Total synthesis of bistramide A

Article abstract of DOI:10.1021/ol062957y

(Chemical Equation Presented) An asymmetric synthesis of the marine metabolite bistramide A is reported. The synthesis relies on the utility of three different organosilane reagents to construct all principle fragments and 8 of the 11 stereogenic centers of the natural product.

Full text of DOI:10.1021/ol062957y

ORGANIC
LETTERS
2007
Vol. 9, No. 2
327-330
Total Synthesis of Bistramide A
Jason T. Lowe, Iwona E. Wrona, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
panek@bu.edu
Received December 6, 2006
ABSTRACT
An asymmetric synthesis of the marine metabolite bistramide A is reported. The synthesis relies on the utility of three different organosilane
reagents to construct all principle fragments and 8 of the 11 stereogenic centers of the natural product.
Bistramide A (1) is a marine metabolite initially isolated in
1988 from Lissoclinum bistratum Sluiter near New Cale-
donia.1 Four additional members of the bistramide family
(bistramides B-D and K) have been identified since this
initial report.2 These compounds have been shown to exhibit
numerous biological properties, including antiproliferative,3
antiparasitic,4 immunomodulatory,5 neurotoxic,3 and cyto-
toxic activities.2 Bistramide A was further implicated in a
unique protein kinase Cδ-activation.6 However, recent studies
indicate actin as the primary cell receptor of the natural
product.7
The structure of bistramide A was originally proposed to
be a 19-membered macrocyclic lactam.8 Extensive 2D NMR
analysis,9 however, revealed an acylic compound containing
a substituted tetrahydropyran and spiroketal subunit, con-
nected by a central γ-amino acid linker. Further NMR
analysis10 and chiroptical measurements11 of other members
of the bistramide family (B-D) allowed for the accurate
prediction of the absolute stereochemistry of 1. Kozmin’s
total synthesis of bistramide A12 then confirmed the predicted
stereochemistry and structure as illustrated in Figure 1.
Subsequent to Kozmin’s report, an additional synthesis of
bistramide A13 and one of structurally related bistramide C14
(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) 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.
(3) Riou, D.; Roussakis, C.; Robillard, N.; Biard, J. F.; Verbist, J. F.
Biol. Cell 1993, 77, 261.
(8) Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey, E. J.; Parry,
D. L.; Watters, D. J. J. Med. Chem. 1989, 32, 1354.
(9) Foster, M. P.; Mayne, C. L.; Dunkel, R.; Pugmire, R. J.; Grant, D.
M.; Kornprobst, J. M.; Verbist, J. F.; Biard, J. F.; Ireland, C. M. J. Am.
Chem. Soc. 1992, 114, 1110.
(4) Gautret, P.; Le Pape, P.; Biard, J. F.; Menard, D.; Verbist, J. F.;
Marjolet, M. Acta Parasitol. 1998, 43, 50.
(5) Pusset, J.; Maillere, B.; Debitus, C. J. Nat. Toxins 1996, 5, 1.
(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.
(10) (a) Gallagher, P. O.; McErlean, C. S. P.; Jacobs, M. F.; Watters, D.
J.; Kitching, W. Tetrahedron Lett. 2002, 43, 531. (b) Solladie´, G.; Baudet,
C.; Biard, J.-F. Tetrahedron Lett. 2000, 41, 7747.
(11) (a) Wipf, P.; Uto, Y.; Yoshimura, S. Chem.-Eur. J. 2002, 8, 1670.
(b) Zuber, G.; Goldsmith, M.-R.; Hopkins, T. D.; Beratan, D. N.; Wipf, P.
Org. Lett. 2005, 7, 5269.
(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.
(12) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004,
126, 9546.
(13) Crimmins, M. T.; DeBaillie, A. C. J. Am. Chem. Soc. 2006, 128,
4936.
10.1021/ol062957y CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/23/2006

Scheme 1. Synthesis of γ-Amino Acid Subunit 3
12 in 90% yield.13 Formation of the protected TIPS acid was
achieved though a two-step oxidation/protection sequence
in 76% yield.14,19 Reduction of the azide provided the fully
functionalized C14-C18 fragment 3.
The construction of the C29-C40 segment is illustrated
in Scheme 2. This fragment was synthesized by incorporating
known building blocks, which are directly accessible from
the chiral pool.20 Thus, (S)-1,2,4-butanetriol derivative 1321
was subjected to a Wittig olefination with phosphonium salt
1422 to give olefin 15 as a mixture of geometric isomers (Z:E
)10/1) in 70% yield. One-pot reduction of the olefin and
benzyl ether deprotection with Raney nickel gave a primary
alcohol in 78% yield. Swern oxidation of this material
provided an aldehyde, which was directly converted to the
R,â-unsaturated ketone 16 using the diethyl 1-methyl-2-
Figure 1. Retrosynthetic analysis of bistramide A.
have been completed. The diverse biological activity and
challenging molecular architecture of 1 motivated us to
explore the utility of crotylsilane-based bond construction
to prepare this interesting marine metabolite. Herein, we
report a convergent, enantioselective synthesis of bistramide
A using organosilane-based methodology to construct 8 of
the 11 stereogenic centers of the natural product.
The retrosynthesis of bistramide A, shown in Figure 1,
reveals three subunits of varying complexity. Each of these
fragments, tetrahydropyran 2, masked amino acid 3, and
spiroketal 4, are accessible from different organosilane
reagents developed in our laboratory. Tetrahydropyran 2 was
previously assembled through a [4+2]-annulation utilizing
(Z)-crotylsilane reagent 5.15 The γ-amino acid subunit 3 of
bistramide A can be constructed through a chelation-
controlled crotylation using (R)-silane reagent 6.16 Finally,
disconnection of the anomeric C-O and C28-C29 bonds
of spiroketal fragment 4 provides tetrahydropyran 7 and
phosphonium salt 8. The relative and absolute stereochem-
istry of tetrahydropyran 7 is readily accessible from our
[4+2]-annulation of crotylsilane 9.17
Scheme 2. Synthesis of C29-C40 Fragment
The preparation of the γ-amino acid fragment of bistra-
mide A is illustrated in Scheme 1. The known homoallylic
alcohol 1018 was protected as its silyl ether using TBSOTf
in 99% yield. Ozonolysis followed by reduction with NaBH4
provided a primary alcohol (92%, two steps), which was
protected as its silyl ether 11. Removal of the benzyl ether
was followed with azide formation using (PhO)2P(O)N3
under Mitsunobu conditions (78%, two steps). Selective silyl
ether deprotection using CSA afforded the desired alcohol
oxopropyl phosphonate reagent.23 Reduction of the resulting
ketone using Corey’s chiral oxazaborolidine24 and protection
of the resulting secondary allylic alcohol as a TBS ether gave
(19) For TEMPO oxidation of alcohols to carboxylic acids, see: Zhao,
M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider,
P. J. J. Org. Chem. 1999, 64, 2564.
(20) For examples of chiral pool reagents, see: Blaser, H. U. Chem.
ReV. 1992, 92, 935.
(14) Wipf, P.; Hopkins, T. D. Chem. Commun. 2005, 3421.
(15) (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231. (b) Lowe, J.
T.; Youngsaye, W.; Panek, J. S. J. Org. Chem. 2006, 71, 3639.
(16) Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron
Lett. 1995, 36, 8727.
(17) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836.
(18) For the synthesis of the enantiomer of 10, see: Huang, H.; Panek,
J. S. Org. Lett. 2004, 6, 4383.
(21) Blakemore, P. R.; Kim, S. K.; Schulze, V. K.; White, J. D.; Yokochi,
A. F. T. J. Chem. Soc., Perkin Trans. 1 2001, 1831.
(22) Gaeta, F. C. A.; Lehman de Gaeta, L. S.; Kogan, T. P.; Or, Y. S.;
Foster, C.; Czarniecki, M. J. Med. Chem. 1990, 33, 964.
(23) Altenbach, H. J.; Korff, R. Tetrahedron Lett. 1981, 22, 5175.
(24) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986
and references cited therein.
328
Org. Lett., Vol. 9, No. 2, 2007

Scheme 3. Preparation of Spiroketal Fragment 4
17 in 77% yield (two steps). Reductive opening of the PMP
quantities of 23 (Table 1, entry 4). The best result was
obtained at 0 °C under anhydrous conditions in the presence
of pyridine to provide the spirocycle in 76% yield (Table 1,
entry 5).29 This transformation presumably occurred through
an intermediate oxocarbenium ion that was trapped by the
nascent homoallylic alcohol after PMB removal. Other
conditions including TMSI,30 I2 in MeOH31 and, the
Me2S‚BCl3 complex32 did not provide the desired secondary
alcohol or spiroketal.
acetal with Dibal-H generated the primary alcohol along with
the secondary PMB ether in 98% yield. Bromination of the
primary alcohol followed by displacement with PPh3 afforded
the advanced coupling partner 8.
Our synthesis of the spiroketal portion of bistramide A is
depicted in Scheme 3 and was initiated with a [4+2]-
annulation employing syn-(E)-crotylsilane reagent 9.17 Ac-
cordingly, the annulation of aldehyde 1825 gave the desired
dihydropyran 19 as a single diastereomer in 97% isolated
yield. The endocyclic olefin was isomerized into conjugation
using tetra-n-butyl ammonium hydroxide. The resulting R,â-
unsaturated ester was converted to its methyl glycoside by
treatment with CSA in MeOH, and reduction of the ester
with Dibal-H afforded aldehyde 7 in 76% yield (two steps).
The key transformation in this synthetic sequence involved
the olefination of aldehyde 7 with phosphonium salt 8.
Gratifyingly, the union through phosphorus-based olefination
provided the PMB-protected (Z)-alkene 21 as a single olefin
isomer in 86% yield. Selective hydrogenation of the C28-
C29 olefin of 21 with Wilkinson’s catalyst provided the
saturated system in 79% yield. The incorporation of a fully
functionalized C40-C32 side chain prior to spirocyclization
underscores the convergent nature of this synthesis.
Our initial approach for the remainder of the synthesis of
4 required a deprotection of the C31 PMB group of the C28-
C29 saturated analogue of 21 followed by spirocyclization.26
However, the unmasking of the alcohol proved to be difficult
(Table 1). Deprotection under standard DDQ conditions
(CH2Cl2/H2O) did not provide the free secondary alcohol 22
as hoped but instead gave a complex mixture of compounds.
Interestingly, the major product identified from this reaction
was spirocycle 23 (Table 1, entry 1).27 In an effort to optimize
the reaction, phosphate buffered water (pH 7) was added to
remove any adventitious acid. Unfortunately, this modifica-
tion gave only a slightly higher yield of 23 (Table 1, entry
2). Anhydrous conditions28 gave only trace amounts of the
desired product upon workup (Table 1, entry 3). Addition
of pyridine to the reaction at room temperature gave useful
Table 1. Oxidative Cyclization to Form Spirocycle 23
yielda
entry
1
conditions
3 equiv of DDQ,
temp
0 °C
22
23
-
21
CH2Cl2/H2O (10:1)
3 equiv of DDQ,
2
3
4
5
0 °C
0 °C
rt
-
-
-
-
23
trace
44
CH2Cl2/buffered H2Ob
3 equiv of DDQ,
CH2Cl2
2 equiv of DDQ,
CH2Cl2, 6 equiv of pyridine
2 equiv of DDQ,
0 °C
76
CH2Cl2, 6 equiv of pyridine
a
All yields are based on isolated product after chromatography over
b
silica gel. Phosphate buffer (pH 7).
Birch reduction of the primary benzyl ether followed by
a Mitsunobu displacement of the alcohol with (C6H5O)2P-
(O)N3 afforded the primary azide. Formation of the primary
amine 4 was carried out by conversion of the azide to an
(29) The conditions found in Table 1 were also applied to 21 with little
success.
(30) Gordon, D. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1992, 114,
659.
(25) Cloarec, J.-M.; Charette, A. B. Org. Lett. 2004, 6, 4731.
(26) Fe´ne´zou, J. P.; Gauchet-Prune, J.; Julia, M.; Pancrazi, A. Tetrahe-
dron Lett. 1988, 29, 3667.
(27) For a previous example of spirocyclization in the presence of DDQ,
see: Paterson, I.; Chen, D. Y.-K.; Franklin, A. S. Org. Lett. 2002, 4, 391.
(28) Ito, Y.; Ohnishi, Y.; Ogawa, T.; Nakahara, Y. Synlett 1998, 1102.
(31) Vaino, A. R.; Szarek, W. A. Synlett 1995, 1157.
(32) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes, A. B.;
Payne, A. N.; Robinson, R. A.; Ward. S. E. Synlett 1993, 663.
Org. Lett., Vol. 9, No. 2, 2007
329

iminophosphorane by treatment with Me3P followed by in
situ hydrolysis of the resulting phosphine imine.33
In summary, a highly convergent, enantioselective syn-
thesis of bistramide A has been described. The synthesis
illustrates considerable synergy derived from the design and
application of three different enantioenriched organosilane
reagents 5, 6, and 9 to construct 8 of the 11 stereogenic
centers. The robust nature of the silane chemistry is
demonstrated in the rapid and efficient assembly of three
principle subunits 2-4 prior to fragment coupling. Synthesis
and biological evaluation of bistramide-like analogues will
be reported at a later date.
With reproducible and reliable routes to advanced subunits
2-4, we were positioned to complete the total synthesis of
bistramide A. Accordingly, fragment coupling commenced
with the union of tetrahydropyran subunit 2 and amine 3 as
facilitated by the PyBOP peptide coupling reagent (Scheme
4). Deprotection of the TIPS acid permits the final peptide
Scheme 4. Completion of the Synthesis of Bistramide A
Acknowledgment. Financial support for this research is
obtained from NIH CA56304. J.S.P. is grateful to Amgen,
Johnson & Johnson, Merck Co., Novartis, Pfizer, and GSK
for financial support. J.T.L. acknowledges an ACS Graduate
Fellowship sponsored by Bristol-Myers Squibb Pharmaceu-
ticals and Merck Graduate Fellowship. I.E.W. acknowledges
a Novartis Graduate Fellowship.
Supporting Information Available: Experimental details
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
coupling of acid 24 and amine 4, completing the carbon
framework of the natural product. Removal of the remaining
silyl protecting groups with PPTS completed the synthesis
of bistramide A.
OL062957Y
(33) For a review of the Staudinger reaction, see: Gololobov, Y. G.;
Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
330
Org. Lett., Vol. 9, No. 2, 2007