Stereoselective approach to pentenocins using RCM: synthesis of 6-epi-pentenocin B

Article abstract of DOI:10.1016/j.tetlet.2006.04.054

The stereoselective synthesis of 6-epi-pentenocin B 3 is described using a stereoselective Grignard reaction and ring-closing metathesis (RCM) as the key steps.

Full text of DOI:10.1016/j.tetlet.2006.04.054

Tetrahedron Letters 47 (2006) 4441–4443
Stereoselective approach to pentenocins using RCM: synthesis of
6-epi-pentenocin Bq
G. Venkata Ramana and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 January 2006; revised 13 March 2006; accepted 12 April 2006
Available online 12 May 2006
Abstract—The stereoselective synthesis of 6-epi-pentenocin B 3 is described using a stereoselective Grignard reaction and ring-clos-
ing metathesis (RCM) as the key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
Oxygenated cyclopentenones are important bioactive
compounds in nature.1 Pentenocin A 1 and B 2 were iso-
lated2 by Omura and co-workers in 1999 from the cul-
ture broth of Trichoderma hamatum FO-6903 as an
active agent against recombinant human interleukin-1b
converting enzyme (ICE). ICE is also known as cas-
pase-1, a unique cystein protease that cleaves the inac-
tive precursor of IL-1b into biologically active IL-1b, a
key mediator in the pathogenesis of acute and chronic
inflammation.3 The absolute stereochemistry of pente-
nocin B was determined by Ohira4 and Sugahara3 inde-
pendently, by synthesizing all the possible dia-
stereomers, and was confirmed to be 4S,5R,6R as shown
in 2 (Fig. 1).
with NaOMe (4 equiv) in anhydrous MeOH for a period
24
of 12 h at room temperature yielded 8 ½aꢀD ꢁ17.83 (c
3.2, CHCl3) as the sole diastereoisomer along with
hydroxymethyl compound 5 (Scheme 1).
The structure of 8 was confirmed from its NOE spectral
analysis (Fig. 2). Oxidation of alcohol 8 using Swern
conditions gave aldehyde 9, which was allowed to react
with methylmagnesium iodide at ꢁ78 °C to give the ex-
24
pected alcohol 10 ½aꢀD ꢁ25.25 (c 2.0, CHCl3) as the
1
major diastereoisomer (9:1 ratio based on H NMR).
Based on chelation control (Fig. 3), we assumed that
the major diastereoisomer was alcohol 10.7 The alcohol
functionality in 10 was protected as the MOM ether 11
using MOM–Cl, DIPEA and TBAI (cat.), and then the
TBDPS group was cleaved with TBAF to give lactol 12.
Wittig olefination of 12 yielded diene 13. Treatment of
diene 13 with Grubbs’ first generation olefin metathesis
catalyst in DCM furnished cyclopentenol 14. TEMPO
In continuation of our efforts on the synthesis of biolog-
ically active oxygenated cyclopentenones by RCM,5 a
new approach was developed for the synthesis of the
pentenocin skeleton. Herein, we report the synthesis of
6-epi-pentenocin B 33,4 using a stereoselective Grignard
reaction and RCM as the key steps. 2,3-O-Isopropylid-
ene-D-ribose 4 was transformed into the hydroxymethyl
compound 5 using a method based on a reported proce-
oxidation of the alcohol 14 gave the required protected
24
epi-pentenocin B8 15 ½aꢀD ꢁ29.4 (c 1.2, CHCl3). The
NMR data was in good agreement with the reported
24
25
dure,6 ½aꢀD ꢁ23.086 (c 2.35, CHCl3), lit.:6a,b ½aꢀD ꢁ26.5
(c 2.19, CHCl3). The primary hydroxyl group in 5 was
O
O
selectively acetylated with AcCl, DIPEA in DCM at
O
24
1
ꢁ78 °C to give compound 6 ½aꢀD ꢁ21.98 (c 2.3, CHCl3).
1
OH
2
2
5
OH
OH
OH
5
OH
OH
OH
4
OH
OH
4
O
3
The anomeric hydroxyl functionality of 6 was protected
with TBDPS–Cl to afford silyl ether 7. Treatment of 7
3
6
6
(+)-pentenocin B
6-epi-pentenocin B
q IICT Communication Number: 060115.
1
3
2
*
Corresponding author. Tel.: +91 40 27160123x2614; fax: +91 40
27160512; e-mail: venky@iict.res.in
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.054

4442
G. Venkata Ramana, B. Venkateswara Rao / Tetrahedron Letters 47 (2006) 4441–4443
O
HO
O
O
O
O
TBDPSO
d
TBDPSO
c
OH
HO
HO
HO
b
a
+
5
HO
O
AcO
O
O
O
O
O
O
AcO
O
O
O
8
7
6
5
4
O
O
O
HO
OH
TBDPSO
f
TBDPSO
e
i
h
8
H
R1O
O
O
O
O
O
O
O
O
O
MOMO
MOMO
R1=H
13
10
11
9
12
g
1
R =MOM
O
O
OH
j
O
OH
OH
OH
k
l
O
O
O
OMOM
MOMO
3
14
15
Scheme 1. Reagents and conditions: (a) (1) CH2@CHMgBr, THF, ꢁ78 °C to rt, 3 h, 75%; (2) NaIO4, CH2Cl2–H2O (1:1), 0 °C to rt, 2 h, 80%; (3)
K2CO3, 37% CH2O, MeOH, 80 °C, 36 h, 85%; (b) Ac2O, DIPEA, CH2Cl2, ꢁ78 °C, 1 h, 56%; (c) TBDPS–Cl, imidazole, CH2Cl2, 0 °C to rt, 6 h, 73%;
(d) NaOMe (4 equiv), MeOH, 0 °C to rt, 12 h, (40% for 8, 38% for 5); (e) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 °C, 3 h; (f) MeMgI, ether, ꢁ78 °C,
3 h, (60% for two steps); (g) MOM–Cl, DIPEA, TBAI (0.1 equiv), CH2Cl2, 0 °C to rt, 48 h, 81%; (h) TBAF, THF, 0 °C to rt, 4 h, 88%; (i)
t
CH3PPh3þIꢁ, BuOK, 18-crown-6, THF, 0 °C to rt, 24 h, 34%; (j) Grubbs’ first-generation olefin metathesis catalyst (0.1 equiv), CH2Cl2, rt, 24 h,
79%; (k) Tempo free radical (cat.), KBr, NaOCl, NaHCO3, EtOAc–toluene–water (1:1:0.2), 0 °C, 1 h, 65%; (l) 90% TFA, 0 °C, 2 h, 30%.
Acknowledgements
H
O
H
TBDPSO
HO
H
G.V.R. thanks the CSIR, New Delhi, for a research
fellowship (SRF). We also thank IFCPAR for their
financial support, Dr. J. S. Yadav and Dr. A. C. Kunwar
for their support and encouragement.
O
O
Figure 2.
References and notes
1. (a) Bickley, J. F.; Roberts, S. M.; Santoro, M. G.; Snape, T.
J. Tetrahedron 2004, 60, 2569–2576; (b) Tilo, L.; Jurgen, S.;
Andrea, P.; Norbert, A.; Ludger, W. Phytochem. 2004, 65,
1061–1071; (c) Masami, I.; Shinji, T.; Jun’ichi, K. Tetra-
hedron Lett. 1993, 34, 3749–3750.
2. Matsumoto, T.; Ishiyama, A.; Yamaguchi, Y.; Masuma,
R.; Ui, H.; Shiomi, K.; Yamada, H.; Omura, S. J. Antibiot.
1999, 52, 754–757.
Nu
Mg
O
O
TBDPSO
H
O
O
O
H
O
O
OTBDPS
O
Mg
Nu
3. Sugahara, T.; Fukuda, H.; Iwabuchi, Y. J. Org. Chem.
2004, 69, 1744–1747.
Figure 3. Transition state leading to the major diastereoisomer of 10.
4. Ohira, S.; Fujiwara, H.; Maeda, K.; Habara, M.; Sakae-
dani, N.; Akiyama, M.; Kuboki, A. Tetrahedron Lett. 2004,
45, 1639–1641.
5. Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2003, 44,
5103–5105.
6. (a) Jeong, A. L.; Hyung, R. M.; Hea, O. K.; Kyung, R. K.;
Kang, M. L.; Bum, T. K.; Ki, J. H.; Moon, W. C.;
Kenneth, A. J.; Jeong, L. S. J. Org. Chem. 2005, 70, 5006–
5013; (b) Hyung, R. M.; Hea, O. K.; Kang, M. L.; Moon,
W. C.; Joong, H. K.; Jeong, L. S. Org. Lett. 2002, 4, 3501–
3503; (c) Ho, P.-T. Can. J. Chem. 1979, 57, 381–383; (d)
Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623–1626; (e) Shing,
T. K. M.; Elsey, D. A.; Gillhouley, J. G. J. Chem. Soc.,
Chem. Commun. 1989, 1280–1282.
data for (+/ꢁ)-15.3 Removal of the MOM and
acetonide protecting groups in 15 with 90% TFA3 com-
pleted a stereoselective synthesis of 6-epi-pentenocin B 3,
whose spectral9 and physical data were in agreement
23
with the reported values, ½aꢀD +84.15 (c 0.16, MeOH)
lit.:4 [a]D ꢁ89 (c 0.42, MeOH for its C-6 enantiomer).
In summary, a new approach for the construction of the
pentenocin skeleton has been utilized for the synthesis of
6-epi-pentenocin B 3.

G. Venkata Ramana, B. Venkateswara Rao / Tetrahedron Letters 47 (2006) 4441–4443
4443
7. Attempts to separate and confirm the stereochemistry at the
newly created hydroxyl centre by preparing Mosher deriv-
atives proved unsuccessful.
9. Spectral data for 3: 1H NMR (300 MHz, DMSO-d6): d 1.15
(d, 3H, J = 6.8 Hz), 3.67 (quint, 1H, J = 6.0 Hz), 3.91
(d, 1H, J = 6.8 Hz), 4.82 (s, 1H), 4.84 (d, 1H, J = 5.3 Hz),
5.45 (d, 1H, J = 6.8 Hz), 6.22 (d, 1H, J = 6.0 Hz), 7.60
(d, 1H, J = 6.0 Hz). 13C NMR (75 MHz, DMSO-d6): d
207.6, 162.2, 133.0, 79.1, 72.7, 68.8, 17.6. ESI MS: 159
(M++1).
8. Compound (ꢁ)-16, which is
a protected form of
(+)-pentenocin B 2, is also reported3 whose rotation and
1H and 13C NMR data were different from 15.
O
O
O
OMOM
(-)-16