Iterative deoxypropionate synthesis based on a copper-mediated directed allylic substitution

Article abstract of DOI:10.1002/anie.200453990

Can't have too much of a good thing: A flexible, iterative strategy based on a highly selective copper-mediated allylic substitution makes the preparation of any desired oligo(deoxypropionate) stereoisomer possible (see scheme; RDG = reagent-directing group). This approach differs from the established enolate-alkylation methodology through the reversed polarity of the reaction partners and avoids several problems associated with the latter method.

Full text of DOI:10.1002/anie.200453990

Communications
Polyketides
ing block 1.Oxidative cleavage of the alkene in the
bis(deoxypropionate) 1 followed by conversion of the prod-
uct into a new organometallic nucleophile should then make
it possible to carry out an iterative process.This approach is
complementary to the known enolate-alkylation strategy, as
the growing propionate chain is introduced as a nucleophile
and not as an electrophile (“Umpolung”).Key to the success
of this strategy is the availability of an allylic substitution
reaction that occurs in acyclic systems with complete chemo-,
regio-, and stereoselectivity, as well as complete 1,3-chirality
transfer.Our recently developed “directed” copper-mediated
allylic substitution reaction with o-diphenylphosphanylben-
zoate (o-DPPB) as the reagent-directing leaving group meets
these requirements.[5] However, its compatibility with enan-
tiomerically pure Grignard reagents 3 that are branched in the
b position remained untested.Furthermore, it was necessary
to develop a practical route to enantiomerically pure building
blocks 2 and 3.
Enzyme catalysis was selected as a suitable method for the
preparation of large quantities of both enantiomers of allylic
electrophiles 2.Thus, the allylic alcohol rac-6 was subjected to
enzymatic resolution with Novozym 435 (Scheme 2).[6] Enan-
tiomerically pure (S)-6 was obtained at 55% conversion
(enantioselectivity factor E = 52).The acetate ( R)-7 (82% ee)
formed in the reaction underwent hydrolysis (also catalyzed
by Novozym 435) to furnish (R)-6 (96–97% ee).Both enan-
tiomers of 6 were transformed into the corresponding o-
diphenylphosphanylbenzoate compounds 8, which were puri-
fied by crystallization.In this way, gram quantities of both
enantiomers of 8 could be prepared in enantiomerically pure
form.The crystalline allylic o-DPPB esters 8 could be stored
Iterative Deoxypropionate Synthesis Based on a
Copper-Mediated Directed Allylic Substitution**
Bernhard Breit* and Christian Herber
Many biologically relevant natural products of polyketide
origin contain a fully reduced 1,3,5,n(“skip”)-polymethyl-
substituted carbon chain.[1] Such structures, referred to as
“deoxypropionate oligomers”, are usually constructed
through an iterative asymmetric enolate alkylation of the
type introduced by Evans et al.[2] Although the use of amide
enolates based on pseudoephedrine[3] and azaenolates
derived from (R)-1-amino-2-(methoxymethyl)pyrrolidine
(RAMP) hydrazones[4] have led to significant improvements
in this methodology, disadvantages still include the often low
reactivity of the enolate intermediate towards the alkylating
agent, and the cost and removability of the chiral auxiliary.
These drawbacks prohibit large-scale applications.We report
herein an alternative iterative strategy based on a stereo-
specific copper-mediated directed allylic substitution.This
flexible approach allows the preparation of any desired
oligo(deoxypropionate) stereoisomer.The strategy is out-
lined in Scheme 1.
The key step of our strategy is an SN2’ reaction of the
organometallic reagent 3 with the electrophile 2 derived from
an allylic alcohol, to furnish the bis(deoxypropionate) build-
Scheme 1. Iterative strategy for the enantioselective construction of
deoxypropionate structures based on a directed copper-mediated allylic
substitution (RDG=reagent-directing group).
[*] Prof. Dr. B. Breit, Dipl.-Chem. C. Herber
Institut für Organische Chemie und Biochemie
Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax:( +49)761-203-8715
E-mail:bernhard.breit@orgmail.chemie.uni-freiburg.de
Scheme 2. Preparation of the enantiomerically pure o-DPPB allylic
esters 8:1) Novozym 435, vinyl acetate, 30 8C; 2) o-diphenylphospha-
nylbenzoic acid, DCC, DMAP, CH2Cl2; 3) Novozym 435, buffer (pH 7),
58C. DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-dimethylamino-
pyridine.
[**] This work was supported by the DFG, the Fonds der Chemischen
Industrie, and the Krupp Foundation (Alfried Krupp Award for
Young Professors to B.B.).
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DOI: 10.1002/anie.200453990
Angew. Chem. Int. Ed. 2004, 43, 3790 –3792

Angewandte
Chemie
for several months without detectable decomposition (e.g.
oxidation to the corresponding phosphane oxide).
nate)s (+)-13 and (À)-14 were verified upon conversion into
the known alcohols (À)-19[13] and (+)-20,[14] respectively
We believed that the Grignard reagent 12 derived from
the known bromide 10 would be a suitable organometallic
building block of the type 3 (Scheme 3).[7] Both enantiomers
of 10 are readily accessible from the commercially available
Roche esters 9[8] or through enzymatic esterification processes
starting from 2-methylpropane-1,3-diol (11)[9] or a derivative
thereof.[10]
(Scheme 4).
To demonstrate the practicability and flexibility of our
strategy, we decided to prepare all possible diastereomers of a
series of bis- and tris(deoxypropionate)s.First the bromide 10
was converted into the corresponding Grignard reagent 12.It
proved essential to activate the magnesium by the dry-stir
method.[11,12] The addition of 12 (1 equiv) as a freshly
prepared solution in diethyl ether to the allylic ester (S)-
(À)-8 in the presence of CuBr·SMe2 (0.5 equiv) initiated a
clean allylic substitution to give the bis(deoxypropionate)
(+)-13 in good yield with perfect regioselectivity (> 99:1) and
excellent stereoselectivity (d.r. 97:3). Even better stereose-
lectivity was observed in the reaction of 12 with the R allylic
ester (+)-8 (d.r. 99:1). Thus, the reaction that leads to the 1,3-
syn relative configuration (in (À)-14) appears to represent a
matched case, whereas the reaction that leads to the 1,3-anti
configuration (in (+)-13) represents a mismatched case.The
relative and absolute configurations of the bis(deoxypropio-
Scheme 4. Determination of the relative and absolute configuration of
(+)-13 and (À)-14.
The iteration of this sequence, starting from (+)-13 and
(À)-14, began with oxidative cleavage of the alkene by
ozonolysis and reductive workup to give the corresponding
alcohols in excellent yields (Scheme 3, step 1).At this stage
we decided to explore an alternative method for the
generation of the Grignard reagent based on a halogen–
metal exchange.This procedure turned out to be operation-
Scheme 3. Enantioselective construction of bis- and tris(deoxypropionate) building blocks based on an iterative o-DPPB-directed copper-mediated allylic sub-
stitution:1) O , NaBH4; 2) I2, Im, PPh3; 3) tBuLi (2 equiv), MgBr2·OEt2, then (S)-(À)-8, CuBr·SMe2, Et2O. Im=imidazole, PMB=p-methoxybenzyl.
3
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3791

Communications
815 – 819; for borrelidin, see: J.Berger, L.M.Jampolsky, M.W.
Goldberg, Arch. Biochem. 1949, 22, 476 – 478; for pectinatone,
see: J.E.Biskupiak, C.M.Ireland, Tetrahedron Lett. 1983, 24,
3055 – 3058.
ally more convenient for small-scale reactions.The primary
alcohols formed in the first step were therefore converted into
the corresponding iodides (Scheme 3, step 2).The halogen–
metal exchange proceeded cleanly upon treatment with tert-
butyllithium and was followed by transmetalation with
MgBr2·OEt2.The directed allylic substitution of the resulting
Grignard reagents with (S)-(À)-8 and (R)-(+)-8 in the
presence of CuBr·SMe2 (0.5 equiv) proceeded cleanly to
give all four possible diastereomeric tris(deoxypropionate)
building blocks 15–18 in good yield, with perfect regioselec-
tivity and excellent stereoselectivity.
[2] D.A.Evans, R.L.Dow, T.L.Shih, J.M.Takacs, R.Zahler,
J.
Am. Chem. Soc. 1990, 112, 5290 – 5313.
[3] A.G.Myers, B.H.Yang, H.Chen, D.J.Kopecky,
457 – 459.
Synlett 1997,
[4] A.A. Birkbeck, D. Enders, Tetrahedron Lett. 1998, 39, 7823 –
7826.
[5] B.Breit, P.Demel, C.Studte,
Angew. Chem. 2004, 116, 3874–
3877; Angew. Chem. Int. Ed. 2004, 43, 3786–3789; B.Breit, P.
Demel, Adv. Synth. Catal. 2001, 343, 429 – 432.
In conclusion, a new flexible iterative strategy has been
developed for the preparation of any desired oligo(deoxy-
propionate) stereoisomer.The key step, which allows perfect
control of all aspects of selectivity, is an o-DPPB-directed
copper-mediated allylic substitution with an enantiomerically
pure Grignard reagent.This fragment-coupling step features
reversed polarity relative to established methodology involv-
ing enolate alkylation.Problems associated with strategies
based on enolate alkylation, such as low enolate reactivity and
the cost of the chiral auxiliary, which is also often difficult to
remove, can thus be avoided.
[6] a) Novozym 435 is a lipase from Candida antarctica (Candida
antarctica lipase B, CAL-B); for more details, see: www.novo-
zymes.com; b) for selected examples of 2-alkanols that have
been resolved with CAL-B, see: U.T. Bornscheuer, R.J.
Kazlauskas in Hydrolases in Organic Synthesis, Wiley-VCH,
Weinheim, 1999, pp.70 – 72.
[7] D.Sawada, M.Kanai, M.Shibasaki, J. Am. Chem. Soc. 2000, 122,
10521 – 10532.
[8] For the synthesis of (S)-10, see: SD. .Meyer, T.Miwa, M.
Nakatsuka, S.L.Schreiber, J. Org. Chem. 1992, 57, 5058 – 5060.
[9] a) E.Santaniello, P.Ferraboschi, P.Grisenti, Tetrahedron Lett.
1990, 31, 5657 – 5660; b) C.Bertucci, A.Petri, G.Felix, B.Perini,
P.Salvadori, Tetrahedron: Asymmetry 1999, 10, 4455 – 4462; c) P.
Grisenti, P.Ferraboschi, A.Manzocchi, E.Santaniello, Tetrahe-
dron 1992, 48, 3827 – 3834; d) Z.-F. Xie, H. Suemune, K. Sakai,
Tetrahedron: Asymmetry 1993, 4, 973 – 980.
Experimental Section
Synthesis of (+)-13: CuBr·SMe2 (20.6 mg, 0.10 mmol) was added to a
solution of (À)-8 (77.7 mg, 0.20 mmol) in diethyl ether (4 mL) at
room temperature, and the reaction mixture was stirred for a further
5 min.The Grignard reagent 12 (2.4 mL, 0.24 mmol, 0.1m solution in
diethyl ether) was added dropwise at room temperature to the
resulting yellow solution, and the mixture was stirred for a further 2 h.
A saturated aqueous solution of NH4Cl (2 mL) was then added to the
reaction mixture, the phases were separated, and the aqueous phase
was extracted with dichloromethane (3 ” 5 mL).The combined
organic phases were dried (Na2SO4) and the solvents were removed
in vacuo.Flash chromatography of the residue (petroleum ether/ tert-
butyl methyl ether 50:1) yielded (+)-13 as a colorless oil (45.9 mg,
83%, d.r. 97:3). HPLC (Macherey-Nagel EC 250/4 Nucleosil 100-5,
[10] T.Akeboshi, Y.Ohtsuka, T.Ishihara, T.Sugai, Adv. Synth. Catal.
2001, 343, 624 – 637.
[11] P.M.Smith, E.J.Thomas, J. Chem. Soc. Perkin Trans. 1 1998,
3541 – 3556.
[12] K.V.Baker, J.M.Brown, N.Hughes, A.J.Skarnulis, A.Sexton,
J. Org. Chem. 1991, 56, 698 – 703.
[13] S.Karlsson, E.Hedenstrꢀm, Acta Chem. Scand. 1999, 53, 620 –
630.
[14] For (À)-20, see: P.J.Kocienski, R.C.D.Brown, A.Pommier, M.
Procter, B.Schmidt, J. Chem. Soc. Perkin Trans. 1 1998, 9 – 40.
0.4 ” 25 cm, 258C, n-heptane/ethyl acetate (200:0.3), 0.8 mLminÀ1
,
275 nm): tR ((À)-13): 52.4 min (2.8%), tR ((+)-13): 55.0 min (97.2%);
[a]2D0 = +18.2 (c = 0.68, CHCl3); 1H NMR (499.873 MHz, CDCl3,
3
3
278C, TMS): d = 0.91 (d, J = 6.8 Hz, 3H, CH3), 0.92 (d, J = 6.8 Hz,
3
2
3
3H, CH3), 0.95 (t, J = 7.5 Hz, 3H, CH3), 1.08 (dt, J = 13.5 Hz, J =
7.5 Hz, 1H, CH2), 1.29 (mc, 1H, CH2), 1.81 (mc, 1H, CH), 1.98 (mc,
2
3
2H, CH2), 2.14 (mc, 1H, CH), 3.18 (dd, J = 9.1 Hz, J = 7.1 Hz, 1H,
CH2), 3.32 (dd, 2J = 9.1 Hz, 3J = 5.4 Hz, 1H, CH2), 3.80 (s, 3H, O-
2
CH3), 4.41 (d, J = 11.7 Hz, 1H, CH2Ar), 4.44 (d, 2J = 11.7 Hz, 1H,
3
4
CH2Ar), 5.25 (ddt, J = 15.3, 7.6 Hz, J = 1.4 Hz, 1H, CH), 5.38 (dtd,
3J = 15.3, 6.2 Hz, 4J = 0.9 Hz, 1H, CH), 6.87 (m, 2H, ArH), 7.26 ppm
(m, 2H, ArH); 13C NMR (125.709 MHz, CDCl3, 278C, TMS): d =
14.0, 17.7, 20.7, 25.5, 31.0, 34.0, 41.2, 55.3, 72.6, 75.6, 113.7 (2 ” C),
129.1 (2 ” C), 129.9, 131.0, 135.6, 159.0 ppm; elemental analysis (%)
calcd for C18H28O2 (276.41): C 78.21, H 10.21; found: C 77.90, H 10.32.
Received: February 11, 2004 [Z53990]
Published Online: May 26, 2004
Keywords: allylation · asymmetric synthesis ·
.
diastereoselectivity · organocopper reagents · polyketides
[1] For ionomycin, see: W-.C.Liu, D.Smith-Slusarchyk, G.Astle,
W.H. Trejo, W.E. Brown, E.J. Meyers,
J. Antibiot. 1978, 31,
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Angew. Chem. Int. Ed. 2004, 43, 3790 –3792