A unified strategy for the stereospecific construction of propionates and acetate-propionates relying on a directed allylic substitution

Article abstract of DOI:10.1002/chem.200901064

A strategy for the stereospecific construction of propionates and acetate-propionates using a directed allylic substitution was reported. The enantiomerically pure allylic o-DPPB esters having an additional oxygen functionality in the homoallylic position served as the building blocks for iterative propionate insertion. It was observed that asymmetric sharpless epoxidation of allylic alcohol followed by an epoxide ring opening with a hydride nucleophile produced the acetate-propionate structures. The process allowed the stereoselective construction of 1,5-skipped oligomethyl chains of isoprenoid or polyketide origin. Crotonaldehyde was used and treated with HCN in the presence of the oxynitrilase from bitter almonds to furnish the (R)-cyanohydrin with high levels of enantioselectivity. The nitrile function was transformed into the ethyl ester using a Pinner reaction protocol.

Full text of DOI:10.1002/chem.200901064

COMMUNICATION
DOI: 10.1002/chem.200901064
A Unified Strategy for the Stereospecific Construction of Propionates and
Acetate–Propionates Relying on a Directed Allylic Substitution
Tomislav Reiss and Bernhard Breit*[a]
Carbon–carbon bond-forming reactions that allow the
predictable, flexible, and stereospecific construction of a de-
sired carbon skeleton are valuable transformations in organ-
ic synthesis. In this context we recently reported on the de-
velopment of the o-DPPB-directed allylic substitution with
Grignard-derived organocopper reagents that occurs with
complete control of the chemo-, regio-, and stereochemistry,
and delivers the corresponding SN2ꢀ substitution products
with either a tertiary or a quarternary stereogenic center
with perfect syn-1,3-chirality transfer (Scheme 1).[1,2] A par-
Scheme 2. Concept of a unified strategy for the flexible and stereospecific
construction of major polyketide structural elements based on the o-
DPPB-directed allylic substitution.
Scheme 1. o-DPPB-directed allylic substitution with Grignard-derived or-
ganocopper reagents (o-DPPB: ortho-diphenylphosphanyl benzoate).
Here, the enantiomerically pure allylic o-DPPB esters 1
served as the key building blocks for iterative propionate in-
sertion. The strength and reliability of this methodology has
ticular value of this reaction is that only a stoichiometric
amount of the Grignard reagent is required to achieve quan-
titative transformation, which allows the economic use of
functionalized valuable Grignard reagents and may be em-
ployed even in a fragment coupling step in the course of a
total synthesis.[3]
Furthermore, based on the directed allylic substitution a
new methodology for the iterative construction of deoxypro-
pionates has been developed (see Scheme 2, left side).[4,5]
been proved in the course of a pheromone synthesis, which
led to the deduction of its absolute configuration.[6]
We herein report on a new strategy for the flexible and
stereospecific preparation of propionates, acetate propio-
nates and acetate deoxypropionate structural motifs relying
on the o-DPPB-directed allylic substitution (see Scheme 2,
right side). The key building block in this strategy is the new
allylic o-DPPB ester 2, which contains an additional oxygen
functionality in the homoallylic position. Thus, the product
of a directed SN2ꢀ reaction becomes an allylic alcohol deriva-
tive 3. Hydrogenation of its alkene function would furnish
acetate deoxypropionates (Scheme 2, route (1)). The process
should be iterable and would allow the stereoselective con-
struction of 1,5-skipped oligomethyl chains of isoprenoid or
polyketide origin. Asymmetric Sharpless epoxidation of al-
lylic alcohol 3 followed by an epoxide ring opening with a
hydride nucleophile would furnish acetate–propionate struc-
tures (Scheme 2, route (2)), whereas ring opening of the
[a] Dipl.-Ing. T. Reiss, Prof. Dr. B. Breit
Institut fꢁr Organische Chemie und Biochemie
Freiburg Institute for Advanced Studies (FRIAS)
Albert-Ludwigs-Universitꢂt Freiburg i. Brsg.
Albertstrasse 21, 79104 Freiburg i. Brsg. (Germany)
Fax : (+49)761-203-8715
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901064.
Chem. Eur. J. 2009, 15, 6345 – 6348
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6345

same epoxide with a methyl nucleophile would allow propi-
onate construction (Scheme 2, route (3)).
For implementation of this synthesis strategy we required
an efficient enantioselective access towards both optical an-
tipodes of allylic o-DPPB ester 2. Thus, crotonaldehyde was
treated with HCN in the presence of the oxynitrilase[7] from
bitter almonds to furnish the (R)-cyanohydrin with high
levels of enantioselectivity (>96% ee). The nitrile function
was transformed into the ethyl ester 4 following a Pinner re-
action protocol (Scheme 3).[8] Ester reduction and protection
Scheme 4. Acetate–deoxypropionate (and isoprenoid) iterative construc-
tion: Stereodivergent synthesis of a natural and an unnatural stereoiso-
mer of tribolure—an aggregation pheromone of the red flour beetle.
PCC=pyridinium chlorochromate.
Scheme 3. Preparation of key allylic o-DPPB esters (R)-2 and (S)-2.
LAH=lithium aluminum hydride; DMAP=4-dimethylaminopyridine;
DCC=dicyclohexylcarbodiimide; DIAD= diisopropyl azodicarboxylate.
was obtained in good yield as a single stereoisomer. Catalyt-
ic alkene reduction, silyl ether cleavage, and a Mukaiayma
redox condensation[15] furnished bromide 7. The sequence
becomes iterable through transformation of 7 into the corre-
sponding Grignard reagent, and subjection to the conditions
of the directed allylic substitution. Thus, reaction with (S)-2
and (R)-2 gave the diastereomers (+)-8 and (À)-9 in good
yield and stereocontrol, respectively. Alkene reduction, silyl
ether deprotection and oxidation to the aldehyde gave the
natural (R,R) stereoisomer, and the unnatural (S,R) stereo-
isomer of tribolure, thus highlighting the stereochemical
flexibility of this strategy. Interestingly, allylic o-DPPB
esters 2 may also be regarded as a chiral isoprenoid building
block for a stereospecific C5 chain extension.
We next turned towards the preparation of the acetate-
propionate structural motif (Scheme 5). Thus, starting from
the allylic substitution product 6, silyl deprotection fur-
nished allylic alcohol 10. Sharpless asymmetric epoxida-
tion[16] with (À)-DET led to the syn-epoxide 11, while em-
ploying (+)-diethyl tartrate ((+)-DET) provided anti-epox-
ide 12 in good yields and diastereoselectivities, respectively.
Reductive epoxide opening with Red-Al[17] furnished syn-
acetate–propionate 13 and anti-14, respectively.
of the primary alcohol as the tert-butyldiphenyl silyl ether
(TBDPS) furnhished (R)-5 on a multigram scale.[9] Steglich
esterification[10] with ortho-diphenylphosphanylbenzoic acid
(o-DPPBA) led quantitatively to the (R)-o-DPPB ester 2.
To access the optical antipode (S)-2, we wondered whether
a Mitsunobu reaction[11] of allylic alcohol (R)-5 employing
o-DPPBA as the nucleophile could be an option. Since o-
DPPBA is a carboxylic acid as well as a triarylphosphine we
expected this to be a nontrivial task since the reagent triphe-
nylphosphine, as well as o-DPPBA may react with the
DIAD electrophile. However, we were pleased to find that
the Mitsunobu reaction of the allylic alcohol (R)-4 with o-
DPPBA proceeded cleanly to furnish the corresponding (S)-
allylic o-DPBB ester 2 with complete inversion of configura-
tion. A simple recrystallization provided both esters 2 in es-
sentially enantiomerically pure form, which could be stored
for months without notable decomposition.
For the implementation of an iterative acetate–deoxypro-
pionate (and isoprenoid) construction we selected the skele-
ton of tribolure, which is an aggregation pheromone of the
red flour beetle (Scheme 4).[12] Indeed, the 1,5-skipped di-
methyl chain has been shown to be of polyketide origin,
while such structural elements are also typical for isopre-
noids.[13,14] The synthesis began with a directed allylic substi-
tution employing EtMgBr. The allylic substitution product 6
Thus, through choice of the absolute configuration of the
allylic electrophile 2, and through selection of the configura-
tion of the Sharpless epoxidation catalyst all four stereoiso-
6346
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6345 – 6348

Stereospecific Construction of Propionates and Acetate–Propionates
COMMUNICATION
calcimycin,[18] while 19 has the correct relative and absolute
configuration of the C11–C22 unit of the anticancer macro-
lide dictyostatin.[19] Furthermore both building blocks are
propionate–deoxypropionate motifs. Thus, in addition to the
implementation of propionate construction these targets
allow simultaneously to demonstrate the flexible combina-
tion with a deoxypropionate structural motif that is encoun-
tered in many natural products of polyketide origin.
Thus, reaction of the Grignard reagent derived from bro-
mine 15 with (S)-2 and (R)-2 furnished the anti- and syn-de-
oxypropionates 16 and 17, respectively (Scheme 6). Depro-
tection, Sharpless epoxidation with (+)- or (À)-DET gave
the corresponding epoxides in excellent stereoselectivity. In-
troduction of the missing methyl group[20] occurred upon re-
[21]
action with Me2CuCNLi2
to give the desired diastereo-
meric propionate–deoxypopionate building blocks in excel-
lent yield and stereoselectivity. Furthermore, 18 was trans-
formed in three further steps[22] into the known thioacetal
20, which has served as an intermediate in a total synthesis
of calcimycin, thus representing a formal total synthesis.[23]
In conclusion, herein we have implemented a new and
unified strategy for the stereospecific and flexible construc-
tion of many major structural motifs of the polyketide class
of natural products relying on the o-DPPB-directed allylic
substitution with Grignard-derived organocopper reagents
as a key step. The key building block of this unified strategy
was the multifunctional allyl-o-DPPB ester 2. Both optical
antipodes are readily available by combining an enzymatic
cyanohydrin synthesis with a Mitsunobu inversion that em-
ploys the o-DPPBA as an unusual nucleophile. Thus, ace-
tate–deoxypropionates, acetate–propionates, and propio-
nates are readily available in enantiomerically pure form.
Hence, this strategy provides an interesting alternative to-
wards established aldol and enolate alkylation chemistry.
Scheme 5. Acetate–propionate construction. TBHP=tert-butyl hydroper-
oxide.
meric acetate–propionate building blocks are available ste-
reoselectively. This again highlights the stereochemical flexi-
bility of this strategy for acetate–propionate construction.
Based on a similar strategy propionates are accessible as
well. To implement the polypropionate synthesis strategy we
selected as targets the diastereomers 18 and 19 (Scheme 6).
The four stereogenic centers in 18 have the correct absolute
and relative configuration to those found for the ionophore
Experimental Section
General methods and further reactions are given in the Supporting Infor-
mation.
Representative procedure for the o-DPPB-directed allylic substitution:
Copper bromide dimethyl sulfide (196 mg, 0.95 mmol, 0.50 equiv) was
added in one portion to a solution of o-DPPB ester (S)-(À)-2 (1.20 g,
1.91 mmol, 99% ee) in diethyl ether (40 mL) and the resulting yellow sus-
pension was stirred for 10 min at room temperature. A solution of ethyl-
magnesium bromide (2.48 mL, 2.48 mmol, 1.30 equiv, 1m in diethyl ether)
was added over 15 min and the bright yellow suspension was stirred for a
further 3 h at room temperature. The reaction was quenched by succes-
sive addition of a saturated aqueous NH4Cl solution (10 mL) and an
aqueous ammonia solution (10 mL, 12.5%) followed by the addition of
diethyl ether (20 mL). The organic phase was separated and the aqueous
phase was extracted with three further portions of dichloromethane
(20 mL). The combined organic layers were dried over Na2SO4, and the
solvent was removed in vacuo. Column chromatography (cyclohexane/
ethyl acetate 10:1) furnished (R)-6 (578 mg, 1.64 mmol, 86%, 99% ee) as
a colorless oil. Analytical data for (R)-6: Chiral-GC: (deprotected allylic
alcohol): Hydrodex-b-TBDAc, 25.0 m
ꢄ 0.25 mm ꢄ 15 mm, injector:
Scheme 6. Propionate construction: Stereodivergent synthesis of a C14–
C20 building block 15 of the ionophore calcimycin, and a C11–C23 build-
ing block 14 of the macrolide dictyostatin.
2008C: 608C (isotherm), 0.7 mLminÀ1 He, (S)-4: tR =41.6 min, (R)-4: tR =
20
43.0 min; [a]D
:
À7.3 (c=1.5 in chloroform); 1H NMR (400 MHz,
CDCl3): d=0.87 (d, 3J(H,H)=7.4 Hz, 3H), 0.98 (d, 3J
ACTHNUTRGENNUG ACHUTTGNREN(NUGN H,H)=6.8 Hz,
Chem. Eur. J. 2009, 15, 6345 – 6348
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6347

B. Breit and T. Reiss
3H), 1.08 (s, 9H), 1.32 (mc, 2H), 2.05 (mc, 1H), 4.19–4.20 (m, 2H), 5.52–
5.54 (m, 2H), 7.37–7.46 (m, 6H), 7.70–7.73 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=11.8, 19.3, 20.1, 27.0 (3C), 29.7, 38.0, 64.9, 127.1,
127.7 (4C), 129.6 (2C), 134.1 (2C), 135.7 (4C), 137.1 ppm; elemental anal-
ysis calcd (%) for C23H32OSi: C 78.36, H 9.05, found: C 78.35, H 9.15.
[7] L. Rosenthaler, Biochem. Z. 1908, 14, 238–253; W. Becker, U. Ben-
thin, E. Eschenhof, E. Pfeil, Biochem. Z. 1963, 337,156–166.
[8] A. Pinner, F. Klein, Ber. 1878, 4, 1475.
[9] E. G. J. C. Warmerdam, A. M. C. H. van den Nieuwendijk, J. Brus-
see, C. G. Kruse, A. van der Gen, Tetrahedron: Asymmetry. 1996, 7,
2539–2550.
[10] G. Hçfle, W. Steglich, H. Vorbrꢁggen, Angew. Chem. 1978, 90, 602–
615; Angew. Chem. Int. Ed. Engl. 1978, 17, 569–583.
[11] O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380–
2382.
Acknowledgements
[12] T. Suzuki, R. Sugawara, Appl. Entomol. Zool. 1979, 14, 228–230; T.
Suzuki, K. Mori, Appl. Entomol. Zool. 1983, 18, 134–136. For other
synthesis of tribolure, see: K. Mori, S. Kuwahara, H. Ueda, Tetrahe-
dron 1983, 39, 2439; C. Fuganti, P. Grasselli, S. Servi, H. E. Hçgberg,
J. Chem. Soc. Perkin Trans. 1 1988, 3061; K. Mori, H. Takikawa, Lie-
bigs Ann. Chem. 1991, 497; B. A. Cheskis, K. V. Lebedeva, A. M.
Moiseenkov, Izv. Akad. Nauk SSSR Ser. Khim. 1988, 4, 865; A. M.
Moiseenkov, B. A. Cheskis, Dokl. Akad. Nauk SSSR 1986, 290,
1379; E. M. Santangelo, A. G. CorrÞa, P. H. G. Zarbin, Tetrahedron
Lett. 2006, 47, 5135–5137.
This work was supported by the DFG, International Research Training
group “Catalysts and Catalytic Reactions for Organic Synthesis” (IRTG
1038) and the Krupp foundation (fellowship to T.R.). We thank Novartis,
BASF, and Wacker for generous gifts of chemicals.
Keywords: allylic substitution
· asymmetric synthesis ·
organocopper reagents · polyketides · synthesis strategy
[13] J. Kim, S. Matsuyama, T. Suzuki, J. Chem. Ecol. 2005, 31, 1381–
1400.
[1] P. Demel, M. Keller, B. Breit, Chem. Eur. J. 2006, 12, 6669–6683; B.
Breit, P. Demel, D. Grauer, C. Studte, Chem. Asian J. 2006, 1, 586–
597; 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.
[14] M. Rohmer, M. Knani, P. Simonin, B. Sutter, H. Sahm, Biochem. J.
1993, 295, 517–524; M. K. Schwarz, PhD Thesis, No. 10951, Eidge-
nçssischen Technischen Hochschule (Switzerland), 1994; S. T. J.
Broers, PhD Thesis, No. 10978, Eidgençssischen Technische Hoch-
schule (Switzerland), 1994.
[2] For other recent important contributions, see: Y. Kioyotsuka, H. P.
Acharya, Y. Katayama, T. Hyodo, Y. Kobayashi, Org. Lett. 2008, 10,
1719–1722; H. Leuser, S. Perrone, F. Liron, F. F. Kneisel, Angew.
Chem. 2005, 117, 4703–4707; Angew. Chem. Int. Ed. 2005, 44, 4627–
4631; N. Harrington-Frost, H. Leuser, M. I. Calaza, F. F. Kneisel, P.
Knochel, Org. Lett. 2003, 5, 2111–2114; C. Spino, C. Beaulieu,
Angew. Chem. 2000, 112, 2006–2008; Angew. Chem. Int. Ed. 2000,
39, 1930–1932; T. Ibuka, N. Akimoto, M. Tanaka, S. Nishii, Y. Ya-
mamoto, J. Org. Chem. 1989, 54, 4055–4061.
[3] C. Rein, P. Demel, R. A. Outten, T. Netscher, B. Breit, Angew.
Chem. 2007, 119, 8824–8827; Angew. Chem. Int. Ed. 2007, 46, 8670–
8673.
[4] C. Herber, B. Breit, Chem. Eur. J. 2006, 12, 6684–6691; B. Breit, C.
Herber, Angew. Chem. 2004, 116, 3878–3880; Angew. Chem. Int.
Ed. 2004, 43, 3790–3792.
[15] T. Mukaiyama, Angew. Chem. 1976, 88, 111–120; Angew. Chem. Int.
Ed. Engl. 1976, 15, 94–103.
[16] T. Katsuki; K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974; K. B.
Sharpless, J. Am. Chem. Soc. 1980, 102, 5974.
[17] P. Ma, V. S. Mardn, S. Masamune, K. B. Sharpless, S. M. Viti, J. Org.
Chem. 1982, 47, 1378–1380; S. M. Viti, Tetrahedron Lett. 1982, 23,
4541–4544.
[18] M. O. Chaney, P. V. Demarco, N. D. Jones, J. L. Occolowitz, J. Am.
Chem. Soc. 1974, 96, 1932–1933.
[19] G. R. Pettit, Z. A. Cichacz, F. Gao, M. R. Boyd, J. M. Schmidt, J.
Chem. Soc. Chem. Commun. 1994, 1111–1112; R. A. Isbrucker, J.
Cummins, S. A. Pomponi, R. E. Longley, A. E. Wright, Biochem.
Pharmacol. 2003, 66, 75–82; I. Paterson, R. Britton, O. Delgado,
A. E. Wright, Chem. Commun. 2004, 632–633.
[20] H. Nagaoka, Y. Kishi, Tetrahedron 1981, 37, 3873–3888.
[21] B. H. Lipshutz, J. Kozlowski, R. Wilhelm, J. Am. Chem. Soc. 1982,
104, 2305–2307.23]; Y. Nakahara, A. Fujita, K. Beppu, T. Ogawa,
Tetrahedron 1986, 42, 6465–6476.
[5] For alternative approaches for deoxypropionate construction, see:
G. Zhu, E. Negishi, Org. Lett. 2007, 9, 2771–2774; B. ter Horst,
B. L. Feringa, A. J. Minnaard, Org. Lett. 2007, 9, 3013–3015; R. Des
Mazery, M. Pullez, F. Lꢅpez, S. R. Harutyunyan, A. J. Minnaard,
B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 9966–9967; J. Zhou,
[22] For details see the Supporting Information.
[23] Y. Nakahara, A. Fujita, K. Beppu, T. Ogawa, Tetrahedron 1986, 42,
6465–6476.
J. W. Ogle, Y. Fan, V. BanphavichitACTHNUGRTNEUNG(Bee), Y. Zhu, K. Burgess, Chem.
Eur. J. 2007, 13, 7162–7170; for earlier approaches see: S. Hanessi-
an, S. Giroux, V. Mascitti, Synthesis 2006, 1057–1076.
[6] C. Herber, B. Breit, Eur. J. Org. Chem. 2007, 3512–3519; C. Herber,
B. Breit, Angew. Chem. 2005, 117, 5401–5403; Angew. Chem. Int.
Ed. 2005, 44, 5267–5269.
Received: April 22, 2009
Published online: May 28, 2009
6348
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6345 – 6348