A cross-metathesis approach to the synthesis of key precursor of the macrolide core of rhizoxin D

Article abstract of DOI:10.1055/s-2008-1078170

The synthesis of key precursor 5 of the macrolide core of rhizoxin D has been achieved by cross metathesis between two olefinic fragments 6 and 7. Both the olefinic fragments are easily synthesized in a diastereoselective manner from the common precursor

Full text of DOI:10.1055/s-2008-1078170

LETTER
2417
A Cross-Metathesis Approach to the Synthesis of Key Precursor of the
Macrolide Core of Rhizoxin D1
Synthesis of
K
r
eyPrecu
i
rsor of
n
the
M
acroli
i
e
v
of Rhizoxin
a
D
s Padakanti,a,b Bukkapattanam R. Sreekanth,a Velisoju Mahendar,a Manojit Pal,a Khagga Mukkanti,b
Javed Iqbal,a Parthasarathi Das*a
a
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, AP, India
Fax +91(40)23045438; E-mail: parthasarathi@drreddys.com
Chemistry Division, Institute of Science & Technology, JNT University, Kukatpally, Hyderabad 500072, AP, India
b
Received 15 April 2008
molecule.6,7 Olefin cross metathesis has became a viable
synthetic strategy for the synthesis of highly functional-
ized alkenes8 and also applied for total synthesis of com-
plex natural products.9 In an approach to the synthesis of
rhizoxin D and its structural analogues, herein we report
the synthesis of the key precursor of its macrolide core us-
ing cross-metathesis reaction10 as the key step.
Abstract: The synthesis of key precursor 5 of the macrolide core of
rhizoxin D has been achieved by cross metathesis between two ole-
finic fragments 6 and 7. Both the olefinic fragments are easily syn-
thesized in a diastereoselective manner from the common precursor
1-benzyloxy-2-methylhex-5-ene-3-ol (8).
Keywords: rhizoxin D, Keck allylation, Crimmins aldol, Takai
olefination, cross metathesis
Our retrosynthesis analysis of rhizoxin D is based on the
synthesis of the corresponding macrolide 3 which ap-
peared to be a suitable precursor on which the side chain
of rhizoxin D could be easily introduced by the following
established synthetic procedures (Scheme 1).6b Macrolide
3 can be achieved via intramolecular Stille coupling on 4,
which can be obtained from primary alcohol 5. Whereas
compound 5 can be assembled by following a cross-meta-
thesis approach between 6 and 7. Both the olefinic frag-
ments 6 and 711 can be synthesized from the common
precursor 8 in a diastereoselective manner.
Rhizoxin (1) is a 16-membered macrolide isolated from
the fungus Rhizopus chinensis by Iwasaki and co-workers
(Figure 1).2 In addition to antibiotic and antifungal activi-
ty, it has been shown to possess potent antitumor activity,3
including activity against vincristine and adriamycin re-
sistant cells.4 The discovery of rhizoxin was soon fol-
lowed by the isolation of several close structural
analogues including rhizoxin D (2), which is believed to
be a biogenetic precursor of 1. Studies have shown that
this desepoxy derivative possesses bioactivity and antitu-
mor activity equivalent to those of rhizoxin, demonstrat-
ing that the epoxide moieties are not needed for in vitro
activity.5 It seems probable that in vivo hydrolysis of the
epoxides may be responsible to some degree for the very
short half-life of rhizoxin in the body, making compound
2 an intriguing potential therapeutic agent. The interesting
biological activity and challenging macrolide structure
prompted several groups to undertake the synthesis of this
As depicted in Scheme 2 our synthesis commenced with
addition of allyltributyltin12 to the known aldehyde 9 in
the presence of SnCl4 resulting in alcohol 8 in 92% yield
and with 36:1 diastereoselctivity. The TBDPS protection
of the allylalcohol followed by oxidative cleavage of the
terminal olefin by using OsO4–NaIO4 in the presence of
2,6 lutidine afforded aldehyde 11.
H
H
O
O
O
O
8
8
7
7
5
5
10
10
O
HO
HO
3
3
O
1
O
15
1
O
N
N
15
20
20
O
O
O
O
19
19
OMe
OMe
rhizoxin D (2)
rhizoxin (1)
Figure 1
SYNLETT 2008, No. 16, pp 2417–2420
x
x
.x
x
.2
0
0
8
Advanced online publication: 10.09.2008
DOI: 10.1055/s-2008-1078170; Art ID: D12208ST
© Georg Thieme Verlag Stuttgart · New York

2418
S. Padakanti et al.
LETTER
H
H
O
O
O
O
Me3Sn
I
PMBO
BnO
rhizoxin D (2)
PMBO
O
O
3
4
O
BnO
O
H
HO
O
O
I
H
O
O
OPMB
BnO
HO
O
O
+
PMBO
BnO
BnO
I
5
O
6
7
O
OH
8
Scheme 1 Retrosynthesis for macrolide
BnO
a
b
BnO
BnO
CHO
OTBDPS
OH
10
9
8
TBDPSO
O
O
OH
O
d
c
O
BnO
O
O
BnO
N
OTBDPS
11
N
O
Bn
12
Bn
TBDPSO
OH
e
BnO
OH
13
Scheme 2 Reagents and conditions: (a) allyl tributyltin, SnCl4, CH2Cl2, –90 to 0 °C, 1 h, 92%; (b) TBDPSCl, imidazole, DMF, r.t., 10 h, 95%;
(c) OsO4, NaIO4, 2,6-lutidine, THF–H2O (3:1), r.t., 5 h, 85%; (d) TiCl4, (–)-sparteine, CH2Cl2, –78 to 0 °C, 2 h, 90%; (e) NaBH4, THF–H2O
r.t., 4 h, 90%.
OMe
Introduction of the C13 stereocenter with the desired ste-
reochemistry was carried out by using Crimmins’ aldol
protocol.13 Addition of the titanium enolate derived from
acyloxazolidinone to aldehyde 11 resulted in the forma-
tion of syn-aldol product 12 in 85% yield and excellent
diastereoselectivity (≥96%). A reductive removal of the
chiral auxiliary with sodium borohydride in THF14 gave
alcohol 13.
TBDPSO
TBDPSO
OH OH
a
b
TBDPSO
O
O
BnO
BnO
BnO
13
14
TBDPSO
OPMB
OPMB
Protection of 1,3-diol 13 with 4-methoxybenzaldehyde
dimethyl acetal afforded the corresponding acetal 14 in
good yield. Regioselective cleavage15 of the acetal group
of 14 using DIBAL-H in CH2Cl2 and protection of the re-
sulting alcohol 15 with tosyl chloride in pyridine resulted
in 16.
c
OH
BnO
OTs
15
16
TBDPSO
OPMB
d
BnO
Subsequently, compound 16 was converted to the corre-
sponding terminal olefin 1716 by heating with NaI and
DBU in 1,2-dimethoxyethane (Scheme 3). The stereo-
chemistry and the anti relationship between the C13 and
17
Scheme 3 Reagents and conditions: (a) (MeO)2CHC6H4OMe,
CSA, CH2Cl2, r.t., 16 h, 85%; (b) DIBAL-H, CH2Cl2, 0 °C, 2 h, 90%;
(c) TsCl, pyridine, r.t., 3 h, 93%; (d) NaI, DBU,1,2-dimethoxyethane,
85 °C, 2.5 h, 96%.
Synlett 2008, No. 16, 2417–2420 © Thieme Stuttgart · New York

LETTER
Synthesis of Key Precursor of the Macrolide Core of Rhizoxin D
2419
H
O
O
OPMB
HO
O
O
a
+
BnO
I
6
7
H
H
O
O
HO
O
O
I
PMBO
BnO
PMBO
BnO
O
O
O
O
Figure 2 ORTEP diagram of fragment 17
5
3
Scheme 5 Reagents and conditions: (a) Grubbs II catalyst, DCE,
85 °C, 24 h, 80%.
TBDPSO
OPMB
TBDPSO
OPMB
a
b
O
BnO
BnO
In conclusion, we have accomplished the synthesis of a
key precursor 5 to the macrolide core of rhizoxin D from
fragments 6 and 7 by using a cross-metathesis approach.
The most interesting features of the synthesis are that both
the olefinic partners required for cross metathesis were
synthesized from the common intermediate 1-benzyloxy-
2-methylhex-5-en-3-ol. This flexible approach has pro-
vided us with a robust route towards the total synthesis of
rhizoxin D and structural analogues for biological studies,
which are currently under way in our laboratory.
18
17
OPMB
OH OPMB
TBDPSO
c
BnO
I
BnO
I
19
20
O
O
OPMB
d
BnO
I
6
Acknowledgment
Scheme 4 Reagents and conditions: (a) OsO4, NaIO4, 2,6-lutidine,
THF–H2O (3:1), r.t., 4 h, 85%; (b) CrCl2/CHI3, THF, r.t., 70 h, 50%;
(c) TBAF, THF, r.t., 12 h, 86%; (d) acryloyl chloride, Et3N, CH2Cl2,
r.t., 2.5 h, 92%.
We would like to thank Dr. Reddy’s Laboratories Ltd. for financial
support and the analytical department for spectroscopic analyses.
References and Notes
C15 alcohols were established by single crystal X-ray dif-
fraction analysis (Figure 2).17
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Oxidative cleavage of terminal olefin with OsO4–NaIO4
in the presence of NMO was followed by Takai
olefination18 (CrCl2/CHI3) and resulted in olefin 19.
Deprotection of the tert-butyldiphenylsilyl ether of 19
provided compound 20, which on acryloylation afforded
compound 619 ready for cross methathesis (Scheme 4).
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Kerr, D. J.; Henrar, R.; Kaye, S. B. J. Natl. Cancer Inst.
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We finally conducted the most crucial bond formation by
subjecting 6 and 7 to Grubbs second-generation catalyst
which led to the desired key intermediate 520 in good yield
(Scheme 5). Among the noteworthy features of this syn-
thesis is the high yield of the cross-metathesis reaction
and comptability of the vinyl iodide group with these re-
action conditions. By following the protocol of Mitchell
and co-workers,6f conversion of the primary alcohol group
into the vinyl stannane present on the d-lactone moiety
and subsequent Stille coupling could give the macrolide
core 3 of rhizoxin D.
Synlett 2008, No. 16, 2417–2420 © Thieme Stuttgart · New York

2420
S. Padakanti et al.
LETTER
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk./data_request/
cif.
Burke, S. D. Org. Lett. 2004, 6, 1445. (f) Mitchell, I. S.;
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108, 7408.
(19) Spectral Data for 6
(7) (a) Rama Rao, A. V.; Sharma, G. V. M.; Bhanu, M. N.
Tetrahedron Lett. 1992, 33, 3907. (b) Rama Rao, A. V.;
Bhanu, M. N.; Sharma, G. V. M. Tetrahedron Lett. 1993, 34,
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Chem. 1993, 58, 3787. (e) Lafontaine, J. A.; Leahy, J. W.
Tetrahedron Lett. 1995, 36, 6029. (f) Provencal, D. P.;
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Lett. 1995, 36, 6033. (g) Davenport, R. J.; Regan, A. C.
Tetrahedron Lett. 2000, 41, 7619.
[a]D23 –21.6 (c 0.5, CHCl3). IR (neat): 2918, 1722, 1614,
1514 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.92 (d, 3 H,
J = 6.8 Hz), 1.72 (ddd, 1 H, J = 14.0, 10.4, 3.6 Hz), 1.77 (d,
3 H, J = 1.2 Hz), 1.89 (ddd, 1 H, J = 12.0, 9.6, 2.4 Hz), 2.14
(ddd, 1 H, J = 11.6, 6.4, 4.8 Hz), 3.29 (dd, 1 H, J = 9.2, 6.4
Hz), 3.46 (dd, 1 H, J = 10.0, 6.4 Hz), 3.78 (s, 3 H), 3.82 (dd,
1 H, J = 9.2, 4.0 Hz), 4.11 (d, 1 H, J = 10.8, Hz), 4.30 (d, 1
H, J = 10.8 Hz), 4.46 (m, 2 H), 5.29 (ddd, 1 H, J = 7.2, 4.8,
2.4 Hz), 5.79 (dd, 1 H, J = 10.4, 1.6 Hz), 6.05 (dd, 1 H,
J = 17.2, 10.4 Hz), 6.20 (s, 1 H), 6.34 (dd, 1 H, J = 17.2, 1.2
Hz), 6.83 (d, 2 H, J = 8.8 Hz), 7.22 (d, 2 H, J = 8.4 Hz), 7.28
(m, 5 H). 13C NMR (50 MHz, CDCl3): d = 13.0, 19.1, 35.7,
37.3, 55.2, 70.3, 71.9, 72.6, 72.9, 79.2, 80.0, 113.8, 127.4,
127.5, 128.3, 129.4, 129.6, 130.0, 130.5, 138.4, 148.0,
159.1, 165.5. ESI-HRMS: m/z calcd for C27H33IO5Na [M +
Na]+: 587.1270; found: 587.1277.
(8) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360.
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127, 5334. (b) Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org.
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M.-A.; Menant, C.; Fenet, B.; Piva, O. Tetrahedron Lett.
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(20) Synthetic Procedure and Spectroscopic Data of 5
A mixture of a solution of 6 (0.035 g, 0.06 mmol) and 7
(0.024 g, 0.123 mmol) in DCE (0.3 mL) was treated with
Grubbs second-generation catalyst (5.25 mg, 0.0056 mmol)
and the dark purple solution stirred at reflux temperature for
48 h. The reaction mixture was then loaded directly on top of
a wet column packed with SiO2 and purified by flash
chromatography (EtOAc–hexane, 1:3) to afford the product
5 (0.036 g, 80%) as light brown oil; [a]D23 –22.0 (c 0.1,
CHCl3). IR (neat): 3468, 2924, 1712, 1414, 1247 cm–1. 1H
NMR (400 MHz, CDCl3): d = 0.92 (d, 3 H, J = 6.8 Hz), 0.97
(d, 3 H, J = 7.2 Hz), 1.42 (m, 1 H), 1.72 (m, 1 H), 1.77 (s, 3
H), 1.88 (m, 2 H), 2.18 (m, 6 H), 2.71 (dd, 1 H, J = 12.0, 2.0
Hz), 3.30 (dd, 1 H, J = 9.2, 6.4 Hz), 3.45 (dd, 1 H, J = 9.6,
6.4 Hz), 3.62 (dd, 1 H, J = 10.4, 5.2 Hz), 3.71 (dd, 1 H,
J = 10.8, 7.6 Hz), 3.78 (s, 3 H), 3.82 (dd, 1 H, J = 8.8, 4.4
Hz), 4.12 (m, 2 H), 4.30 (d, 1 H, J = 10.8), 4.57 (s, 2 H), 5.26
(ddd, 1 H, J = 7.2, 4.8, 2.8 Hz), 5.81 (d, 1 H, J = 15.6 Hz),
6.20 (s, 1 H), 6.79 (m, 1 H), 6.83 (d, 2 H, J = 8.4 Hz), 7.21
(d, 2 H, J = 8.8 Hz), 7.38 (m, 5 H). 13C NMR (50 MHz,
CDCl3): d = 10.4, 12.4, 19.0, 30.9, 32.0, 35.4, 35.9, 37.2,
38.5, 39.6, 55.1, 63.9, 70.2, 71.9, 72.6, 72.8, 79.3, 80.0, 80.2,
113.7, 123.9, 127.4, 128.2, 129.2, 129.5, 129.9, 138.3,
144.5, 147.8, 159.0, 165.4, 170.9. ESI-HRMS: m/z calcd for
C36H47IO8Na [M + Na]+: 757.2213; found: 757.2210.
(10) (a) Saibaba, V.; Das, P.; Mukkanti, K.; Iqbal, J. Tetrahedron
Lett. 2006, 47, 7927. (b) Saibaba, V.; Sampath, A.;
Mukkanti, K.; Iqbal, J.; Das, P. Synthesis 2007, 2797.
(11) Srinivas, P.; Pal, M.; Mukkanti, K.; Iqbal, J. Tetrahedron
Lett. 2006, 47, 5969.
(12) Keck, G. E.; Park, M.; Krishnamurthy, D. J. Org. Chem.
1993, 58, 3787.
(13) (a) Crimmins, M. T.; Bryan, W. K.; Tabet, E. A.; Kaleem, C.
J. Org. Chem. 2001, 66, 894. (b) Crimmins, M. T.;
Caussanel, F. J. Am. Chem. Soc. 2006, 128, 3128.
(c) Narasimhulu, C.; Iqbal, J.; Mukkanti, K.; Das, P.
Tetrahedron Lett. 2008, 49, 3185.
(14) Phukan, P.; Sasmal, S.; Maier, M. E. Eur. J. Org. Chem.
2003, 1733.
(15) Saibaba, V.; Das, P.; Mukkanti, K.; Iqbal, J. Tetrahedron
Lett. 2006, 47, 6083.
(16) Phukan, P.; Bauer, M.; Maier, M. E. Synthesis 2003, 1324.
(17) Crystal Data for Fragment 17
C40H50O4Si1, M = 622.92, monoclinic, space group P21,
a = 14.79 (2) Å, b = 9.29 (1) Å, c = 15.09 (2) Å, b = 102.33
(2)°, V = 2026 (4) Å3, Z = 2, Dc = 1.021 g cm–3, reflections
collected = 20735, unique reflections = 4637,
[Rint = 0.0682], final R indices [I > 2s(I)]: R1 = 0.065,
wR2 = 0.114, CCDC-662327 contains the supplementary
crystallographic data for this letter. These data can be
Synlett 2008, No. 16, 2417–2420 © Thieme Stuttgart · New York