Protection-free, short, and stereoselective synthesis of ieodomycin A and B

Article abstract of DOI:10.1016/j.tetlet.2013.06.071

A concise, protection-free, and improved stereoselective total synthesis of ieodomycin A and ieodomycin B is described. The key steps involved in the synthesis are Evans aldol reaction and nucleophilic addition of potassium salt of mono methyl malonate.

Full text of DOI:10.1016/j.tetlet.2013.06.071

Accepted Manuscript
Protection-free, short and stereoselective synthesis of ieodomycin A and B
N. Nageswara Rao, H. M. Meshram
PII:
S0040-4039(13)01038-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.071
TETL 43124
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 May 2013
13 June 2013
15 June 2013
Please cite this article as: Nageswara Rao, N., M. Meshram, H., Protection-free, short and stereoselective synthesis
of ieodomycin A and B, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.071
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Protection-free, short and stereoselective
synthesis of ieodomycin A and B
N. Nageswara Rao, H. M. Meshram *
OH
O
OH OH
O
OH
O
S
OH
O
N
O
S
Ieodomycin A
Ieodomycin B
Total 7 Steps
9

Tetrahedron Letters
1
Protection-free, short and stereoselective synthesis of ieodomycin A and B
N. Nageswara Rao, H. M. Meshram *
Medicinal Chemistry and Pharmacology Division
Indian Institute of Chemical Technology,
Hyderabad–500 007, India.
hmmeshram@yahoo.com, Ph. No. 9140271640
Abstract. A concise, protection-free and improved stereoselective total synthesis of ieodomycin A and ieodomycin B is described. The
key steps involved in the synthesis are Evans aldol reaction and nucleophilic addition of potassium salt of mono methyl malonate.
Keywords: Evans aldol, ieodomycin, 4-pentyn-1-ol, lactonization, protection-free.
Marine life serves as a good resource of food, medicine and
other raw materials that are important to mankind.1 For
decades, many biological active compounds which possess
antitumor and antimicrobial activities have been discovered
that are produced by a variety of marine organisms.2 Of late,
new compounds called ieodomycins A-D (Figure 1) were
isolated from marine bacteria belonging to Bacillus species
and are known to exhibit broad spectrum of antibacterial
activity through inhibiting the growth of both gram positive
and gram negative bacteria.3
In a word, the proposed synthesis aims to better the existing
synthesis by reducing the number of steps involved and it
takes only 7 steps.
OH
OH OH
O
N
O
O
O
1
2
OH
O
S
OH
O
O
S
Due to their promising biological activity, unique structure,
and scarce availability from the natural source, the
ieodomycins have attracted the attention to synthetic organic
chemists. Recently, ieodomycin C and D were synthesized
from propylene epoxide4 and later ieodomycin A and B were
synthesized from D-glucose based on chiral pool approach in
as many as 15 steps.5 Based on promising biological activity
of ieodomycin A & B, we herein reported a short
stereoselective synthesis of the ieodomycin A and B.
O
9
10
OH
OH
6
Scheme 1. Retrosynthetic analysis to 1 and 2
The synthesis of target compounds ieodomycin A and B was
illustrated in the Scheme 2. The synthesis started with 4-
pentyne-1-ol converted to a methylaluminated intermediate
using trimethyl aluminium and zirconcene dichloride which
on treatment with iodine gave desired vinyl iodide. Coupling
OH
OH OH
O
O
O
O
6
B 2
Ieodomycin ( )
of vinyliodide with vinyltributyltin catalyzed by palladium
Ieodomycin A (1)
catalyst afforded diene 6 in 75% yield as a single isomer. The
primary alcoholic functionality of compound 6 was subjected
to Swern oxidation to afford the aldehyde 7.7 After the usual
workup procedures, the aldehyde was used for the next step
without further purification. Secondary alcohol 9 can be
obtained by an asymmetric aldol addition of known
acetylthiazolidine–thione 8 and aldyhde 7.8 The titanium
enolate generated with titanium tetrachloride and DIPEA
gave the predominantly desired isomer 9 in excellent yield.
OH
O
OH
OH
O
OH
OH
Ieodomycin D (4)
Ieodomycin C (3)
Figure1. Chemical structure of ieodomycin products 1-4.
The retrosynthetic analysis of the target molecule was
outlined in the Scheme 1. The synthesis of the target
compound 2 was envisioned to be obtained from the anti-1,3-
diol 1, which could be derived from 10 by anti-hydroxy
induced reduction. Compound 10 would be constructed by
nucleophilic addition of aldol adduct 9 with potasium salt of
mono methyl malonate. Precursor 9 was proposed to obtain
from by asymmetric aldol addition of acetylthiazolidinethione
onto aldehyde 7. The compound 7 can be easily prepared by
4-pentyne-1-ol by using known literature procedures.
The thiazolidinethione auxiliary of compound 9a can be
displaced by a carbon nucleophile without the need for
protection of the free hydroxyl group. This protocol is
adopted from an existing method.9 Thus, treatments of aldol
adduct 9 with the potassium salt of mono methyl malonate10
and MgCl2 in the presence of imidazole led to β-keto-ester 10.
But the reaction was too sluggish with an unacceptable yield.
To enhance the rate of the reaction and yield, the reaction was
performed with MgI2. The reaction was completed within 8 h

2
Tetrahedron Letters
with 87% yield. The β-hydroxy ketone was subjected to
hydroxyl-directed reduction to give anti-1, -3-diol 1 in good
yield and diastereoselectivity (85%).11 The acid mediated
lactonization of the compound afforded the target compound
2 (Scheme 2). Finally, the compound 1 was readily lactonized
to compound 2 by p-toluene sulfonic acid or camphor
sulfonic acid in benzene in 87% yield.5 The anti-1, -3-diol
undergoes lactonization even with silica gel to afford the
target compound 2. The optical rotation and spectral data of
synthetic compounds 1 and 2 (1H NMR and 13C NMR) were
found to be in good agreement with those of isolated natural
products.3
2. (a) Oguntoyinbo, F. A. Afr. J. Biotechnol. 2007, 6, 163; b)
Devi, P.; Wahidullah, S.; Rodrigues, C.; Souza, L. D.
Mar. Drugs 2010, 8, 1203; c) Lu, X. L.; Xu, Q. Z.; Liu,
X. Y.; Cao, X.; Ni, K. Y.; Jiao, B. H. Chem. Biodiversity
2008, 5, 1669.
3. Mondol, M. A. M.; Kim, J. H.; Lee, M. A.; Tareq, F. S.;
Lee, H. S.; Lee. Y. J.; Shin. H. J. J. Nat. Prod. 2011, 74,
1606.
4. Chinnababu, B.; Reddy, S. P.; Reddy, D. K.; Rao, D. C.;
Venkateswarlu, Y. Synthesis 2012, 44, 311.
5. Videsh, T. S.; Sandeep, B.; Prasad, P.; Debnath, B.;
Summon, K. Tetrahedron Lett. 2013, 54, 2489.
6. Parkinson, C. J.; Stoermer, M. J. J. Organomet. Chem.
1996, 507, 207.
I
OH
c
a
OH
OH
b (85%)
75%
6
5
7. (a) Wender, P. A.; Tebbe, M. J. Synthesis 1991, 1089; (b)
Clausen, D. J.; Wan, S.; Floreancig, P. E. Angew. Chem.,
Int. Ed. 2011, 50, 5178.
8. (a) Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima J., Asai,
N.; Mizui, Y.; Abe, S.; Kotake, Y. Angew. Chem., Int. Ed.
2007, 46, 4350; (b) Skaanderup, P. R.; Jensen, T. Org.
Lett. 2008, 10, 2821.
9. (a) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C.
W.; Carroll, K. A.; Van Alphen, S. Org. Lett. 2004, 6,
2317; (b) Brooks, D. W.; Lu, D. -L.; Masamune, S.
Angew. Chem., Int. Ed. Engl. 1979, 18, 72.
OH
O
S
O
S
N
N
S
e
d
S
O
75% (9:1)
85%
9
8
7
O
O
OH OH
O
OH
O
O
KO
O
g
O
O
f
85%
87%
1
10
OH
h
10.Shang, R.; Ji, D.-S.; Fu, Y.; Liu, L. Angew. Chem., Int. Ed.
2011, 50, 4470;
11.Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1988, 110, 3561.
O
O
88%
2
Scheme 2. Synthesis of iedomycin A (1) and ieodomycin B
(2). Reagents and conditions: (a) Cp2ZrCl2, AlMe3, CH2Cl2 -
15 C-r.t, 12 h; (b) I2, THF, -30 C, K2CO3, 1 h; (c) Vinyl
tributyltin, Pd(PPh3)2Cl2, DMF, rt, 8 h; (d) (COCl)2, DMSO,
0
0
Spectral data of representative compounds:
0
0
Et3N, -78 C, 2 h; (e) TiCl4, CH2Cl2, DIPEA, -78 C; 7 h; (f)
MgI2, Imidazole, THF,
5
h; (g) Me4NBH(OAc)3,
(E)-5-iodo-4-methylpent-4-en-1-ol (5): IR: νmax 3377, 2940,
AcOH/CH3CN (1:2), -40 0C, 10 h; (h) (5 mol%) p-TsOH or
CSA, C6H6, 0 0C.
1
2873, 1616, 1443, 1269, 1044, 765 cm-1; H NMR (300MHz,
CDCl3): δ 5.91 (s, 1H), 3.60 (t, J = 6.4 Hz, 2H), 2.50 (br. s,
1H), 2.29 (t, J = 7.6 Hz, 2H), 1.84 (s, 3H), 1.63-1.75 (m, 2H);
13C NMR (75 MHz, CDCl3): δ 147.4, 75.0, 61.7, 35.7, 30.4,
23.8; m/z (ESI); 227 [M+H]+.
In conclusion, we have successfully completed the
stereoselective total synthesis of ieodomycin A and B from
commercially available 4-pentyne-1-ol in a highly concise
way and the overall yield is 26.44%. The present strategy
improved an existing synthesis by achieving the target in
lesser steps. A modified form of an existing methodology of
chopping the auxiliary after the Evans aldol reaction was
found extremely useful in this synthesis.
(E)-4-methylhepta-4,6-dien-1-ol (6): IR: νmax 3356, 2931,
1
2869, 1646, 1434, 1056, 989, 898 cm-1; H NMR (300MHz,
CDCl3): δ 6.57 (ddd, J = 10.5, J = 10.5, J = 16.6 Hz, 1H),
5.88 (d, J = 10.5 Hz, 1H), 5.10 (d, J = 16.6 Hz, 1H), 5.00 (d, J
= 10.5 Hz , 1H), 3.64 (q, J =12.0 Hz, 2H), 2.14 (t, J = 7.5 Hz,
2H), 1.77 (s, 3H), 1.62-1.75 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 133.1, 125.7, 114.9, 62.5, 35.9, 30.5, 16.4; m/z
(ESI); 127 [M+H]+.
Acknowledgments
N N R thanks UGC for the award of a fellowship and Dr. A.
Kamal, HOD, MCP Division for his support and
encouragement.
(R, E)-1-((R)-4-benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy-6-
methylnona-6,8-dien-1-one (9): [α]25 = -110 (c 1.9, CHCl3);
D
1
IR: νmax 3447, 2925, 1696, 1341, 765 cm-1; H NMR (300
References
MHz, CDCl3): δ 7.24-7.38 (m, 5H), 6.57 (ddd, J = 10.5, J =
10.5, J = 16.6 Hz, 1H), 5.91 (d, J = 10.5 Hz, 1H), 5.35-5.44
(m, 1H), 5.11 (d, J = 16.6 Hz, 1H), 5.00 (d, J = 10.5 Hz, 1H),
4.08-4.19 (m, 1H), 3.65 (dd, J = 3.0, J = 17.3 Hz, 1H), 3.41
(dd, J = 7.5, J = 11.3 Hz, 1H), 3.22 (dd, J = 3.7, J = 11.3 Hz,
1H), 2.99-3.18 (m, 2H), 2.89 (d, J = 11.3 Hz, 1H), 2.68 (br. s,
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.

Tetrahedron Letters
1H), 2.10-2.31 (m, 2H), 1.78 (s, 3H), 1.61-1.76 (m, 2H); 13C
3
NMR (75 MHz, CDCl3): δ 201.2, 172.9, 138.5, 136.2, 130.0,
129.2, 128.7, 127.1, 125.7, 114.8, 68.1, 67.2, 45.7, 36.6, 35.5,
34.1, 31.9, 16.5; m/z (ESI); 398 [M+Na]+. HRMS: m/z calc.
for C20H25NO2S2Na: 398.1222, found: 398.1218.
(R,E)-methyl-5-hydroxy-8-methyl-3-oxoundeca-8,10-dienoate
(10): [α]25 = -33 (c 1.5, CHCl3); IR: νmax 3445, 2926, 1713,
D
1
1647, 1258, 760 cm-1; H NMR (300 MHz, CDCl3): δ 6.56
(ddd, J = 10.5, J = 10.5, J = 16.7 Hz, 1H), 5.89 (d, J = 10.5
Hz, 1H), 5.10 (d, J = 16.7 Hz, 1H), 5.00(d, J = 10.5 Hz, 1H).
4.03-4.10 (m, 1H), 3.75 (s, 3H), 3.28 (d, J = 4.5 Hz, 1H), 2.81
(br, 1H), 2.73 (d, J = 3.2 Hz, 1H), 2.70 (d, J = 8.6 Hz, 1H),
2.17-2.25 (m, 1H), 2.09-2.16 (m, 1H), 1.72-1.82 (m, 1H),
1.77 (s, 3H), 1.62-1.68 (s, 1H), 1.52-1.60 (M, 1H); 13C NMR
(75 MHz, CDCl3): δ 203.4, 167.2, 133.0, 125.8, 119.3, 115.0,
76.9, 67.0, 49.5, 41.3, 35.5, 34.3, 16.5; m/z (ESI); 263
[M+H]+. HRMS: m/z calc. for C13H20O4Na: 263.1252, found:
263.1253.
(3S,5R,E)-methyl-3,5-dihydroxy-8-methylundeca-8,10-
dienoate (1): [α]25 = +17.42 (c 0.7, CHCl3); IR: νmax 3422,
D
1
2925, 2855, 1730, 1250, 1076 cm-1; H NMR (500 MHz,
CD3OD): δ 6.57 (ddd, J = 10.5, J = 10.5, J = 16.7 Hz, 1H)
5.86 (d, J = 10.5 Hz, 1H), 5.04 (d, J = 16.7 Hz, 1H), 4.93 (d, J
= 10.5 Hz, 1H), 4.22-4.28 (m, 1H), 3.73-3.79 (m, 1H), 3.66
(s, 3H), 2.40-2.59 (m, J = 4.9, J = 9.9 Hz, 2H), 2.16-2.21 (m,
1H), 2.07-2.14 (m, 1H), 1.75 (s, 3H), 1.49-1.58 (m, 4H); 13C
NMR (125 MHz, CD3OD): δ 173.9, 140.0, 134.6, 126.9,
115.0, 68.7, 66.5, 52.0, 45.2, 43.8, 37.4, 36.9, 16.7; m/z
(ESI); 265 [M+H]+. HRMS: m/z calc. for C13H22O4Na:
265.1405, found: 265.1410.
(4S,6R)-4-hydroxy-6-((E)-3-methylhexa-3,5-dienyl)
tetrahydro-2H-pyran-2-one (2): [α]25 = +19.63 (c 0.9,
D
CHCl3); IR: νmax 3425, 2961, 2925, 1725, 1260, 1088, 1021,
799 cm-1; 1H NMR (300 MHz, CD3OD): δ 6.58 (ddd, J =
10.6, J = 10.6, J = 16.6 Hz, 1H), 5.88 (d, J = 10.6 Hz, 1H),
5.07 (d, J = 16.6 Hz, 1H), 4.97 (d, J =10.6 Hz, 1H), 4.13-4.32
(m, 2H), 2.86 (dd, J = 5.3, J = 16.6 Hz, 1H), 2.36 (dd, J = 7.2,
J = 16.8 Hz, 1H), 2.21-2.31 (m, 2H), 2.10-2.21 (m, 1H), 1.77
(s, 3H), 1.78-1.85 (m, 1H), 1.45-1.58 (m, 1H); 13C NMR (75
MHz, CD3OD): δ 173.9, 140.0, 134.6, 126.9, 115.0, 68.7,
66.5, 52.0, 45.2, 43.8, 37.4, 36.9, 16.7; m/z (ESI); 233
[M+H]+. HRMS: m/z calc. for C15H14N2O2F: 233.1145,
found: 233.1144.