A cross metathesis approach to the synthesis of the C11-C23 fragment of (-)-16-normethyldictyostatin

Article abstract of DOI:10.1016/j.tetlet.2006.09.004

The synthesis of the C11-C23 fragment 2 of (-)-16-normethyldictyostatin has been achieved by cross metathesis between two olefinic fragments 4 and 5 followed by a reduction of the double bond at C16-C17. Both the olefinic fragments are easily synthesized

Full text of DOI:10.1016/j.tetlet.2006.09.004

Tetrahedron Letters 47 (2006) 7927–7930
A cross metathesis approach to the synthesis of the
C11–C23 fragment of (ꢀ)-16-normethyldictyostatinI
V. Sai Baba,a,b Parthasarathi Das,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 20 July 2006; revised 21 August 2006; accepted 1 September 2006
Available online 25 September 2006
Abstract—The synthesis of the C11–C23 fragment 2 of (ꢀ)-16-normethyldictyostatin has been achieved by cross metathesis between
two olefinic fragments 4 and 5 followed by a reduction of the double bond at C16–C17. Both the olefinic fragments are easily
synthesized in a diastereoselective manner from the common precursor alcohol 7.
Ó 2006 Elsevier Ltd. All rights reserved.
Around half of the drugs currently in clinical use are of a
natural product origin.1,2 Among them marine macro-
lides have recently gained a significant importance as
potent disrupters of cell cycle events. Dictyostatin
(Fig. 1) is a marine-derived macrolide that was first iso-
lated by Pettit et al. from Spongia sp.3 It was demon-
strated that dictyostatin inhibited the growth of
human cancer cells with GI50 from 50 pm to 1 nM.4
Most importantly, it retains the activity against taxol
resistant cancer cells that express an active P-glycopro-
tein. Initial studies demonstrated that dictyostatin
arrests the cell in the G2/M phase by potently inducing
tubulin polymerization and suppressing microtubule
dynamics, leading to an apoptosis similar to that seen
in cells exposed to palcitaxel.5 With the promising anti-
mitotic properties of dictyostatin and other polyketides
of marine origin, which include laulimalide,6 peloruside
A7 and discodermolide,8 natural products may lead to
the development of anticancer drugs. The significant
biological properties of dictyostatin coupled with its
scarcity in nature and densely functionalized structure
has prompted numerous studies directed towards its
synthesis. So far, the total synthesis of dictyostatin has
been achieved by the groups of Curran9 and Paterson.10
More recently, an analogue (ꢀ)-16-normethyldictyosta-
tin was shown to be essentially equipotent to its parent
compound against human ovarian carcinoma 1A9 cells
and its clones 1A9PTX22.11 In considering a strategy
for the synthesis of (ꢀ)-16-normethyldictyostatin, herein
we report a cross metathesis approach for the synthesis
of the C11–C23 fragment.
R
26
OH
16
23
HO
1
O
O
The retrosynthetic analysis revealed that the C11–C23
fragment of (ꢀ)-16-normethyldictyostatin 2 can be
assembled by following a cross metathesis approach be-
tween 4 and 5, followed by the reduction of the double
bond at the C16–C17 position in 3. Both the olefinic
fragments 4 and 5 with the desired stereochemistry are
easily accessible from the common precursor aldehyde
6, which in turn can be synthesized from alcohol 7 in
a diastereoselective manner in a few steps (Scheme 1).
11
1
OH OH
(-)-dictyostatin, R = Me
(-)-16-normethyldictyostatin, R = H
Figure 1.
q DRL Publication No. 598.
As depicted in Scheme 2, our synthesis commenced with
the addition of the titanium enolate derived from
the acyloxazolidinone to aldehyde 8 (synthesized from
*
Corresponding authors. Tel.: +91 40 2304 5439; fax: +91 40
2304 5438 (J.I.); e-mail addresses: parthasarathi@drreddys.com;
javediqbalpr@yahoo.co.in; javediqbaldrf@hotmail.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.004

7928
V. Sai Baba et al. / Tetrahedron Letters 47 (2006) 7927–7930
TBS
alcohol 11.18 Swern oxidation of 11 yielded the crucial
O
OTBS
aldehyde 6 with the required contiguous stereocentres.
The two step sequential homologation19 of aldehyde 6
via 12 followed by Wittig olefination20 afforded frag-
ment 421 in a 76% yield over three steps.
23
MPMO
2
3
OTBS
TBS
11
OH
The synthesis of the olefinic fragment 5 via SnCl4 med-
iated diastereoselective addition of allyltributyltin to
aldehyde 6 gave a 70:30 ratio in favour of the undesired
stereocentre at C19 of alcohol 13.22 This result can be
explained by considering the syn diastereomeric (nonre-
inforcing) relationship between a-alkyl and b-alkoxy
substituents23 influencing the incoming nucleophile to
the aldehyde in the anti-Felkin mode. The oxidation of
13 using Dess–Martin periodinane24 followed by depro-
tection of the MPM group with DDQ25 yielded the
hydroxy ketone 14 in a 77% yield (Scheme 3). The
reduction of 14 with DIBAL-H in THF produced 1,3-
syn diol 15 with a high diastereoselectivity (P90%).26
Finally, the benzyl group of 15 was deprotected using
boron trichloride22,27 followed by a global protection
of the resulting triol with TBSOTf28 to afford 529 in a
93% yield.
O
OTBS
23
MPMO
OTBS
11
OBn
TBS
O
OTBS
MPMO
4
5
OTBS
OBn
O
MPMO
BnO
OH
6
7
OBn
Scheme 1. Retrosynthesis of the C11–C23 fragment 2.
With the two main fragments 4 and 5 in hand, the cross
metathesis30 (CM) strategy was adopted using Grubbs’
2nd generation catalyst (10 mol %) to yield the desired
product 331 in a 50% yield along with the homodimer
of the starting olefinic compound 4. Deprotection of
the benzyl ether and reduction32 of the double bond of
compound 3 using excess Raney Ni under a H2 atmo-
sphere provided the required C11–C23 core fragment 2
in a good yield and with the required stereocentres
(Scheme 4).33
OH
O
b
a
O
O
BnO
BnO
7
8
N
O
O
Bn
HO
HO
O
O
HO
N
c
Bn
10
BnO
d
9
OBn
MPMO
In summary, we have developed an efficient route for the
synthesis of the C11–C23 fragment of (ꢀ)-16-nor-
methyldictyostatin using a cross metathesis approach.
The most interesting feature of this synthesis is that both
the olefinic partners required for cross metathesis were
synthesized from a common intermediate 6 and the cross
OH
O
MPMO
f
e
11
6
OBn
OBn
O
MPMO
g
MPMO
O
OH OBn
12
4
MPMO
a
b
OBn
OBn
OMPM
Scheme 2. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2,
ꢀ78 °C, 30 min, then 7, Et3N, ꢀ78 to rt, 1 h, 95%; (b) TiCl4, (ꢀ)-
sparteine, CH2Cl2, 0 °C, 1.5 h, 97%; (c) NaBH4, THF/H2O 5:1, 0 °C to
rt, 12 h, 90%; (d) (i) (OMe)2CHC6H4OMe, CSA, CH2Cl2, rt, 4 h, 70%;
(ii) DIBAL-H, CH2Cl2, 0 °C, 3 h, 80%; (e) (COCl)2, DMSO, CH2Cl2,
ꢀ78 °C, then Et3N, 0 °C, 1 h, 91%; (f) (i) MeOCH2PPh3Cl, NaHMDS,
THF, ꢀ40 to 0 °C, 2 h; (ii) PPTS, dioxane/H2O 9:1, 50 °C, 12 h, 85%;
(g) CH3PPh3Br, NaHMDS, Et2O, 0 °C, 4.5 h, 90%.
6
13
OBn
OH OBn
OH
O
OBn
c
15
14
OH
TBS
O
OTBS
d
alcohol 712 by Swern oxidation13) resulting in the forma-
tion of syn aldol product 914 in a 97% yield and excellent
diastereoselectivity (P96%). A reductive removal of the
chiral auxiliary with NaBH4 in THF/H2O15 gave 1,3-
diol 10,16 which was protected with 4-methoxybenzalde-
hyde dimethylacetal17 followed by a selective opening of
the benzylidene ring using DIBAL-H to give primary
5
OTBS
Scheme 3. Reagents and conditions: (a) Bu3SnCH2CH@CH2, SnCl4,
CH2Cl2, ꢀ90 °C, 1 h, 90%; (b) (i) DMP, CH2Cl2, rt, 1 h, 90%; (ii)
DDQ, CH2Cl2/H2O 20:1, 0 °C, 1 h, 77%; (c) DIBAL-H, THF, ꢀ78 °C,
5 h, 70%; (d) (i) BCl3, toluene, ꢀ78 to 0 °C, 3 h, 65%; (ii) TBSOTf,
i-Pr2NEt, CH2Cl2, 0 °C, 1.5 h, 93%.

V. Sai Baba et al. / Tetrahedron Letters 47 (2006) 7927–7930
7929
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TBS
O
OTBS
MPMO
a
+
4
5
OTBS
OBn
TBS
O
OTBS
b
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
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MPMO
14. (a) Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de
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2002, 3455–3464.
OTBS
TBS
3
OBn
O
OTBS
MPMO
OTBS
2
OH
Scheme 4. Reagents and conditions: (a) Grubbs’ II catalyst
18. Marshall, J. A.; Blough, B. E. J. Org. Chem. 1990, 55,
1540–1547.
(10 mol %), rt, 36 h, 50%; (b) H2, Raney Ni (excess), EtOH, rt, 85%.
19. Nicolaou, K. C.; Ritzen, A.; Namoto, K.; Buey, R. M.;
Fernando Diaz, J.; Andreu, J. M.; Wartmann, M.;
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hedron 2002, 58, 6413–6432.
metathesis between fragments 4 and 5 gave an apprecia-
ble yield of the desired product 3. This flexible approach
has provided us with a robust route towards the total
synthesis of (ꢀ)-16-normethyldictyostatin and structural
analogues for biological studies, which are currently
under way in our laboratory.
20. Calter, M. A.; Guo, X. Tetrahedron 2002, 58, 7093–7100.
20
21. Spectral data for compound 4: ½aꢁD ꢀ20.1 (c 1.00, CHCl3);
IR (neat, cmꢀ1) 2965, 2929, 2857, 1613, 1513, 1457, 1247,
1090, 1039, 821; 1H NMR (CDCl3, 400 MHz) d 7.40–7.25
(m, 5H), 7.21 (d, J = 8.60 Hz, 2H), 6.84 (d, J = 8.60 Hz,
2H), 5.83–5.74 (m, 1H), 5.04–4.99 (m, 2H), 4.60–4.41 (m,
4H), 3.80 (s, 3H), 3.56–3.51 (m, 2H), 3.29 (dd, J = 8.33,
3.22 Hz, 1H), 2.27–2.20 (m, 1H), 2.10–1.96 (m, 2H), 1.82–
1.77 (m, 1H), 1.00 (d, J = 6.98 Hz, 3H), 0.91 (d,
J = 6.98 Hz, 3H); 13C NMR (CDCl3, 50 MHz) d 158.97,
138.75, 137.83, 131.37, 128.98, 128.26, 127.56, 127.38,
115.84, 113.65, 83.40, 74.29, 73.03, 72.68, 55.20, 39.29,
36.90, 35.39, 15.13, 13.33; MS (ESI) 369 [M+H+].
22. White, J. D.; Blakemore, P. R.; Green, N. J.; Hauser,
E. B.; Holoboski, M. A.; Keown, L. E.; Nylund Kolz,
C. S.; Phillips, B. W. J. Org. Chem. 2002, 67, 7750–
7760.
Acknowledgements
We thank Dr. Reddy’s Laboratories Ltd. for the finan-
cial support and encouragement. Help from the analyti-
cal department in recording spectral data is appreciated.
References and notes
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S. A.; Longley, R. E.; Isbrucker, R. A. Dictyostatin
compounds for stabilization of microtubles WO 0162239,
2001; Chem. Abstr. 2001, 635882.
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Livingston, A. B. J. Am. Chem. Soc. 1995, 117, 6619–6620.
24. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
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Yonemitsu, O. Chem. Pharm. Bull. 1994, 42, 683–685; (b)
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Lett. 1986, 27, 3009–3012; (b) Solsona, J. G.; Nebot, J.;
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20
29. Spectral data for compound 5: ½aꢁD ꢀ22.8 (c 1.00, CHCl3);
IR (neat, cmꢀ1) 2957, 2930, 2858, 1472, 1463, 1255, 1078,
1
1031, 836, 773; H NMR (CDCl3, 400 MHz) d 5.88–5.79
(m, 1H), 5.06–5.02 (m, 2H), 3.72–3.63 (m, 3H), 3.42–3.38
(m, 1H), 2.33–2.29 (m, 2H), 1.83–1.68 (m, 2H), 0.93–0.86
(m, 33H), 0.07–0.00 (m, 18H); 13C NMR (CDCl3,
50 MHz) d 134.73, 117.00, 73.84, 72.80, 65.01, 40.55,
39.80, 39.51, 26.22, 25.98, 25.71, 18.54, 18.32, 18.16, 14.77,

7930
V. Sai Baba et al. / Tetrahedron Letters 47 (2006) 7927–7930
10.27, ꢀ2.95, ꢀ3.43, ꢀ3.72, ꢀ3.93, ꢀ4.41, ꢀ5.33; MS
(ESI) 531 [M+H+].
30. (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs,
R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370; (b)
Crimmins, M. T.; Caussanel, F. J. Am. Chem. Soc. 2006,
128, 3128–3129.
128.29, 127.59, 127.41, 126.36, 113.67, 83.94, 74.45,
74.06, 73.06, 72.74, 64.98, 55.23, 40.48, 40.15, 39.78,
38.31, 36.97, 26.23, 25.99, 18.53, 18.31, 18.17, 15.18, 14.87,
13.16, 10.24, ꢀ3.40, ꢀ3.68, ꢀ3.88, ꢀ4.38, ꢀ5.27; MS (ESI)
893 [M+Na+]; HRMS calcd for C50H90O6NaSi3 [M+Na+]
893.5942, found: 893.5924.
31. Experimental procedure and spectral data for compound
3: In a 10 mL round bottom flask charged with 5 (270 mg,
0.51 mmol) and 4 (375 mg, 1.02 mmol) and Grubbs’ 2nd
generation catalyst was added as a solid (0.051 mmol,
43.2 mg) to the flask and the dark purple reaction mixture
was stirred at room temperature for 36 h. The crude
reaction mixture was purified directly by flash chroma-
tography (0.8–1% EtOAc/Hexane) to provide 222 mg
32. Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles,
D. C. J. Org. Chem. 2003, 68, 6646–6660.
20
33. Spectral data for compound 2: ½aꢁD ꢀ15.6 (c 1.00, CHCl3);
IR (neat, cmꢀ1) 3421, 2929, 2857, 1716, 1513, 1464, 1251,
1109, 838, 666; 1H NMR (CDCl3, 400 MHz) d 7.26 (d,
J = 8.60 Hz, 2H), 6.87 (d, J = 8.60 Hz, 2H), 4.59 (d,
J = 10.48 Hz, 1H), 4.48 (d, J = 10.75 Hz, 1H), 3.80 (s,
3H), 3.70–3.58 (m, 5H), 3.43–3.39 (m, 1H), 3.26–3.23 (m,
1H), 2.74 (br s, –OH, 1H), 1.91–1.81 (m, 2H), 1.80–1.70
(m, 2H), 1.54–1.41 (m, 2H), 1.39–1.26 (m, 6H), 0.97–0.81
(m, 39H), 0.07–0.03 (m, 18H); 13C NMR (CDCl3,
50 MHz) d 159.30, 130.53, 129.39, 113.88, 88.53, 74.90,
74.27, 73.39, 66.68, 64.99, 55.25, 40.49, 39.83, 37.64, 36.28,
34.87, 29.69, 28.23, 26.22, 25.99, 24.56, 18.54, 18.31, 18.17,
15.49, 15.05, 14.24, 10.58, 1.01, ꢀ3.47, ꢀ3.66, ꢀ3.91,
ꢀ4.29, ꢀ5.23, ꢀ5.32; MS (ESI) 783 [M+]; HRMS calcd for
C43H86O6Si3 [M+] 783.5810, found: 783.5801.
20
(50%) of cross product 3 as a colourless oil: ½aꢁD ꢀ19.3
(c 1.00, CHCl3); IR (neat, cmꢀ1) 2956, 2931, 2858, 1465,
1252, 1083, 1034, 835, 773; 1H NMR (CDCl3, 400 MHz) d
7.34–7.33 (m, 5H), 7.20 (d, J = 8.60 Hz, 2H), 6.84 (d,
J = 8.60 Hz, 2H), 5.46–5.42 (m, 2H), 4.50–4.39 (m, 4H),
3.79 (s, 3H), 3.70–3.63 (m, 3H), 3.56–3.50 (m, 2H), 3.42–
3.25 (m, 2H), 2.27–1.71 (m, 8H), 1.00 (d, J = 6.98 Hz, 3H),
0.92–0.86 (m, 36H), 0.06–0.00 (m, 18H); 13C NMR
(CDCl3, 50 MHz)
d 158.99, 138.81, 131.64, 129.05,