A stereoselective synthesis of the hexahydroazepine core of (-)-balanol

Article abstract of DOI:10.1016/j.tetlet.2005.12.123

A stereoselective synthesis of the hexahydroazepine core of (-)-balanol is described. The key step of the route includes the bromosulfonamidation of an olefin using the intramolecular sulfilimine group as the nucleophile and the Pummerer ene reaction.

Full text of DOI:10.1016/j.tetlet.2005.12.123

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1585–1588
A stereoselective synthesis of the hexahydroazepine core of
(À)-balanolq
Sadagopan Raghavan* and Ch. Naveen Kumar
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 17 November 2004; revised 22 December 2005; accepted 26 December 2005
Available online 20 January 2006
Abstract—A stereoselective synthesis of the hexahydroazepine core of (À)-balanol is described. The key step of the route includes
the bromosulfonamidation of an olefin using the intramolecular sulfilimine group as the nucleophile and the Pummerer ene reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
(À)-Balanol 1, a fungal metabolite, was isolated inde-
pendently by Kulanthaivel et al.1 from Verticillium
balanoides and by Ohshima et al.2 from Fusarium mer-
ismoides. Balanol is a potent inhibitor of protein kinase
C (PKC), a family of phospholipid dependent serine/
threonine protein kinases, implicated in a number of dis-
eases including AIDS, cancer, asthma, diabetes, cardio
vascular disorders and central nervous system dysfunc-
tion. Investigations have revealed that the remarkable
inhibitory activity of balanol is due to its binding to
the ATP docking site of protein kinase.3 The unique
structure and the biological activity of balanol have at-
tracted the attention of synthetic chemists and a number
of reports have disclosed the total synthesis4 or the syn-
thesis of the fragments.5 Balanol consists of the hexa-
hydroazepine fragment and the benzophenone
fragment (Fig. 1).
We recently described a methodology for the stereo-
selective elaboration of vicinal amino alcohol derivatives
from allyl alcohols/ethers using an intramolecular sulfil-
imine as the nucleophile.6 As a demonstration of the po-
tential of the methodology, we describe herein a concise
stereoselective synthesis of the hexahydroazepine sub-
unit 2, of balanol. By a retrosynthetic analysis (Scheme
1), the azidoaldehyde 3 was envisaged as the key inter-
mediate, which could be derived from the alkene 4.
Compound 4 can be obtained from amino alcohol 5,
which in turn can be traced back to the allyl alcohol 7
via sulfilimine 6.
The synthesis began with alcohol 7 (88% ee) obtained by
Sharpless’ kinetic resolution.7 Treatment of 7 with thio-
phenol in the presence of DBU8 yielded sulfide 8.9 Sul-
fide 8 on treatment with Chloramine-T afforded an
HO
O
O
HO
O
O
O
HO2C
OH
HO2C
OH
H
OH
OH
N
NH2
OH
OH
OH
N
N
O
H
H
Hexahydroazepine fragment
(-)-Balanol, 1
Figure 1.
Keywords: (À)-Balanol; Sulfilimine; Bromosulfonamidation; Pummerer ene reaction.
q IICT Communication No. 051216.
*
Corresponding author. Tel.: +91 04027160123; fax: +91 04027160512; e-mail: purush101@yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.123

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S. Raghavan, Ch. N. Kumar / Tetrahedron Letters 47 (2006) 1585–1588
PhS
OP
PhS
OP
OP
NHP
N3
NHP
NHP
N3
OHC
N
P
n
3
2
4
O
OH
NP OH
PhS
OH
PhS
TsO
Br
NHP
7
5
6
P = Protecting group
Scheme 1.
equimolar mixture of sulfilimines 6s and 6a. Compound
6 on reaction with N-bromosuccinimide yielded cleanly
bromosulfonamides 5a and 5s.6 The reaction proceeds
via the intermediates I and II, formed by the 5-exo
nucleophilic attack of the sulfilimine onto the olefin p-
complexed to the bromonium ion. Hydrolysis by the at-
tack of water on sulfur afforded the products (Scheme
2). Protection of 5 as an acetonide, followed by displace-
ment of the bromide by azide gave 10 which on treat-
ment with trifluoroacetic anhydride10 yielded the
Pummerer intermediate 11. The intermediate without
isolation was subjected to reaction with 1-hexene in
the presence of SnCl4 to afford the ene reaction product
4.11 The crude 1H NMR spectrum of 4 revealed the pres-
ence of one compound only. The configuration at the
newly created stereogenic center was not established
since it was to be removed in the subsequent step. Elabo-
ration of 4 to the hexahydroazepine core of balanol
was planned by ozonolysis of the double bond followed
by reductive cyclization of the resulting azidoaldehyde
using Raney-Nickel with concurrent removal of the thio-
phenyl group. In the event, ozonolysis of 4 in dichloro-
methane did not yield 3 but 12 only. Under the reaction
conditions, the sulfide is probably converted to the
sulfone and the double bond into an ozonide. a,b-
Unsaturated aldehyde 12 is presumably formed via
b-elimination of phenylsulfinic acid (Scheme 3). Reduc-
tive amination of 12 would directly afford the hexa-
hydroazepine moiety. Indeed, treatment of 12 with Pd/
C in EtOH/EtOAc under an atmosphere of hydrogen
afforded 13. However, the reaction proved irreproduc-
ible; many spots were observed on TLC examination
during scale up and the crude 1H NMR spectrum
revealed tosyl deprotection. Therefore, the hexa-
hydroazepine fragment was elaborated in a stepwise
manner. Aldehyde 12 was reduced using Luche’s proto-
col12 to afford allyl alcohol 14. Hydrogenation of 14
with Pd/C in the presence of di-tert-butyl di carbonate
in EtOAc afforded carbamate 15. Mesylation of the
alcohol cleanly yielded mesylate 16, which without puri-
fication was treated with potassium tert-butoxide in
anhydrous THF to cleanly afford 2. During the work
up, the acetonide group underwent deprotection to pro-
duce a small amount of alcohol 17. Treatment of 2 with
catalytic amount of PPTS in ethanol afforded 17.13
In summary, we have disclosed a concise stereoselective
synthesis of the hexahydroazepine core of balanol. The
key steps of the synthesis include elaboration of bromo-
sulfonamide 5 via intramolecular sulfilimine participa-
tion and Pummerer ene reaction. Efforts are in
progress to synthesize other bioactive target molecules
OH
NTs
OH
NTs OH
PhS
+
b
R
PhS
7, R = OTs
6s
6a
a
8, R = SPh
Ph
S
O
OH
NTs OH
PhS
H2O
N
Ts
Br
c
PhS
Br
Br
6s
OH
NHTs
5a
I
O
OH
NTs OH
N
H2O
Ts
Br
c
S
PhS
PhS
Ph
OH
6a
NHTs
5s
II
Scheme 2. Reaction conditions: (a) PhSH, DBU, toluene, rt, 1 h, 80%; (b) NaNTsCl, CH3CN, rt, 30 min, 90%; (c) NBS, toluene, rt, 1 h, 80%.

S. Raghavan, Ch. N. Kumar / Tetrahedron Letters 47 (2006) 1585–1588
1587
O
OH
O
O
O
a
c(i)
PhS
PhS
NTs
X
PhS
NTs
N3
Br
NHTs
CF3(O)CO
5
9, X = Br
11
b
10, X = N3
O
O
Ph
S
PhS
2
NTs
N3
c(ii)
NTs
N3
d
O
O
H
CHO
4
e
OX
O
O
g
i
NTs
N3
NTs
NHBoc
NTsY
N
X
P
X
12, X = CHO
15, X = OH
16, X = OMs
13, P = H; X, Y =CMe2
2, P = Boc; X, Y = CMe2
17, P = Boc; X =Y =H
h
f
14, X = CH2OH
j
Scheme 3. Reaction conditions: (a) 2,2-dimethoxypropane, cat. CSA, acetone, 70 °C, 6 h, 70%; (b) NaN3, DMSO, 80 °C, 6 h, 90%; (c) (i) TFAA,
CH2Cl2, 0 °C, 30 min, (ii) 1-hexene, SnCl4, 0 °C, 5 min, 70%; (d) O3, CH2Cl2, À78 °C, 30 min, then Me2S, À78 to 0 °C, 30 min, 75%; (e) H2, Pd/C,
EtOH/EtOAc, rt, 6 h; (f) NaBH4, CeCl3, MeOH, 0 °C, 30 min, 70%; (g) (Boc)2O, Pd/C, H2, rt, 6 h, 90%; (h) Ms-Cl, Et3N, cat. DMAP, CH2Cl2, 0 °C,
30 min, 88%; (i) KOtBu, THF, rt, 1 h, 70%; (j) PPTS, EtOH, 80 °C, 1 h, 83%.
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Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I. J.
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Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J. Org.
Chem. 1996, 61, 4572; (f) Barbier, P.; Stadlwieser, J.
Chimia 1996, 50, 530; (g) Tanner, D.; Tedenborg, L.;
Almario, A.; Petersson, I.; Csoeregh, I.; Kelly, N. M.;
Andersson, P. G.; Hogberg, T. Tetrahedron 1997, 53,
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possessing the vicinal amino alcohol unit using our
methodology and the results from these investigations
will be reported in the near future.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Director, IICT, for
his constant support and encouragement, Dr. A. C.
Kunwar for NMR spectra and Dr. M. Vairamani for
the mass spectra. Ch.N.K. is thankful to CSIR (New
Delhi) for the senior research fellowship.
5. For synthetic approaches to the hexahydroazepine unit,
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Benetti, S.; DeRisi, C.; Pollini, G. P.; Zanirato, V. Synlett
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Coulon, E.; CanodeAndrade, M. C.; Ratovelomanana-
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Herdeis, C.; Mohareb, R. M.; Neder, R.; Schwabenlander,
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