Concise syntheses of stereoisomeric hexahydroazepine derivatives related to the protein kinase inhibitor balanol

Article abstract of DOI:10.1016/j.tetlet.2008.07.031

A stereodivergent route to four stereoisomeric azepane derivatives related to the important protein kinase inhibitor balanol is developed which utilises (-)- or (+)-serine as starting material, and a ring-closing metathesis as the key ring forming step.

Full text of DOI:10.1016/j.tetlet.2008.07.031

Tetrahedron Letters 49 (2008) 5498–5501
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise syntheses of stereoisomeric hexahydroazepine derivatives
related to the protein kinase inhibitor balanol
*
Sankar P. Roy, Shital K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereodivergent route to four stereoisomeric azepane derivatives related to the important protein
kinase inhibitor balanol is developed which utilises (À)- or (+)-serine as starting material, and a ring-
closing metathesis as the key ring forming step.
Received 30 May 2008
Revised 27 June 2008
Accepted 5 July 2008
Available online 9 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Balanol
Ring-closing metathesis
Garner’s aldehyde
Azepane
Protein kinase C is a prime target for therapeutic agents, since
unregulated protein kinase activities are linked to a myriad of
diseases including carcinogenesis.1 Of the various known protein
kinase C (PKC) inhibitors, the fungal metabolite2 balanol (1, Fig.
1) was demonstrated as one of the most potent, having inhibitory
activity in the nanomolar range. This, in turn, has rendered it an
attractive synthetic target over the last 15 years.3 One feature of
balanol, as remarkable as its high potency, is its lack of isozyme
selectivity.4 Compounds that selectively modulate certain PKC iso-
zymes hold promise in the development of novel therapeutics. In
the dual quest for delineating the functional requirements for
PKC inhibition and achieving selectivity, several balanoids with
modification at one or more positions have been prepared and
evaluated.5 The perhydroazepine ring has remained the centre of
focus of most of these studies, since very subtle changes in this
moiety have resulted in compounds of desired potency and/or
selectivity. A number of elegant routes to the azepane core in
(À)-balanol have been described.6 However, a general preparation
of all the stereoisomers of this important moiety has not been re-
ported to the best of our knowledge. In continuation of our studies7
on the asymmetric synthesis of bioactive molecules utilising chiral
pool materials and our interest8 in medium ring heterocyclic sys-
tems, we became interested in developing a flexible synthetic
route to balanoids. Ophiocordin (2) is a closely related metabolite
which shows antifungal activity.9 Herein, we report a concise
synthesis of all four stereoisomers of the hexahydroazepine
subunit common to these two important natural products.
O
HO2C
O
OH
O
O
HO
NH
HN
OH
OH
O
O
OH
O
NH
HN
HO2C
OH
OH
O
HO
1
2
Figure 1. Balanol (1) and ophiocordin (2).
Our retrosynthetic analysis (Fig. 2) of the azepane unit 3 of nat-
ural configuration, hinged on the successful outcome of two crucial
steps, viz. ring-closing metathesis (RCM) of the diene 5 for con-
struction of the tetrahydroazepine ring and a chelation-controlled
addition of vinylmagnesium bromide to the a-chiral aldehyde 6 to
establish the desired anti-configuration of the stereogenic centres
present in 3. The aldehyde 6 was thought to be obtainable from
functional group manipulation of the known10
L-serine derived
Garner’s aldehyde 7.
Thus, compound 7 (Scheme 1), prepared following a modified
procedure,11 was converted to the corresponding N-allylimine 8
by dehydrative condensation with allylamine. Compound 8 was
obtained essentially pure for carrying over to the next step. Reduc-
tion of the imine 8 with sodium borohydride followed by protec-
tion of the resulting amine 9 with Cbz-Cl in the usual manner
* Corresponding author. Tel.: +91 33 25828750; fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S. K. Chattopadhyay).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.031

S. P. Roy, S. K. Chattopadhyay / Tetrahedron Letters 49 (2008) 5498–5501
5499
PGO
PGO
H2
O
RCM
PGO
MgBr
NPG
PGHN
NPG
PGHN
NPG
PGHN
NPG
PGHN
5
3
4
6
CHO
Boc
FGI
O
N
7
Figure 2.
CHO
Boc
i
N
N
R
Boc
iv
ii
HO
BocHN
N
O
O
O
N
Cbz
N
N
Boc
9, R = H
10, R = Cbz
7
iii
8
11
OH
OH
v
+
N
Cbz
N
Cbz
BocHN
BocHN
vi, vii
12
13
CHO
Boc
i
N
N
R
Boc
iv
ii
HO
BocHN
N
O
O
O
N
Cbz
N
N
Boc
16, R = H
17, R = Cbz
14
iii
15
18
OH
OH
v
+
N
N
Cbz
Cbz
BocHN
BocHN
20
19
Scheme 1. Reagents and conditions: (i) allyl amine, molecular sieves 4 Å, CH2Cl2, 0 °C, 24 h; (ii) NaBH4, THF, 0 °C to rt, 15 h; (iii) benzyl chloroformate, NaHCO3, EtOAc, rt,
12 h, 10 (89%), 17 (87%); (iv) HCl (5%), MeOH, rt, 6 h, 11 (90%), 18 (92%); (v) oxalyl chloride, DMSO, N,N-DIPEA, À78 to À35 °C, 1 h, then vinylmagnesium bromide, THF, À78 °C
to rt, 8 h, 12 + 13 (64%), 19 + 20 (61%); (vi) DEAD, PPh3, p-nitrobenzoic acid, THF, 0 °C to rt, 2 h, 89%; (vii) K2CO3, MeOH–H2O, 1 h, 91%.
provided the protected amine 10 in an overall yield of 89% over
three steps. Acid-catalysed deprotection of the oxazolidine unit
in the latter followed by oxidation of the resulting alcohol 11 under
modified Swern conditions12 led to the corresponding chiral alde-
hyde which was used as such in the next step. Addition of this
aldehyde to vinylmagnesium bromide in one-pot furnished the
With the four stereoisomeric diene precursors in hand, we next
focused on their RCM reaction for construction of the tetra-
hydroazepine ring. Initial attempts on RCM of diene 12 with
Grubbs’ first and second generation catalysts under a range of con-
ditions met with failure. Problems associated with RCM of allyl
alcohols have been recognised in many instances.15 We, therefore,
converted the alcohol 12 to the corresponding acetate 21 (Scheme
2) under conventional conditions. However, attempted RCM of 21
in the presence of Grubbs’ first generation catalyst, benzylidenebi-
stricyclo-hexylphosphino-ruthenium(IV) dichloride, proved to be
sluggish and low yielding. Pleasingly, use of Grubbs’ second
generation catalyst, benzylidene[1,3-bis(2,4,6-trimethylphenyl)-
2-imidazolidinylidene]dichloro(tricyclohexylphosphine)-ruthenium16
(22), effected smooth ring closure and the desired cycloalkene 23,
syn- and anti-allyl alcohols 12, [
a
]
À8 (c 1.5, CHCl3), and 13,
D
respectively, in a combined yield of 64%. The isomers were readily
separated by column chromatography, and the diastereomeric
ratio was observed to be 68:32 in favour of the syn-alcohol 12.
Similarly, starting from the
D-serine derived Garner’s aldehyde
14, the amino alcohols 19 and 20 were prepared in comparable
yield and selectivity (63:37) following an identical sequence of
events.
Chelation-controlled addition of Grignard reagents to
-amino aldehydes has been studied13 extensively, and such addi-
tions usually proceed with high level of selectivity. However, addi-
tion to -chiral ,b-diamino aldehydes has not been studied in
detail, to the best of our knowledge. Although the syn-selectivity
in the present instance is somewhat less, the amount of the syn-
product could be raised by simple Mitsunobu-type inversion14 of
the anti-isomer 13 to the desired syn-isomer 12.
a
-chiral
[a] +12 (c 2.0, CHCl3), was obtained in an isolated yield of 89%.
D
a
Sequential removal of the protecting groups from compound 23,
that is, hydrolysis of the acetyl group leading to the alcohol 24,
removal of the Boc-group to afford amine 25 and subsequent
hydrogenolytic removal of the Cbz-group in the latter with
concomitant saturation of the double bond led to the parent
azepane derivative 26 in an overall yield of 41% from 13 over five
steps. Similarly, each of the stereoisomeric dienes 13, 19 and 20
a
a

5500
S. P. Roy, S. K. Chattopadhyay / Tetrahedron Letters 49 (2008) 5498–5501
OH
OH
OR
BocHN
OAc
H2N
H2N
H2N
H2N
H2N
i
i
i
i
v
v
ii
ii
ii
ii
iv
iv
iv
iv
12
13
19
20
N
Cbz
CbzN
CbzN
BocHN
HN
23, R = Ac
24, R = H
21
25
26
iii
iii
iii
iii
OH
OH
OAc
BocHN
OAc
H2N
H2N
H2N
N
Cbz
CbzN
CbzN
BocHN
HN
31
28, R = Ac
29, R = H
30
27
OH
OH
OAc
BocHN
OAc
v
v
N
Cbz
CbzN
CbzN
BocHN
HN
33, R = Ac
34, R = H
32
35
36
OH
OH
OAc
BocHN
OAc
N
Cbz
CbzN
CbzN
BocHN
HN
41
38, R = Ac
39, R = H
40
37
Scheme 2. Reagents and conditions: (i) Ac2O, DMAP, CH2Cl2, rt, 12 h, 21 (84%), 27 (92%), 32 (85%), 37 (84%); (ii) Grubbs’ catalyst 22 (5 mol %), CH2Cl2, reflux, 6 h, 23 (89%), 28
(85%), 33 (84%), 38 (87%); (iii) K2CO3, MeOH, rt, 4 h, 24 (89%), 29 (92%) 34 (92%), 39 (91%); (iv) TFA–CH2Cl2 (1:1), 0 °C to rt, 2 h then NaHCO3, 25 (76%), 30 (74%), 35 (72%), 40
(75%); (v) H2, Pd–C (10%), MeOH, rt, 24 h, 26 (81%), 31 (79%), 36 (77%), 41 (71%).
BnO
O
OH
OR
OH
H2N
BocHN
HN
v
iv
i,ii
23
CbzN
CbzN
CbzN
42, R = Ac
43, R = H
45
44
iii
Scheme 3. Reagents and conditions: (i) Pd–C (10%), MeOH, H2, rt, 12 h, 80%; (ii) Cbz-Cl, NaHCO3, EtOAc–H2O, rt, 7 h, 90%; (iii) K2CO3, MeOH, rt, 4 h, 89%; (iv) TFA–CH2Cl2 (1:1),
0 °C to rt, 2 h; (v) Et3N, 4-benzyloxybenzoyl chloride, CH2Cl2, rt, 4 h, 72% over two steps.
was converted to the corresponding azepane derivatives 31, 36
and 41, respectively, following the same sequence of events
detailed for the conversion 12?26. The azepane derivatives thus
prepared showed spectroscopic properties consistent with their
structures.17
Whilst the configuration of the major product in each of the
vinylation reactions has been assigned syn based on the assump-
tion that chelation control had predominated during addition,
further support came from the following synthetic work (Scheme
3). Cycloalkene 23 was converted into the corresponding saturated
compound 42 via a two-step sequence involving hydrogenation
and re-introduction of the Cbz-protecting group lost concomitantly
during saturation. Deacetylation of compound 42 then led
smoothly to the corresponding alcohol 43 which on treatment with
trifluoroacetic acid provided the amine 44 in readiness for amide
bond formation with 4-benzyloxybenzoyl chloride to provide com-
In conclusion, we have developed a stereocontrolled route to
the azepane core of two important natural products, balanol and
ophiocordin, using inexpensive L-serine as starting material and
inexpensive reagents. The stereoisomeric intermediates prepared
may provide access to some of their analogues. The methodology
developed may complement those existing in the literature and
may also find application in the synthesis of other azepane deriva-
tives of interest.
Acknowledgements
We are thankful to DST, Government of India (Grant No. SR/S1/
OC-51/2005), for financial assistance and UGC (New Delhi) for a
fellowship to one of us (S.P.R.).
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a
]
À72 (c 2.0, CHCl3).
D
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17. Data for selected compounds. 26: [a]
+19 (c 2.2, MeOH). 1H NMR (500 MHz,
D
D2O): d 4.18 (1H, td, J = 2.7, 5.8), 3.60 (1H, td, J = 2.8, 9.5), 3.42 (1H, dd, J = 13.9,
9.6), 3.31–3.23 (2H, m), 3.12 (1H, ddd, J = 13.5, 9.8, 3.6), 2.01–1.90 (2H, m),
1.80–1.67 (2H, m). 13C NMR (75 MHz, D2O+MeOD): d 69.2, 52.5, 47.8, 43.6,
31.8, 19.3. MS (TOF MS ES+): m/z 131 (M+H). 31: [
a
]
À18 (c 2.0, MeOH). 1H
D
NMR (500 MHz, D2O): d 3.52 (1H, dt, J = 3.8, 8.5), 3.12 (1H, dd, J = 2.7, 13.9),
3.04–3.00 (2H, m), 2.98 (1H, dd, J = 2.6, 8.5), 2.89 (1H, dd, J = 9.1, 13.9), 1.99–
1.94 (1H, m), 1.87–1.81 (1H, m), 1.70–1.61 (2H, m). 13C NMR (75 MHz,
D2O+MeOD): d 75.4, 56.2, 47.3, 46.9, 32.6, 20.9. MS (TOF MS ES+): m/z 131
(M++H). 36: [
a
]
D
À18 (c 2.8, MeOH). 1H NMR (600 MHz, D2O): d 4.07 (1H, td,
J = 2.4, 7.2), 3.35 (1H, td, J = 2.5, 7.5), 3.25–3.19 (2H, m), 3.16 (1H, dd, J = 4.2,
8.4), 3.12 (1H, dd, J = 3.0, 13.8), 1.99–1.88 (2H, m), 1.82–1.72 (m, 2H). 13C NMR
(75 MHz, D2O+MeOD): d 71.8, 52.4, 46.7, 45.7, 30.4, 19.9. MS (TOF MS ES+): m/z
131 (M++H). 41: [ +19 (c 2.0, MeOH). 1H NMR (500 MHz, D2O): d 3.45 (1H,
a]
D
dt, J = 3.5, 8.3), 3.01 (1H, dd, J = 2.8, 14.0), 2.94–2.92 (2H, m), 2.88 (1H, dt,
J = 2.8, 8.8), 2.76 (1H, dd, J = 8.9, 14.0), 1.94–1.88 (1H, m), 1.80 (1H, dt, J = 5.2,
13.2), 1.63–1.58 (2H, m). 13C NMR (75 MHz, D2O+MeOD): d 76.3, 57.2, 47.9,
46.7, 32.0, 21.8. MS (TOF MS ES+): m/z 131 (M++H).