Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins

Article abstract of DOI:10.1021/ja0672932

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]-hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]-hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-β-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.

Full text of DOI:10.1021/ja0672932

Published on Web 03/21/2007
Intramolecular Cyclopropanation of Unsaturated Terminal
Epoxides and Chlorohydrins
David M. Hodgson,*,† Ying Kit Chung,† Irene Nuzzo,† Glo`ria Freixas,†
Krystyna K. Kulikiewicz,† Ed Cleator,‡ and Jean-Marc Paris§
Contribution from the Department of Chemistry, UniVersity of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K., Department of Process Research, Merck
Sharp and Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, U.K., and
Rhodia Recherches, Centre de Recherches de Lyon, 85 AVenue des Fre`res Perret,
69192 Saint Fons, France
Received October 11, 2006; E-mail: david.hodgson@chem.ox.ac.uk
Abstract: Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsatur-
ated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-
2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]-
hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted
bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount
of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]-
hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a
concise asymmetric synthesis of (+)-â-cuparenone. The related unsaturated chlorohydrins also undergo
intramolecular cyclopropanation via in situ epoxide formation.
Scheme 1. Construction of Bicyclo[3.1.0]hexane and
Bicyclo[4.1.0]heptane Systems
Introduction
Cyclopropanes fused to normal-sized rings constitute impor-
tant structural features widely found in natural products1,2 as
well as, increasingly, in pharmaceutical agents,3 and their
formation, especially in an enantioselective manner, has been
an important research topic for many years.4 Such bicyclic
structures 2 can conventionally be accessed by carbene addition
to a cycloalkene 1, for example by Simmons-Smith5 cyclo-
propanation or sulfur ylide chemistry6 (Scheme 1). In general,
oxygen-directed Simmons-Smith reactions5b,c generate bicyclic
alcohols with excellent diastereoselectivity. However, utility of
the latter in asymmetric synthesis is dependent on availability
and enantiopurity of the cycloalkenol starting material. Follow-
ing the pioneering work of Stork and Ficini,7 the transition-
metal-catalyzed intramolecular cyclopropanation of unsaturated
R-diazocarbonyl compounds 3 is now also established as
important methodology to access bicyclic cyclopropanes.8
Recently, rhodium complexes have 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 substrates.9 Furthermore, R-diazocar-
bonyl compounds are typically synthesized in modest yields
via one-carbon homologation of carboxylic acids using
hazardous diazomethane and, once formed, possess limited
stability.
† University of Oxford.
‡ Merck Sharp and Dohme Limited.
§ Rhodia Recherches.
(1) (a) Liu, H.-W.; Walsh, C. T. In The Chemistry of the Cyclopropyl Group;
Rappoport, Z., Ed.; John Wiley & Sons Ltd.: New York, 1987; pp 959-
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1, July 2006, Chapman & Hall/CRC) for bicyclo[3.1.0]hexane and bicyclo-
[4.1.0]heptane motifs gave 416 and 1978 hits, repectively.
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M. D., et al. J. Med. Chem. 2006, 49, 2294-2310. (c) Boatman, D. P.;
Schrader, T. O.; Semple, G.; Skinneer, P. J.; Jung, J.-K. PCT Int. Appl.
WO 2006069242, 2006. (d) Ashwood, M. S.; Bio, M.; Cleator, E.; Hands,
D.; Sheen, F. J.; Wilson, R. D. PCT Int. Appl. WO 2006114581, 2006.
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10.1021/ja0672932 CCC: $37.00 © 2007 American Chemical Society

Intramolecular Cyclopropanation of Terminal Epoxides
A R T I C L E S
An unusual intramolecular cyclopropanation process was
reported in 1967 by Crandall and Lin,10 in which reaction of
t-BuLi with 1,2-epoxy-5-hexene (4a) gave small amounts of
trans-bicyclo[3.1.0]hexan-2-ol (5a) (9%), along with alkene 6
(34%) derived from reductive alkylation (reaction of the
R-lithiated epoxide intermediate with more of the original
organolithium base, followed by loss of Li2O)11 and alcohol 7
(11%) arising from direct nucleophilic ring-opening (Scheme
2). The completely stereocontrolled cyclopropanation of epoxide
4a can be attributed to a chairlike transition state for the
R-lithiated epoxide 8, an electrophilic carbenoid,12 in which
Arising out of the above observations and our interest in
R-lithiated epoxides 15,17 we considered whether a more
selective base might be used to provide more efficient access
to bicyclic alcohols from terminal epoxides. Highly enantioen-
riched terminal epoxides have recently become readily available
via Jacobsen hydrolytic kinetic resolution (HKR),18 and expan-
sion of the utility of such chiral building blocks would have
special value for asymmetric synthesis. With these ideas in mind,
we were attracted to the efficient lithium 2,2,6,6-tetramethylpi-
peridide (LTMP)-induced isomerization of terminal epoxides
14 to aldehydes 17, reported in 1994 by Yamamoto and co-
workers19 (Scheme 3). Deuterium labeling studies conducted
in that work indicated the reaction proceeds via a trans-R-
lithiated epoxide 15. Our further investigation into the reaction
pathway revealed that lithiated epoxide 15 undergoes further
reaction with LTMP (this time with the latter as nucleophile),
followed by elimination of Li2O to give an enamine 16, which
can be isolated or hydrolyzed to aldehyde 17.20
π
alkene/σ*C-O and σC-Li/π*alkene interactions are important.13
Although an interesting intramolecular cyclopropanation reac-
tion, the low yield and competing side-reactions detracted from
its further application in synthesis. Apparu and Barelle14 later
showed that the conversion of 4a into 5a was also possible using
N-lithioethylenediamine in HMPA as solvent, although in this
case the reaction was complicated by the concurrent formation
of unwanted allylic cyclopropane 9 (R ) H), likely arising from
competing allylic deprotonation-cyclization,15 and amino al-
cohol 10 (yields not reported). More recently, Mioskowski and
co-workers reported organolithium-induced intramolecular cy-
clopropanation of fused R-alkoxy epoxides11c,16 (e.g., 11 f 12
f 13); however, modest yields were obtained due to competing
reductive alkylation.
Scheme 3. Isomerization of Terminal Epoxides to Aldehydes
Scheme 2 . Intramolecular Cyclopropanations via R-Lithiated
Epoxides
Based on the ability of LTMP to effect clean lithiation of
terminal epoxides (Scheme 3), we considered whether such a
bulky lithium amide would be compatible with terminal
epoxides bearing an alkene tether in the Crandall-Lin intramo-
lecular cyclopropanation process. For such a reaction to be
viable, allylic deprotonation15 would have to be avoided/
minimized and the R-lithiated epoxide would have to prefer-
entially react with the tethered alkene, rather than with LTMP
(which would result in enamine/aldehyde), or undergo dimer-
ization.21 In a preliminary examination of such chemistry, we
have shown that this process can provide an efficient and highly
stereoselective synthesis of functionalized bicyclic alcohols from
unsaturated terminal epoxides and related chlorohydrin precur-
sors.22 In the present article, we provide a detailed account of
the scope and limitations of this intramolecular cyclopropanation
(17) For reviews, see: (a) Hodgson, D. M.; Gras, E. Synthesis 2002, 1625-
1642. (b) Chemla, F.; Vrancken, E. In The Chemistry of Organolithium
Reagents; Rappoport, Z., Marek, I., Eds.; Wiley and Sons: New York,
2004; pp 1165-1242. (c) Hodgson, D. M.; Bray, C. D. In Aziridines and
Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,
2006; pp 145-184. (d) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G.
Synlett 2006, 1-22. (e) Hodgson, D. M.; Humphreys, P. G.; Hughes, S. P.
Pure Appl. Chem. 2007, 79, 269-279.
(18) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936-938. (b) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J.
Org. Chem. 1998, 63, 6776-6777. (c) Salve, P. S.; Lamoreaux, M. J.;
Berry, J. F.; Gandour, R. D. Tetrahedron: Asymmetry 1998, 9, 1843-
1846. (d) 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. (e) Nielsen, L. P. C.; Stevenson, C. P;
Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-
(19) Y13a6n2a.gisawa, A.; Yasue, K.; Yamamoto, H. J. Chem. Soc., Chem. Commun.
1994, 2103-2104.
(10) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4526-4527.
(11) (a) Crandall, J. K.; Lin, L-H. C. J. Am. Chem. Soc. 1967, 89, 4527-4528.
(b) Dechoux, L.; Doris, E.; Mioskowski, C. Tetrahedron Lett. 1997, 38,
4071-4074. (c) Doris, E.; Dechoux, L.; Mioskowski, C. Synlett 1998, 337-
343. (d) Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. J. Am. Chem.
Soc. 2004, 126, 12250-12251.
(12) (a) Closs, G. L.; Closs, L. E. Angew. Chem., Int. Ed. Engl. 1962, 1, 334-
335. (b) Boche, G.; Lohrenz. Chem. ReV. 2001, 101, 697-756. (c) Braun,
M. In The Chemistry of Organolithium Reagents; Rappoport, Z., Marek,
I., Eds.; Wiley and Sons: New York, 2004; pp 829-900.
(13) Stiansy, H. C.; Hoffmann, R. W. Chem. Eur. J. 1995, 1, 619-624.
(14) Apparu, M.; Barelle, M. Tetrahedron 1978, 34, 1691-1697.
(15) Mordini, A.; Peruzzi, D.; Russo, F.; Valacchi, M.; Reginato, G.; Brandi,
A. Tetrahedron 2005, 61, 3349-3360.
(16) (a) Doris, E.; Dechoux, L.; Mioskowski, C. J. Am. Chem. Soc. 1995, 117,
12700-12704. (b) Doris, E.; Dechoux, L.; Mioskowski, C. Chem Commun.
1996, 549-550. (c) Dechoux, L.; Agami, C.; Doris, E.; Mioskowski, C.
Tetrahedron 2003, 59, 9701-9706.
(20) Hodgson, D. M.; Bray, C.; Kindon, N. D. J. Am. Chem. Soc. 2004, 126,
6870-6871.
(21) Hodgson, D. M.; Bray, C.; Kindon, N. D. Org. Lett. 2005, 7, 2305-2307.
(22) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem. Soc. 2004, 126,
8664-8665.
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A R T I C L E S
Hodgson et al.
Table 1. Synthesis of Bicyclo[3.1.0]hexan-2-ols 5
reaction, including its utility in the asymmetric synthesis of (+)-
â-cuparenone, and further elaborations of tributylstannyl-
substituted bicyclic alcohols. We also provide details of a
conceptually new protocol using substoichiometric 2,2,6,6-
tetramethylpiperidine (TMP), making large-scale syntheses of
bicyclic alcohols more convenient and economically viable.
Results and Discussion
Due to the availability of 1,2-epoxy-5-hexene (4a) and its
previous appearance in Crandall’s work (Scheme 2), this simple
unsaturated terminal epoxide was chosen for optimization of
the LTMP-induced intramolecular cyclopropanation reaction.23
The best conditions were initially determined to be slow (45-
60 min) addition via cannula of LTMP (2 mmol, 2.0 equiv, 0.2
M in Et2O) at 0 °C to a stirred solution of epoxide 4a (1 mmol,
0.2 M in Et2O) at 0 °C, followed by warming to room
temperature over 12 h, which gave bicyclic alcohol 5a in 79%
yield (Scheme 4).
Scheme 4. LTMP-Induced Intramolecular Cyclopropanation
In order to examine the scope of the cyclopropanation
chemistry, a variety of unsaturated terminal epoxides 4a-j were
synthesized and examined under the above cyclopropanation
conditions (Table 1). Highly enantioenriched terminal epoxide
R-4a (accessed via HKR18d) gave chiral bicyclic alcohol (+)-
5a with no loss of enantiopurity (entry 1). This result confirms
that the stereochemical outcome of the cyclopropanation is
dictated by the epoxide stereocenter and that there is preservation
of enantiointegrity in the reaction, making the methodology
especially attractive for asymmetric synthesis. Alkyl substitution
at the double bond or elsewhere in the tether was previously
shown to be compatible with this chemistry,22 and entry 2
provides an example containing both types. Note that, with more
substituted alkenes such as this latter example, incomplete
consumption of starting epoxide was observed in Et2O, but this
problem could be resolved using t-BuOMe24 as solvent and
subsequent examples in this article use t-BuOMe as solvent
unless otherwise indicated. An R-substituted styrene underwent
efficient cyclopropanation (entry 3), although the regioisomeric
trans-â-substituted styrene gave an inseparable 1:2 mixture of
the desired bicyclic cyclopropane and allylic cyclopropane 9
(R ) Ph). Cyclopropanation involving a tetrasubstituted alkene
proceeded smoothly, with possible complications arising from
competitive doubly allylic deprotonation not being observed
(entry 4). Epoxides bearing alkenylstannane substitution gave
the corresponding bicyclic cyclopropylstannanes 5e and 5f
(entries 5 and 6), which provides opportunities for further
elaboration of the cyclopropyl moiety (vide infra). However,
on treatment with LTMP the trans-vinylsilane corresponding
to 4e (SnBu3 ) SiMe3) gave an inseparable mixture of the
desired bicyclic cyclopropane and allylic cyclopropane 9 (R )
SiMe3),23 and the trans-pinacolboronate corresponding to 4e
a t-BuOMe as solvent unless otherwise indicated. Reaction time 8-24
h. b Isolated yield. c Et2O as solvent.
(SnBu3 ) B(OCMe2)2) underwent rapid decomposition. In-
tramolecular cyclopropanation of an epoxide bearing multiple
alkene tethers was successful, to give potentially useful diallyl
groups for further structural modification (entry 7). Two
epoxides containing diastereotopic allyl groups proceeded to
react in a highly diastereoselective manner to give cyclopropanes
containing an additional stereocenter (entries 8 and 9). The
stereocontrol can be rationalized by invoking the proposed
chairlike transition state 8 (Scheme 2), in which the more
sterically demanding group prefers to occupy a pseudo-
equatorial position. The chemistry also proved viable even
when a bulky group (TBSO) is forced to occupy the
pseudoaxial position in the proposed chairlike transition state
(entry 10).
As vinylcyclopropanes are useful synthetic intermediates,25
we investigated carbenoid insertion into conjugated dienes with
the aim of generating the corresponding vinylcyclopropane
(25) (a) Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247-
335. (b) Hudlicky, T.; Reed, J. W. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford, 1992;
Vol. 5, pp 899-970. (c) Oxgaard, J.; Wiest, O. Eur. J. Org. Chem. 2003,
1454-1462. (d) Zuo, G.; Louie, J. Angew. Chem., Int. Ed. 2004, 43, 2277-
2279.
(23) See Supporting Information for details.
(24) Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. J. Org. Chem. 1987, 52, 448-
450.
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Intramolecular Cyclopropanation of Terminal Epoxides
A R T I C L E S
tion,21 whereas decomposition was observed with epoxide 21],
or to intermolecular cyclopropanation,27 or C-H insertion using
epoxide 22.
Table 2. Terminal Epoxides Containing Conjugated Dienes
As terminal epoxides bearing carbonyl groups had earlier been
found to be incompatible with the intramolecular cyclopropa-
nation conditions, we considered methods to allow elaboration
of the bicyclic alcohol products into more complex structures
containing such functionality or other groups which may be
sensitive to LTMP. The tributylstannyl-substituted bicyclic
products 5e and 5f were considered to be suitable substrates,
because cyclopropylstannanes are versatile synthetic intermedi-
ates capable of wide-ranging transformations, among which tin-
lithium exchange/electrophile trapping and Stille cross-coupling
chemistry are the most commonly utilized.28 In order to avoid
potential interference by the secondary hydroxy group of 5e in
this chemistry, it was first protected as the corresponding silyl
ether 23 (Scheme 5).
Scheme 5. Electrophile Trapping of Cyclopropylstannane 23
a t-BuOMe as solvent. Reaction time 16-24 h. b Isolated yield. c Isolated
as 1:1.5 mixture with allylic cyclopropane 9 (R ) CHdCH2).
adducts (Table 2). However, attempted cyclopropanation of
epoxide 4k produced a chromatographically inseparable 1:1.5
mixture (65%) of 5k and allylic cyclopropane 9 (R ) CHd
CH2) (Table 2, entry 1). The presence of the conjugated diene
likely increases the acidity at the adjacent allylic position in
epoxide 4k, making deprotonation at that site competitive
with R-lithiation of the epoxide (cf. 9 in Scheme 2). This
issue could be overcome by full substitution at the allylic
position. Thus, epoxides 4l and 4m were transformed in a
stereospecific manner12a into the desired bicyclic vinylcyclo-
propanes 5l and 5m (entries 2 and 3). Unwanted allylic
deprotonation was not observed with conjugated diene systems
4n and 4o (entries 4 and 5). However, in these latter cases the
carbenoid insertion step was not regioselective, resulting in the
formation of a chromatographically inseparable mixture of
unsaturated five- and six-membered ring-fused cyclopropanes
5n/18a (2.4:1) and 5o/18b (1.1:1), respectively. In contrast, the
N-tert-butylsulfonyl (Bus) aziridine corresponding to 4n did
undergo regioselective cyclopropanation to give 5n (OH )
NHBus).26
Tin-lithium exchange reactions are the most useful and
widely studied transformations of cyclopropylstannanes, because
the facile transmetallation with organolithium reagents at a wide
range of temperatures (0 °C to -100 °C) renders such building
blocks a convenient source of stereodefined cyclopropyllithi-
ums.28 Transmetallation of stannane 23 with n-BuLi followed
by electrophile trapping was investigated and was found to allow
rapid access to a diverse range of substituted cyclopropanes in
satisfactory yields (Scheme 5). Stannane 25 was also trapped
with N,N-dimethylbenzamide to give ketone 26 in 82% yield
(Scheme 6).
Scheme 6. Electrophile Trapping of Cyclopropylstannane 25
The results in entries 4 and 5 of Table 2 demonstrate that
formation of cyclopropanes fused to six-membered rings is also
possible, and this chemistry has been extended to trishomoallylic
epoxides 19 (Figure 1), which allows access to trans-bicyclo-
[4.1.0]heptan-2-ols.22 However, the chemistry could not be
extended to give cyclopropanes fused to four- or seven-
membered rings [epoxide 20 (Figure 1) underwent dimeriza-
Stille cross-coupling reactions of cyclopropylstannanes with
aryl halides or triflates are also potentially an attractive method
for the preparation of diversely substituted cyclopropanes.
However, most examples currently known provide coupled
products in low to modest yields at best.28 Recently, Fu and
(26) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2006, 8, 995-
998.
(27) (a) Olofson, R. A.; Dougherty, C. M. J. Am. Chem. Soc. 1973, 95, 581-
582. (b) Dougherty, C. M.; Olofson, R. A. Org. Synth. Coll. Vol. VI, 1988,
571-571.
(28) For a recent review, see: Rubina, M.; Gevorgyan, V. Tetrahedron 2004,
60, 3129-3159.
Figure 1. Other terminal epoxides studied with LTMP.
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A R T I C L E S
Hodgson et al.
Table 3. Intramolecular Cyclopropanation Catalytic in TMP
co-workers reported the use of Pd/Pt-Bu3 as a mild and general
catalytic system for Stille coupling reactions of aryl chlorides
and bromides.29 The use of aryl chlorides are favored over
bromides because the former are generally more readily avail-
able and stable, although prior to our work there were no
examples of cross-coupling between cyclopropylstannanes and
aryl chlorides. We briefly investigated the reaction of stannane
23 with p-chloroanisole under the conditions reported by Fu
and co-workers, and also under microwave (75 W/110 °C)
irradiation23 (Scheme 7). Despite the incomplete consumption
of starting material in both cases, good yields of coupled product
27 were obtained with respect to recovered starting cyclopro-
pylstannane 23. Under microwave conditions the reaction
progress was considerably faster. This cross-coupling protocol
provides an indirect solution to the incompatibility of the
â-substituted styrene motif in the intramolecular cyclopropa-
nation (vide supra).
Entrya
TMP (equiv)
n-BuLi (equiv)
Yield (%)b
1
1
2
2
1.1
1.1
1.1
1.1
95
97
95
85
75e
63
2
0.5
0.5
0.25
0.1
0.05
3c
4
5d
6
a RLi was added dropwise to a stirred solution of 4a (1 g, 10 mmol) and
TMP in t-BuOMe (10 mL), unless otherwise indicated. After complete
consumption of the epoxide, aqueous workup was performed using 3 N
AcOH (1.6 equiv) to give crude 5a. b GC yield with biphenyl as internal
standard unless otherwise indicated. c n-HexylLi under these conditions gave
5a (90%). d 50 mL of t-BuOMe used. e Isolated yield after column
chromatography.
Scheme 7. Stille Cross-Coupling of Cyclopropylstannane 23
amounts of TMP and n-BuLi. The conversion of epoxide 4a to
bicyclic alcohol 5a under this latter set of optimized conditions
has been performed on numerous occasions and on various
scales (1 g-7.5 kg), giving yields consistently in the range of
92-97%.31
In order to demonstrate the catalytic process, we focused on
a synthesis of (+)-â-cuparenone (+)-28 (Scheme 8). (+)-â-
Cuparenone (+)-28 is a sesquiterpene from the essential oil of
Mayur pankhi and the liverwort Mannia fragrans and has been
a popular target to illustrate new procedures for cyclopentanone
construction and/or methods for juxtaposing quaternary cen-
ters.32 (+)-â-Cuparenone (+)-28 has previously been accessed
from ketone (+)-29 by reduction with lithium in liquid
ammonia,32c and we anticipated ketone (+)-29 could arise from
intramolecular cyclopropanation of epoxide (R)-30; a synthesis
of the latter therefore became our initial goal.
Thus far, conversion of unsaturated terminal epoxides to
bicyclic alcohols had been performed on relatively small scales
(<1 g of epoxide), using 2 equiv of TMP.30 However, this
standard protocol is less favorable for large-scale syntheses from
an economic and practical standpoint, since it involves the use
of excess TMP and typically silica gel chromatography for
purification. In order to demonstrate that such constraints can
be circumvented, we have developed a straightforward protocol
for the large-scale synthesis (up to multikilo quantities) of
bicyclic alcohol 5a using only a catalytic quantity of TMP. For
this to be a viable concept, the amount of free organolithium
available that could undergo an unwanted reaction with the
epoxide11 (cf. Scheme 2, 4a f 5a) must be kept to a minimum.
We considered that slow addition of the organolithium to a
mixture of the epoxide and a substoichiometric amount of TMP
might fulfill this criterion, provided deprotonation of TMP and
reaction of the so-generated LTMP with the epoxide (to
regenerate TMP) were comparatively rapid steps.
Scheme 8. Retrosynthesis of (+)-â-Cuparenone (+)-32
The optimization studies involved slow (over 4 h) addition
of n-BuLi to a stirred solution of epoxide 4a (10 mmol) and
TMP in t-BuOMe or hexane at 0 °C to -5 °C (Table 3).
Initially, the use of 1 equiv of TMP and 2 equiv of n-BuLi
gave bicyclic alcohol 5a in 95% yield (entry 1). Similar yields
were obtained with 0.5 equiv of TMP (entry 2), and then by
also reducing the amount of n-BuLi to 1.1 equiv (entry 3).
Further reduction of the amount of TMP (0.25 equiv) led to
successively lower yields (entries 4-6), although 63% yield
(GC) was still observed using 5 mol % TMP (entry 6). The
conditions in entry 3 (0.5 equiv of TMP and 1.1 equiv of
n-BuLi) gave the highest yield while using the most economical
As a model for the TMP-catalyzed synthesis of (+)-â-
cuparenone, we first studied intramolecular cyclopropanation
of epoxide 4c using substoichiometric TMP. Epoxide 4c was
converted to the secondary alcohol 5c in 80% yield using 0.5
equiv of TMP and 2 equiv of n-BuLi; using 0.5 equiv of TMP
and 1.1 equiv of n-BuLi, 5c was obtained in 53% yield (58%
yield brsm).
The synthesis of (+)-â-cuparenone commenced with com-
mercially available 4-iodotoluene, Bu3SnSiMe3 and 3-methyl-
1,2-butadiene, which underwent a Pd(dba)2-catalyzed three-
(29) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343-
6348.
(30) For an improved laboratory preparation of TMP, see: Kampmann, D.;
Stuhlmu¨ller, G.; Simon, R.; Cottet, F.; Leroux, F.; Schlosser, M. Synthesis
2005, 1028-1029.
(31) Bio, M.; Brands, K. M. J.; Cleator, E. PCT Int. Appl. WO 2007015111,
2007.
9
4460 J. AM. CHEM. SOC. VOL. 129, NO. 14, 2007

Intramolecular Cyclopropanation of Terminal Epoxides
A R T I C L E S
Scheme 9 . Synthesis of (+)-â-Cuparenone (+)-28
bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. The
methodology can be considered as a useful alternative to
intramolecular cyclopropanation of unsaturated R-diazocarbonyl
compounds. Indeed, the chemistry has already been applied to
a range of 6-substituted bicyclo[3.1.0]hexan-2-ols as intermedi-
ates in the synthesis of fused pyrazole derivatives for the
treatment of metabolic-related disorders.3c,d The ready avail-
ability of (highly enantioenriched) terminal epoxides and
excellent stereocontrol in the carbenoid insertion process make
this methodology especially attractive for asymmetric synthesis.
Further elaboration at the cyclopropane of stannyl-substituted
bicyclic alcohols can be achieved via tin-lithium exchange/
electrophile trapping and Stille coupling. Modifications to the
standard cyclopropanation conditions provide a protocol catalytic
in terms of TMP for the conversion of 4a to 5a on a large scale
(up to multikilo quantities). Concise syntheses of (-)-sabina
ketone22 and (+)-â-cuparenone (+)-28 have been successfully
developed employing this synthetic technology.
Experimental Section
A Typical Intramolecular Cyclopropanation, Using Unsaturated
Terminal Epoxide 4c. n-BuLi (1.6 M in hexane, 1.3 mL, 2.0 mmol)
was added to a stirred solution of 2,2,6,6-tetramethylpiperidine (0.34
mL, 2.00 mmol) in t-BuOMe (10 mL) at -78 °C. The pale yellow
LTMP solution formed was stirred at rt for 15 min and cooled to 0 °C
in an ice bath. To a stirred solution of terminal epoxide 4c (174 mg,
1.00 mmol) in t-BuOMe (5 mL) at 0 °C was added the LTMP solution
dropwise via cannula over 45-60 min. The resulting mixture was stirred
at rt for 16 h, quenched with MeOH (0.5 mL), and concentrated. The
residue was dry-loaded onto a small amount of silica and purified by
chromatography on silica gel (30% Et2O in petrol) to give the bicyclic
alcohol 5c (139 mg, 0.80 mmol, 80%) as a colorless oil, Rf ) 0.2 (30%
Et2O in petrol); IR (film) 3346 (OH), 3060 (cyclopropane), 3028, 2933,
component coupling reaction33 to give allylsilane 31 in 50%
yield (Scheme 9). A mixture of allylsilane 31 and (R)-
epichlorohydrin (>99% ee) was then treated with TiCl434 at -78
°C to give (R)-chlorohydrin (R)-33 in 60% yield. Under similar
conditions, the simple tetrasubstituted alkene (31, Me3Si ) H)
only underwent partial dimerization, indicating a crucial role
for the trimethylsilyl group. Ring-closure of (R)-33 to give (R)-
epoxide (R)-30 was achieved in quantitative yield by treatment
with NaOH in MeOH. Intramolecular cyclopropanation of
terminal epoxide (R)-30 under standard LTMP conditions
proceeded smoothly to give the desired secondary alcohol (-)-
34, in 72% yield. The chlorohydrin (R)-33 could also be directly
converted to cyclopropanol (-)-34 (59%) using LTMP, presum-
ably via in situ epoxide formation (Scheme 9). This latter
protocol has been shown to be applicable to a range of
unsaturated chlorohydrins directly accessed from unsaturated
Grignard reagents and epichlorohydrin.35 Significantly, using
epoxide (R)-30 with substoichiometric TMP (0.5 equiv) also
proved viable, giving cyclopropanol (-)-34 in 85% yield using
2 equiv of n-BuLi; even 1.1 equiv of n-BuLi with 0.5 equiv of
TMP gave (-)-34 in good yield (72%). Subsequent oxidation
of alcohol (-)-34 with catalytic TPAP and NMO afforded (99%)
the known ketone (+)-29,32c which then underwent regioselec-
tive36 reductive opening with lithium in liquid ammonia to give
(R)-(+)-â-cuparenone (+)-28 (85% yield, 97% ee by chiral GC).
1
1603, 1498, 1447, 1326, 1166, 1107, 1031 cm-1; H NMR (CDCl3,
400 MHz) δ 0.76 (t, J ) 4.8 Hz, 1H, H-6), 0.94 (dd, J ) 5.2, 8.4 Hz,
1H, H-6′), 1.51-1.61 (m, 1H, H-4), 1.69 (s, 1H, OH), 1.73-1.78 (m,
2H, H-1, H-4′), 2.08 (dd, J ) 8, 12.4 Hz, 1H, H-3), 2.29 (td, J ) 8.4,
12.1 Hz, 1H, H-3′), 4.34 (d, J ) 3.6 Hz, 1H, H-2), 7.17-7.32 (m, 5H,
5 × Ar-H); 13C (CDCl3, 100 MHz) δ 17.1 (C-6), 29.7 (C-3), 31.6
(C-4), 32.1 (C-5), 33.6 (C-1), 74.7 (C-2), 125.6 (Ar-C), 126.5 (Ar-
C), 128.2 (Ar-C), 144.3 (Ar-C); MS (CI+) m/z: 157 ([M - OH]+,
100%), 173 ([M - H]+, 10%). HMRS: [M - OH]+ found 157.1017,
C12H13 requires 157.1017.
A Typical Electrophile Trapping of Stannane 23: With N,N-
Dimethylbenzamide. n-BuLi (1.6 M in hexane, 1.4 mL, 2.2 mmol,
1.8 equiv) was added to a stirred solution of stannane 23 (501 mg,
1.00 mmol) in THF (6 mL) at 0 °C. After 1 h, the mixture was cooled
to -78 °C, treated with a solution of N,N-dimethylbenzamide (298
mg, 2.00 mmol, 2.0 equiv) in THF (2 mL), and then stirred at the same
temperature for a further 2 h. The resulting mixture was warmed to rt,
dry-loaded onto a small amount of silica, and purified by chromatog-
raphy on silica gel, followed by Kugelrohr distillation (70 °C and 0.07
mmbar) to give cyclopropane 24a (273 mg, 0.86 mmol, 86%) as a
white solid, Rf ) 0.3 (5% Et2O in petrol); mp ) 57-58 °C; IR (film)
2930s, 2857s (CsH), 1668s (CdO), 1599m, 1582m, 1449s, 1401s,
1360s, 1267s, 1220s, 1168s, 1097s, 1034s cm-1; 1H NMR (CDCl3, 400
MHz) δ 0.09 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.91 (s, 9H, SiC-
(CH3)3), 1.43-1.52 (m, 1H, H-3), 1.64 (dd, J ) 8.4, 14.4 Hz, 1H, H-3′),
Conclusion
We have developed intramolecular cyclopropanation of
unsaturated terminal epoxides as a process for the synthesis of
(32) For a review, see: (a) Pirrung, M. C.; Morehead, A. T., Jr.; Young, B. G.
In The Total Synthesis of Natural Products; Goldsmith, D., Ed.; Wiley,
New York, 2000; pp 196-199. For more recent syntheses of enantiomeri-
cally enriched â-cuparenone, see: (b) Castro, J.; Moyano, A.; Perica`s, M.
A.; Riera, A.; Greene, A. E.; Alvarez-Larena, A.; Piniella, J. F. J. Org.
Chem. 1996, 61, 9016-9020. (c) Aavula, B. R.; Cui, Q.; Mash, E.
Tetrahedron: Asymmetry 2000, 11, 4681-4686. (d) Acherar, S.; Audran,
G.; Cecchin, F.; Monti, H. Tetrahedron 2004, 60, 5907-5912.
(33) Wu, M. Y.; Yang, F. Y.; Cheng, C. H. J. Org. Chem. 1999, 64, 2471-
2474.
(36) Interestingly, Li/NH3 reduction of the ketone derived from alcohol 5c gave
an ∼1:1 mixture of 4-phenylcyclohexanone and 4-phenylcyclohexanol,
indicating the presence of either, or both, of the methyl groups on the five-
membered ring of ketone (+)-33 is important in controlling the desired
regioselective cyclopropane cleavage (Casares, A.; Maldonado, L. A. Synth.
Commun. 1976, 6, 11-16. Abad, A.; Agullo´, C.; Cuna˜t, A. C.; Jime´nez,
D.; Perni, R. H. Tetrahedron 2001, 57, 9727-9735).
(34) Imai, T.; Nishida, S. J. Org. Chem. 1990, 55, 4849-4852.
(35) Hodgson, D.M.; Chung, Y. K.; Paris, J.-M. Synthesis 2005, 2264-226.
9
J. AM. CHEM. SOC. VOL. 129, NO. 14, 2007 4461

A R T I C L E S
Hodgson et al.
1.83 (dd, J ) 8.4, 12.8 Hz, 1H, H-4), 2.11-2.24 (m, 3H, H-4′, H-5,
H-6), 2.29 (t, J ) 2.8 Hz, 1H, H-6), 4.37 (d, J ) 5.2 Hz, 1H, H-2),
7.47 (t, J ) 8.0 Hz, 2H, 2 × Ar-H), 7.56 (t, J ) 6.8 Hz, 1H, Ar-H),
7.94 (d, J ) 8.4 Hz, 2H, 2 × Ar-H); 13C NMR (CDCl3, 100 MHz) δ
-4.7 (SiCH3), -4.6 (SiCH3), 18.2 (SiC(CH3)3), 25.5 (C-4), 25.9 (SiC-
(CH3)3), 26.7 (C-6), 31.8 (C-3), 32.2 (C-5), 38.1 (C-1), 74.3 (C-2),
127.9 (ArsC), 128.4 (ArsC), 133.0 (ArsC), 138.0 (ArsC), 198.8
(CdO); MS (CI+) m/z: 334.2 (MNH4+, 4%), 317.2 (MH+, 100%),
259.1 (23%), 185.1 (20%), 131.1 (17%). Elemental analysis: found
C, 72.08; H, 8.93. C19H28O2Si requires: C, 72.10; H, 8.92.
Large-Scale Catalytic Intramolecular Cyclopropanation of Ep-
oxide 4a. n-BuLi (2.5 M in hexane, 89.6 mL, 224 mmol) was added
slowly over 4 h to a stirred solution of epoxide 4a (20.0 g, 204 mmol)
and 2,2,6,6-tetramethylpiperidine (17.2 mL, 102 mmol) in t-BuOMe
(200 mL) at 0 to -5 °C. The resulting mixture was stirred at 0 °C
until complete consumption of the epoxide. The reaction mixture was
quenched with 3 N AcOH (1.1 equiv). The layers were separated, the
organic layer was washed with 3 N AcOH (0.5 equiv), and the combined
aqueous layers were extracted with t-BuOMe (2 × 100 mL). The
combined organic layers were dried (MgSO4), filtered, and concentrated
to give bicyclic alcohol 5a (19.2 g, 196 mmol, 96%) as a pale yellow
oil (sufficiently pure for direct use). Alternatively, the product may be
distilled (bp 63-65 °C at 15 mbar, lit.37 61-65 °C at 15 mbar). This
procedure has been successfully performed on 7.5 kg of 4a, Rf ) 0.2
(30% Et2O in petrol); IR (film) 3338bs (OH), 3036w, 3068w (cyclo-
propane), 2944s, 2869s (C-H), 1636m, 1466m, 1452m, 1330m, 1257w,
1178m, 1102m, 1045s, 1024m; 1H NMR (CDCl3, 400 MHz) δ -0.07-
0.00 (m, 1H, H-6), 0.38-0.47 (m, 1H, H-6′), 1.27-1.37 (m, 2H, H-1,
H-4′), 1.38-1.43 (m, 1H, H-5), 1.53 (dd, J ) 8.4, 14.4 Hz, 1H, H-4),
1.65 (dd, J ) 8.0, 12.4 Hz, 1H, H-3), 1.83 (s, 1H, OH), 1.87-1.98 (m,
1H, H-3′), 4.21 (d, J ) 4.8 Hz, 1H, H-2); 13C NMR (CDCl3, 100 MHz)
δ 6.8 (C-6), 16.1 (C-5), 24.3 (C-1), 24.5 (C-3), 30.3 (C-4), 74.4 (C-2).
Acknowledgment. We thank Rhodia, Universita` di Bari, and
Universitat de Barcelona for studentship support (for Y.K.C.,
I.N., and G.F., respectively), the EPSRC for a research grant
(GR/S46789/01), and the European Community for a Marie
Curie Fellowship (to K.K.K.; MEIF-CT-2003-501722). We also
thank the EPSRC National Mass Spectrometry Service Centre
for mass spectra; Dr. A. Cowley for X-ray crystallographic
analyses; and Jos Brands, Matt Bio, and Tony Davies for useful
discussions.
Supporting Information Available: The full list of authors
for ref 3a,b, experimental procedures and NMR spectra for
compounds described in this article. This material is available
free of charge via the Internet at http://pubs.acs.org.
(37) Brown, A.; Schmid, G. H. Can. J. Chem. 1972, 50, 2432-2436.
JA0672932
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4462 J. AM. CHEM. SOC. VOL. 129, NO. 14, 2007