Spiroacetal formation through telescoped cycloaddition and carbon-hydrogen bond functionalization: Total synthesis of bistramide A

Article abstract of DOI:10.1002/anie.201406819

Spiroacetals can be formed through a one-pot sequence of a hetero-Diels-Alder reaction an oxidative carbon-hydrogen bond cleavage and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramideA.

Full text of DOI:10.1002/anie.201406819

Angewandte
Chemie
DOI: 10.1002/anie.201406819
Natural Product Synthesis
Spiroacetal Formation through Telescoped Cycloaddition and Carbon–
Hydrogen Bond Functionalization: Total Synthesis of Bistramide A**
Xun Han and Paul E. Floreancig*
Abstract: Spiroacetals can be formed through a one-pot
sequence of a hetero-Diels–Alder reaction, an oxidative
carbon–hydrogen bond cleavage, and an acid treatment. This
convergent approach expedites access to a complex molecular
subunit which is present in numerous biologically active
structures. The utility of the protocol is demonstrated through
its application to a brief synthesis of the actin-binding cytotoxin
bistramide A.
used as precursors for spiroacetals through multistep sequen-
ces.[6,7] However the electron-rich alkene and cation-stabiliz-
ing oxygen atom make the dihydropyran an ideal substrate for
in situ oxidative carbon–hydrogen bond cleavage by 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in accord
with our studies on related transformations.[8] The resulting
dihydropyrone can undergo intramolecular nucleophilic
addition[9] to yield the target product in which two rings and
three bonds are created from readily available precursors.
Scheme 2 details the initial demonstration of the process.
Condensing the aldehyde 1 with diene 2 (neat) in the presence
T
ransformations that generate multiple product-relevant
bonds facilitate complex molecule synthesis.[1] Intermolecular
cycloaddition reactions such as the hetero-Diels–Alder reac-
tion[2] are ideally suited for this objective. Oxidative carbon–
hydrogen bond functionalization[3] also introduces product-
relevant bonds from structurally simple precursors. This
manuscript describes a telescoped sequence comprising an
asymmetric hetero-Diels–Alder reaction and oxidative
carbon–hydrogen bond functionalization to access spiroace-
tals. These units are components of numerous biologically
active structures[4] and have inspired multiple synthetic
approaches.[5] The mild and convergent protocol described
herein provides a step-economical approach to the construc-
tion of these structures. The applicability of the sequence to
complex molecule synthesis is demonstrated through the total
synthesis of the cytotoxin bistramide A.
The strategy is illustrated in Scheme 1. The fragment-
coupling phase of this transformation can be achieved
through the union of a silyloxy diene with an aldehyde to
yield a 4-silyloxy dihydropyran. Related structures have been
Scheme 2. One-pot enantioselective cycloaddition/oxidation spiroace-
tal construction. TBDPS=tert-butyldiphenylsilyl.
of Jacobsenꢀs catalyst (3a)[10] provided the adduct 4. Diluting
the crude reaction mixture with CH2Cl2 followed by adding
DDQ yielded 5 nearly instantaneously through carbon–
hydrogen bond cleavage and silyl group loss from the
intermediate oxocarbenium ion. The sequence was completed
by protodesilylation with p-TsOH·H2O to deliver the spiroa-
cetal 6 in 78% yield upon isolated with 91% ee. The oxygen
atom in the ring appears to be essential for promoting rapid
oxidation in consideration of the studies from Guo and
Mayr,[11] who showed that carbocyclic enolsilanes add to
DDQ rather than form enones.
Scheme 1. Convergent approach to spiroacetal synthesis.
[*] X. Han, Prof. P. E. Floreancig
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: florean@pitt.edu
A brief study on the scope of the process is shown in
Table 1. Tetrahydrofuran-containing products can be pre-
pared (entry 1) by shortening the tether between the diene
and silyl ether units. Nonfunctionalized aliphatic aldehydes
[**] This work was supported by a grant from the National Institutes of
Health, Institute of General Medicine (P50-GM067082).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406819.
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Table 1: Scope exploration.[a]
Entry
Diene
Aldehyde
Product
Yield [%][b]
(ee [%])
72
(85)
1
1
50
(>99)
2
3
2
2
53
(84)
Scheme 3. Retrosynthetic analysis of bistramide A. PG=protecting
group.
71
4
5
1
1
(>99)[c]
75
(>99)[c]
[a] See the Supporting Information for detailed procedures, substrate
syntheses, and stereochemical determination. [b] Yield of isolated,
purified product. [c] Diastereomeric products were removed by chro-
matography.
are suitable substrates (entry 2), thus providing the products
in excellent enantiomeric purity. Aromatic aldehydes yield
aryl-substituted spiroacetals (entry 3). Chiral dienes can be
employed in the process (entries 4 and 5). These reactions
deliver products as single enantiomers in accord with the
Horeau principle.[12] The molecular complexity of the targets
in these examples suggests that this strategy is viable for late-
stage fragment-coupling syntheses of spiroacetal-containing
natural products.
The total synthesis of the sponge-derived cytotoxin
bistramide A (17; Scheme 3)[13] was initiated to illustrate the
merits of this protocol. The structure of bistramide A was
confirmed through total synthesis by the group of Kozmin.[14]
Several total and partial syntheses of 17 and related structures
subsequently appeared.[15] Crystallographic studies[16] showed
that interactions between actin (the biological target)[17] and
17 are dominated by the spiroacetal subunit, thus leading to
rational analogue designs.[18]
Scheme 4. Synthesis of the spiroacetal subunit. Reagents and condi-
tions: a) (COCl)2, DMSO, Et3N, CH2Cl2, À788C, 83%; b) trans-2-
butene, nBuLi, KOtBu, (À)-(Ipc)2BOMe, THF, then BF3·OEt2; then
aldehyde, À788C to RT, 67%, 90% ee; c) TESCl, imidazole, CH2Cl2,
quantitative; d) (9-BBN)2, THF, 08C to RT; then 26, [Pd(dppf)Cl2],
K3PO4, H2O, CH2Cl2, 73%; e) TESOTf, Et3N, CH2Cl2, 08C, 96%; f) 28,
3b, 4 ꢀ M.S., then DDQ, CH2Cl2; then p-TsOH·H2O, 58%; g) p-
TsNHNH2, MeOH; h) NaBH3CN, THF, MeOH, pH>4, 08C; i) NaOAc,
EtOH, 758C, 54% (three steps); j) methacrolein, 30, CH2Cl2, 408C,
68%; k) Me2Zn, 32, hexanes, 86%; l) NaN3, DMF, 608C, quantitative.
BBN=borabicyclononane, dppf=diphenylphosphinoferrocene, Ipc=
isopinocamphenyl, OTf=trifluoromethanesulfonate, Mes=2,4,6-tri-
methylphenyl, M.S.=molecular sieves, TES=triethylsilyl, THF=tetra-
hydrofuran, Ts=toluenesulfonyl.
We envisioned bistramide A to arise from the fragments
18 and 19 through amide bond formation. The core spiro-
acetal unit of 18 will be formed from the cycloaddition/
oxidative cyclization between the aldehyde 20 and diene 21.
The righthand fragment can result from the union of the
amine 23 and a tetrahydropyran-contaning carboxylic acid
derived from the alcohol 24.
Our approach to the spiroacetal subunit (Scheme 4)
commenced with the oxidation, Brown crotylation,[19] and
silylation of 4-choloro-1-butanol to yield 25. Suzuki cou-
pling[20] with the iodo enone 26[21] yielded a ketone which was
2
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converted into the silyloxy diene 27 under standard reaction
conditions. The spiroacetal was constructed by coupling 27
with the aldehyde 28, which can be accessed in one step from
(+)-b-citronellene,[22] in the presence of ent-3b. DDQ treat-
ment and acid-mediated ring closure yielded the spirocycle 29
in 58% yield as a single stereoisomer. Ketone deoxygenation
through a mild variant of the Wolff–Kishner reduction[23] and
cross-metathesis with methacrolein mediated by the Grela–
Grubbs catalyst (30)[24] provided the aldehyde 31. A diaste-
reoselective addition of Me2Zn in the presence of (À)-MIB
(32)[25] and the conversion of the chloride into an azido group
completed the synthesis of the spiroacetal subunit 33 as
a single stereoisomer within the limits of NMR detection.
We prepared the 2,6-trans-tetrahydropyran in the right
fragment through homoallylic alcohol hydroformylation,
oxocarbenium ion formation, and nucleophilic addition
(Scheme 5).[26] Conversion of 1,3-propanediol into the homo-
Scheme 6. Completion of the synthesis. Reagents and conditions:
a) PMe3, THF, H2O; b) 40, DMF, 69% (two steps).
39[14] provided an amide which was transformed into the
activated ester 40 without purification.
The synthesis was completed (Scheme 6) by reducing 33
with PMe3 in aqueous THF. The crude amine mixture was
combined with 40 to provide bistramide A in 69% yield. The
longest linear sequence in this route is 14 steps from
commercially available starting materials, thus making this
the shortest reported synthesis of this natural product (the
shortest previous synthesis took 17 steps from commercially
available materials). Significantly, this strategy results in
a substantial reduction in the overall step count in comparison
to published sequences to this family of molecules.
We have demonstrated that the benefits of fragment-
coupling asymmetric cycloaddition reactions can be merged
with the complexity-increasing capabilities of oxidative
carbon–hydrogen bond cleavage for a convergent synthesis
of spiroacetals. The substrates are easily prepared, functional-
group tolerance is high, and stereocontrol is excellent, thus
indicating that this protocol will be applicable to natural
product synthesis. The rapid complexity that this sequence
provides was exploited in the shortest reported synthesis of
the actin-binding cytotoxin bistramide A.
Received: July 2, 2014
Published online: && &&, &&&&
Scheme 5. Synthesis of the right-hand fragment. Reagents and con-
ditions: a) TBSCl, imidazole, THF, 95%; b) SO3·Py, DMSO, Et3N,
CH2Cl2, 88%; c) cis-2-butene, nBuLi, KOtBu, (+)-(Ipc)2BOMe, THF,
then BF3·OEt2; then aldehyde, À788C to RT, 67%, 90% ee;
d) [Rh(CO)2acac], 35, H2/CO (1:1, 8 atm); then Ac2O Et3N, DMAP,
91%; e) (E)-3-penten-2-one, TMSOTf, Et3N, CH2Cl2, À788C, 57%;
f) H5IO6, CrO3, CH3CN, H2O, 08C; g) N-hydroxysuccinimide, DCC,
CH3CN, 81% (two steps); h) 39, iPr2NEt, DMF; i) N-Hydroxysuccin-
imide, DCC, CH3CN, 50% (two steps). acac=acetylacetonate,
DCC=dicyclohexyl carbodiimide, DMAP=4-dimethylaminopyridine,
DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide, Py=pyri-
dine, TMS=trimethylsilyl.
À
Keywords: C H activation · cycloaddition · natural products ·
spiro compounds · stereoselectivity
.
[1] a) J. B. Hendrickson, J. Am. Chem. Soc. 1975, 97, 5784; b) P. A.
Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res.
2008, 41, 40; c) T. Newhouse, P. S. Baran, R. W. Hoffmann,
Chem. Soc. Rev. 2009, 38, 3010; d) T. Gaich, P. S. Baran, J. Org.
Chem. 2010, 75, 4657.
[2] For reviews, see: a) H. Pellissier, Tetrahedron 2009, 65, 2839;
b) S. J. Danishefsky, Aldrichimica Acta 1986, 19, 59.
[3] a) W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976;
b) T. Brꢁckl, R. D. Baxter, Y. Ishihara, P. S. Baran, Acc. Chem.
Res. 2012, 45, 826; c) J. Yamaguchi, A. D. Yamaguchi, K. Itami,
Angew. Chem. Int. Ed. 2012, 51, 8960; Angew. Chem. 2012, 124,
9092; d) D. Y.-K. Chen, S. W. Youn, Chem. Eur. J. 2012, 18, 9452.
[4] a) W. Francke, W. Kitching, Curr. Org. Chem. 2001, 5, 233;
b) M. F. Jacobs, W. Kitching, Curr. Org. Chem. 1998, 2, 395.
[5] a) J. A. Palmes, A. Aponick, Synthesis 2012, 3699; b) B. R. Raju,
A. K. Saikia, Molecules 2008, 13, 1942; c) J. E. Aho, P. M. Pihko,
T. K. Rissa, Chem. Rev. 2005, 105, 4406; d) K. T. Mead, B. N.
Brewer, Curr. Org. Chem. 2003, 7, 227.
allylic alcohol 34 proceeded through selective monosilylation,
oxidation, and asymmetric crotylation. Hydroformylation was
achieved through rhodium catalysis in the presence of Breitꢀs
exceptional DPPon ligand (35).[27] The resultant lactol was
converted into an acetate group in situ to yield 36 in 91%
overall yield. The addition of (E)-3-penten-2-one to 36 in the
presence of TMSOTf[15b,d] provided 37, with concomitant
cleavage of the silyl ether through an acidic work-up.
Oxidizing the primary alcohol into a carboxylic acid was
achieved through CrO3 and H5IO6. The crude acid was
converted into the activated ester 38 with N-hydroxysuccin-
imide and DCC. Coupling 38 with the known b-amino acid
[6] a) S. J. Danishefsky, W. H. Pearson, J. Org. Chem. 1983, 48, 3865;
b) S. J. Danishefsky, D. M. Armistead, F. E. Wincott, H. G.
Selnick, R. Hungate, J. Am. Chem. Soc. 1989, 111, 2967.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[7] For reviews of oxidative and cycloaddition-based approaches to
spiroacetals, see: a) J. Sperry, Y.-C. Liu, M. A. Brimble, Org.
Biomol. Chem. 2010, 8, 29; b) M. A. Rizzacasa, A. Pollex, Org.
Biomol. Chem. 2009, 7, 1053.
Biophys. Res. Commun. 1996, 222, 802; c) M. P. Foster, C. L.
Mayne, R. Dunkel, R. J. Pugmire, D. M. Grant, J.-M. Korn-
probst, J.-F. Verbist, J.-F. Biard, C. M. Ireland, J. Am. Chem. Soc.
1992, 114, 1110.
[8] a) G. R. Peh, P. E. Floreancig, Org. Lett. 2012, 14, 5614; b) X.
Han, P. E. Floreancig, Org. Lett. 2012, 14, 3808; c) Y. Cui, P. E.
Floreancig, Org. Lett. 2012, 14, 1720; d) G. J. Brizgys, H. H. Jung,
P. E. Floreancig, Chem. Sci. 2012, 3, 438; e) H. H. Jung, P. E.
Floreancig, Tetrahedron 2009, 65, 10830; f) L. Liu, P. E. Flor-
eancig, Org. Lett. 2009, 11, 3152; g) L. Liu, P. E. Floreancig,
Angew. Chem. Int. Ed. 2010, 49, 5894; Angew. Chem. 2010, 122,
6030; h) L. Liu, P. E. Floreancig, Angew. Chem. Int. Ed. 2010, 49,
3069; Angew. Chem. 2010, 122, 3133; i) W. Tu, P. E. Floreancig,
Angew. Chem. Int. Ed. 2009, 48, 4567; Angew. Chem. 2009, 121,
4637; j) W. Tu, L. Liu, P. E. Floreancig, Angew. Chem. Int. Ed.
2008, 47, 4184; Angew. Chem. 2008, 120, 4252.
[14] A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126,
9546.
[15] a) P. Wipf, T. D. Hopkins, Chem. Commun. 2005, 3421; b) M. T.
Crimmins, A. C. DeBaille, J. Am. Chem. Soc. 2006, 128, 4936;
c) J. T. Lowe, I. E. Wrona, J. S. Panek, Org. Lett. 2007, 9, 327;
d) J. S. Yadav, L. Chetia, Org. Lett. 2007, 9, 4587; e) L. Tomas,
G. B. af Gennꢄs, M. A. Hiebel, P. Hampson, D. Gueyrard, B.
Pelotier, J. Yli-Kauhaluoma, O. Piva, J. M. Lord, P. G. Goekjian,
Chem. Eur. J. 2012, 18, 7452; f) M. Commandeur, C. Comman-
deur, J. Cossy, Org. Lett. 2011, 13, 6018.
[16] S. A. Rizvi, V. Tereshko, A. A. Kossiakoff, S. A. Kozmin, J. Am.
Chem. Soc. 2006, 128, 3882.
[9] For another example of spiroacetal formation through a formal
hydride loss from an oxacycle, see: T. J. Donohoe, R. M.
[17] a) A. V. Statsuk, R. Bai, J. L. Baryza, V. A. Verma, E. Hamel,
P. A. Wender, S. A. Kozmin, Nat. Chem. Biol. 2005, 1, 383;
b) S. A. Rizvi, D. S. Courson, V. A. Keller, R. S. Rock, S. A.
Kozmin, Proc. Natl. Acad. Sci. USA 2008, 105, 4088.
´
Lipinski, Angew. Chem. Int. Ed. 2013, 52, 2491; Angew. Chem.
2013, 125, 2551.
[10] A. G. Dossetter, T. F. Jamison, E. N. Jacobsen, Angew. Chem.
Int. Ed. 1999, 38, 2398; Angew. Chem. 1999, 111, 2549.
[11] a) X. Guo, H. Mayr, J. Am. Chem. Soc. 2013, 135, 12377; for
related earlier studies, see: b) I. Ryu, S. Murai, Y. Hatayama, N.
Sonoda, Tetrahedron Lett. 1978, 19, 3455; c) A. Bhattacharya,
L. M. DiMichele, U.-H. Dolling, E. J. J. Grabowski, V. J. Grenda,
J. Org. Chem. 1989, 54, 6118; d) D. M. Hodgson, E. Moreno-
Clavijo, S. E. Day, S. Man, Org. Biomol. Chem. 2013, 11, 5362.
[12] The Horeau principle describes the statistical enantiomeric
excess enhancement, when two enantiomerically enriched
species are coupled, as a result of diastereomer formation. For
a review, see: V. Rautenstrauch, Bull. Soc. Chim. Fr. 1994, 131,
515.
[18] S. A. Rizvi, S. Liu, Z. Chen, C. Skau, M. Pytynia, D. R. Kovar,
S. J. Chmura, S. A. Kozmin, J. Am. Chem. Soc. 2010, 132, 7288.
[19] H. C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 293.
[20] N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh, A.
Suzuki, J. Am. Chem. Soc. 1989, 111, 314.
[21] M. R. Rivero, S. L. Buchwald, Org. Lett. 2007, 9, 973 – 976.
[22] A. Fꢁrstner, F. Feyen, H. Prinz, H. Waldmann, Angew. Chem.
Int. Ed. 2003, 42, 5361; Angew. Chem. 2003, 115, 5519.
[23] V. Nair, A. Sinhababu, J. Org. Chem. 1978, 43, 5013.
[24] K. Grela, S. Harutyunyan, A. Michrowska, Angew. Chem. Int.
Ed. 2002, 41, 4038; Angew. Chem. 2002, 114, 4210.
[25] W. A. Nugent, Chem. Commun. 1999, 1369.
[26] H. H. Jung, J. R. Seiders II, P. E. Floreancig, Angew. Chem. Int.
Ed. 2007, 46, 8464; Angew. Chem. 2007, 119, 8616.
[27] a) B. Breit, W. Seiche, J. Am. Chem. Soc. 2003, 125, 6608; b) U.
Gellrich, W. Seiche, M. Keller, B. Breit, Angew. Chem. Int. Ed.
2012, 51, 11033; Angew. Chem. 2012, 124, 11195.
[13] a) D. Gouiffꢂs, S. Moreau, N. Helbecque, J. L. Bernier, J. P.
Hꢃnichart, Y. Barbin, D. Laurent, J. F. Verbist, Tetrahedron 1988,
44, 451; b) G. Griffiths, B. Garrone, E. Deacon, P. Owen, J.
Pongracz, G. Mead, A. Bradwell, D. Watters, J. Lord, Biochem.
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Natural Product Synthesis
X. Han, P. E. Floreancig*
&&&& — &&&&
Spiroacetal Formation through
Telescoped Cycloaddition and Carbon–
Hydrogen Bond Functionalization: Total
Synthesis of Bistramide A
Actin’ out: Spiroacetals can be prepared
from aldehydes and functionalized dienes
through a convergent, telescoped
accessibility of the components render
this protocol suitable for the synthesis of
structurally complex natural products
such as the actin-binding cytotoxin bis-
tramide A.
À
sequence of cycloaddition, oxidative C H
bond cleavage, and acid treatment. The
functional-group tolerance and facile
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