Stereoselective total synthesis of bistramide A

Article abstract of DOI:10.1021/ol702095n

(Chemical Equation Presented) A highly stereoselective and convergent total synthesis of bistramide A is described. The salient feature of this synthesis is the construction of the spiroketal subunit by hydrolysis of dialkylated tosylmethyl isocyanide derivative derived via alkylation of TosMIC with suitably substituted halohydrin derivatives.

Full text of DOI:10.1021/ol702095n

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4587-4589
Stereoselective Total Synthesis of
Bistramide A
J. S. Yadav* and Lakshindra Chetia
Organic Chemistry DiVision-I, Indian Institute of Chemical Technology,
Hyderabad 500007, India
yadaVpub@iict.res.in
Received August 25, 2007
ABSTRACT
A highly stereoselective and convergent total synthesis of bistramide A is described. The salient feature of this synthesis is the construction
of the spiroketal subunit by hydrolysis of dialkylated tosylmethyl isocyanide derivative derived via alkylation of TosMIC with suitably substituted
halohydrin derivatives.
Bistramides, A-D and K, constitute a novel class of
bioactive marine natural products that were isolated from
the marine ascidian Lissoclinum bistratum.1-3 They exhibit
high cytotoxicity and significant effects on cell cycle
regulation.3 Bistramide A displayed an IC50 of 0.03-0.32
µg/mL for the P388/dox, B16, HT29, and NSCLC-N6 cell
lines,4 inhibits Na+ conductance,5 and is selective toward
the activation of a single protein kinase C (PKC) isotype
δ.6 It is also believed that bistramide A can inhibit nucleotide
exchange by stabilizing the closed actin conformation.7 These
promising biological activities of bistramide A have mani-
fested it as a potential candidate for anticancer therapy.
The bistramide A skeleton consists of a substituted
tetrahydropyran and spiroketal subunit connected by a central
γ-amino acid linker. The first synthesis of bistramide A was
reported by Kozmin and co-workers in 20048 confirming the
assigned stereochemistry and structure as illustrated in Figure
1. Afterward, Kozmin, Crimmins9 and Panek10 have also
reported the synthesis of this molecule using two different
strategies. Additionally, Wipf et al.11 reported the synthesis
of bistramide C that is structurally related to bistramide A.
Intrigued by its excellent biological activity and interesting
molecular architecture, we became interested in the total
synthesis of bistramide A. In continuation of the synthesis
of complex natural products, we herein disclose the stereo-
selective total synthesis of bistramide A.
(1) Gouiffe`s, D.; Moreau, S.; Helbecque, N.; Bernier, J. L.; He´nichart,
J. P.; Barbin, Y.; Laurent, D.; Verbist, J. F. Tetrahedron 1988, 44, 451.
(2) Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey, E. J.; Parry,
D. L.; Watters, D. J. J. Med. Chem. 1989, 32, 1354.
(3) Biard, J. F.; Roussakis, C.; Kornprobst, J. M.; Gouiffes-Barbin, D.;
Verbist, J. F.; Cotelle, P.; Foster, M. P.; Ireland, C. M.; Debitus, C. J. Nat.
Prod. 1994, 7, 1336.
(4) Johnson, W. E.; Watters, D. J.; Suniara, R. K.; Brown, G.; Bunce,
C. M. Biochem. Biophys. Res. Commun. 1999, 260, 80.
(5) (a) Sauviat, M. P.; Gouiffes-Barbin, D.; Ecault, E.; Verbist, J. F.
Biochim. Biophys. Acta 1992, 1103, 109. (b) Sauviat, M. P.; Verbist, J. F.
Gen. Phys. Biophys. 1993, 12, 465.
The retrosynthetic analysis of bistramide A is shown in
Figure 1; disconnection at C13 and C18 amide linkages
(7) (a) Statsuk, A. V.; Bai, R.; Baryza, J. L.; Verma, V. A.; Hamel, E.;
Wender, P. A.; Kozmin, S. A. Nat. Chem. Biol. 2005, 1, 383. (b) Rizvi, S.
A.; Tereshko, V.; Kossiakoff, A. A.; Kozmin, S. A. J. Am. Chem. Soc.
2006, 128, 3882.
(8) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126,
9546.
(6) Griffiths, G.; Garrone, B.; Deacon, E.; Owen, P.; Pongracz, J.; Mead,
G.; Bradwell, A.; Watters, D.; Lord, J. Biochem. Biophys. Res. Commun.
1996, 222, 802.
(9) Crimmins, M. T.; DeBaillie, A. C. J. Am. Chem. Soc. 2006, 128,
4936.
(10) Lowe, J. T.; Wrona, I. E.; Panek, J. S. Org. Lett. 2007, 9, 327.
10.1021/ol702095n CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/06/2007

reduction (88%) followed by treatment with iodine and
triphenylphosphine yielded iodo compound 7 (94%).
Scheme 2. Synthesis of Compound 5
Compound 5 (Scheme 2) was synthesized starting from
dithiane 12, obtained by following a known procedure.15
Metalation of dithiane 12 with n-BuLi at room temperature16
followed by treatment of the anion with epoxide 13 afforded
an alcohol (72%) and was protected as its TBS ether 14
(96%) with TBSOTf and 2,6-lutidine. Treatment of 14 with
Raney-nickel under H2 atmosphere in EtOH afforded the
primary alcohol (75%) by a concomitant debenzylation,
which was further converted into corresponding iodo com-
pound 5 (90%).
Figure 1. Retrosynthetic analysis of bistramide A.
Synthesis of spiroketal fragment 2 of bistramide A is
shown in Scheme 3. TosMIC 6 was first alkylated with iodo
afforded spiroketal fragment 2, γ-amino acid fragment 3,
and pyran fragment 4. Fragment 2 was envisaged to be
obtained by alkylation of TosMIC 6 with use of iodo
compounds 5 and 7.12
Scheme 3. Synthesis of Spiroketal Fragment 2
Scheme 1. Synthesis of Compound 7
The synthesis of compound 7 is depicted in Scheme 1.
Thus, lactone 10, which was obtained (97% de, 61% yield
over three steps) from allyl alcohol 9 (93% ee)13 as reported
earlier,13,14 was reduced to the corresponding diol with
LiAlH4 (82%). The primary hydroxyl group of the diol was
protected as its pivalate ester (86%) by using pivaloyl
chloride and triethylamine and the secondary hydroxyl group
as TBS ether by using TBSOTf and 2,6-lutidine to furnish
11 (97%). Deprotection of the pivalate ester by DIBAL
compound 7 in the presence of n-BuLi to afford 15 (90%).
Further alkylation of the anion generated from 15 with iodo
compound 5 gave dialkylated product (83%), which on
treatment with aq. HF in MeOH/THF afforded spiroketal 16
(85%).12 Swern oxidation of alcohol 16 followed by Horner-
Wadsworth-Emmons olefination17 with 1-methyl-2-oxopro-
pyl phosphonate18 provided an R,â-unsaturated ketone 17
(E/Z, 10:1). Reduction of ketone 17 with Corey’s chiral
(11) (a) Wipf, P.; Hopkins, T. D. Chem. Commun. 2005, 3421. (b) Wipf,
P.; Uto, Y.; Yoshimura, S. Chem. Eur. J. 2002, 8, 1670.
(12) Yadav, J. S.; Gadgil, V. R. Tetrahedron Lett. 1990, 31, 6217.
(13) A similar alcohol with opposite center at the C4 position was
prepared earlier by our group as given in: Yadav, J. S.; Joyasawal, S.;
Dutta, S. K.; Kunwar, A. C. Tetrahedron Lett. 2007, 48, 5335.
(14) (a) Yadav, J. S.; Gadgil, V. R. J. Chem. Soc., Chem. Commun. 1989,
1824. (b) Stork, G.; Mook, R.; Biller, S. A.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1983, 105, 3741.
(15) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L.,
Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947.
(16) Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491.
(17) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774.
(18) Corbel, B.; Medinger, L.; Haelters, J. P.; Sturtz, G. Synthesis 1985,
1048.
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Org. Lett., Vol. 9, No. 22, 2007

oxazaborolidine19 (94% de, 93% yield) and protection of the
resulting alcohol as its TBS ether yielded 18 (91%).
Compound 18 was subsequently converted into 2 in three
steps.10
After synthesizing amine 2, we further proceeded to
synthesize γ-amino acid fragment 3 (Scheme 4). Accord-
product 22 (92%). One-pot olefin reduction and benzyl ether
deprotection with Raney-nickel gave a mixture of hydroxy
ester and lactone, which on treatment with PPTS in refluxing
CH2Cl2 afforded the later exclusively (78%).9 The free
hydroxyl group was protected as TBS ether to obtain
compound 23 (93%). The acetate (78%) derived from lactone
23 following Rychnovsky’s protocol26 was treated with silyl
enol ether derived from ketone 24 in the presence of
TMSOTf to afford exclusively alcohol 25 (62%),9 which was
further oxidized to corresponding acid 4.8,27
Scheme 4. Synthesis of γ-Amino Acid Fragment 3
Having synthesized all three fragments 2, 3, and 4, their
coupling to obtain bistramide A was accomplished by
following a procedure reported in the literature (Scheme 6).10
Scheme 6. Completion of the Synthesis of Bistramide A
ingly, the pure anti aldol adduct 1920 was converted into the
corresponding Weinreb amide (84%)21 and its free hydroxyl
group was protected as TBS ether to afford 20 (95%).
Ozonolysis of 20 followed by reductive workup provided a
primary alcohol (75%), which was converted into the
corresponding azide 21 (80%) by using (PhO)2P(O)N3 under
Mitsunobu conditions. Hydrolysis of the amide22 followed
by protection of the resulting acid with TIPSOTf gave TIPS
ester (72%, two steps) that was converted into γ-amino acid
3 via catalytic hydrogenation.23
Coupling of tetrahydropyran subunit 4 and amine 3 in the
presence of PyBOP furnished TIPS ester (62%), which was
selectively deprotected with TBAF to yield acid 26 (89%).
The final peptide coupling of acid 26 with amine 2 led to
the formation of a complete carbon skeleton (65%). Removal
of the silyl protecting groups with PPTS completed the
synthesis of bistramide A (79%). The synthetic compound
was found to be identical with that reported in earlier
Scheme 5. Synthesis of Pyran Fragment 4
1
synthesis based on the comparison of H NMR, 13C NMR,
HRMS, and optical rotation data.
In summary, we have accomplished a highly convergent
and stereoselective synthesis of bistramide A. The spiroketal
functionality was obtained via dialkylation of TosMIC with
suitably substituted halohydrin derivatives. The C15 and C16
streocenters of the γ-amino acid fragment were prepared by
Evans anti aldol method. The C9 and C11 stereocenters of
the pyran fragment were prepared by Me3Al-mediated
opening of cis epoxide.
Synthesis of pyran fragment 4 is shown in Scheme 5. The
known cis epoxy alcohol 8 (92% ee)24 was converted into a
γ,δ-epoxy acrylate (92% in two steps) followed by treatment
with Me3Al in the presence of water following Miyashita’s
protocol25 to furnish regio- and stereoselectively the syn
Acknowledgment. L.C. thanks CSIR, New Delhi, India,
for financial assistance.
(19) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987.
(20) Adduct 19 (90% de) was prepared by following the known procedure
as given in: Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org.
Lett. 2002, 4, 1127.
(21) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
1982, 12, 989. (c) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 18, 4171.
Supporting Information Available: Experimental de-
tails, selected spectral data, copies of 1H NMR and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am. Chem.
Soc. 1976, 98, 1275.
OL702095N
(23) To avoid the unwanted γ-lactone formation after ozonolysis/
reduction reaction we did not prepare the methyl or TIPS ester by displacing
the chiral auxiliary.
(24) Schomaker, J. M.; Pulgam, V. R.; Borhan, B. J. Am. Chem. Soc.
2004, 126, 13600.
(25) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991,
56, 6483.
(26) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(27) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231.
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