Stereoselective synthesis of the C1-C10 fragment of rhizoxin D

Article abstract of DOI:10.1016/j.tetlet.2006.06.046

A novel approach towards the synthesis of the C1-C10 fragment of the biologically active antimitotic agent rhizoxin D is described. The synthesis involves a stereoselective Michael addition reaction of lithium diallyl cuprate with an α,β-unsaturated six m

Full text of DOI:10.1016/j.tetlet.2006.06.046

Tetrahedron Letters 47 (2006) 5969–5971
Stereoselective synthesis of the C1–C10 fragment of rhizoxin DI
Srinivas Padakanti,a,b Manojit Pal,a K. Mukkantib and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
Received 14 April 2006; revised 31 May 2006; accepted 7 June 2006
Available online 27 June 2006
Abstract—A novel approach towards the synthesis of the C1–C10 fragment of the biologically active antimitotic agent rhizoxin D is
described. The synthesis involves a stereoselective Michael addition reaction of lithium diallyl cuprate with an a,b-unsaturated six
membered lactone.
Ó 2006 Elsevier Ltd. All rights reserved.
Rhizoxin (1, Fig. 1), a 16-membered macrolide 2 is
known to be an anti-tumour and tubulin-interactive
antimitotic agent and was isolated by Iwasaki et al.1
from the fungus Rhizopus chinensis. Later a biogenetic
precursor, that is, a didesepoxy analogue of rhizoxin,
namely rhizoxin D, (2, Fig. 1) was isolated from the
same fungus.2 This has superior therapeutic properties
over rhizoxin because of the absence of epoxides at
C2–C3 and C11–C12 which leads to a shorter half-life
of rhizoxin in the body. Due to its significant biological
activity and highly functionalized macrolide structure
rhizoxin D continues to be an attractive target for syn-
thetic organic chemists.
Initially we planned to synthesize compound 3 from the
known aldehyde 84 according to the reaction sequence
shown in Scheme 2. Thus allylation of (R)-3-benzyloxy-
2-methylpropanal 8 afforded the corresponding alcohol
9 in 93% yield, which was converted to the desired syn
stereoisomer 10 using a Mitsunobu inversion.5 Subse-
quently, esterificaton of 10 with acryloyl chloride fol-
lowed by a Grubbs’ RCM (first generation catalyst)
afforded 11.6 The 1,4-Michael addition of compound
11 using lithium diallyl cuprate afforded product 127 with
100% diastereomeric excess. Deprotection of the hydro-
xyl group with boron trichloride afforded alcohol 13,5b
which was found to possess the undesired configuration
Due to our interest in the development of novel
approaches towards the synthesis of macrolides3 we
became interested in the synthesis of rhizoxin D and a
retrosynthetic strategy is outlined in Scheme 1. Discon-
nection of the ester linkage of the macrolide core 2 at
C1–C15 and the C10–C11 bond leads to key fragment
3. Crucial steps in the synthesis of fragment 3 could be
the cross metathesis of lactone 4 with t-butyl acrylate
and a Takai reaction. Compound 4 may be accessed
via the acrylic ester of alcohol 6 by RCM followed by
Michael addition using allylic cuprate. Alcohol 6 may
be generated by allylation of aldehyde 7.
H
O
O
8
7
5
10
O
HO
3
13
O
1
O
N
O
20
15
H
O
19
OMe
Rhizoxin (1)
H
O
O
8
7
5
10
HO
3
13
1
O
15
N
O
20
H
O
Keywords: Rhizoxin; Stereoselective Michael addition.
q DRL Publication No. 578.
19
OMe
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail addresses: javediqbaldrf@hotmail.com; javediqbalpr@
yahoo.co.in
Rhizoxin D (2)
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.046

5970
S. Padakanti et al. / Tetrahedron Letters 47 (2006) 5969–5971
H
7
O
5
O
8
10
HO
3
13
1
O
N
O
20
19
15
H
O
OMe
Rhizoxin D (2)
H
RO
O
H
O
O
O
HO
OR1
N
I
O
H
OMe
t-BuO2C
4
3
H
O
O
BnO
O
BnO
BnO
6
7
OH
5
Scheme 1.
1, 4-nitrobenzoic
acid, DEAD, PPh3,
H
H
SnBu3
1, Acryloyl chloride,
Et3N, CH2Cl2, 80%
OH
BnO
OH
BnO
BnO
CHO
SnCl4, CH2Cl2
-90 0C, 93%
THF, 65%,
2, NaOH, MeOH,
80%
2, Grubbs I catalyst
(20 mol%).
DCM, 24 h, 80%
8
10
9
H
H
O
Dess Martin
oxidation,
H
O
)2CuLi
BnO
BnO
O
(
O
HO
O
O
BCl3, toluene,
75%
THF, -78 0C-40 0C,
90%
100%
11
12
13
H
H
H
CrCl2, CHI3,
O
O
O
O
O
O
O
Grubbs II catalyst (10 mol%)
t-butyl acrylate, 24 h,
THF-dioxane,
60%
I
I
t-BuO2C
80%
14
15
15a
Scheme 2.
at the C-5 chiral centre of rhizoxin D as revealed by the
literature data.8 However, we decided to continue our
synthetic work according to Scheme 2 as we were also
interested in isolating the unnatural C5 diastereomer of
rhizoxin D in order to study its chemical and biological
properties. Thus alcohol 13 was oxidized to aldehyde
149 which was converted to 15 using a Takai olefination10
(CrCl2/CHI3) followed by a Grubbs’ cross metathesis11
reaction with t-butyl acrylate to afford 15a12 in good
yield.
Accordingly we changed our strategy as illustrated in
Scheme 3.
Esterification of 9 with acryloyl chloride followed by
Grubbs’ RCM afforded lactone 16, which upon Michael
addition with lithium diallyl cuprate furnished 17 having
the desired configuration at C5. We then installed the
desired configuration at C7 by opening lactone 17 by
hydrolysis followed by methylation of the resulting acid
with diazomethane to give 18. A Mitsunobu inversion on
18 followed by selective cleavage of the 4-nitrobenzoic
ester using K2CO3 in methanol13 afforded lactone 19
with the correct stereochemistry at C-5. Debenzylation
of 19 and Grubbs’ cross metathesis with t-butyl acrylate
afforded 20 which was transformed into the desired key
intermediate 314 by the route outlined in Scheme 3.
Since 15a was found to be the undesired isomer, we
revisited our strategy, the Michael addition of com-
pound 11 being of particular interest. It is known6 that
the C7 stereocentre of lactone 11 plays a key role in con-
trolling the stereochemistry of the Michael addition.

S. Padakanti et al. / Tetrahedron Letters 47 (2006) 5969–5971
5971
1, Acryloyl chloride,
H
H
H
)2CuLi
Et3N, CH2Cl2, 80%
O
(
OH
O
BnO
BnO
O
O
BnO
2, Grubbs I catalyst
(20 mol%),
80%
THF, -78 ºC-40 ºC,
85%
9
16
17
H
H
1, BCl3, tolune,
75%
4-nitrobenzoic acid,
DEAD, THF, K2CO3, MeOH,
1, LiOH, MeOH,
100%
OH
BnO
O
O
BnO
2, CHN2, DCM
90%
65%
2, t-butyl acrylate,
Grubbs II catalyst
(10 mol%), 80%
CO2Me
18
19
H
H
O
O
O
HO
O
1, Dess Martin
100%
2, CrCl2, CHI3,
THF-dioxane
65%
I
20
3
t-BuO2C
t-BuO2C
Scheme 3.
correct isomer of 13 see: Lafonatine, J. A.; Provencal, D.
P.; Gardilli, C.; Lehay, J. W. J. Org. Chem. 2003, 68, 4251.
9. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156;
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277; (c) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58,
2899.
In summary, we have accomplished the synthesis of the
C1–C10 fragment of rhizoxin D in ten steps. Further
work towards the total synthesis of rhizoxin D by
employing fragment 3 is in progress.
10. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408.
Acknowledgements
11. Lautens, M.; Maddess, M. L. Org. Lett. 2004, 6, 1883.
23
We would like to thank Dr. Reddy’s Laboratories Ltd.
for financial support and the analytical department for
spectral data.
12. Spectral data of compound 15a: ½aꢀD +1.8 (c 0.5,
CHCl3); IR (neat) 1730, 1710, 1152 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 1.12 (d, 3H, J = 6.7 Hz, CH3-8), 1.49
(s, 9H), 1.55 (m, 1H, Hax-6), 1.81 (m, 1H, Heq-6), 2.01 (m,
1H, Heq-5a), 2.21 (m, 1H, 1H-5), 2.29 (m, 2H, H-4), 2.50
(m, 1H, H-8), 2.55 (dd, 1H, J = 10.7, 3.2 Hz, Hax-5a),
4.14 (m, 1H, H-7), 5.79 (d, 1H, J = 15.5 Hz, H-2), 6.21
(dd, 1H, J = 14.5, 0.8 Hz, H-10), 6.46 (dd, 1H, J = 14.5,
8.3 Hz, H-9), 6.73 (d, 1H, J = 15.5 Hz, H-3); 13C NMR
(50 MHz, CDCl3) d 15.0 (CH3-8), 28.1 (–(CH3)3), 28.2 (C-
5), 29.7 (C-6), 35.1 (C-5a), 37.7 (C-4), 44.9 (C-8), 76.3 (O–
C), 78.7 (C-10), 80.6 (C-7), 125.9 (C-2), 142.8 (C-3), 145.4
(C-9), 165.0 (CO), 170.8 (CO); MS (ESI) 438 (M+NH4þ);
HRMS calcd. for C17H29NO4I (M+NH4þ) 438.1141,
found 438.1126.
References and notes
1. (a) Iwasaki, S.; Kobayashi, J.; Furukawa, J.; Namikoshi,
M.; Okuda, S.; Sato, Z.; Matsuda, I.; Noda, T. J. Antibiot.
1984, 37, 354; (b) Iwasaki, S.; Namikoshi, M.; Kobayashi,
H.; Furukawa, J.; Okuda, S.; Itai, A.; Kasuya, A.; Iitaka,
Y.; Sato, Z. J. Antibiot. 1986, 39, 424.
2. (a) Iwasaki, S.; Namikoshi, M.; Kobayashi, H.; Furu-
kawa, J.; Okuda, S. Chem. Pharm. Bull. 1986, 34, 1387; (b)
Kiyoto, S.; Kawai, Y.; Kawakita, T.; Kino, E.; Okuhara,
M.; Uchida, I.; Tanaka, H.; Hashimoto, M.; Terano, H.;
Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1986, 39,
762.
3. Srinivasa Rao, K.; Mukkanti, K.; Reddy, D. S.; Pal, M.;
Iqbal, J. Tetrahedron Lett. 2005, 46, 2287.
4. Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I. H.;
Crawford, J. J. Org. Chem. 2003, 68, 6096.
5. (a) Keck, G. E.; Park, M.; Krishnamurthy, D. J. Org.
Chem. 1993, 58, 3787; (b) White, J. D.; Blakemore, P. R.;
Green, N. J.; Hauser, E. B.; Holoboski, M. A.; Keown, L.
E.; Nylund Kolz, C. S.; Philips, B. W. J. Org. Chem. 2002,
67, 7750.
13. After completion of the reaction, the mixture was treated
with 2 N hydrochloric acid to give the lactone.
23
14. Spectral data of compound 3: ½aꢀD +6.5 (c 1.0, CHCl3);
IR (neat) 1729, 1710, 1152 cmꢁ1; 1H NMR (400 MHz,
CDCl3) d 1.11 (d, 3H, J = 6.7 Hz, CH3-8), 1.19 (td,
1H, J = 14.2, 13.9 Hz, Hax-6), 1.41 (s, 9H, O-t-Bu),
1.90 (dddd, 1H, J = 20.1, 13.4, 4.8, 3.2 Hz, Heq-6),
2.11 (m, 1H, Heq-5a), 2.13 (m, 1H, H-5), 2.22 (m, 2H,
H-4), 2.50 (m, 1H, H-8), 2.70 (dd, 1H, J = 11.8,
1.6 Hz, Hax-5a), 4.14 (ddd, 1H, J = 14.5, 9.1, 2.6 Hz,
H-7), 5.80 (d, 1H, J = 15.5 Hz, H-2), 6.20 (d, 1H,
J = 15.0 Hz, H-10), 6.49 (dd, 1H, J = 14.5, 8.0 Hz, H-
9), 6.84 (dt, 1H, J = 15.3, 7.2 Hz, H-3); 13C NMR
(50 MHz, CDCl3) d 14.6 (CH3-8), 28.1 (–(CH3)3),
29.6 (C-5), 30.9 (C-6), 35.9 (C-5a), 38.4 (C-4), 45.1 (C
8), 76.3 (O–C), 77.6 (C-10), 82.1 (C-7), 125.8 (C-2),
142.7 (C-3), 145.8 (C-9), 165.2 (CO), 170.8 (CO); MS
(ESI) 438 (M+NH4þ); HRMS calcd. for C17H29NO4I
(M+NH4þ) 438.1141, found 438.1129.
6. Held, C.; Frohlich, R.; Metz, P. Angew. Chem., Int. Ed.
2001, 40, 1058.
7. Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.;
Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652.
8. In the 1H NMR spectra the C5 proton of 13 was found to
appear at d 1.62 (m, 1H), whilst that of the desired isomer
appeared at d 1.38 (m, 1H). For spectral data of the