A concise total synthesis of lyngbic acid, hermitamides A and B

Article abstract of DOI:10.1016/j.tetlet.2014.08.125

A concise total syntheses of lyngbic acid, hermitamides A and B have been accomplished in a highly enantioselective manner involving CBS asymmetric reduction, hydroboration, and stereospecific Julia-Lythgoe olefination.

Full text of DOI:10.1016/j.tetlet.2014.08.125

Accepted Manuscript
A concise total synthesis of lyngbic acid, hermitamides A and B
S. Satyanarayana, B.V. Subba Reddy, R. Narender
PII:
S0040-4039(14)01487-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.125
TETL 45092
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 June 2014
28 August 2014
31 August 2014
Please cite this article as: Satyanarayana, S., Subba Reddy, B.V., Narender, R., A concise total synthesis of lyngbic
acid, hermitamides A and B, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.125
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A concise total synthesis of lyngbic acid,
hermitamides A and B
Leave this area blank for abstract info.
S.Satyanarayana, B.V.Subba Reddy, R.Narender*
Graphical Abstract

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
A concise total synthesis of lyngbic acid, hermitamides A and B
a
S.Satyanarayana, B.V.Subba Reddy, R.Narender *
Crop Protection Chemicals, Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad –500 007,
India. E-mail:raviralanarender@gmail.com; basireddy@iict.res.in; Fax: 91-40-27160512.
b
a
a
b
Abstract: A concise total syntheses of lyngbic acid, hermitamides A and B have been accomplished in a highly
enantioselective manner involving CBS asymmetric reduction, hydroboration and stereospecific Julia-Lythgoe olefination.
Keywords: Hermitamides, marine natural products, CBS asymmetric reduction, hydroboration, Julia-Lythgoe olefination
5
epoxide, lipase mediated kinetic resolution, and
6
Hermitamides A and B are lipopeptides that were
1
7
asymmetric allylation of the requisite aldehyde. In
isolated from Lyngbya majuscula cyanobacteria.
Lyngbic acid was also isolated from the marine
addition, a rhodium catalyzed conjugate addition of
chiral potassium trifluoroalkenylborate has been
employed to construct the side chain of
2
cyanophyte Lyngbya majuscule (Figure 1). They act
3
as sodium channel blockers and also exhibit
8
important
biological
activities
such
as
hermitamides. Recently, Sharpless asymmetric
epoxidation has successfully been used in the
immunosuppressive activity (ED50 6 µg/mL on culture
cells with concanavaline K and LPS). Hermitamides
A (1) and B (2) also display IC50 values of 2.2 µM
and 5.5 µM against Neuro-2a neuroblastoma cells in
tissue culture.
9
synthesis of novel malyngamide derivatives. Keck
allylation and the stereospecific formation of E-olefin
by Johnson–Claisen rearrangement have been utilized
to accomplish the total synthesis of hermitamides A
3
(1) and B (2).
In this article, we wish to report a short and efficient
enantioselective synthesis of hermitamide natural
products employing CBS reduction, hydroboration and
Julia-Lythgoe olefination as key steps. The
retrosynthesis of hermitamide A (1) and B (2) and
lyngbic acid 3 is illustrated in Scheme 1. 7-
Methoxytetradec-4-enoic acid 3 is
a
common
structural unit in both natural products. Therefore, we
proposed the synthesis of 7-methoxytetradec-4-enoic
acid to be achieved by the Julia-Lythgoe olefination
strategy. Hermitamides A (1) and B (2) could be
cleaved into two main fragments, i.e. alkyl sulfone 10
and aldehyde 14. Chiral alkyl sulfone 10 could be
conveniently prepared from the methoxy alcohol 8.
The chiral center of the key intermediate 10 can be
generated from the CBS reduction of 6, followed by
methylation of the hydroxyl group and subsequent
hydroboration of the terminal olefin. Compound 6 could
easily be obtained from n-octanal 4 through vinylation
followed by oxidation of the allylic alcohol 5.
Figure 1. Natural products from L. majuscula
cyanobacteria
As a result, a racemic synthesis of hermitamides A
and B has been reported using ruthenium catalyzed
cross-metathesis reaction as a key step to install the
4
alkene fragment. Subsequently, enantioselective
synthesis of lyngbic acid has been accomplished by
various approaches such as the ring-opening of chiral

2
Tetrahedron Letters
EDCI and HOBt in DCM gave 1 and 2 in good yields
as presented in Scheme 2.
O
O
R
N
H
(
1-2)
R = Phenyl and
R = 3-Indolyl
O
O
OH
H
3
O
N
N
+
OBn
S
O O
N
N
O
9
14
Ph
O
OH
8
OH
O
H
(S)-5
4
Scheme 1. Retrosynthesis of hermitamides A and B
Synthesis of hermitamides A (1) and B (2) are
depicted in Scheme 1 commenced from n-octanal.
Vinylation of n-octanal 4 with vinyl magnesium
bromide gave the allylic alcohol 5 in 92% yield.
Oxidation of the secondary allylic alcohol 5 with IBX
in DMSO afforded the enone 6 in 96% yield.
Asymmetric reduction of the ketone 6 using CBS
catalyst gave the chiral allylic alcohol (S)-5 in 80%
1
0
yield with high enantiomeric excess (>99%).
’
Methylation of (S)-5 using Meerwein s reagent
Scheme 2: Reagents and conditions: (a) vinyl magnesium
o
bromide, THF, 0 C, 3h, 92%; (b) IBX, DMSO, r.t., 3 h;
o
(
Me
furnished the compound 7 in 80%. Hydroboration of
the terminal olefin in compound 7 using BH .DMS in
THF followed by oxidation with hydrogen peroxide
3 4
OBF ) in DCM at 0 C to room temperature
o
6%; (c) R-CBS catalyst, THF, -40 C, BH
9
3
. DMS, 3 h,
Cl , 0 °C
8
0%, (dr 95:5); (d) Me
3
OBF4, proton spong, CH
. DMS, THF, 5h, 0 C, (ii)
O, 3h, 83%. (f) 13, Ph P, DIAD, THF, -20
Mo O, 30% H , EtOH, r.t., (85%,
two steps); (h) 14, KHMDS, THF, –78 °C, 16 h, 83%; (i)
Li, naphthalene, THF, -20 °C, 90%; (j) (i) DMP, CH Cl
r.t.; (ii) NaClO , NaH PO , 2-methyl-2-butene, BuOH,
2
2
o
3
to r.t., 2 h, 80%; (e) (i) BH
, NaOH, H
C; (g) (NH
3
H
°
O
2 2
2
3
1
1
afforded the primary alcohol 8 in 83% yield.
Conversion of alcohol 8 into aryl sulfide 9 was
achieved using TPP/DIAD and 1-phenyltetrazole-5-
4
)
6
7
O
24·4H
2
2 2
O
2
2
,
1
2
t
thiol under Mitsunobu conditions. Oxidation of the
aryl sulfide 9 using ammonium molybdate and
hydrogen peroxide gave the sulfone 10 in 85% yield
2
2
4
2
H O, r.t. (94%, two steps); (k) (i)2-phenylethyl amine,
EDCI, HOBt, DIPEA, DCM, 0 °C to r.t., 10 h, 77%, (ii) 3-
indolylethyl amine, EDCI, HOBt, DIPEA, DCM, 0 °C to
r.t., 10 h, 75%.
1
2
over two steps. Having both the aldehyde 14 and
sulfone 9 in hand, we then attempted Julia-Lythgoe
1
2,13
o
using KHMDS at -78 C.
olefination
The
In conclusion, we have developed an efficient
approach for the synthesis of lyngbic acid,
hermitamides A and B starting from n-octanal. The
key steps involved in this synthesis are Grignard
reaction, CBS asymmetric reduction, hydroboration
and Julia-Lythgoe olefination. Chiral alkoxy alcohol 8
was constructed from the allyl alcohol (S)-5, which in
turn was derived from n-octanal. Coupling of alkyl
sulfone 10 with aldehyde 14 via Julia-Lythgoe
olefination provides the corresponding E-olefin
exclusively. The present synthetic approach involves
corresponding olefin 11 was obtained in 83% yield
with E-geometry exclusively. Debenzylation of 11
with Li/naphthalene in THF gave the primary alcohol
1
2, which was then subjected to oxidation with DMP
followed by NaClO to furnish the lyngbic acid in
4% yield over two steps.
2
1
4
9
Once lyngbic acid 3 was in hand, we carried out the
synthesis of hermitamides A (1) and B (2). Therefore,
the coupling of 3 with different amines like 2-
phenylethyl amine and 3-indolylethyl amine using
10 steps from n-octanal with 22.% overall yield of

Tetrahedron Letters
3
-
1
hermitamides
hermitamides B.
A
and 21% overall yield of
2954, 2924, 2854, 1631, 1091, 918 cm ; MS (ESI)
+8.2 (c 0.3,
)].
+
20
D
m/z for C10
CHCl
H
20O [M+H] 157; [α]
10
20
3
) . [Lit. [α]
D
+8.2 (c, 1.2, CHCl
3
Acknowledgements
1
S)-3-Methoxydec-1-ene (7): H NMR (300 MHz,
(
CDCl
1
6
3
): δ 0.88 (t, J = 7.6 Hz, 3H), 1.20 - 1.31 (m,
0H), 1.42 - 1.52 (m, 2H), 3.27 (s, 3H), 3.49 (q, J =
.8, 14.4 Hz, 1H), 5.16 (d, J = 9.1 Hz, 1H), 5.20 (m,
S.S, thank CSIR, New Delhi, for the award of a
fellowship.
13
References and Notes
1H), 5.64 (ddd, J = 16.6, 9.1, 6.0 Hz, 1H); C NMR
75 MHz, CDCl ): δ 138.9, 116.9, 83.1, 56.1, 35.3,
1.8, 29.6, 29.2, 25.3, 22.6, 14.1. IR (KBr): υ 2924,
(
3
1
.
(a) Tan, L. K.; Okino, T.; Gerwick, W. H. J. Nat.
Prod. 2000, 63, 952. (b) Elayshberg, M. E.; Blinov,
K. A.; Williams, A. J.; Martirosian, E. R.;
Molodtsov, S. G. J. Nat. Prod. 2002, 65, 693. (c)
Molodtsov, S. G.; Elyashberg, M. E.; Blinov, K. A.;
Williams, A. J.; Martirosian, E. E.; Martin, G. E.;
Lefebvre, B. J. Chem. Inf. Comput. Sci. 2004, 1737.
Cardellina, J. H., II; Dalietos, D.; Marner, F.-J.;
Mynderse, J. S.; Moore, R. E. Phytochemistry 1978,
3
-1
2854, 1598, 1552, 1441, 1049, 798 cm ; MS (ESI)
+
m/z for C11
CHCl ).
3
20
D
H22O [M+H] 171; [α]
+6.25 (c, 0.4,
1
S)-3-Methoxydecan-1-ol (8): H NMR (300 MHz,
(
CDCl
3
): δ 3.77 (m, 2H), 3.41 (m, 1H), 3.36 (s, 3H),
2.
2
1
.62 (brs, 1H), 1.88-1.55 (m, 2H) 1.48 (m, 2H),
1
3
C
.37-1.22 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H);
): δ 81.2, 61.1, 56.3, 35.3,
2.8, 31.7, 29.7, 29.1, 24.9, 22.6, 14.0; IR (KBr): υ
927, 2855, 1463, 1376, 1135, 1093, 1054, 772, 722
1
7, 2091.
De Oliveira, E. O.; Graf, K. M.; Patel, M. K.; Baheti,
A.; Kong, H.-S.; MacArthur, L. H.;
NMR (75 MHz, CDCl
3
3.
3
2
Dakshanamurthy, S.; Wang, K.; Brown, M. L.;
Paige, M. Bioorg. Med. Chem. 2011, 19, 4322.
Virolleaud, M.-A.; Menant, C.; Fenet, B.; Piva, O.
Tetrahedron Lett. 2006, 47, 5127.
-1
+
cm ; HRMS (ESI) m/z calcd for C11
H O
25 2
[M+H]
20
1
88.1776, found 188.1773; [α]
CHCl ).
S)-5-((3-Methoxydecyl)sulfonyl)-1-phenyl-1H-
D
+15.8 (c 1.2,
4.
3
(
5.
Mueller, C.; Voss, G.; Gerlach, H. Liebigs Ann.
Chem. 1995, 4, 673.
1
tetrazole (10): H NMR (300 MHz, CDCl ): δ 7.70
(m, 2H), 7.62 (m, 3H), 3.82 (m, 2H), 3.36 (m, 1H),
3
6.
Sankaranarayanan, S.; Sharma, A.; Chattopadhyay,
S. Tetrahedron: Asym. 1996, 7, 2639.
3
(
3
1
2
1
.33 (s, 3H), 2.22 (m, 1H), 2.03 (m, 12H), 1.48-1.37
m, 2H), 1.35-1.23 (m, 10H), 0.88 (t, J = 6.9 Hz,
H); C NMR (75 MHz, CDCl ): δ 153.4, 131.4,
3
29.6, 125.03, 78.2, 56.4, 52.5, 32.8, 31.7, 29.5,
7
8.
.
Li, Y.; Chen, J.; Cao, X.-P. Synthesis 2006, 320.
Frost, C. G.; Penrose, S. D.; Gleave, R. Org. Biomol.
Chem. 2008, 6, 4340.
13
9.1, 25.8, 24.9, 22.5, 14.0; IR (KBr): υ 2925, 2853,
598, 1499, 1463, 1340, 1157, 1092, 1013, 869, 765
9.
Reddy, G. V.; Kumar, T. V.; Siva, B.; Babu, K. S.;
Srinivas, P. V.; Sehar, I.; Saxena, A. K.; Rao, J. M.;
Med. Chem. Res. 2013, 22, 4581.
-1
cm ; HRMS (ESI) m/z calcd for C18
H
29
O
3
N
4
S
+
20
D
[
M+H] 381.1961, found 381.1954; [α]
.9, CHCl ).
7S,4E)-(((Methoxytetradec-en-1-yl)oxy)methyl)
+10.9 (c
1
0. (a) Fu, R.; Ye, J. L.; Dai, X. J.; Ruan, Y. P.; Huang,
P. Q.; J. Org. Chem. 2010, 75, 4230. (b) Yun, H.;
Danishefsky, S. J. J. Org. Chem. 2003, 68, 4519. (c)
Fu, R.; Chen, J.; Guo, L.-C.; Ruan, Y.-P.; Huang, P.-
Q. Org. Lett. 2009, 11, 5242.
1
(
3
1
benzene (11): H NMR (500 MHz, CDCl
(
3
): δ 7.34
m, 2H), 7.33 (m, 2H), 5.44 (q, J = 5.8, 12.4 Hz,
2
3
1
H), 4.50 (s, 2H), 3.47 (t, J = 6.5 Hz, 2H), 3.32 (s,
H), 3.13 (q, J = 5.7, 11.5 Hz, 1H), 2.18 (q, J = 5.6,
1.2 Hz, 2H), 2.10 (q, J = 7.7, 14.3 Hz, 2H), 1.69 (q,
1
1. (a) Yadav, J. S.; Jayaprakash, S.; Gangadhar, Y.
Tetrahedron: Asym. 2005, 16, 2722. (b) Yadav, J. S.;
Narasimhulu, G.; Reddy, N. M.; Reddy, B. V. S.
Tetrahedron Lett. 2010, 51, 1574.
J = 7.7, 14.3 Hz, 2H), 1.46-1.39 (m, 2H), 1.35-1.22
13
(
m, 10H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (75
MHz, CDCl ): δ 138.6, 131.9, 128.3, 127.5, 127.4,
26.3, 80.8, 72.8, 69.7, 56.4, 36.3, 33.3, 31.8, 29.7,
12. Reddy, B. V. S.; Kishore, Ch.; Reddy, A. S.
Tetrahedron Lett. 2014, 55, 49.
3
1
2
2
1
3. (a) Chin,Y.-J.; Wang, S.-Y.; Loh, T. P. Org. Let.
2009, 11, 3674. (b) Liu, J.; Xu, K.; He, J.; Zhang, L.;
Xinfu Pan, X.; She, X. J. Org. Chem. 2009, 74,
9.5, 29.2, 25.2, 22.6, 14.08; IR (KBr): υ 2924,
853, 1633, 1458, 1376, 1218, 968, 771 cm ;
-1
+
37 2
HRMS (ESI) m/z calcd for C22H O [M+H]
5
063. (c) Kaliappan, K. P.; Si, D. Synlett 2009, 2441.
20
3
CHCl ).
33.2786, found: 333.2785; [α]
D
-10.6 (c 0.3,
1
4. (S)-Dec-1-en-3-ol (5): H NMR (500 MHz, CDCl
1
3
) δ
3
1
7S,4E)-Methoxytetradec-en-1-ol (12): H NMR
(
0
1
.88 (t, J = 7.0 Hz, 3H), 1.23 - 1.34 (m, 10H), 1.46 -
.56 (m, 2H), 4.10 (q, J = 6.9, 12.9 Hz, 1H), 5.10
(300 MHz, CDCl ): δ 5.47 (m, 2H), 3.66 (t, J = 5.2
3
Hz, 2H), 3.32 (s, 3H), 3.13 (m, 1H), 2.20 (t, J = 5.7
Hz, 2H), 2.11 (q, J = 7.1, 12.9 Hz, 2H), 1.69-1.52
(
1
dt, J = 10.4, 1.4 Hz, 1H), 5.22 (dt, J = 17.2, 1.4 Hz,
1
3
H), 5.87 (ddd, J = 17.1, 10.5, 6.4 Hz, 1H);
): δ 141.3, 114.5, 73.3, 37.0,
1.8, 29.5, 29.2, 25.3, 22.6, 14.1. IR (KBr): υ 3437,
C
(
m, 4H), 1.30-1.24 (m, 10H), 0.88 (t, J = 7.1 Hz,
1
NMR (75 MHz, CDCl
3
3
3
3
H); C NMR (75 MHz, CDCl ): δ 132.1, 126.8,
3

4
Tetrahedron Letters
1
3
8
2
1
0.8, 62.5, 56.4, 36.3, 33.3, 32.9, 31.8, 30.0, 29.7,
9.3, 29.2, 22.6, 14.1; IR (KBr): υ 3026, 2929, 2857,
634, 1455, 1375, 1056, 971, 784 cm ; HRMS (ESI)
3
C NMR (75 MHz, CDCl ): δ 172.39, 136.4, 130.8,
127.4, 122.1, 121.9, 119.4, 118.6, 115.2, 112.9,
111.2, 80.6, 56.4, 39.5, 36.5, 36.2, 33.4, 33.2, 31.7,
29.7, 29.2, 28.5, 25.2, 22.6, 14.0; IR (KBr): υ 2926,
2854, 1647, 1544, 1456, 1358, 1222, 1094, 970, 771,
-1
742 cm ; HRMS (ESI) m/z calcd for C25
-
1
+
m/z calcd for C15
found: 265.2237; [α]
H
30
O
2
Na [M+Na] 265.2245,
- 7.3 (c 0.5, CHCl ).
2
0
D
3
1
(
(
7S,4E)-Methoxytetradecenoic acid (3): H NMR
300 MHz, CDCl ): δ 5.48 (m, 2H), 3.33 (s, 3H),
.16 (quin, J = 6.0, 5.2, 12.0 Hz, 1H), 2.41 (d, J =
39
H O
2
N
2
+
20
3
[M+H] 399.3005, found: 399.3006; [α]
D
–4.2 (c
).
Phenethyl-(7S,4E)-methoxytetradecenamide (1): H
NMR (500 MHz, CDCl ): δ 7.31(t, j = 7.2 Hz, 2H),
1
26
D
3
6
1
6
1
2
1
0.65, CHCl
3
). Lit. [α]
–4.5 (c, 0.10, CHCl
3
1
.0 Hz, 2H), 2.35 (m, 2H), 2.20 (t, J = 4.5 Hz, 2H),
.46-1.40 (m, 2H), 1.34-1.23 (m, 10H), 0.89 (t, J =
3
1
.0 Hz, 3H); C NMR (75 MHz, CDCl
3
3
): δ 178.75,
7.24 (t, j = 6.9 Hz, 1H), 7.19(d, j = 6.9 Hz, 2H),
5.53 (brs, 1H), 5.44 (m, 2H), 3.52 (q, J = 6.7 Hz,
12.9 Hz, 2H), 3.31 (s, 3H), 3.14 (quin, J = 5.7 Hz,
1H), 2.81 (t, J = 7.0 Hz, 2H), 2.38 -2.28 (m, 2H),
2.25 - 2.15 (m, 4H), 1.46 - 1.39 (m, 2H), 1.32 - 1.21
30.1, 127.7, 80.7, 56.4, 36.2, 33.8, 33.2, 31.8, 29.6,
9.2, 27.6, 25.2, 22.6, 14.0; IR (KBr): υ 2927, 2856,
711, 1458, 1372, 1190, 1096, 970, 768 cm ;
-
1
+
HRMS (ESI) m/z calcd for C15
2
CHCl
H
29
O
3
[M+H]
-10.8 (c 1.4,
-11.1 (c, 3.9, CHCl ).
2
D
0
13
57.2113, found: 257.2111; [α]
(m, 10H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (75
1
26
3
). Lit. [α]
D
3
3
MHz, CDCl ): δ 172.4, 138.9, 130.8, 128.7, 128.6,
2
amide (2): H NMR (300 MHz, CDCl
-(1H-Indol-3-yl)-ethyl-(7S,4E)-methoxytetradecen
1
127.5, 126.4, 80.6, 56.4, 40.5, 36.5, 36.2, 35.7, 33.3,
31.8, 29.7, 29.6, 28.6, 25.3, 22.6, 14.0; IR (KBr): υ
3026, 2961, 2931, 2865, 1636, 1534, 1452, 1364,
3
): δ 8.11 (brs,
1
1
1
H), 7.60 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.3 Hz,
H), 7.22 (t, J = 8.3 Hz, 1H), 7.13 (t, J = 7.5 Hz,
H), 7.04 (d, J = 2.2 Hz, 1H) 5.55 (brs, 1H), 5.43
-1
1218, 1031, 887, 747 cm ; HRMS (ESI) m/z calcd
for
+
NNa [M+Na] 382.2719, found:
C
23
H
37
O
2
2
0
1
26
(m, 2H), 3.61 (q, J = 6.0, 12.8 Hz, 2H), 3.31 (s, 3H),
382.2716; [α]
D
-9.1 (c 0.43, CHCl
).
3
). Lit. [α]
D
-
3
2
2
.13 (t, J = 6.0 Hz, 1H), 2.98 (t, J = 6.7 Hz, 2H),
.37-2.26 (m, 2H), 2.20-2.14 (m, 4H), 1.45-1.38 (m,
H), 1.33-1.22 (m, 10H), 0.89 (t, J = 6.7 Hz, 3H);
9.3 (c, 0.45, CHCl
3