A non-iterative, flexible, and highly stereoselective synthesis of polydeoxypropionates-synthesis of (+)-vittatalactone

Article abstract of DOI:10.1039/c0cc05215a

A short sequence comprising an oxy-Cope rearrangement, iridium-catalyzed hydrogenation, and enolate methylation provides trideoxypropionates with excellent diastereocontrol. A straightforward synthesis of the cucumber beetle pheromone (+)-vittatalactone i

Full text of DOI:10.1039/c0cc05215a

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COMMUNICATION
A non-iterative, flexible, and highly stereoselective synthesis
of polydeoxypropionates—synthesis of (+)-vittatalactonew
Christian F. Weise,a Matthias Pischl,a Andreas Pfaltzb and Christoph Schneider*a
Received 26th November 2010, Accepted 11th January 2011
DOI: 10.1039/c0cc05215a
A short sequence comprising an oxy-Cope rearrangement,
iridium-catalyzed hydrogenation, and enolate methylation
provides trideoxypropionates with excellent diastereocontrol. A
straightforward synthesis of the cucumber beetle pheromone
(+)-vittatalactone illustrates this new strategy.
Polydeoxypropionates are central subunits of a broad range of
naturally occurring compounds with diverse biological activities.
Most prominent among them are natural products such as the
calcium ionophore ionomycin,1 the cytotoxic metabolite
borrelidin,2 the pheromones hexamethyldocosane3 and lardolure4
as well as the lipid component mycoceranic acid.5 Accordingly,
numerous powerful and highly stereoselective syntheses have
been developed for their assembly employing both chiral
auxiliaries and catalysts in recent years.6 All strategies share
a linear-iterative principle with one deoxypropionate unit
being attached to the other and incorporated into the growing
alkyl chain successively. For the conversion of the product of
the previous cycle into the substrate for the next cycle
additional transformations have to be performed, however,
which affect the overall yield and elegance of the processes. We
report herein the first non-iterative strategy which furnishes
trideoxypropionates in a few steps and with high stereocontrol
and which allows for further selective manipulations being
demonstrated in a synthesis of the pheromone vittatalactone.
Based upon our studies on the oxy-Cope rearrangement of
syn-aldol products7 we envisioned compounds 2 as potentially
suitable substrates for a novel synthetic access to trideoxy-
propionates. Starting out from syn-aldol product 17b obtained
through asymmetric aldol reaction8 and subsequent O-protection
a highly diastereoselective Cope rearrangement was expected
to deliver 2 which already carries the first methyl-branching
stereogenic center (Scheme 1). Of crucial importance to the
success of this strategy was the subsequent catalyst-controlled
hydrogenation of the prochiral enol moiety which would give
rise to the establishment of the second stereogenic center. In a
Scheme 1 Projected synthetic strategy.
third step an auxiliary-controlled enolate methylation on the
now saturated N-acyl oxazolidinone 4 was expected to
complete the synthesis of the desired trideoxypropionate 5.
Central to the success of this envisioned strategy was the
identification of a suitable enol derivative and a highly
selective metal catalyst to control the stereochemical outcome
of the hydrogenation.9 Enol esters and enol carbamates
derived from prochiral ketones have been shown to be
hydrogenated with high enantioselectivity using chiral metal
catalysts.10 Prochiral enol derivatives derived from aldehydes
have not been investigated so far, however. Thus, benzoyl-
and carbamoyl-protected syn-aldol products 1a and 1b,
respectively, were submitted to the [3.3]-sigmatropic process
which proceeded with excellent yields and exceptional
diastereoselectivity in both cases (Scheme 2). The longer
reaction times in comparison to our previously studied
silylated aldols are the result of the electronwithdrawing
nature of the O-substituents which increase the activation
energy but do not affect the diastereoselectivity of the
rearrangement.11
Cope products 2a and 2b were subsequently investigated in
iridium-catalyzed hydrogenation reactions (see Table 1 for
selected results). Eventually it turned out that a cationic
a Institut fur Organische Chemie, Universitat Leipzig, Johannisallee
¨
¨
29, D-04103 Leipzig, Germany.
E-mail: schneider@chemie.uni-leipzig.de
b Institut fur Organische Chemie, Universitat Basel, St. Johanns-Ring
¨
¨
19, CH-4056 Basel, Switzerland. E-mail: andreas.pfaltz@unibas.ch
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for all new compounds. See DOI:
10.1039/c0cc05215a
Scheme 2 Oxy-Cope rearrangement of 1a and 1b.
c
3248 Chem. Commun., 2011, 47, 3248–3250
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Table 1 Hydrogenation of Oxy-Cope substratesa
Scheme 3 Synthesis of trideoxypropionates syn,syn-5 and anti,syn-5.
(a) NaHMDS, MeI, THF, À78 1C, each 93% (>98 : 2).
Entry
2
R
Ligand syn/antib,c Conversionb,d (%)
1
2
3
4
5
6
7
8
9
2a Bz
2a Bz
3a
3b
70 : 30
67 : 33
95 : 5
72 : 28
97 : 3
4 : 96
2 : 98
97 : 3
97 : 3
>99
65
25
>99
35
>99 (99)
>99 (95)
>99 (98)
>99 (96)
2b CONHtBu 3b
2a Bz 3c
2b CONHtBu 3c
2a Bz 3d
2b CONHtBu 3d
2a Bz ent-3d
2b CONHtBu ent-3d
a
Reaction conditions: 2 (0.10 mmol), [Ir(cod)L]BArF(0.002 mmol),
b
85 bar H2, 0.5 mL CH2Cl2, 18 h, rt. Determined by chiral HPLC
c
(see ESIw). For assignment of absolute configuration see ESI.w
Isolated yield after chromatography in parentheses.
d
Scheme 4 Synthesis of trideoxypropionates anti,anti-5 and syn,anti-5.
(a) toluene, 200 1C, 6 h; (b) [Ir(cod)ent-3d]BArF (2 mol%), CH2Cl2,
85 bar H2, 95% (94 : 6 anti/syn); (c) [Ir(cod)3d]BArF (2 mol%),
CH2Cl2, 85 bar H2, 97% (92 : 8 syn/anti); (d) NaHMDS, MeI,
THF, À78 1C, 93% and 92% (>98 : 2).
iridium complex carrying a novel and carefully optimized
chiral PHOX9b,12-ligand 3d was capable of catalyzing the
hydrogenation of both 2a and 2b with excellent diastereo-
selectivity. Thus, the benzoate anti-4a and the carbamate anti-4b
were obtained with 96 : 4 and 98 : 2 diastereoselectivity,
respectively, and >95% isolated yield (entries 6 and 7). Quite
interestingly the diastereofacial selectivity was almost
completely reversed in contrast to all other PHOX-ligands
studied. At the same time this pronounced catalyst control
suggested that the opposite configuration might be readily
accessible using the enantiomeric catalyst. Indeed the corres-
ponding syn-diastereomers syn-4a and syn-4b were obtained
with 97 : 3-diastereoselectivity each using enantiomeric ligand
ent-3d in the hydrogenation event (entries 8 and 9). On the
basis of the more facile synthetic manipulation of an ester
relative to a carbamate we decided to employ the benzoate for
all subsequent steps.
catalyst to furnish benzoates anti-8 and syn-8 with 94 : 6 anti/
syn- and 92 : 8 syn/anti-diastereoselectivity, respectively
(Scheme 4). Final a-methylation gave rise to trideoxypropionates
anti,anti-5 and syn,anti-5, respectively. On the basis of this
unified synthetic strategy all four diastereomeric trideoxy-
propionates were obtained in a highly straightforward fashion
and with excellent stereocontrol.
The chemoselective cleavage of the chiral auxiliary was
effected through hydrolysis (LiOH/H2O2) as well as reduction
(NaBH4/H2O) in good yields while completely retaining the
benzoate moiety (see ESIw). In addition, further elongation
toward a tetradeoxypropionate was easily possible. For this
purpose syn,syn-5 was converted into iodide 9 and treated with
the enolate of N-propionyl-S,S-pseudoephedrine amide
according to the Myers protocol13 which gave rise to all-syn-
configured tetradeoxypropionate 10 in good yield as a single
diastereomer (Scheme 5).
The subsequent auxiliary-controlled a-methylation of
syn- and anti-4a proceeded without incident to furnish trideoxy-
propionates syn,syn-5 and anti,syn-5, respectively, in excellent
yields and diastereocontrol (Scheme 3).
In order to demonstrate the utility of this new strategy in the
context of a natural product synthesis we chose the sex
The stereospecific reaction path of the oxy-Cope rearrange-
ment was now taken to advantage to access the two other
diastereomers without changing the chiral auxiliary. Along
these lines the Z-configured syn-aldol product 67b was
converted into the epimeric Cope product 7 in 84% yield and
96 : 4-diastereoselectivity (Scheme 4). After chromatographic
purification 7 was hydrogenated with the optimized iridium
Scheme
5 Chain elongation toward tetradeoxypropionate 10.
(a) LDA, LiCl, THF, 75% (>98 : 2); XP = (S,S)-pseudoephedrine.
c
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Notes and references
1 Isolation: (a) W. C. Liu, D. Smith-Slusarchyk, G. Astle,
W. H. Trejo, W. E. Brown and E. Meyers, J. Antibiot., 1978, 31,
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J. M. Takacs and R. Zahler, J. Am. Chem. Soc., 1990, 112, 5290;
(c) S. Hanessian, N. G. Cooke, B. DeHoff and Y. Saikito, J. Am.
Chem. Soc., 1990, 112, 5276; (d) M. Lautens, J. T. Colucci,
S. Hiebert, N. D. Smith and G. Bouchain, Org. Lett., 2002, 4, 1879.
2 Isolation: (a) J. Berger, L. M. Jampolsky and M. W. Goldberg,
Arch. Biochem., 1949, 22, 476; Syntheses: (b) M. O. Duffey,
A. LeTiran and J. P. Morken, J. Am. Chem. Soc., 2003, 127,
1458; (c) S. Hanessian, Y. Yang, S. Giroux, V. Mascitti, J. Ma and
F. Raeppel, J. Am. Chem. Soc., 2003, 127, 13784; (d) B. G. Vong,
S. H. Kim, S. Abraham and E. A. Theodorakis, Angew. Chem.,
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(e) T. Nagamitsu, D. Takano, K. Marumoto, T. Fukuda,
K. Furuya, K. Otoguro, K. Takeda, I. Kuwaiyama, Y. Harigaya
and S. Omura, J. Org. Chem., 2007, 72, 2744.
3 Isolation: (a) M. T. Fletcher, S. Chow, L. K. Lambert,
O. P. Gallagher, B. W. Cribb, P. G. Allsopp, C. J. Moore and
W. Kitching, Org. Lett., 2003, 5, 5083; Syntheses: (b) C. Herber
and B. Breit, Angew. Chem., 2005, 117, 5401 (Angew. Chem.,
Int. Ed., 2005, 44, 5267); (c) C. Herber and B. Breit, Eur. J. Org.
Chem., 2007, 3512; (d) J. Zhou, Y. Zhu and K. Burgess, Org. Lett.,
2007, 9, 1391; (e) G. Zhu, B. Liang and E. Negishi, Org. Lett.,
2008, 10, 1099.
4 (a) K. Mori and S. Kuwahara, Tetrahedron, 1986, 42, 5539;
(b) M. Kaino, Y. Naruse, K. Ishihara and H. Yamamoto,
J. Org. Chem., 1990, 55, 5814; (c) M. Morr, C. Proppe and
V. Wray, Liebigs Ann., 1995, 2001; (d) R. Des Mazery,
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B. L. Feringa and A. J. Minnaard, Chem.–Eur. J., 2008, 14, 4157.
6 Excellent reviews: (a) B. ter Horst, B. L. Feringa and
A. J. Minnaard, Chem. Commun., 2010, 46, 2535;
(b) S. Hanessian, S. Giroux and V. Mascitti, Synthesis, 2006, 1057.
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(b) C. Schneider and M. Rehfeuter, Tetrahedron, 1997, 53, 133;
Review: (c) C. Schneider, Synlett, 2001, 1079.
Scheme 6 Synthesis of (+)-vittatalactone (11). (a) NaOMe, MeOH,
71%; (b) PPh3, I2, imidazole, 94%; (c) iPrMgCl, Li2CuCl4, NMP,
77%; (d) DIBAH, THF, À90 1C, 90%; (e) propionyl-XN, (c-Hex)2-
BOTf, NEt3, À78 1C, 86%; (f) LiOH, THF, H2O, 81%;
(g) TsCl, DMAP, pyridine, 81%. NMP = N-methylpyrrolidinone,
XN = (1R,2S)-N-benzyl-N-mesitylsulfonylnorephedrine.
pheromone (+)-vittatalactone (11) as an attractive target
which had been isolated from the cucumber beetle Acalymma
vittatum by Francke and coworkers in 2005.14 11 contains an
all-syn-configured 1,3,5,7-tetramethyl-substituted alkyl chain
and a trans-configured b-lactone as structural elements. Very
recently, Breit and coworkers were able to unambiguously
assign its relative and absolute configuration through total
syntheses of the unnatural as well as the naturally occurring
enantiomer.15
Starting from all-syn-configured trideoxypropionate 5 the
corresponding hydroxy ester was prepared through trans-
esterification with NaOMe and further converted into iodide
12 (Scheme 6). A chemoselective copper-catalyzed alkylation
of 12 was performed according to the procedure developed by
Cahiez et al.16 using iPrMgCl and catalytic amounts of
17
Li2CuCl4
in the presence of N-methyl-2-pyrrolidinone
without affecting the ester moiety. DIBAL-H reduction at
low temperature furnished aldehyde 13 in good overall yield.
In order to install the trans-configured b-lactone we opted for
an anti-selective boron aldol reaction as developed by Abiko
and Masamune et al. which delivered anti-aldol product 14 as
a single diastereomer in 86% yield.18 Hydrolysis and lacton-
ization with p-toluenesulfonyl chloride and pyridine eventually
completed the synthesis of (+)-vittatalactone (11).
8 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981,
103, 2128.
9 Reviews: (a) X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272;
(b) S. J. Roseblade and A. Pfaltz, Acc. Chem. Res., 2007, 40, 1402;
(c) A. J. Minnaard, B. L. Feringa, L. Lefort and J. G. de Vries,
Acc. Chem. Res., 2007, 40, 1267.
10 (a) S. Wu, W. Wang, W. Tang, M. Lin and X. Zhang, Org. Lett.,
2002, 4, 4495; (b) M. T. Reetz, L. J. Goossen, A. Meiswinkel,
J. Paetzold and J. Feldthusen Jensen, Org. Lett., 2003, 5, 3099;
(c) L. Panella, B. L. Feringa, J. G. de Vries and A. J. Minnaard,
Org. Lett., 2005, 7, 4177.
11 C. F. Weise, F. Richter, S. Immel, C. Schneider, unpublished.
12 For PHOX-ligands see: A. Lightfoot, P. Schnider and A. Pfaltz,
Angew. Chem., 1998, 110, 3047 (Angew. Chem., Int. Ed., 1998, 37,
2897).
In conclusion, we have developed a novel strategy for the
first non-iterative and yet very flexible synthesis of polydeoxy-
propionate building blocks. Starting from readily available
chiral aldol products just 3 steps—a thermal oxy-Cope rear-
rangement, an iridium-catalyzed hydrogenation, and enolate
methylation—suffice to access trideoxypropionates of any
configuration in high overall yields and with typically excellent
diastereoselectivity. Their differently functionalized termini
allow for selective modifications as well as the use of this
strategy in the context of natural product synthesis. Further
synthetic applications are currently being studied in our
laboratories.
13 (a) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry,
D. J. Kopecky and J. L. Gleason, J. Am. Chem. Soc., 1997, 119,
6496; (b) A. G. Myers, B. H. Yang, H. Chen and D. J. Kopecky,
Synlett, 1997, 457; (c) see also L. F. Tietze, C. Raith, C. C. Brazel,
S. Holsken and J. Magull, Synthesis, 2008, 229.
¨
14 D. B. Morris, R. R. Smyth, S. P. Foster, M. P. Hoffmann,
W. L. Roelofs, S. Franke and W. Francke, J. Nat. Prod., 2005,
68, 26.
15 (a) Y. Schmidt and B. Breit, Org. Lett., 2009, 11, 4767;
(b) Y. Schmidt, K. Lehr, U. Breuninger, G. Brand, T. Reiss and
B. Breit, J. Org. Chem., 2010, 75, 4424.
16 G. Cahiez, C. Chaboche and M. Jezequel, Tetrahedron, 2000, 56,
2733.
17 M. Tamura and J. Kochi, Synthesis, 1971, 303.
18 (a) A. Abiko, J. F. Liu and S. Masamune, J. Am. Chem. Soc., 1997,
119, 2586; (b) T. Inoue, J. F. Liu, D. C. Buske and A. Abiko,
J. Org. Chem., 2002, 67, 5250.
Generous financial support was provided by the Deutsche
Forschungsgemeinschaft (Schn 441/6-1). We thank the
Studienstiftung des deutschen Volkes for a doctoral fellowship
(awarded to C. F. W.), Andreas Schumacher (University of
Basel) for assistance with the iridium catalyst and Prof.
Bernhard Breit (University of Freiburg) for sharing information
prior to publication. We are grateful to Evonik and BASF for
providing chemicals.
c
3250 Chem. Commun., 2011, 47, 3248–3250
This journal is The Royal Society of Chemistry 2011