Synthetic studies toward potent cytotoxic agent amphidinolide B: Synthesis of the C8-C18 fragment

Article abstract of DOI:10.1055/s-1999-2544

A practical synthesis of the C₈-C₁₈ fragment 1 of amphidinolide B is described in which the Stille coupling method was employed to construct the trisubstituted C₂₈=C₁₃-C₁₄=C₁₅ 's-cis-1,3-diene' moiety from suitably functionalized vinyl iodide (4) and vinyl stannane (5) fragments, the former being prepared from an acetylene precursor using Negishi's carboalumination/iodination method.

Full text of DOI:10.1055/s-1999-2544

150
LETTER
Synthetic Studies toward Potent Cytotoxic Agent Amphidinolide B: Synthesis
of the C8-C18 Fragment
T. K. Chakraborty* and D. Thippeswamy
Indian Institute of Chemical Technology, Hyderabad - 500 007, India
Fax 0091-40-7173387/7173757; E-mail: tkc@csiict.ren.nic.in
Received 16 November 1998
Retrosynthetic analysis (scheme 1) revealed that 1 could
Abstract: A practical synthesis of the C8-C18 fragment 1 of amphi-
be obtained from chiral epoxide 2 by regioselective hy-
dinolide B is described in which the Stille coupling method was em-
dride opening of its epoxy ring. The triene 3, precursor of
ployed to construct the trisubstituted C28=C13–C14=C15 “s-cis-1,3-
diene” moiety from suitably functionalized vinyl iodide (4) and vi-
epoxide 2, was planned to be assembled, using Stille cou-
nyl stannane (5) fragments, the former being prepared from an acet- pling method,4 from smaller units, viz., the dienyl iodide
ylene precursor using Negishi’s carboalumination/iodination
method.
4 which was to be prepared by Negishi reaction and the vi-
nyl stannane 5.
Key words: Negishi reaction, Stille coupling, Amphidinolide B
Scheme 25 delineates the synthesis of the fragments 4 and
5. The former was synthesized in a single step starting
from Z-enynol 6.6 Treatment of 6 with Me3Al and
The potent cytotoxic activities and challenging structural
features of amphidinolide molecules are attracting the
attention of many synthetic organic chemists.1 Though
known for quite some time now, the total synthesis of
none of these molecules has so far been achieved.2 Re-
cently Pattenden et al. have reported the synthesis of C14-
C26 fragment of amphidinolide B,2c where an initial at-
tempt to apply Negishi’s carboalumination/iodination
method3 to an a-alkoxy-substituted acetylene compound
failed to provide an essential E-vinyl iodide intermediate,
forcing them to devise an alternate lengthy route for its
synthesis. This has prompted us to communicate our stud-
ies on the synthesis of the C8-C18 fragment 1 of amphidi-
nolide B where Negishi’s method was successfully
employed, albeit on a different substrate, to build the tar-
get E-vinyl iodide moiety required for the construction of
the unique trisubstituted “s-cis-1,3-diene” moiety
(C28=C13–C14=C15).
Cp2ZrCl2, followed by quenching the intermediate alumi-
nate with I2,3 provided the desired iodide 4 in 65% yield.7
The E-isomer of 6 happened to be the starting material for
Pattenden et al. where Sharpless asymmetric epoxidation/
hydride-reduction preceded the making of vinyl iodide
moiety.2c It is noteworthy that by altering the sequence of
reactions, i.e., subjecting 6 first to the Negishi reaction,
we could successfully synthesize the desired E-vinyl io-
dide.
Scheme 2. Synthesis of 4 and 5. Reagents and conditions : (a) Me3Al
(4 eq., 2 M in toluene), Cp2ZrCl2 (1 eq.), 1,2-dichloroethane, 48 h,
then I2 in THF (4 eq.), -20 to 0 °C, 0.5 h, 65%; (b) NaH (1.1 eq.), BnBr
(1.1 eq.), TBAI (cat.), THF, 0 to 25 °C, 95%; (c) (i) O3, CH2Cl2, -78
°C, 0.5 h, then Me2S, -78 to 25 °C, 1 h; (ii) NaBH4 (1 eq.), MeOH, 0
°C, 15 min, 90% from 8; (d) (i) TsCl (1.2 eq.), Et3N (1.5 eq.), DMAP
Scheme 1. Retrosynthetic analysis
Synlett 1999, No. 1, 150–152 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Studies toward Amphidinolide B
151
(0.1 eq.), CH2Cl2, 25 °C, 1 h; (ii) PhSeSePh (1 eq.), NaBH4 (2 eq.),
EtOH, 25 °C, 1 h, 85% from 9; (e) mCPBA (1.5 eq.), DIPA (2 eq.),
CH2Cl2, 15 min, and then add to refluxing CCl4, 5 min, 80%; (f) (i)
AD-mix-b (1.4 g/mmol of 11), tBuOH-H2O (1:1), 0 °C, 5 h; (ii) 2,2-
dimethoxypropane, CSA (0.1 eq.), 0 °C, 0.5 h, 70% from 11; (g) (i)
H2, Pd-C, MeOH, 25 °C, 0.5 h; (ii) Ph3P (4 eq.), CBr4 (2 eq.), CH2Cl2,
25 °C, 15 min; (iii) EtMgBr (2 eq.), THF, 0 °C, 15 min, 75% from 12;
(h) (i) NaI (4 eq.), TMSCl (4 eq.), H2O (2 eq.), CH3CN, 25 °C, 1 h;
(ii) same as in f(ii), 74%; (i) nBuLi (1 eq.), nBu3SnCl (1 eq.), THF, -
78 °C, 15 min, 72%.
ence of N,N-diisopropylethylamine gave the desired cou-
pled product 312 in 60% yield (scheme 35). Sharpless
asymmetric epoxidation13 of 3 with unnatural (-)-diiso-
propyl-D-tartrate gave the expected epoxy alcohol 2 in
85% yield. Regioselective opening of the epoxy ring us-
ing Red-Al in THF at 0 °C gave the 1,3-diol intermediate
which was converted to the target C8-C18 fragment 1,14
following standard protection-deprotection protocol, in
65% yield from 2.
In conclusion, a concise synthesis of C8-C18 segment 1 of
amphidinolide B is described here which contains the cru-
cial trisubstituted C28=C13–C14=C15 “s-cis-1,3-diene”
moiety. The intermediate 1 also carries suitable functional
groups at both ends which are amenable to further extrap-
olation, work on which is currently under progress.
The starting material for the synthesis of 5 was (S)-(-)-b-
citronellol (7, scheme 2) which was benzylated to get the
Bn-ether 8 in 95% yield. Ozonolysis of the double bond of
8 was followed by the borohydride reduction of the result-
ing aldehyde to get alcohol 9 in 90% yield in two steps.
Next, a three-step protocol8 was employed to convert 9 to
the terminal double bond containing intermediate 11. To-
sylation of the primary hydroxyl of 9 was followed by nu-
cleophilic substitution of the tosylate group by PhSe-,
generated in-situ by sodium borohydride reduction of
diphenyl diselenide, giving the phenylselenide intermedi-
ate 10, in 85% overall yield, which was then subjected to
an oxidation-elimination process. Oxidation of selenide
10 using mCPBA and subsequent b-elimination of the re-
sulting selenoxide generated the terminal olefin 11 in 80%
yield. Sharpless asymmetric dihydroxylation of 11 with
AD-mix-b9 in tBuOH-H2O (1:1) at 0 °C gave the syn-
product as the major isomer (3:1 ratio). The minor isomer
could be separated chromatographically. The diol moiety
of the major isomer was protected as acetonide to get 12
in 70% yield from 11. Debenzylation of 12 gave the free
alcohol which was converted to the terminal acetylene 13
by a standard two-step procedure (75% from 12). Treat-
ment of 13 with trimethylsilyl iodide (TMSI), generated
in situ from NaI and TMSCl, in the presence of requisite
amount of water led to the formation of HI-adduct with in-
ternal iodide as the only product.10 During the reaction,
the acetonide also got deprotected which was restored to
furnish 14 in 74% yield. The Li-anion generated from vi-
nyl iodide 14 was reacted with tri-n-butyltin chloride to
get the vinylstannane 511 in 72% yield.
Acknowledgements
We thank UGC (D.T.) for research fellowship and CSIR for CSIR
Young Scientist Award Research Grant (T.K.C.).
References and Notes
(1) (a) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543-
572. (b) Kobayashi, J.; Ishibashi, M. Chem. Rev. 1993, 93,
1753-1789.
(2) (a) The total synthesis of amphidinolide J has just appeared:
Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120,
11198-11199. For previous synthetic studies toward various
amphidinolides see: (b) Chakraborty, T. K.; Suresh, V. R. Te-
trahedron Lett. 1998, 39, 7775-7778. (c) Cid, M. B.; Patten-
den, G. Synlett 1998, 540-542. (d) Hollingworth, G. J.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 703-706. (e) Koba-
yashi, J.; Hatakeyama, A.; Tsuda, M. Tetrahedron 1998, 54,
697-704. (f) Tsuda, M.; Hatakeyama, A.; Kobayashi, J. J.
Chem. Soc., Perkin Trans. 1 1998, 149-155. (g) Lee, D. -H.;
Lee, S. -W. Tetrahedron Lett. 1997, 38, 7909-7910. (h) Cha-
kraborty, T. K.; Suresh, V. R. Chemistry Lett. 1997, 565- 566.
(i) Chakraborty, T. K.; Thippeswamy, D.; Suresh, V. R.; Jaya-
prakash, S. Chemistry Lett. 1997, 563-564. (j) Eng, H. M.;
Myles, D. C. Abstracts of the papers of the American Chemi-
cal Society 1995, 209, No. Pt 2, 405 ORGN1. (k) Ishibashi,
M.; Ishiyama, H.; Kobayashi, J. Tetrahedron Lett. 1994, 35,
8241- 8242. (l) Tsuda, M.; Sasaki, T.; Kobayashi, J. J. Org.
Chem. 1994, 59, 3734-3737. (m) Boden, C.; Pattenden, G.
Synlett 1994, 181-182. (n) O’Connor, S. J.; Williard, P. G. Te-
trahedon Lett. 1989, 30, 4637-4640.
(3) (a) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem.
Soc. 1985, 107, 6639-6647. (b) Rand, C. L.; Van Horn, D. E.;
Moore, M. W.; Negishi, E. J. Org. Chem. 1981, 46, 4093-
4096.
(4) (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-
817. (b) For a review see: Mitchell, T. N. Synthesis 1992, 803-
815.
(5) All compounds were characterized by NMR, IR and mass
spectral analysis. Yields refer to chromatographically and
spectroscopically homogeneous materials.
(6) Compound 6 can be purchased from Aldrich. We prepared it
from but-2-yn-1-ol in 3 steps: (i) treatment with Red-Al in
ether at 0 °C followed by quenching with I2 in THF at -78 °C
to get (Z)-3-iodo-2-buten-1-ol; (ii) Pd-catalyzed coupling of
this vinyl iodide with TMS-acetylene to get (Z)-5-trimethylsi-
lyl-3-methyl-2-penten-4-yn-1-ol; and finally, (iii) deprotec-
tion of silyl group using anhydrous K2CO3 in MeOH to get 6.
Scheme
3 Synthesis of 1. Reagents and conditions : (a)
Pd(CH3CN)2Cl2 (10 mol %), DIPEA (3 eq.), DMF, 25 °C, 12 h, 60%;
(b) Ti(iPrO)4 (0.2 eq.), (-)-DIPT (0.22 eq.), TBHP (2 eq.), CH2Cl2,
-10 °C, 12 h, 85%; (c) (i) Red-Al (1.2 eq.), THF, 0 °C, 1 h; (ii) TB-
SOTf (2.2 eq.), 2,6-lutidine (3 eq.), CH2Cl2, 0 °C, 0.5 h; (iii) HF-Py,
THF, 25 °C, 1 h, 65% from 2.
The stage was now set to try the Stille coupling reaction
between 4 and 5. Treatment of a mixture of equimolar
amounts of 4 and 5 in DMF with Pd(CH3CN)2Cl2 in pres-
Synlett 1999, No. 1, 150–152 ISSN 0936-5214 © Thieme Stuttgart · New York

152
T. K. Chakraborty, D. Thippeswamy
LETTER
(7) Synthesis of vinyl iodide 4: A suspension of Cp2ZrCl2 (0.584
g, 2 mmol) in dry 1,2-dichloroethane (10 mL) was treated with
Me3Al (4 mL, 2 M solution in toluene, 8 mmol) at room tem-
perature (r.t.), followed by the addition of a solution of 6
(0.192 g, 2 mmol) in the same solvent (2 mL). The reaction
mixture was stirred at r.t. for 48 h. It was then cooled to -20 °C
and I2 (1.016 g, 8 mmol) in THF (3 mL) was slowly added.
The mixture was stirred for 30 min., during which time it was
allowed to warm up to 0 °C. It was then quenched by slow ad-
dition of H2O (5 mL), extracted with EtOAc (2x10 mL), was-
hed with brine (5 mL), dried (Na2SO4), and concentrated in
vacuo. Purification by column chromatography (SiO2, 5-10%
EtOAc in petroleum ether eluant) gave the iodide 4 (0.309 g,
65%) as a syrupy liquid. Rf = 0.3 (silica gel, 25% EtOAc in pe-
troleum ether). 1H NMR (CDCl3, 200 MHz, amphidinolide B
numbering): d 6.0 (s, 1 H, C14-H), 5.4 (t, J = 7 Hz, 1 H, C17-H),
4.1 (d, J = 7 Hz, 2 H, C18-H2), 1.95 (s, 3 H, CH3), 1.85 (s, 3 H,
CH3). EIMS: m/z 111 (M+-I).
(8) (a) Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.; Wen-
delborn, D. F. J. Org. Chem. 1978, 43, 1697-1705. (b) Clark,
R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41, 1396-1403.
(9) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Grispino, G.
A.; Hartung, J.; Jeong, K. -S.; Kwong, H. -L.; Morikawa, K.;
Wang, Z. -M.; Xu, D.; Zhang, X. -L. J. Org. Chem. 1992, 57,
2768-2771.
(10) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675-676.
(11) Vinyl stannane 5: 1H NMR (CDCl3, 200 MHz, amphidinolide
B numbering): d 5.6 (s, 1 H, olefin H), 5.12 (s, 1 H, olefin H),
4.1 (dq, J = 8 Hz, 1 H, C9-H), 3.96 (t, J = 8 Hz, 1 H, C8-H),
3.38 (t, J = 8 Hz, 1 H, C8-H'), 2.32 (dd, J = 5 and 14 Hz, 1 H,
C12-H), 1.96 (dd, J = 8 and 14 Hz, 1 H, C12-H'), 1.6-1.2 (m, 15
H, CH2 and CH), 1.36 and 1.3 (two s, 6 H, acetonide CH3),
1.05-0.65 (m, 15 H, CH2 and CH3).
(12) Synthesis of triene 3: A solution of 4 (0.15 g, 0.63 mmol) and
5 (0.298 g, 0.63 mmol) in dry DMF (3 mL) was degassed by
bubbling argon through it for 15 min. Then a solution of diiso-
propylethylamine (0.33 mL, 1.89 mmol) in degassed THF (1
mL) and Pd(CH3CN)2Cl2 (0.016 g, 0.063 mmol) in degassed
DMF (1 mL) were added, successively. The reaction mixture
was stirred in the dark at r.t. for 12 h, diluted with water (10
mL), and extracted with EtOAc (3x10 mL). The combined or-
ganic extracts were washed with brine (5 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, 5-10% EtOAc
in petroleum ether eluant) to afford the triene 3 (0.111g, 60%)
as a syrupy liquid. Rf = 0.3 (silica gel, 25% EtOAc in petrole-
um ether). 1H NMR (CDCl3, 200 MHz, amphidinolide B num-
bering): d 5.55 (s, 1 H, C14-H), 5.05 (s, 1 H, C28-H), 4.9 (s, 1
H, C28-H'), 4.2-4.05 (m, 3 H, C9-H, C18-H2), 4.0 (dd, J = 5.6
and 8 Hz, 1 H, C8-H), 3.43 (t, J = 8 Hz, 1 H, C8-H'), 2.35-1.95
(m, 2 H, C12-H2), 1.88 (s, 3 H, C15-CH3), 1.85 (s, 3 H, C16-
CH3), 1.9-1.5 (m, 3 H, CH2, CH), 1.4 and 1.35 (two s, 6 H, ace-
tonide CH3), 0.95 (d, J = 7 Hz, C11-CH3). EIMS: m/z 279 (M+-
CH3).
(13) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamu-
ne, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-
5780.
(14) Diene 1: 1H NMR (CDCl3, 400 MHz, amphidinolide B num-
bering): d 6.0 (s, 1 H, C14-H), 5.0 (s, 1 H, C28-H), 4.8 (s, 1 H,
C28-H'), 4.1, 4.0, 3.65 and 3.4 (m, 5 H, CH2-O and CH-O), 2.2-
1.8 (m, 3 H, CH2, CH), 1.8 (s, 3 H, C15-CH3), 1.45 (s, 3 H, C16-
CH3), 1.37 and 1.32 (two s, 6 H, acetonide CH3), 0.92 (d, J =
7 Hz, 3 H, C11-CH3), 0.9 (s, 9 H, Si-t-butyl), 0.05 and 0.07 (s,
6 H, SiMe2).
Synlett 1999, No. 1, 150–152 ISSN 0936-5214 © Thieme Stuttgart · New York