Catalytic enantioselective desymmetrization of COT-monoepoxide. Maximum deviation from coplanarity for an SN2′-cuprate alkylation

Article abstract of DOI:10.1021/ol034554t

(Matrix presented) The first alkylative and enantioselective ring-opening of COT-monoepoxide (1) without the occurrence of any ring-contraction-isomerization by the use of in situ-formed organocuprates is reported. Because of the particular geometric constraint of compound 1, this work reports the largest deviation from coplanarity between the π-orbital of the double bond and the σ-bond connecting the leaving group ever observed for an S_N2′-cuprate alkylation.

Full text of DOI:10.1021/ol034554t

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1971-1974
Catalytic Enantioselective
Desymmetrization of COT-Monoepoxide.
Maximum Deviation from Coplanarity for
an SN2′-Cuprate Alkylation
Federica Del Moro, Paolo Crotti, Valeria Di Bussolo, Franco Macchia, and
Mauro Pineschi*
Dipartimento di Chimica Bioorganica e Biofarmacia, UniVersita` di Pisa,
Via Bonanno 33, 56126 Pisa
pineschi@farm.unipi.it
Received March 31, 2003
ABSTRACT
The first alkylative and enantioselective ring-opening of COT-monoepoxide (1) without the occurrence of any ring-contraction−isomerization
by the use of in situ-formed organocuprates is reported. Because of the particular geometric constraint of compound 1, this work reports the
largest deviation from coplanarity between the π-orbital of the double bond and the σ-bond connecting the leaving group ever observed for
an SN2′-cuprate alkylation.
1,3,5,7-Cyclooctatetraene (COT) is a nonaromatic compound
that exists in a nonplanar tub form.1 The corresponding
symmetrical monoepoxide 1, easily obtainable by m-CPBA
or peracetic acid oxidation of COT, has been known for a
long time.2 There have been several papers indicating the
easy isomerization of COT-monoepoxide in reactions with
cationic3 or anionic reagents.4 On the other hand, there are
very few reports dealing with the ring-opening reactions of
epoxide 1 with nucleophiles. The reaction of 1 with organo-
metallic nucleophiles was previously investigated in order
to determine whether cleavage of the epoxide ring would
result in the formation of substituted cyclooctatrienols, but
only ring-isomerized products were obtained.2,5,6 The only
reported addition of an alkyl group to 1 without ring
contraction makes use of RLi (R ) ethyl, tert-butyl) in Et2O
and affords 4-alkyl-2,6-cyclooctadien-1-ones through a 1,5-
sigmatropic rearrangement.6,7 We report here a new catalytic
alkylation of COT-monoepoxide 1 with hard alkylmetals
without any concomitant rearrangement (including hydride
shift) of the eight-membered ring. Moreover, a highly
enantioselective desymmetrization8 of 1 with dialkylzinc
reagents and chiral copper complexes of phosphoramidite
ligands is reported as well.9
(5) Matsuda, T.; Sugishita, M. Bull. Chem. Soc. Jpn. 1967, 40, 174.
(6) Ogawa, M.; Sugishita, M.; Takagi, M.; Matsuda, T. Tetrahedron
1975, 31, 299. In particular, the reaction of 1 with Et2CuLi under various
conditions resulted in the formation of polymeric material.
(7) Miller, M. J.; Lyttle, M. H.; Streitwieser, A., Jr. J. Org. Chem. 1981,
46, 1977.
(8) For reviews, see: (a) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P.
Tetrahedron 1996, 52, 14361. (b) Jacobsen, E. N.; Wu, M. H. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: New York, 1999; Chapter 35.
(1) For a recent review, see: Kla¨rner, F.-G. Angew. Chem., Int. Ed. 2001,
40, 3977 and references therein.
(2) Cope, A. C.; Tiffany, B. D. J. Am. Chem. Soc. 1951, 73, 4158.
(3) (a) Cope, A. C.; Nelson, N. A.; Smith, D. S. J. Am. Chem. Soc.
1954, 76, 1100. (b) Grigg, R.; Hayes, R.; Sweeney, A. Chem. Commun.
1971, 1248.
(4) Treatment of 1 with LDA constitutes an important synthetic method
for preparing 1,3,5-cyclooctatrien-7-one. For a recent review on oxiranyl
anions, see: Satoh, T. Chem. ReV. 1996, 96, 3303.
10.1021/ol034554t CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003

We found dramatic differences in reactivity and selectivity
using different sources of organocopper reagents (Table 1).
primary organometallics and chiral copper complexes as
catalysts.13 Although the Cu(II)-catalyzed reaction of Et2Zn
with 1 afforded 2,4,6-cycloheptatriene-1-carbaldehyde as the
main product (ca. 8% conversion after 5 h at 0 °C), the
preventive addition of a catalytic amount of Feringa’s
phosphoramidite14 (S,R,R)-2 to the reaction mixture cleanly
afforded the corresponding SN2′ addition product 3b with a
high yield (90%) and a 93:7 enantiomeric ratio (er) (Scheme
1).15 The copper-phosphoramidite-catalyzed addition of Bu2-
Table 1. Addition of Organocopper Reagents to
COT-Monoepoxide 1
Scheme 1. Copper-phosphoramidite-Catalyzed
Enantioselective Addition of Dialkylzinc Reagents to 1
entry
“RCu”
conditions
3/4 ratio
1
2
3
4
5
6
7
Me2CuLi, Et2O
3 h, 0°C
<2/98
62/38
>98/2
82/18
94/6
>96/4
>95/5
MeMgBr/CuCN (cat) Et2O
MeCuCN(MgBr), THF
Me2CuCN(MgBr)2 THF
EtMgBr/CuCN (cat), Et2O
PhCuCN(MgBr), THF
(vinyl)CuCN(MgBr),THF
2.5 h, 0 °C
1.5 h, 0 °C
1.5 h, 0 °C
2 h, 0 °C
24 h, 0 °C
24 h, 0 °C
The reaction of 1 with 3.0 equiv of Me2CuLi in Et2O (3 h at
0 °C) resulted in the formation of the 2,4,6-cycloheptatrienyl
methyl carbinol 4a (70% yield) as the sole product (entry
1).10 The CuCN-catalyzed11 addition of MeMgBr (3.0 equiv)
afforded as the main reaction product the new trans-
cyclooctatrienol 3a (62%), deriving from the epoxide alky-
lation in the allylic position (SN2′ process) (entry 2). The
same product was selectively obtained (88% yield) when a
“lower order cuprate”12 such as MeCuCN(MgBr) was used
(entry 3). The use of a “higher order cyanocuprate” Me2-
CuCN(MgBr)2 afforded 3a as the main reaction product
together with a minor amount of alcohol 4a (18%, entry 4).
The CuCN-catalyzed addition of EtMgBr afforded 3b (75%
yield) with only a marginal isomerization pathway (ca. 6%
of 4b, entry 5). The addition of phenyl and vinyl cuprates
gave a relatively complex mixture of products from which
it was possible to isolate the cyclooctatrienols 3c (40% yield)
and 3d (8% yield), respectively (entries 6 and 7).
Zn afforded compound 3e with 78% yield and a good
enantioselectivity (91:9 er). The less reactive Me2Zn deliv-
ered the corresponding SN2′ adduct 3a (65% yield) with the
best enantioselectivity (>95:5 er), and the use of dicyclo-
hexylzinc gave a good yield of the corresponding product
3f.16 Unexpectedly, compounds of type 3 (except for 3d)
showed good stability,17 although related cyclooctatrienols
are very prone to a 1,5-hydride shift to give the corresponding
4-alkyl-cycloocta-2,6-dienones.7,18
(13) For reviews, see: (a) Nakamura, E.; Mori, S. Angew. Chem., Int.
Ed 2001, 39, 3750. (b) Krause, N.; Hofmann-Ro¨der, A. Synthesis 2001,
171.
(14) For a review, see: Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(15) Typical Procedure: Preparation of 3b. A solution of Cu(OTf)2
(10.8 mg, 0.03 mmol) and chiral ligand (S,R,R)-2 (32.2 mg, 0.06 mmmol)
in anhydrous toluene (3 mL) was stirred at room temperature for 40 min.
The colorless solution was cooled to -78 °C followed by subsequent
addition of a solution of 1 (240 mg, 2.0 mmol) in toluene (1 mL). After 5
min, Et2Zn (2.72 mL of a 1.1 M solution in toluene, 3.0 mmol) was added
and the stirred reaction mixture was allowed to warm slowly to 0 °C. After
3 h (>98% conversion), the reaction was quenched with saturated aqueous
NH4Cl solution (5 mL). Extraction with Et2O (2 × 35 mL) and evaporation
of the dried (MgSO4) organic phase afforded a very clean crude mixture
(300 mg) consisting only of alcohol 3b (>90% crude yield) and chiral ligand
2. Alcohol 3b was obtained in a pure state as an oil after flash
chromatography (195 mg, 65% isolated yield). Rf ) 0.27 (hexanes/AcOEt
A very common method for the in situ generation of
organocopper reagents is the use dialkylzinc reagents as
(9) (a) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;
Feringa, B. L. Org. Lett. 2000, 2, 933. (b) Bertozzi, F.; Crotti, P.; Del Moro,
F.; Feringa, B. L.; Macchia, F.; Pineschi, M. Chem. Commun. 2001, 2606.
(10) Formation of the cycloheptatrienyl alcohols of type 4 is connected
with the intermediate formation, through a ring-contraction-isomerization
process, of cyclohepta-2,4,6-trienecarbaldehyde, which in turn adds the
organometallic reagent.
(11) (a) Marshall, J. A. Chem. ReV. 1989, 89, 1503. (b) Lipshutz, B. H.
In Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley & Sons,
Ltd., Chichester, UK, 1994; p 283. (c) Persson, E. S. M.; van Klaveren,
M.; Grove, D. M.; Ba¨ckvall, J.-E.; van Koten, G. Chem. Eur. J. 1995, 351
and pertinent references therein.
(12) In this paper, “lower order cuprate” and “higher order cuprate”
terms are used to indicate the 1:1 and 2:1 composition of RMgX and CuCN,
respectively. For a review regarding the structure and reactivity of
cyanocuprates, see: Krause, N. Angew. Chem., Int. Ed. 1999, 38, 79. For
a recent discussion about the strong influences by the composition of the
reagents and the solvent used in a metal-catalyzed addition of Grignard
reagents to allylic acetates, see: Ito, M.; Matsuumi, M.; Murugesh, M. G.;
Kobayashi, Y. J. Org. Chem. 2001, 66, 5881 and references therein.
1
8:2). [R]20D +277 (c 1.0, MeOH). H NMR: δ 6.07-6.17 (m 2H), 5.55-
5.61 (m, 1H), 5.15-5.43 (m, 3H), 4.86 (m, 1H, CHOH), 2.65-2.75 (m,
1H), 1.51-1.65 (m, 2H), 0.90 (t, 3H, J ) 7.3 Hz). 13C NMR: δ 133.5,
133.0, 132.6, 131.5, 128.3, 127.0, 70.5, 39.6, 29.6, 12.4. Anal. Calcd for
C10H14O: C, 79.96; H, 9.39. Found: C, 78.96; H, 8.76. The enantiomeric
ratio (93:7) of 3b was calculated on the corresponding hydrogenated product
10b (see Supporting Information).
(16) On the other hand some attempts at arylation using Ph2Zn afforded
mainly the alcohol 4c. The use of “salt free” divinylzinc (Bussche-
Hu¨nnefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719) gave a complex
reaction mixture containing 4d.
(17) In our hands, it was possible to isolate compounds 3a,b,c,f by
chromatography on SiO2, albeit with partial decomposition, and to store
them for several weeks at +5 °C. However, the corresponding 4-alkyl-
cycloocta-2,6-dienones can be quantitatively obtained by vacuum distillation
of compounds of type 3.
1972
Org. Lett., Vol. 5, No. 11, 2003

The absolute and relative configurations of compounds of
type 3 were determined by application of the regiodivergent
kinetic resolution (RKR)19 to racemic 1,3-cyclooctadiene
monoepoxide 5 with Me2Zn catalyzed by Cu(OTf)2/(S,S,S)-7
(Scheme 2). At complete conversion, the reaction gave a 38:
For the allylic alkylation of a vinyloxirane to occur, a
coplanarity between the double bond and the medium plane
containing the two oxirane carbons appeared to be necessary
for attaining the overlap between the nucleophilic d orbitals
of the copper and the π*-orbital of the double bond and of
the σ*-orbital of the oxirane moiety (as shown in A, Figure
1).11a,24,25 In the case of COT-monoepoxide, the correspond-
Scheme 2. Determination of Absolute Configurations via
Copper-phosphoramidite-Catalyzed RKR of 5
Figure 1. Orbital overlap for SN2′ addition of organocuprates to
vinyloxiranes.
ing dihedral angle is ca. 60° (see arrows in Figure 1).1 It is
noticeable that despite this geometric constraint, an SN2′-
cuprate addition is achieved by the appropriate in situ
generation of an organocopper reagent. This is the highest
deviation from coplanarity ever observed in an allylic-type
alkylation reaction.26
Another interesting peculiarity of the ring opening of
epoxide 1 is the complete absence of regioisomeric trienic
alcohols derived from an SN2 addition of the organometallic
reagent. In this connection, it is worth mentioning that the
application of some ring-opening reactions to 1 by some
-
common heteronucleophiles (N3 , H2O, RO-, RSH) did not
afford in any case the corresponding 1,2-addition product.
In the (Lewis) acid-promoted reactions, a complex reaction
mixture was obtained, whereas under basic conditions, mostly
unreacted 1 was recovered.27
62 inseparable mixture of the regioisomeric alcohols 820 and
921 (eq a). The subsequent catalytic hydrogenation afforded
a separable mixture of alcohols 6 and 10a, in which alcohol
6 has a known absolute configuration (eq b).22 As a
consequence, the regioisomeric alcohol 10a has the opposite
configuration at the carbon atom bearing the hydroxyl group.
Comparison of the optical rotation of 10a obtained with the
RKR protocol with respect to the same product 10a obtained
by the desymmetrization of COT-monoepoxide with Cu-
(OTf)2/(S,R,R)-2 and subsequent catalytic hydrogenation
allowed the complete assignment of the absolute configura-
tions of all the stereocenters (see eq c in Scheme 2 and
Supporting Information).23
In conclusion, the present work reports a novel copper-
catalyzed allylic-type substitution of COT-monoepoxide with
organometallic reagents with complete maintenance of the
eight-membered ring and without the occurrence of any
rearrangement. Moreover, an unprecedented copper-phos-
phoramidite-catalyzed alkylative desymmetrization of 1 with
dialkylzinc reagents was developed, allowing a simple and
(23) This is a new way to obtain enantiomerically pure 2-alkyl-substituted
cyclooctanols. The direct asymmetric ring opening of cyclooctene oxide
remains a difficult challenge. For some recent reports, see: (a) Jacobsen,
E. N. Acc. Chem. Res. 2000, 33, 421. (b) Denmark, S. E.; Barsanti, P. A.;
Wong, K.-T.; Stavenger, R. A. J. Org. Chem. 1998, 63, 2428. (c) Denmark,
S. E.; Wynn, T.; Jellerichs, B. G. Angew. Chem., Int. Ed. 2001, 40, 2225.
(24) In general, the prerequisite for an allylic alkylation to occur is the
ability of the system to attain a conformation in which the π-orbitals of the
double bond and the σ-bond connecting the leaving group are aligned. For
example, see: Farthing, C. N.; Kocovsky, P. J. Am. Chem. Soc. 1998, 120,
6661 and pertinent references therein.
(25) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063. For a
molecular orbital description of the effect of π-accepting ligands such as
cyanide in cuprate reactions, see: Hamon, L.; Levisalles, J. Tetrahedron
1989, 45, 489.
(26) Maximum deviation tolerated from the perfect alignment seems to
be ca. 30° (see ref 24).
(18) Gridnev, I. D.; Gurskii, M. E.; Buevich, A. V.; Potapova, T. V.;
Bubnov, Y. N. J. Org. Chem. 1996, 61, 3514.
(19) For the concept and application of the RKR strategy, see: Bertozzi,
F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L. Angew. Chem., Int.
Ed. 2001, 40, 930 and references therein.
(20) Racemic trans-homoallylic alcohol 8 can be selectively obtained
by the application of the MeLi-BF3 protocol. See: Alexakis, A.; Vranken,
E.; Mangeney, P.; Chemla, F. J. Chem. Soc., Perkin Trans. 1 2000, 3352.
(21) Racemic trans-allylic alcohol 9 can be obtained by addition of
MeCuCNLi to 5. See: Penman, K.; Kitching, W.; Tagliavini, G. Organo-
metallics 1991, 10, 1320.
(27) The following conventional ring-opening reactions were at-
tempted: NaN3/NH4Cl in MeOH/H2O (9:1); LiClO4/NaN3 in CH3CN; NaN3/
DMF; aqueous 0.01 N H2SO4; MeONa/MeOH; RSH/NEt3 in MeOH.
(22) Danchet, S.; Bigot, C.; Azerad, R. Tetrahedron: Asymmetry 1997,
8, 1735.
Org. Lett., Vol. 5, No. 11, 2003
1973

complete stereo- and regioselective formation of 4-substituted
cyclooctatrienols not previously described.
Supporting Information Available: Text giving experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by M.I.U.R.
(Rome) and by the University of Pisa. P.C. gratefully
acknowledges Merck for the generous financial support
deriving from the 2002 ADP Chemistry Award.
OL034554T
1974
Org. Lett., Vol. 5, No. 11, 2003