Morgan, A. J.; Panek, J. S. Org. Lett. 2000, 2, 2571; (o)
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rotation of ½a 2D3
ꢀ5.6 (c 0.2, CHCl3).
ꢁ
In summary, the synthesis of (ꢀ)-3 (R = Bn) was accomplished
in 12 steps from diol 7 in order to provide accurate optical rotation
data. The synthesis of the corresponding (+)-3 (R = Bn) may be
envisioned from the
a-isomer of aziridine 8. Full details of the
enantiodivergent synthesis of
3 from bromobenzene will be
reported in due course.
Acknowledgements
The authors are grateful to the following agencies for financial
support: Natural Science and Engineering Research Council
(NSERC), TDC Research Foundation, Canada Foundation for Innova-
tion (CFI), Ontario Innovation Trust (OIT), Research Corporation,
TDC Research, Inc., and Brock University.
5. (a) Hudlicky, T.; Gonzales, D.; Gibson, D. Aldrichim. Acta. 1999, 32, 35; (b)
Johnson, R. A. Org. React. 2004, 63, 117.
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525.
7. Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989, 264, 14940.
8. Yeung, Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310.
References and notes
9. Painter, G. F.; Eldridge, P. J.; Falshaw, A.
225.
. Bioorg. Med. Chem. 2004, 12,
1. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen, W. P.; Ballas,
L. M.; Loomis, C. R.; Jiang, J. B.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1993, 115,
6452–6453.
10. Analytical data for (ꢀ)-3-yellow oil: Rf 0.31 (3:2 ethyl acetate–hexanes); ½a D23
ꢁ
ꢀ5.6 (c 0.2, CHCl3); Standard deviation for (ꢀ)-menthol standard: ½ ꢁ
a 2D3
ꢀ48.65 0.068 (c 10, EtOH); Literature value for (ꢀ)-menthol: ½a D22
ꢀ50 (c
ꢁ
2. For total synthesis of balanol see: (a) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J.
Am. Chem. Soc. 1994, 116, 8402; (b) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.;
Smith, S. H.; Hu, H. J. Org. Chem. 1994, 59, 5147; (c) Nicolaou, K. C.; Koide, K.;
Bunnage, M. E. Chem. Eur. J. 1995, 1, 454; (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. 1995, 1, 2355; (e) Tanner, D.; Almario, A.;
Högberg, T. Tetrahedron 1995, 51, 6061; (f) Lampe, J. W.; Hughes, P. F.; Biggers,
C. K.; Smith, S. H.; Hu, H. J. Org. Chem. 1996, 61, 4572; (g) Barbier, P.;
Stadlwieser, J. Chimia 1996, 50, 530; (h) Tanner, D.; Tedenborg, L.; Almario, A.;
Pettersson, I.; Csöregh, I.; Kelly, N. M.; Andersson, P. G.; Högberg, T. Tetrahedron
1997, 53, 4857; (i) Miyabe, H.; Torieda, M.; Kiguchi, T.; Naito, T. Synlett 1997,
580; (j) Miyabe, H.; Toreida, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J. Org.
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10, EtOH).11 Optical purity of the Mosher ester of (ꢀ)-3 >95% [Within the
detection limits of 19F NMR of the (S)-(+)-Mosher ester of (ꢀ)-3: d ꢀ71.26; ( )-
3: d ꢀ71.26 and ꢀ71.58.]. IR (film)
m 3407, 3377, 2955, 1638, 1611, 1298,
1140 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.55–1.99 (m, 4H), 2.50 (m, 1H), 2.73
;
(dd, J = 1.9, 14.3 Hz, 1H), 2.93 (dd, J = 2.0, 14.2 Hz, 1H), 3.00 (m, 1H), 3.42 (d,
J = 13.2 Hz, 1H), 3.74–3.78 (m, 2H), 3.88 (m, 1H), 5.15 (s, 2H), 6.54 (d, J = 8.7 Hz,
1H), 6.99 (d, J = 6.8 Hz, 2H), 7.22–7.50 (m, 12H) 13C NMR (150 MHz, CDCl3) d
29.7, 31.5, 54.4, 58.0, 59.9, 64.2, 70.1, 77.5, 114.5, 126.4, 127.4, 127.5 (2 ꢂ C),
128.2, 128.7 (2 ꢂ C), 128.9 (2 ꢂ C), 129.0, 129.5 (2 ꢂ C), 136.4, 161.4,
167.8 ppm; MS (FAB) m/z (%) 431 (M+H+); 41(34), 43(43), 57(51), 71(34),
91(71), 149(100); HRMS calcd for C27H31N2O3 431.2310, found 431.2312.
11. Optical data for (ꢀ)-menthol: (a) ½a D22
ꢀ50 (c 10, EtOH) Vegh, D.; Boireau, G.;
ꢁ
Henry-Basch, E. J. Organomet. Chem. 1984, 267, 127; (b) ½a D25
ꢀ50 (c 10, EtOH)
ꢁ
3. For survey of biological activities see: (a) Kulanthaviel, P.; Hallock, Y. F.; Boros,
C.; Hamilton, S. M.; Janzen, W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B.; Steiner,
Daniewski, A. R.; Warchol, T. Pol. J. Chem. 1992, 66, 1985.