Synthesis of the C21-C28 segment of pectenotoxin-4

Article abstract of DOI:10.1016/j.tetlet.2007.04.148

The synthesis of the C21-C28 segment of pectenotoxin-4 as the C21 Weinreb amide is described. Feasibility studies for the union of a related Weinreb amide and a functionalized alkyne are also reported.

Full text of DOI:10.1016/j.tetlet.2007.04.148

Tetrahedron Letters 48 (2007) 4761–4764
Synthesis of the C21–C28 segment of pectenotoxin-4
Robert V. Kolakowski and Lawrence J. Williams*
Contribution from the Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey,
Piscataway, NJ 08854, USA
Received 27 March 2007; revised 30 April 2007; accepted 30 April 2007
Available online 5 May 2007
Abstract—The synthesis of the C21–C28 segment of pectenotoxin-4 as the C21 Weinreb amide is described. Feasibility studies for
the union of a related Weinreb amide and a functionalized alkyne are also reported.
Ó 2007 Elsevier Ltd. All rights reserved.
We were attracted to the synthetic challenges posed by
macrolide pectenotoxin-4 (1, Fig. 1) and its impressive,
albeit only partially documented, biological profile.1
The pectenotoxins are a small but structurally imposing
class of substances from isolates collected off the coast
of Japan. These natural products were thought to orig-
inate from the pecten scallops. Subsequent investiga-
tions revealed that dinoflagellates, in this case
Dinophysis fortii, within the shellfish are the source of
these metabolites. Highlights of the biological profile
include potent actin depolymerization activity2 and tumor
cell repression3 in P53 deficient cells.4
Several routes toward the pectenotoxins have appeared,
highlighted by the elegant total synthesis by Evans,
et al.5 Ignoring for the present discussion the important
issue of exact timing, we focused on an approach to the
endgame that set as the goal the late-stage formation of
the C20–C21 junction. A Weinreb amide–alkynylide
coupling seems an attractive solution, owing to the
anticipated reliability of such a union. To test the feasi-
bility of this proposal, the coupling of a suitable C21–
C28 fragment (2) with complex model alkynes of general
structure 3 was examined (Fig. 1). Although any serious
synthetic venture would have to coordinate creation of
the 19 stereocenters, the C40 backbone, and formation
of the eight oxygen heterocycles either ancillary to or
subsumed within the 34-membered macrolide, we report
here the synthesis of segment 2 and preliminary
investigations related to a planned C1–C20/C21–C40
coupling.
O
10
15
O
O
O
Me
Me
O
HO
H
A
O
1
O
18
33
21
OH
E
28
O
O
O
20
HO
The synthesis of 2, summarized in Schemes 1–3, com-
menced with the preparation of aldehyde 7. Implemen-
tation of the Jacobsen hydrolytic kinetic resolution of
glycidol 4,6 followed by selective protection of the pri-
mary alcohol with pivaloyl chloride (!5), gave a single
product, as assessed by Mosher ester analysis (>95%
ee).7 Protection of 5 using p-methoxybenzyl imidate8
gave 6 in an overall yield of 68%. Removal of the pivo-
late followed by Swern oxidation9 provided differentially
protected L-glyceraldehyde 7. This five-step sequence
from commercial reagents proceeded in 52% overall
yield.10
O
Me
H
Me Me
1
Me
40
HO
O
OTES
Me
H
28
O
Me
R''
TBDPSO
N
21
18
Me
OMe
R'
2
3
Figure 1. Pectenotoxin-4.
Alkyne 10 was prepared by alkylation of 8 with com-
mercially available (TMS) propargyl bromide 9 (dr
9:1, 63%).11 Cleavage of the oxazolidinone with lithium
Keywords: Pectenotoxin; Tetrahydrofuran synthesis; Weinreb amide;
Marshall cyclization.
*
Corresponding author. E-mail: ljw@rutchem.rutgers.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.148

4762
R. V. Kolakowski, L. J. Williams / Tetrahedron Letters 48 (2007) 4761–4764
union of the titaniumisopropoxide alkynylide13 derived
OH
O
c
a, b
OTBS
from 10 with aldehyde 7 provided 11 in 1.5:1 dr and
53% yield.14 Use of the lithium alkynylide in THF and
in the presence of 5 equiv of HMPA15 offered only a
modest improvement (dr 2:1, 62% yield). Carreira alky-
nylation of 7 with 10, however, proved significantly
more efficient and selective (85%, dr 4:1).16a The so-
called matched amino alcohol ligand of the Carreira
reaction has been shown to enhance selectivity of anti-
Felkin–Anh addition to a-siloxy aldehydes. Further-
more, and consistent with formation of 11, the antipodal
amino alcohol ligand has been shown to override
intrinsic selectivity and give Felkin–Ahn addition as
the major product.16b
OTBS
PivO
5
4
OPMB
OTBS
OPMB
d, e
PivO
O
OTBS
7
6
Scheme 1. Reagents and conditions:19 (a) (R,R)-salen-Co(III)-OAc
(0.49 equiv), H2O, Et2O, rt, 18 h, 47%; (b) Piv-Cl (1 equiv), pyr
(5 equiv), CH2Cl2, 0 °C–rt, 4 h, 94%; (c) PMBOC(@NH)CCl3
(1.2 equiv), TfOH (0.01 mol %), Et2O, rt, 0.5 h, 77%; (d) DiBAl-H
(1.5 equiv), hexanes, 0 °C–rt, 4 h, 85%; (e) DMSO (4 equiv), (COCl)2
(2.2 equiv), i-Pr2EtN (4.0 equiv), ꢀ78 °C, 90%.
Addition of mesyl chloride and then excess methyl cup-
rate effected the single-flask conversion of 11 to allene 12
in an efficient (95%) and convenient procedure. Cleavage
of the PMB ether with DDQ (88%) and then subjection
of the resultant allenol to Marshall cyclization condi-
tions provided dihydrofuran 13 in 93% yield.17 Hydro-
genation with concomitant hydrogenolysis of 13
(93%), protection of the primary alcohol with
TBDPSCl, and then removal of the TBS group in the
same flask gave 14 in 82% yield. Sequential oxidation
of 14 to the carboxylic acid and then amidation gave
2. [Compound 2 characterization data. 1H NMR,
500 MHz (CDCl3) given as d (multiplicity, J in Hz; inte-
gration): 7.67 (d, 7.9; 4H), 7.40 (m; 6H), 4.73 (br s; 1H),
3.69 (s; 3H) 3.46 (dq, 6.6; 2H) 3.19 (s; 3H), 2.13 (br s;
2H), 1.83 (m; 1H), 1.76 (q, 8.0; 2H), 1.67 (dd, 6.9; 1H)
1.33 (m; 1H), 1.29 (s; 3H), 1.06 (s; 9H), 1.01 (d, 6.6;
3H); 13C NMR, 100 MHz, (CDCl3) d 173.9, 135.8,
134.5, 129.7, 127.7, 85.6, 75.1, 69.8, 61.6, 44.1, 37.5,
32.8, 32.3, 29.0, 27.1, 26.4, 19.4, 18.9; ESI/MS
calculated for NaC28H41NO4Si (M+23) 506.28, found
506.3.]
O
O
Br
+
OBn
a, b, c
O
N
Me
TMS
Me
Ph
8
9
10
Scheme 2. Reagents and conditions:19 (a) LiHMDS (1.2 equiv), THF,
ꢀ78 °C–rt, 4 h, 9:1 dr, 63%; (b) LiBH4 (2.5 equiv), THF, 0 °C, 84%; (c)
BnOC(@NH)CCl3 (1.5 equiv), TfOH; (0.01 mol %), Et2O, rt, 1 h then
MeOH, K2O3 excess, 1 h, 86%.
borohydride followed by protection of the primary alco-
hol with benzyl imidate9 and then in situ cleavage of the
TMS group with MeOH and potassium carbonate pro-
vided 10. The yield of 10 from this three-step sequence
was 46% overall.
The synthetic sequence to 2 from 7 and 10 is shown in
Weinreb amide alkynylation has proven a reliable and
convergent approach to establish new carbon connectiv-
Scheme 3. Initial evaluation of a Felkin–Anh type12
OH
BnO
HO
OTBS
Me
10
Me
d
a
b, c
OTBS
OPMB
BnO
BnO
Me
•
O
Me
H
OTBS
11
12
OPMB
7
O
H
Me
H
Me
Me
H
O
O
g, h, i
O
2
e, f
Me
BnO
OTBS
TBDPSO
OH
TBDPSO
N
CH3
Me
Me
OMe
13
14
Scheme 3. Reagents and conditions:19 (a) 10 (1.2 equiv), TEA (1.2 equiv), Zn(OTf)2 (1.1 equiv), (ꢀ)-N-methylephedrine (1.2 equiv), tol., rt, 85%, dr
4:1; (b) TEA (1.5 equiv), MsCl (1.5 equiv), Et2O, ꢀ78 °C–rt, 1 h, then, Cu(Me)CNLi (5.0 equiv) in Et2O, ꢀ78 °C–rt, 0.5 h, 95%; (c) DDQ (1.2 equiv),
1:1 CH2Cl2–PBS 7.8 pH, 88%; (d) AgNO3 (1.1 equiv), CaCO3 (2.0 equiv), 4:1 acetone–H2O, 93%; (e) 10 wt % Pd/C (0.05 equiv), EtOAc, 24 h, 93%;
(f) (i) TEA (1.3 equiv), DMAP (0.1 equiv), TBDPSCl (1.5 equiv), CH2Cl2, 0 °C, (ii) solvent removal in vacuo then TFA–AcOH–H2O 4:1:1 (v/v),
0 °C, 1 h, 82%; (g) TPAP (0.1 equiv), NMO (2.0 equiv), CH2Cl2, rt, 1 h; (h) NaClO2 (10 equiv), NaH2PO4 (20 equiv), 2-methyl-2-butene 2.0 M in
THF (50 equiv), THF–t-BuOH–H2O 4:1:4 (v/v) 89% (two steps). (i) IBCF (2.0 equiv), i-Pr2EtN (2.0 equiv), DMAP (0.1 equiv), THF, 0 °C, 0.5 h,
then i-Pr2EtN (2.0 equiv), HClÆHN(CH3)OCH3 (3.0 equiv), 1 h, 89%.

R. V. Kolakowski, L. J. Williams / Tetrahedron Letters 48 (2007) 4761–4764
4763
O
Me
H
OTES
R''
n
-BuLi, THF
O
O
Me
H
TBDPSO
O
Me
OTES
R''
-78 ºC - rt, 1 h
TBDPSO
N
Me
R'
Me
OMe
R'
2
16-18
19-21
O
Me
H
O
Me
OTES
Me
TBDPSO
19
Me
OTES
Me
16
Me
73 %
Me
Me
OTES
O
Me
H
O
17
18
20
21
TBDPSO
OTES
Me
88%
OTES
Me
H
O
Me
H
O
H
H
OTES
TBDPSO
Me
OMe
Me
H
74%
H
H
OMe
Scheme 4.
ity in the assembly of ynones late in a synthesis.18 We
chose to evaluate in a model the viability of a Weinreb
amide/alkyne coupling for the late-stage union of a
C1–C20 fragment with a C21–C40 fragment (Scheme
4). Weinreb amide 2 served to model the C21–C40 pect-
enotoxin fragment and alkynes 16–18 served to model
the C1–C20 fragment. The coupling was found to be
effective (73–88%), even on small scale (5 mg). In each
instance, the alkyne (THF, 0.2 M) was treated with base
(1.0 equiv of 1.6 M n-BuLi in hexanes) at ꢀ78 °C and
the mixture was allowed to warm to 0 °C. The alkyny-
lide was then added dropwise to the Weinreb amide
(0.2 M), at ꢀ78 °C. The final ratio of alkyne to amide
in this study was 2:1. The mixture was allowed to warm
to room temperature over the course of 45 min and stir-
red until TLC analysis showed complete consumption of
2 (1 h). [Compound 21 characterization data. 1H NMR,
500 MHz (CDCl3) given as d (multiplicity, J in Hz): 7.65
(d, 7.5; 4H), 7.39 (m, 6H), 7.20 (d, 8.8; 1H), 6.71 (dd,
8.2; 1H), 6.63 (d, 8.6; 1H), 4.39 (t, 8.1; 1H), 3.78 (s,
3H), 3.43 (m, 3H), 2.33 (m, 2H), 2.23 (m, 2H), 2.11
(m, 1H), 2.00 (t, 12.0H; 1H), 1.86 (m, 2.00), 1.78 (m,
5), 1.67 (m, 3), 1.46 (m, 4H), 1.36 (m, 1), 1.28 (s, 3H),
1.05 (s, 9H), 0.98 (m, 12H), 0.87 (s, 3H), 0.69 (m, 6H);
13C NMR, 100 MHz, (CDCl3) d, 188.7, 157.7, 138.3,
135.8, 134.2, 132.8, 129.7, 127.8, 126.6, 114.0, 111.7,
99.7, 86.3, 84.5, 81.0, 69.7, 55.4, 49.4, 48.9, 43.8, 40.5,
40.4, 37.5, 32.9, 32.5, 30.9, 29.6, 27.5, 27.1, 26.6, 26.4,
23.4, 19.5, 19.0, 13.8, 7.2, 6.2 ESI/MS calcd for
C53H74O5Si2 (M+23) 869.5, found 869.4.] The high iso-
lated yields of 19–21 augur well for C1–C20/C21–C40
coupling en route to the pectenotoxins.18
Acknowledgments
Generous financial support from Merck & Co., NIH
(GM-078145), and Rutgers, The State University of
New Jersey is gratefully acknowledged.
References and notes
1. Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.;
Matsumoto, K. G.; Clardy, J. Tetrahedron 1985, 41, 1019.
2. (a) Zhou, Z.-H.; Komiyama, M.; Terao, K.; Shimada, Y.
Nat. Toxins 1994, 2, 132; (b) Leira, F.; Cabado, A. G.;
Vieytes, M. R.; Roman, Y.; Alfonso, A.; Botana, L. M.;
Yasumoto, T.; Malaguti, C.; Rossini, G. P. Biochem.
Pharmacol. 2002, 63, 1979; Review: (c) Allingham, J. S.;
Klenchin, V. A.; Rayment, I. Cell Mol. Life Sci. 2006, 63,
2119.
3. Hung, J. H.; Sim, C. J. J. Nat. Prod. 1995, 58, 1722.
4. Chae, H.-D.; Choi, T.-S.; Kim, B.-M.; Jung, J. H.; Bang,
Y.-J.; Shin, D. Y. Oncogene 2005, 24, 4813.
5. Synthetic approaches: (a) Halim, R.; Brimble, M. A.;
Merten, J. Org. Lett. 2005, 7, 2659; (b) Bondar, D.; Liu, J.;
Muller, T.; Paquette, L. A. Org. Lett. 2005, 7, 1813; (c)
Peng, X.; Bondar, D.; Paquette, L. A. Tetrahedron 2004,
60, 9589; (d) Paquette, L. A.; Peng, X.; Bondar, D. Org.
Lett. 2002, 4, 937; (e) Micalizio, G. C.; Roush, W. R. Org.
Lett. 2001, 3, 1949; (f) Amano, S.; Fujiwara, K.; Murai, A.
Synlett 1997, 1300; (g) Fujiwara, K.; Kobayashi, M.;
Yamamoto, F.; Aki, Y.; Kawamura, M.; Awakura, D.;
Amano, S.; Okano, A.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 5067; (h) O’Connor, P. D.;
Knight, C. K.; Friedrich, D.; Peng, X.; Paquette, L. A. J.
Org. Chem. 2007, 72, 1747; (i) Lotesta, S. D.; Hou, Y.;
Williams, L. J. Org. Lett. 2007, 9, 869; (j) Pihko, P. M.;

4764
R. V. Kolakowski, L. J. Williams / Tetrahedron Letters 48 (2007) 4761–4764
Aho, J. E. Org. Lett. 2004, 6, 3849; (k) Vellucci, D.;
12. (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
1968, 18, 2199; (b) Cherest, M.; Felkin, H. Tetrahedron
Lett. 1968, 18, 2205; (c) Anh, N. T.; Eisenstein, O. Nouv. J.
Chim. 1977, 1, 61.
13. Shimizu, M.; Kawamoto, M.; Niwa, Y. Chem. Commun.
1999, 1151.
Rychnovsky, S. D. Org. Lett. 2007, 9, 711; Total synthesis:
(l) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4569; (m) Evans, D. A.;
Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4573.
6. (a) Tokunga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 936, 277; (b) Furrow, M. E.; Schaus, S.
E.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 6776.
7. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
14. For a review of alkynylation of chiral aldehydes see:
´
Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudre-
chey, A. Chem. Rev. 2006, 106, 2355.
15. Bhupathy, M.; Cohen, T. Tetrahedron Lett. 1985, 26,
2619.
8. Preparation of trichloroacetimidates: (a) Wessel, H.-P.;
Iverson, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1
1985, 2247; Hydroxyl protection: (b) Nakajima, N.;
Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 4139.
16. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 1806; (b) El-Sayed, E.; Anand, N.
K.; Carreira, E. M. Org. Lett. 2001, 3, 3017.
17. Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58,
7180.
9. (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
18. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815; (b) Marshall, J. A.; Yanik, M. M. J. Org. Chem.
2001, 66, 1373; (c) Bourbeau, M. P.; Marshall, J. A. Org.
Lett. 2003, 5, 3197; (d) Shimizu, T.; Kusaka, J.; Ishiyama,
H.; Nakata, T. Tetrahedron Lett. 2003, 44, 4695; (e) Lerm,
M.; Gais, H.-J.; Cheng, K.; Vermeeren, C. J. Am. Chem.
Soc. 2003, 125, 9653; (f) Klein, M.; Zabel, M.; Bernhardt,
G.; Burkhard, K. J. Org. Chem. 2003, 68, 9379; (g) Shin,
Y.; Fournier, J.-H.; Fukui, Y.; Bruckner, A. M.; Curran,
P. D. Angew. Chem., Int. Ed. 2004, 43, 4634; (h) Rauhala,
V.; Nattinen, K.; Rissanen, K.; Koskinen, A. M. P. Eur. J.
Org. Chem. 2005, 4119; (i) Shimizu, T.; Satoh, T.;
Murakoshi, K.; Sodeoka, M. Org. Lett. 2005, 7, 5573; (j)
Pan, Y.; De Brabander, J. K. Synlett 2006, 0853.
19. Acronyms and abbreviations: DDQ = dichloro dicyano
´
1978, 43, 2481; General procedure: (b) Fernandez, M.;
Tojo, G. Oxidation of Alcohol to Aldehydes and Ketones;
Springer: New York, 2006; p 141.
10. Selective reduction of A proved to be an inferior alterna-
tive; treatment of A with DiBAl-H in toluene or sodium
cyanoborohydride and TMSCl in acetonitrile gave a 1:1
mixture of regioisomers: (a) Takano, S.; Akiyama, M.;
Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593; (b)
Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin
Trans. 1 1984, 2371.
PMB
O
O
OTBS
quinone,
DiBAl-H = diisobutylaluminum
hydride,
DMAP = 4-(N,N-Dimethylamino)pyridine,
dimethyl sulfoxide, EtOAc = ethyl acetate, LiHMDS =
lithium hexamethyldisilazane, MeOH = methanol,
MsCl = mesyl chloride, PivCl = pivaloyl chloride,
TBDPSCl = tert-butyldiphenylsilyl chloride, TEA = tri-
ethylamine, TfOH = triflic acid, THF = tetrahydrofuran,
TPAP = tetrapropylammonium perruthenate.
DMSO =
A
11. Stereochemical assignment of the alkylation product is
based on analogy to: (a) Evans, D. A.; Ennis, M. D.;
Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737; (b)
Lerm, M.; Gais, H.-J.; Cheng, K.; Vermeeren, C. J. Am.
Chem. Soc. 2003, 125, 9653.