Total synthesis and structure validation of (+)-bistramide C

Article abstract of DOI:10.1039/b505100b

The convergent total synthesis of the marine natural product (+)-bistramide C confirms the a priori assignments of its relative and absolute configurations, which were originally based on the combined application of [α]_D analysis, NMR, and synthesis. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505100b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Total synthesis and structure validation of (+)-bistramide C{{
Peter Wipf* and Tamara D. Hopkins
Received (in Bloomington, IN, USA) 12th April 2005, Accepted 6th May 2005
First published as an Advance Article on the web 1st May 2005
DOI: 10.1039/b505100b
yield. The linear chain was further elaborated into 1,3-diol 12 via a
The convergent total synthesis of the marine natural product
(+)-bistramide C confirms the a priori assignments of its relative
and absolute configurations, which were originally based on the
combined application of [a]D analysis, NMR, and synthesis.
DiBAl-H reduction followed by a Sharpless asymmetric epoxida-
tion and reductive opening of the resulting epoxy alcohol with
Red-Al in toluene. The primary alcohol was selectively protected
as a benzyl ether in 87% yield. Following a TBAF deprotection of
the silyl ether, the resultant 1,5-diol 13 was bis-protected with TES-
OTf. The primary silyl ether was preferentially cleaved upon
exposure to a dilute solution of acetic acid.12 Subsequently, the
alcohol product was oxidized to the key aldehyde intermediate 14.
Aldehyde 14 provided us with an opportunity to utilize Evans’
methodology for the construction of trans-2,6-substituted tetra-
hydropyrans via a tandem etherification–allylation process.11
Thus, treatment of 14 with catalytic BiBr3 and excess allyltri-
methylsilane afforded 15 in 72% yield and .5:1 diastereomeric
ratio. We recognized the potential to manipulate the termini of
both pyran side chains simultaneously. Thus, oxidation of 15 with
ozone followed by in situ reduction with PPh3 transformed the
benzyl ether into the benzoate ester and the allyl group into the
aldehyde. Treatment of a 2100 uC solution of this aldehyde-ester
with a 278 uC solution of propenyl lithium in Et2O resulted in the
exclusive addition of the organolithium reagent to the aldehyde
function. The secondary allylic alcohol was obtained as a .10:1
mixture of epimers, but the configuration of the major isomer was
inconsequential for the bistramide C synthesis and was not
assigned. Silyl protection of the allylic alcohol, cleavage of the
benzoate 16 with NaOMe in MeOH, and two-step oxidation led to
the requisite carboxylic acid fragment 3.
The bistramides or bistratenes have posed structural puzzles to the
scientific community from the very beginning of their isolation
from the marine ascidian Lissoclinum bistratum. Gouiffe`s et al.
obtained bistramide A from New Caledonia,1 shortly before the
report of Hawkins et al. of the isolation of bistratenes A and B
from the coast of Heron Island.2 Bistratenes A and B turned out to
be identical to bistramides A and B, and the originally proposed
macrocyclic scaffold2 was corrected by 2D INADEQUATE spectro-
scopy.1b Even the 1992 structural reassignment did not shed light
on any relative or absolute configuration, leaving instead the
possibility of 2048 possible stereoisomers for the natural product.
Since bistramides demonstrate attractive biological properties,
including antiproliferative effects,3 sodium channel blockage,4 and
unique protein kinase Cd activation,5 it was of interest to elucidate
their actual configuration. We embarked on solving this problem
by combining novel computational and optical rotation analyses,6
NMR spectroscopy and organic synthesis, and in 2002 reported a
prediction for the relative and absolute configuration of (+)-bis-
tramide C (1) as well as a total synthesis of a stereoisomer.7,8 In
2004, Kozmin et al. completed an elegant synthesis of (+)-bis-
tramide A (2) and were able to confirm our stereochemical
prediction for the parent structure in this family.9 We now report
the first total synthesis of (+)-bistramide C which further validates
For the preparation of spiroketal segment 5, the D-glucal
derived 177 was converted to the primary triflate (Scheme 3).
our
a priori structure assignment and presents improved
methodology for the convergent preparation of this natural
product.
The major features of our retrosynthetic strategy were a triple
convergency and a late-stage linkage of acid 3 to ester 4 and
spiroketal 5 by azide couplings (Scheme 1). The synthesis of pyran
3 was based on asymmetric carbometalation10 followed by a
tandem etherification–allylation11 of aldehyde 6, whereas a
hypervalent iodine mediated C–H insertion was used to convert
alcohol 7 into the spiroketal 5.
The preparation of segment 3 showcases the MAO-mediated
asymmetric methylalumination of terminal alkene 8 (Scheme 2).10
In the presence of 2.8 mol% of Erker’s chiral zirconocene 9, the
b-methylated alcohol 10 was obtained in 78% yield and 83% ee.
Oxidation with NaOCl and catalytic TEMPO, followed by a
Horner–Wadsworth–Emmons reaction provided enoate 11 in 84%
{ Electronic supplementary information (ESI) available: spectroscopic
data and copies of 1H and 13C NMR, DEPT, COSY, HSQC, HMBC, and
NOESY for 1. See http://www.rsc.org/suppdata/cc/b5/b505100b/
{ Dedicated to the memory of Jacqueline H. Smitrovich.
*pwipf@pitt.edu
Scheme 1 Retrosynthetic strategy for 1.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3421–3423 | 3421

View Article Online
Scheme 3 (a) Tf2O, pyr., CH2Cl2, 245 uC to 0 uC, 45 min; then,
(CH2CHCH2)2Cu(CN)Li2 (1.5 equiv), THF, 278 to 260 uC, 4 h, 79%; (b)
9-BBN, THF, 0 uC to rt, 14 h; then, 0.5 M NaOH, 30% H2O2, 0 uC to rt,
65%; (c) Dess–Martin periodinane, CH2Cl2, 0 uC to rt, 1 h, 77%; (d) 19
(30 mol%), AlMe3, acetyl bromide, (iPr)2NEt, CH2Cl2, 250 uC, 20 h; (e)
LAH, Et2O, 0 uC to rt, 1 h 15 min, 88%; (f) pivaloyl chloride, pyr., rt, 24 h,
83%; (g) PhI(OAc)2, I2, CCl4, hn, rt, 2 h; (h) LAH, Et2O, 0 uC to rt, 2 h,
26%; (i) (n-Bu)3SnH, AIBN, 80 uC, 14 h, 94% (j) PCC, NaOAc, CH2Cl2,
rt, 1.5 h, 84%; (k) 22, (iPr)2NEt, LiCl, THF, 12 h, 87%; (l) Pt/C, H2,
MeOH, rt, 1.5 h, 79%; (m) NaHMDS, MeI, THF, 278 uC, 4.5 h, 67%; (n)
LiBH4, EtOH, Et2O, 225 uC to 0 uC (2.5 h) to 5 uC (12 h), 77%; (o) Dess–
Martin periodinane, CH2Cl2, rt, 25 min, 77%; (p) EtO2CC(Me)LPPh3,
toluene (degassed), rt, 10 d; (q) LAH, THF, 0 uC to rt, 2 h, 68%; (r) Dess–
Martin periodinane, 0 uC to rt, 1 h 10 min, 93%; (s) MeMgBr, Et2O, 0 uC,
93%; (t) TBAF, THF, 0 uC to rt, 18 h, quant.; (u) Ms2O, (iPr)2NEt,
CH2Cl2, 0 uC to rt, 1 h; then, NaN3, DMF, 70 uC, 48 h, 49%.
Scheme 2 (a) AlMe3 (4.3 equiv), 9 (2.8 mol%), MAO (1.5 equiv),
CH2Cl2, 3–5 uC, 15 h; then, O2, 220 uC to rt, 78%; (b) NaOCl, TEMPO,
KBr, NaHCO3/Na2CO3, CH2Cl2, 0 uC, 3 h, 92%; (c) trimethylpho-
sphonacetate, DBU, LiCl, CH3CN, 0 uC to rt, 6 h, 91%; (d) DiBAl-H,
˚
CH2Cl2, 278 uC, 2 h, 98%; (e) TBHP, D-(2)-DIPT, Ti(O-iPr)4, 4A MS,
CH2Cl2, 220 uC, 15 h, 96%; (f) Red-Al, toluene, 278 uC to rt, 13 h,
quant.; (g) NaH, THF, 0 uC; then, BnBr, n-Bu4NI, 0 uC to rt, 36 h, 87%;
(h) TBAF, THF, 0 uC to rt, 15 h, 98%; (i) TES-OTf, 2,6-lutidine, CH2Cl2,
0 uC, 30 min, quant.; (j) H2O, AcOH, THF (1:3:10), 0 uC to rt, 4 h, 79%;
(k) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 uC to rt, 2 h, 81%; (l)
allyl-TMS, BiBr3 (cat.), CH3CN, rt, 23 h, 72%; (m) O3/O2, methyl
pyruvate, CH2Cl2, 278 uC, 30 min; then, PPh3, 278 uC to rt, 16 h, 60–
65%; (n) trans-2-propenyl bromide, t-BuLi, Et2O, 278 uC (45 min) to 0 uC
to 278 uC; then addition to 2100 uC solution of aldehyde in Et2O; (o)
TBDMS-Cl, imid., CH2Cl2, 0 uC to rt, 21 h, 82%; (p) NaOMe, MeOH/
THF, 0 uC to rt, 24 h, 90%; (q) Dess–Martin periodinane, NaHCO3,
CH2Cl2, 0 uC to rt, 1 h; (r) NaClO2, NaH2PO4?H2O, 2-methyl-2-butene,
t-BuOH, rt, 1 h, 67%.
and oxidation of the primary alcohol to the aldehyde with PCC,
the a,b-unsaturated oxazolidinone was obtained in 87% yield via a
Horner–Wadsworth–Emmons reaction with phosphonate 22.16
Catalytic hydrogenation of both alkenes with Pt/C in MeOH
delivered the precursor for the late-stage methylation at bistramide
C(34). The methyl group was installed in 67% yield using the
alkylation conditions reported by Evans.17 Next, the chiral
auxiliary Xc in 23 was reductively removed, and oxidation of the
intermediate alcohol led to the aldehyde. Wittig reaction, followed
by reduction of the resultant enoate with lithium aluminum
hydride and oxidation of the allylic alcohol to the a,b-unsaturated
aldehyde transformed 23 into 24 in an overall yield of 37%. An
unselective low temperature addition of methylmagnesium bro-
mide to 24 followed by TBAF deprotection of the silyl group gave
the intermediate diol in high yield. Finally, the key azide fragment
5 was accessed by selective mesylation of the 1u alcohol followed
by an SN2-displacement of the crude mesylate with sodium azide.
The stage was now set for the final segment condensation.
The c-amino carboxylate 4,7 derived in six steps and 35% yield
from D-malic acid, was converted to azide 25 via saponification of
the ethyl ester and temporary re-protection of the resultant
carboxylic acid as the TIPS ester in a two-step yield of 82%. This
late-stage protective group switch was due to an unexpectedly
Nucleophilic displacement of the triflate with allylmagnesium
bromide in the presence of catalytic CuBr?DMS was capricious,
and after extensive experimentation we determined that the
corresponding higher-order allyl cuprate13 was a more reliable
method for the desired side chain extension. Selective hydrobora-
tion–oxidation of the terminal olefin followed by Dess–Martin
oxidation provided the key aldehyde intermediate 18. We
employed Nelson’s acyl halide-aldehyde condensation methodo-
logy (AAC)14 for the installation of the (S)-configured stereocenter
at the bistramide C(31). The Al(III)-triamine complex was prepared
in situ from the (S)-valinol-derived triamine ligand 19 and AlMe3.
This catalyst proved to be quite effective in facilitating the
condensation of acetyl bromide and 18 in high yield and excellent
diastereoselectivity (.95% de). Reduction of the b-lactone with
LAH and pivaloylation of the primary alcohol delivered the
spirocyclization precursor 7 as a single diastereomer in 73% overall
yield from aldehyde 18.
Oxidative spirocyclization15 in the presence of iodobenzene
diacetate and iodine transformed 7 into a mixture of partially
iodinated spiroketals 20 and 21 upon irradiation with a 250 W
tungsten lamp. Following the reductive removal of the pivaloate
3422 | Chem. Commun., 2005, 3421–3423
This journal is ß The Royal Society of Chemistry 2005

View Article Online
This research was supported by the National Science
Foundation (CHE-0315205) as well as by unrestricted grants from
Merck Research Laboratories and Eli Lilly & Co. The authors
thank Drs. Patricia S. Wilkinson and Robert Krull from Bruker
Biospin Corp. for their kind assistance in the NMR analysis of 1,
and Prof. Biard of the University of Nantes for a sample of natural
bistramide C.
Peter Wipf* and Tamara D. Hopkins
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA,
15260, USA. E-mail: pwipf@pitt.edu; Fax: +412-624-0787;
Tel: +412-624-8606
Scheme 4 (a) LiOH?H2O, EtOH, 0 uC to rt, 15 h; (b) TIPS-Cl, NEt3,
THF/DMF (1:1), 0 uC, 30 min, 82%; (c) H2 (1 atm), Pd/C, THF, rt, 3.5 h;
(d) 3, PyBOP, NEt3, CH2Cl2, rt, 16 h; (e) TBAF (0.1 M), THF, 0 uC,
25 min, 86%; (f) 5, PPh3 (1.0 M in THF), H2O, THF (degassed), rt, 41 h;
then, 26, PyBOP, (iPr)2NEt, DMF, rt, 47 h, 58%; (g) PPTS, MeOH, rt,
48 h; (h) Dess–Martin periodinane (15 wt% in CH2Cl2), CH2Cl2, 0 uC to
rt, 1 h, 77%.
Notes and references
1 (a) D. Gouiffe`s, S. Moreau, N. Helbecque, J. L. Bernier, J. P. Henichart,
Y. Barbin, D. Laurent and J. F. Verbist, Tetrahedron, 1988, 44, 451; (b)
M. P. Foster, C. L. Mayne, R. Dunkel, R. J. Pugmire, D. M. Grant,
J.-M. Kornprobst, J.-F. Verbist, J.-F. Biard and C. M. Ireland, J. Am.
Chem. Soc., 1992, 114, 1110; (c) J.-F. Biard, C. Roussakis,
J.-M. Kornprobst, D. Gouiffes-Barbin, J.-F. Verbist, P. Cotelle,
M. P. Foster and C. M. Ireland, J. Nat. Prod., 1994, 57, 1336.
2 B. M. Degnan, C. J. Hawkins, M. F. Lavin, E. J. McCaffrey,
D. L. Parry and D. J. Watters, J. Med. Chem., 1989, 32,
1354–1359.
3 D. Riou, C. Roussakis, N. Robillard, J. F. Biard and J. F. Verbist, Biol.
Cell, 1993, 77, 261.
4 M. P. Sauviat, D. Gouiffes-Barbin, E. Ecault and J. F. Verbist, Biochim.
Biophys. Acta, 1992, 1103, 109.
5 M. R. Freya, O. Leontieva, D. J. Watters and J. D. Black, Biochem.
Pharm., 2001, 61, 1093.
6 (a) G. Zuber, M.-R. Goldsmith, P. Wipf and D. N. Beratan, 56th ACS
Southeast Regional Meeting, November 10–13, 2004; (b) S. Ribe,
R. K. Kondru, B. N. Beratan and P. Wipf, J. Am. Chem. Soc., 2000,
122, 4608; (c) R. K. Kondru, P. Wipf and D. N. Beratan, J. Am. Chem.
Soc., 1998, 120, 2204; (d) E. Giorgio, M. Roje, K. Tanaka, Z. Hamersak,
V. Sunjic, K. Nakanishi, C. Rosini and N. Berova, J. Org. Chem. ACS
ASAP, and references cited therein.
facile hydrolysis of the newly-formed amide bond in the coupling
product with 3 under a variety of ester saponification conditions.
Reduction of azide 25 under standard catalytic hydrogenation
conditions followed by a PyBOP-mediated condensation of the
resultant amine with acid 3 led to the desired C(13) amide. The
labile amino ester intermediate was submitted to the acylation
reaction without purification. Subsequent to a fluoride-induced
deprotection of the TIPS ester, carboxylic acid 26 was obtained in
an overall yield of 86%. Prior to the final segment coupling,
spiroketal azide 5 was treated with PPh3 in degassed THF at room
temperature. Upon the completion of the redox reaction, the
solvent was removed in vacuo and the crude amine was treated
with a DMF solution of 26, followed by PyBOP and Hu¨nig’s base.
The diamide product was isolated in a two step yield of 58%.
Global deprotection under mildly acidic conditions followed by
selective oxidation7 of the two allylic alcohols provided target
molecule 1. The overall yield of the longest linear sequence, 31
steps from triacetyl-D-glucal via spiroketal 5, was 0.03%. The
spectroscopic properties (1H and 13C NMR, CD, [a]D) of 1 were in
agreement with those obtained from an authentic sample of
(+)-bistramide C. Accordingly, our original assignment7 of the
stereochemistry of the natural product was confirmed.
7 P. Wipf, Y. Uto and S. Yoshimura, Chem. Eur. J., 2002, 8,
1670.
8 For related synthetic studies, see: (a) G. Solladie, C. Bauder and
J.-F. Biard, Tetrahedron Lett., 2000, 41, 7747; (b) P. O. Gallagher, C. S.
P. McErlean, M. F. Jacobs, D. J. Watters and W. Kitching, Tetrahedron
Lett., 2002, 43, 531; (c) M. T. Crimmins and A. C. DeBaillie, 228th ACS
National Meeting, Philadelphia, August 22–26, 2004.
9 A. V. Statsuk, D. Liu and S. A. Kozmin, J. Am. Chem. Soc., 2004, 126,
9546.
10 (a) T. Novak, Z. Tan, B. Liang and E. Negishi, J. Am. Chem. Soc.,
2005, 127, 2838; (b) P. Wipf and S. Ribe, Org. Lett., 2001, 3, 1503; (c)
S. Ribe and P. Wipf, Chem. Commun., 2001, 299.
11 P. A. Evans, J. Cui, S. J. Gharpure and R. J. Hinkle, J. Am. Chem. Soc.,
2003, 125, 11456.
12 A. Rodriguez, M. Nomen, B. W. Spur and J. J. Godfroid, Tetrahedron
Lett., 1999, 40, 5161.
In conclusion, key methodology highlights of this total synthesis
are a MAO-mediated asymmetric methylalumination of a terminal
alkene,
a tandem bismuth(III)-initiated cyclization–allylation
for the formation of a 2,6-trans-substituted pyran, and a hyper-
valent iodine promoted remote functionalization–spiroketalization
reaction.
13 B. H. Lipshutz and T. R. Elworthy, J. Org. Chem., 1990, 55, 1695.
14 S. G. Nelson, T. J. Peelen and Z. Wan, J. Am. Chem. Soc., 1999, 121,
9742.
15 (a) R. L. Dorta, A. Martin, J. A. Salazar, E. Suarez and T. Prange,
J. Org. Chem., 1998, 63, 2251; (b) S. J. Danishefsky, D. M. Armistead,
F. E. Wincott, H. G. Selnick and R. Hungate, J. Am. Chem. Soc., 1989,
111, 2967; (c) S. Rodriguez and P. Wipf, Synthesis, 2004, 2767.
16 C. A. Broka and J. Ehrler, Tetrahedron Lett., 1991, 32, 5907.
17 D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc., 1982,
104, 1737.
Total synthesis continues to play an important role in the
structure elucidation of natural products, in particular those
obtained from the marine environment or rare life forms.18 Both
synthesis and NMR methodology are significantly augmented by
the judicious use of chiroptical tools such as optical rotatory
dispersion (ORD) and circular dichroism (CD) that give direct
information about the absolute configuration of an analyte.6
18 (a) P. Wipf, Chem. Rev., 1995, 95, 2115; (b) K. C. Nicolaou and
S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3421–3423 | 3423