Total synthesis of arenamide A and its diastereomer

Article abstract of DOI:10.1016/j.tetlet.2009.09.119

Arenamide A and its diastereomer have been synthesized in a convergent fashion. The key steps involved in this synthesis are Sharpless asymmetric epoxidation, C-C bond formation, and macrolactamization.

Full text of DOI:10.1016/j.tetlet.2009.09.119

Tetrahedron Letters 50 (2009) 6851–6854
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of arenamide A and its diastereomer
*
S. Chandrasekhar , G. Pavankumarreddy, K. Sathish
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Arenamide A and its diastereomer have been synthesized in a convergent fashion. The key steps involved
in this synthesis are Sharpless asymmetric epoxidation, C–C bond formation, and macrolactamization.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 31 August 2009
Revised 17 September 2009
Accepted 22 September 2009
Available online 25 September 2009
This manuscript is dedicated to beloved
teacher of G.P., Vennapusa Raja Reddy
The marine organisms continue to provide new chemicals as
leads for better health care.1 Recently, Fenical et al. reported the
isolation, structure elucidation, and NFjB inhibition activities of
derivative 4.7,12 Selective tosylation of 1° alcohol (TsCl, NEt3) and
silylation of 2° alcohol (TBSOTf) were rather routine to yielded 5
in over 75% for two steps. A copper-mediated C–C bond formation8
on tosylate 5 with pentyl magnesium bromide furnished 6 in 72%
yield. This reaction in principle will allow one to synthesize other
arenamides by simply changing the alkyl halides. The debenzyla-
tion9 under Li–naphthalene provided alcohol 6a which underwent
a smooth oxidation10 with TEMPO to carboxylic acid which was
protected as p-nitro benzyl ester using p-nitro benzyl alcohol with
EDC and DMAP furnished 7 in 97% yield. The desilylation11 of 7
with HF–pyridine provided alcohol 813 (Scheme 2), which is useful
for coupling with the peptide part of the target. The ent-8 (Scheme
2) was prepared by simply changing the SAE condition on allyl
alcohol 3.
three cyclic depsipeptides and named them as arenamides A–C
from the extracts of Salinispora arenicola strain CNT-088.2 These
natural cyclic depsipeptides are characterized by 19-membered
macrocycle with six subunits—Phe, Ala, Val, Gly, Leu, and 3-hydro-
xy-4-methyl decanoic acid (HMDA). The relative configuration of
HMDA (at C-28, C-29) has been assigned ‘syn’ based on NOE studies
and absolute configuration was determined by Mosher ester data.
The arenamides A and B blocked TNF induced activation in a dose
and time dependent manner with IC50 values of 3.7 and 1.7
respectively (Fig. 1).
lM,
Encouraged by these interesting properties coupled with our
interest in total synthesis3 of scarce, marine natural products, we
embarked on the challenge of taking up an approach amicable
for making diastereomers as well as analogues with ease. Herein,
we report the first total synthesis of (28R,29R) arenamide A (1)
and (28S,29S) arenamide A (2) using a stereoconvergent strategy.4
Retrosynthetically, arenamide A (1 and 2) (Scheme 1) can be ob-
tained by the macrolactamization of the linear hexadepsipeptide
21/21a which, in turn, could be prepared by coupling of the two
key intermediates, the Phe-HMDA 20/20a and the tetrapeptide
component 15a. The key HMDA segment was synthesized relying
on Sharpless asymmetric epoxidation (SAE) wherein it was possi-
ble for us to synthesize both enantiomers (28R,29R) and (28S,29
S) by simply changing from (ꢀ) DET to (+) DET, respectively, during
epoxidation of 3.
With both enantiomers in hand, the further total synthesis of
both isomers of arenamide A (1 and 2) has been taken up following
a linear strategy (Schemes 3 and 4).
The tetrapeptide segment 15a (Scheme 3) was synthesized from
the commercially available protected (L)-amino acids. The conden-
sation of Boc-Leu-OH 9 and alanine methyl ester 10 using EDC and
HOBt as coupling reagents gave dipeptide (Boc-Leu-Ala-OMe) 11 in
82% yield. The Boc group of 11 was removed using TFA in CH2Cl2
resulting in amine 11a, which was coupled with Cbz-Gly-Val-OH
14a to yield tetrapeptide 15 in 64% yield. The dimer acid 14a in
turn was prepared by coupling of valine methyl ester 12 with
Cbz-protected glycine 13 followed by hydrolysis using lithium
hydroxide.
The saponification of ester functionality of tetrapeptide 15
using lithium hydroxide in THF and water (3:1) furnished tetra-
peptide acid 15a. The other partner Phe-HMDA 20/20a was synthe-
sized from HMDA 8/ent-8 by coupling with Boc-protected phenyl
alanine (Boc-Phe-OH) 18 under EDC and DMAP conditions. Boc-
Phe-HMDA 19/19a, which was treated with TFA in CH2Cl2 gave free
amine 20/20a for further coupling with tetrapeptide 15a. The
Thus, the known allyl alcohol 35 was subjected to SAE6 using (ꢀ)
DET, Ti(OiPr)4, and tBHP followed by reductive opening with NaC-
NBH4 catalyzed by BF3ꢁEt2O furnished exclusively the 1,3-diol
* Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.119

6852
S. Chandrasekhar et al. / Tetrahedron Letters 50 (2009) 6851–6854
O
O
H
N
H
N
28
28
29
NH
29
NH
O
O
O
O
O
O
O
O
HN
O
HN
O
NH
NH
NH
O
NH
O
(28R, 29R) Arenamide A 1
Figure 1. Structure of arenamides A 1 and 2.
(28S, 29S) Arenamide A 2
O2N
O
NHCbz
NH
H
N
28
O
NH
O
29
( )5
O
O
O
O
O
O
O
O
HN
O
O
NH
HN
NH
NH
O
N
O
H
21 or 21a
(28R, 29R) Arenamide A 1
(28S, 29S) Arenamide A 2
O2N
O
O
H
N
O
( )5
O
CbzHN
OH
+
N
H
N
H
O
O
O
O
H2N
20/ 20a
15a
O2N
SAE
HO
OBn
3
O
( )5
4
D(-)DET for 1
L(+)DET for 2
OH
O
3
(3R, 4R) = 8 or (3S, 4S) = ent- 8
Scheme 1. Retrosynthetic analysis of arenamide A.
e
a, b
c, d
HO
OBn
OR
HO
OBn
TsO
OBn
OH
OTBS
5
3
4
NO2
NO2
g, h,
O
O
5
5
5
OR
OTBS
6
O
OH
O
R = TBS 7
R = H 8
i
ent - 8
R = Bn 6
R = H 6a
f
Scheme 2. Synthesis of HMDA derivative 8 and ent-8. Reagents and conditions: (a) Ti(OiPr)4, (ꢀ) DET, tBuOOH, CH2Cl2, ꢀ23 °C, 8 h, 82%; (b) BF3ꢁEt2O, NaCNBH4, THF, 0 °C to
reflux for 3 h, 64%; (c) Et3N, p-TSCl, CH2Cl2, 0 °C to rt, 16 h, 78%; (d) Et3N, TBSOTf, CH2Cl2, 0 °C, 30 min, quantitative; (e) C5H11MgBr, CuBrꢁMe2S, dry THF, ꢀ78 °C to rt, 12 h,
72%; (f) Li, naphthalene, dry THF, 0 °C, 10 min, 83%; (g) BAIB, TEMPO, CH3CN:H2O (1:1), rt, 7 h, 92%; (h) 4-NO2C6H4CH2OH, EDC, DMAP, 0 °C, 3 h, 97%; (i) HF–pyridine, THF, rt,
12 h, 88%.

S. Chandrasekhar et al. / Tetrahedron Letters 50 (2009) 6851–6854
6853
O
O
MeO
NHR
O
a
N
H
NHBoc
NH2
HO
HO
+
+
O
MeO
R = Boc (11)
R = H (11a)
b
10
9
O
O
O
a
RO
NHCbz
NH2
NHCbz
N
H
MeO
O
c
R = Me (14)
R = H (14a)
13
12
O
O
H
a,
11a
NHCbz
RO
N
N
H
N
H
O
O
R = Me (15)
R = H (15a)
c
Scheme 3. Synthesis of tetrapeptide segment 15a. Reagents and conditions: (a) EDC, HOBt, DIPEA, CH2Cl2, 0 °C to rt 82% for 11, 77% for 14, 64% for 15; (b) TFA, CH2Cl2, rt; and
(c) LiOH, THF:H2O (3:1), 0 °C.
In conclusion, the first total syntheses of (28R,29R) and (28S,29
S) diastereomers of arenamide A have been achieved and the spec-
NO2
O
troscopic data have been compared to provide insight into the cor-
rect stereochemistry of the natural product.
5
O
O
O
R = Boc 19
R = H 20
b
Acknowledgments
NHR
O
a
G.P.K. thanks UGC and K.S. thanks CSIR New Delhi for
fellowship.
or
OH
NHBoc
NO2
O
18
References and notes
5
O
O
R = Boc 19a
R = H 20a
1. Blunt, J. W.; Copp, B. R.; Hu, W. P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M.
R. Nat. Prod. Rep. 2009, 26, 170–244.
2. Asolkar, R. N.; Freel, K. C.; Jensen, P. R.; Fenical, W.; Kondratyuk, T. P.; Park, E. J.;
Pezzuto, J. M. J. Nat. Prod. 2009, 72, 396–402.
O
b
NHR
3. Chandrasekhar, S.; Rao, C. L.; Seenaiah, M.; Naresh, P.; Jagadeesh, B.; Manjeera,
D.; Sarkar, A.; Bhadra, M. P. J. Org. Chem. 2009, 74, 401–404.
4. Fenical et al. confirmed the configuration in arenamide A at C-28 and C-29
(28R,29R) as mentioned in the text, but according to the structure shown in the
graphical abstract the configuration was (28S,29S). Due to this ambiguity we
synthesized both isomers of Arenamide A (1 and 2), see Ref. 2.
5. Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007, 48, 5177–5180.
6. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
7. Hiscock, S. D.; Hitchcock, P. B.; Parsons, P. J. Tetrahedron 1998, 54, 11567–
11580.
c, 20/20a
d
e
1/2
15a
21/21a
Scheme 4. Synthesis of arenamides A (28R,29R) 1 and (28S,29S) 2. Reagents and
conditions: (a) EDC, DMAP, 8/ent-8, CH2Cl2, 0 °C, 86%; (b) TFA, CH2Cl2, rt; (c) EDC,
HOBt, DIPEA, CH2Cl2, 0 °C to rt, 74%; (d) Pd/C (10 mol %), H2, IPA:THF (2.5:1); and (e)
EDC, HOBt, DIPEA, CH2Cl2 (0.05 ꢂ 10ꢀ3 M), 0 °C to rt, 60% for 1, 58% for 2 (for two
steps).
8. Mori, K. Tetrahedron 1981, 37, 1341–1342.
9. Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38, 2253–2256.
10. Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293–295.
11. Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453–461.
12. Analytical and spectral data of compound 4: ½a D30
ꢃ
ꢀ6.5 (c 1.0 CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.40–7.27 (m, 5H), 4.53 (s, 2H), 4.03 (dt, J = 10.0, 2.2 Hz,
1H), 3,80–3.62 (m, 4H), 3.53 (br s, 1H), 3.0 (br s, 1H), 2.0–1.7 (m, 2H), 1.63 (m,
1H), 0.90 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): 137.7, 128.4, 127.7,
127.6, 74.5, 73.3, 69.7, 66.5, 39.4, 32.8 and 10.8; EIMS: [M+H]+ = 225.
tetrapeptide acid 15a was coupled with amine 20/20a under stan-
dard coupling conditions as mentioned above for amide bond for-
mation to give hexadepsipeptide 21/21a in good yield. Finally,
deprotection of p-nitro benzyl and Cbz group by hydrogenation
using Pd/C in isopropyl alcohol and THF mixture (3:2), followed
by cyclization of linear hexadepsipeptide under high dilution
(0.5 ꢂ 10ꢀ3 M) CH2Cl2 using EDC and HOBt as coupling reagents
provided arenamide A 1/214,15 (Scheme 4) in 60% yield.
The careful spectroscopic comparison of synthetic (28R,29 R)
arenamide A (1) and (28S, 29S) arenamide A (2) with the reported
natural product, clearly indicated that the natural product has
(28S,29 S) configuration. Also the optical rotation of synthetic
(28S,29S) isomer was closer to the reported natural product com-
pared to (28R,29R) isomer.
13. Analytical and spectral data of compound 8: ½a D30
ꢃ
+19.5 (c 2.0 CHCl3); 1H NMR
(300 MHz, CDCl3): d 8.23 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 5.25 (s, 2H),
3.99 (m, 1H), 2.59–2.49 (m, 3H), 1.60–1.39 (m, 1H), 1.39–1.06 (m, 10H), 0.92 (d,
J = 6.1 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): 172.8, 147.6,
142.8, 128.3, 123.7, 71.2, 64.8, 38.8, 38.0, 32.6, 31.7, 29.4, 27.1, 22.6, 14.1 and
14.0; EIMS: [MꢀH2O+H]+ = 320.0; HRMS (ESI): calcd for C18H27NO5Na
[M+Na]+ = 360.1781, found: 360.1788.
14. Analytical and spectral data of compound 1: ½a D30
ꢃ
ꢀ43.0 (c 0.07 CH3OH); 1H NMR
(600 MHz, DMSO-d6): d 8.16 (d, J = 7.3 Hz, 1H), 8.14 (d, J = 5.1 Hz, 1H), 7.87 (t,
J = 5.8, 5.1 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.66 (d, J = 7.1 Hz, 1H), 7.33–7.12 (m,
5H), 5.09 (m, 1H), 4.39 (m, 1H), 4.06–3.90 (m, 4H), 3.85 (dd, J = 9.8, 5.8 Hz, 1H),
3.13 (dd, J = 14.3, 5.6 Hz, 1H), 2.96 (dd, J = 14.3, 8.3 Hz, 1H), 2.41 (m, 2H), 2.05
(m, 1H), 1.70–1.42 (m, 4H), 1.33–1.05 (m, 13H), 0.95–0.81 (m, 15H), 0.76 (d,
J = 6.6 Hz, 3H); 13C NMR (200 MHz, DMSO-d6): 171.6, 171.2, 170.8, 170.0,
169.8, 169.4, 138.3, 129.0, 128.2, 126.2, 75.2, 59.8, 54.2, 52.4, 48.8, 42.4, 40.0,

6854
S. Chandrasekhar et al. / Tetrahedron Letters 50 (2009) 6851–6854
37.4, 36.3, 35.8, 31.3, 31.2, 28.9, 26.4, 24.3, 23.0, 22.1, 21.3, 19.2, 18.2, 17.6,
15.7, 8.3 Hz, 1H), 2.57 (dd, J = 14.6, 9.4 Hz, 1H), 2.18 (d, J = 14.6 Hz, 1H), 1.93
(m, 1H), 1.60–1.49 (m, 3H), 1.45–1.35 (m, 1H), 1.29–1.09 (m, 13H), 0.94–0.77
(m, 15H), 0.52 (d, J = 6.2 Hz, 3H); 13C NMR (200 MHz, DMSO-d6): 171.6, 171.2,
171.0, 170.8, 169.4, 169.1, 136.6, 129.1, 128.4, 126.8, 75.2, 60.3, 54.8, 51.5,
47.5, 42.5, 40.0, 37.2, 36.5, 35.9, 31.4, 31.3, 29.8, 29.0, 26.4, 24.4, 23.3, 22.2,
20.7, 19.1, 19.0, 18.4, 14.5 and 13.9; White solid mp 228–230 °C; ESIMS:
[M+H]+ = 672.3; HRMS (ESI): calcd for C36H58N5O7 [M+H]+ = 672.4331, found:
672.4336.
14.8, 14.1 and 13.9; White solid mp 239–240 °C; ESIMS: [M+H]+ = 672.3; HRMS
(ESI): calcd for C36H58N5O7 [M+H]+ = 672.4331, found: 672.4336.
15. Analytical and spectral data of compound 2: ½a D30
ꢃ
ꢀ65.0 (c 0.09 CH3OH); 1H NMR
(500 MHz, DMSO-d6): d 8.35 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.96 (d,
J = 8.3 Hz, 1H), 7.70 (t, J = 5.2, 4.1 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.28–7.18 (m,
5H), 4.93 (dd, J = 9.4, 2.0 Hz, 1H), 4.29 (q, J = 13.6, 7.3 Hz, 1H), 4.27–4.09 (m,
3H), 3.92 (t, J = 8.3, 7.3 Hz, 1H), 3.69 (dd J = 16.8, 4.1 Hz, 1H), 2.92 (dq, J = 22.0,