Intramolecular cyclopropanation of unsaturated terminal epoxides

Article abstract of DOI:10.1021/ja047346k

Efficient lithium amide-induced intramolecular cyclopropanation of bishomoallylic and trishomoallylic epoxides is described. The methodology is used in an asymmetric synthesis of sabina ketone. Copyright

Full text of DOI:10.1021/ja047346k

Published on Web 06/24/2004
Intramolecular Cyclopropanation of Unsaturated Terminal Epoxides
David M. Hodgson,* Ying Kit Chung, and Jean-Marc Paris†
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford OX1 3TA, U.K.
Received May 6, 2004; E-mail: david.hodgson@chem.ox.ac.uk
Cyclopropanes fused to five- and six-membered carbocycles are
found widely in natural products, and there has been considerable
interest in the synthesis of such bicycles, especially in an enanti-
oselective manner.1 Following the pioneering work of Stork and
Ficini,2 the transition-metal-catalyzed intramolecular cyclopropa-
nation of unsaturated R-diazocarbonyl compounds is now estab-
lished as important methodology to access such structures.3
However, the R-diazocarbonyl substrates normally possess limited
stability and are typically synthesized in modest yields via one-
carbon homologation of carboxylic acids using hazardous diaz-
omethane. For enantioselective cyclopropanation, conditions have
recently been developed to obtain high levels of asymmetric
induction, but it remains the case that yields and enantioselectivities
are highly susceptible to structural variation in the substrate.4
R-Lithiated epoxides constitute an alternative to diazo compounds
as a carbene source.5 Indeed, in 1967 Crandall and Lin reported
that the reaction of t-BuLi with 1,2-epoxy-5-hexene 1a gave small
amounts of trans-bicyclo[3.1.0]hexan-2-ol (3a) (9%), along with
other products involving incorporation of the organolithium.6
in the transformation (entry 3), and a trisubstituted alkene and a
2,2-disubstituted-1-alkene also underwent cyclopropanation suc-
cessfully (entries 4 and 5). However, in these latter two cases the
reactions were incomplete after 8 h, and a further 2 equiv of LTMP
were subsequently added. t-BuOMe was examined as an alternative
solvent to Et2O on the basis that in this solvent LTMP would have
a longer half-life;10 pleasingly, use of t-BuOMe allows the reaction
shown in entry 5 to proceed without the requirement for a second
addition of LTMP, and subsequent examples in this communication
use t-BuOMe as solvent.
Table 1. Bicyclo[3.1.0]hexanols 3 from Epoxides 1 and LTMPa
In 1994, Yamamoto and co-workers reported the efficient
isomerization of terminal epoxides to aldehydes using lithium
2,2,6,6-tetramethylpiperidide (LTMP), for which deuterium labeling
studies indicated that the reaction proceeded via an R-lithiated
epoxide.7 We have recently reinvestigated this reaction and
established that it proceeds through trapping of the lithiated epoxide
with LTMP to give an enamine, which can be isolated or hydrolyzed
to the aldehyde on workup.8 During this study we considered
whether, in the presence of tethered unsaturation, an LTMP-
generated lithiated terminal epoxide could preferentially undergo
intramolecular cyclopropanation. The present communication re-
ports our promising results of this latter investigation.
Direct application of Yamamoto’s conditions to epoxide 1a
(addition of 1a to LTMP (2 equiv, 0.2 M in THF, 25 °C)) gave
after 1 h the alcohol 3a in 47% yield (volatile 5-hexenal was also
observed). Variation of the reaction conditions indicated that the
yield of alcohol 3a was unchanged (48%) if the reaction was
initiated at 0 °C and the LTMP (2 equiv, 0.2 M in THF) was added
dropwise to the epoxide 1a (0.2 M in THF). However, under these
latter conditions the yield did improve on switching the solvent to
hexane (62%) and then to Et2O (79%). To examine the scope of
this cyclopropanation, a variety of bishomoallylic terminal epoxides
1 were examined (Table 1). The reaction works with 1,2-
disubstituted alkenes and is stereospecific (entries 1 and 2).9 A
quaternary center adjacent to a terminal alkene presents no problems
a t-BuOMe as solvent unless otherwise indicated. b Isolated yield. c Et2O
as solvent.
The cyclopropanation reaction efficiently distinguishes between
diastereotopic allyl groups (entry 6);9 this presumably reflects the
preference for a substituent to reside equatorial if possible in the
suggested chairlike transition state 2. Substitution adjacent to the
† Rhodia Recherches, Centre de Recherches de Lyon, 85 Avenue des Fre`res
Perret, 69192 Saint Fons, France.
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J. AM. CHEM. SOC. 2004, 126, 8664-8665
10.1021/ja047346k CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
terminal epoxide functionality is tolerated (entries 7 and 8). In entry
7 a quaternary stereocenter is generated in a controlled fashion,9
and this is likely due to the preference of the i-Pr group to be
equatorial in the transition state. For entry 8 aromatic insertion was
not observed as a competing reaction. Cyclopropanation of a
tethered cycloalkene leads to a tricyclic alcohol 3j (entry 9); possible
complications arising from potentially competitive deprotonation
in the substrate at the doubly allylic positions were not observed.
The structure of tricyclic alcohol 3j was supported by X-ray
crystallographic analysis following dihydroxylation.11
The chemistry could be extended to trishomoallylic epoxides 4,
thus allowing access to trans-bicyclo[4.1.0]heptan-2-ols 5 (Table
2);12 allylic C-H insertion was not observed as a competing
reaction.
riched) epoxides and the completely diastereoselective nature of
the transformation. The diastereoselectivity is due to a combination
of an initial trans-lithiation of the epoxide,7 the fact that the
cyclopropane must form cis-fused to a five- or six-membered ring,
and probably, that the cyclopropanation occurs at the stage of the
lithium carbenoid (as suggested in 2), rather than an R-lithiooxy
carbene.17
Table 2. Bicyclo[4.1.0]heptanols 5 from Epoxides 4 and LTMPa
Acknowledgment. We thank Rhodia for a studentship, the
EPSRC for a research grant (GR/S46789/01), and the EPSRC
National Mass Spectrometry Service Centre for mass spectra.
Supporting Information Available: Experimental procedures and
NMR spectra of 3a-j, 5a-c, 7, and 8 and details regarding starting
epoxides (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
a
b
t-BuOMe as solvent, reaction time 20 h. Isolated yield.
(1) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003,
103, 977-1050.
(2) Stork, G.; Ficini, J. J. Am. Chem. Soc. 1961, 83, 4678.
(3) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley & Sons: New York,
1998.
It was considered important to ascertain whether an enantioen-
riched epoxide would undergo cyclopropanation under the reaction
conditions without any degradation in ee. This was established by
chiral GC analysis on the TBDMS ether of alcohol (+)-3a (98%
ee)13 formed using (R)-1,2-epoxy-5-hexene R-1a (99% ee).14 To
illustrate the utility of this chemistry in targeted asymmetric
synthesis, (-)-sabina ketone 815 was synthesized according to
Scheme 1. The strategy additionally demonstrates the use of readily
available highly enantioenriched epichlorohydrin to prepare bis-
homoallylic epoxides of high ee. Thus, commercially available 2,3-
dimethyl-1-butene (6) was converted to the corresponding allylic
Grignard16 and reacted with (S)-epichlorohydrin (>99% ee) to give
chlorohydrin 7 (53%). The derived epoxide S-1f underwent
cyclopropanation in a similar yield (80%) to the racemate (Table
1, entry 5). Cyclopropanation could also be achieved directly from
the chlorohydrin 7 using 3 equiv of LTMP (69%). Finally, oxidation
using TPAP gave sabina ketone 8 (>99% ee).13
(4) (a) Barberis, M.; Pe´rez-Prieto, J.; Herbst, K.; Lahuerta, P. Organometallics
2002, 21, 1667-1673. (b) Saha, B.; Uchida, T.; Katsuki, T. Tetrahe-
dron: Asymmetry 2003, 14, 823-836.
(5) (a) Hodgson, D. M.; Gras, E. Synthesis 2002, 1625-1642. (b) Dechoux,
L.; Agami, C.; Doris, E.; Mioskowski, C. Tetrahedron 2003, 59, 9701-
9706.
(6) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4526-4527.
See also: Apparu, M.; Barelle, M. Tetrahedron 1978, 34, 1691-1697.
(7) Yanagisawa, A.; Yasue, K.; Yamamoto, H. J. Chem. Soc., Chem. Commun.
1994, 2103-2104.
(8) Hodgson, D. M.; Bray, C. D.; Kindon, N. D. J. Am. Chem. Soc. 2004,
126, 6870-6871.
(9) Stereochemistry determined by NOE experiments (see Supporting Infor-
mation).
(10) Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. J. Org. Chem. 1987, 52,
448-450.
(11) CCDC 237603 available at the Cambridge Crystallographic Data Centre
Website. http://www.ccdc.cam.ac.uk.
(12) Erzen, E.; Cerkovnik, J.; Plesnicar, B. J. Org. Chem. 2003, 68, 9129-
9131.
(13) See Supporting Information.
(14) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K.
B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 1307-1315.
In summary, we report conditions for the efficient intramolecular
cyclopropanation of bishomoallylic and trishomoallylic epoxides,
together with a preliminary evaluation of the scope of this process.
The methodology can be considered as a useful alternative to
intramolecular cyclopropanation of unsaturated R-diazocarbonyl
compounds, because of the ready availability of (highly enantioen-
(15) (a) Galopin, C. C. Tetrahedron Lett. 2001, 42, 5589-5591. (b) Barberis,
M.; Pe´rez-Prieto, J. Tetrahedron Lett. 2003, 44, 6683-6685.
(16) Fujita, K.; Schlosser, M. HelV. Chim. Acta 1982, 65, 1258-1263.
(17) Boche, G.; Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697-756.
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