Enantioselective Synthesis of Bicyclo[6.1.0]nonane-9-carboxylic Acids via Me2AlOTf-Promoted Intramolecular Friedel-Crafts Alkylation of Arenes with the γ-Lactone Moiety of 3-Oxabicyclo[3.1.0]hexan-2-ones

Article abstract of DOI:10.1021/jo0351419

A strategy to rapidly assemble enantiomerically pure bicyclo [6.1.0]nonane-9-carboxylic acids via Me₂AlOTf-promoted intramolecular Friedel-Crafts alkylation of tethered π-nucleophiles with the γ-lactone moiety of 3-oxabicyclo-[3.1.0]hexan-2-ones is described. The approach begins with the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-2-ones bearing a tethered π-nucleophile at the 6-position by intramolecular Rh(II)-catalyzed cyclopropanation of allylic diazoacetates, prepared from the corresponding (Z)-allylic alcohols. Me ₂AlOTf-induced intramolecular Friedel-Crafts cyclization provides medium-sized carbocycles and heterocycles in high yields without requiring high-dilution or slow substrate addition techniques. The scope and limitations of this synthetic methodology are presented.

Full text of DOI:10.1021/jo0351419

SCHEME 1. Cr en u lid e Diter p en oid s
En a n tioselective Syn th esis of
Bicyclo[6.1.0]n on a n e-9-ca r boxylic Acid s via
Me2AlOTf-P r om oted In tr a m olecu la r
F r ied el-Cr a fts Alk yla tion of Ar en es w ith
th e γ-La cton e Moiety of
3-Oxa bicyclo[3.1.0]h exa n -2-on es
Eric Fillion* and Rachel L. Beingessner
Department of Chemistry, University of Waterloo,
Waterloo, Ontario N2L 3G1, Canada
Simmons-Smith cyclopropanation completed the syn-
thesis of the bicyclo[6.1.0]nonane skeleton.
In view of the observations made by Paquette and the
difficulties generally associated with eight-membered
carbocycle and heterocycle formation, the development
of synthetic strategies for their rapid and efficient
construction is of interest.4
efillion@uwaterloo.ca
Received August 1, 2003
Abstr a ct: A strategy to rapidly assemble enantiomerically
pure bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-
promoted intramolecular Friedel-Crafts alkylation of teth-
ered π-nucleophiles with the γ-lactone moiety of 3-oxabicyclo-
[3.1.0]hexan-2-ones is described. The approach begins with
the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-
2-ones bearing a tethered π-nucleophile at the 6-position by
intramolecular Rh(II)-catalyzed cyclopropanation of allylic
diazoacetates, prepared from the corresponding (Z)-allylic
alcohols. Me2AlOTf-induced intramolecular Friedel-Crafts
cyclization provides medium-sized carbocycles and hetero-
cycles in high yields without requiring high-dilution or slow
substrate addition techniques. The scope and limitations of
this synthetic methodology are presented.
We report here a new method for the direct conversion
of 3-oxa-bicyclo[3.1.0]hexan-2-ones into bicyclo[6.1.0]-
nonane-9-carboxylic acid derivatives. The strategy, il-
lustrated in Scheme 2, begins with readily available (Z)-
allylic diazoacetates. Intramolecular Rh(II)-catalyzed
alkene cyclopropanation provides the 3-oxabicyclo[3.1.0]-
hexan-2-one cyclization precursors bearing a tethered
π-nucleophile at the 6-position, in a highly enantioselec-
tive fashion. The γ-lactone moiety of the bicyclic precursor
then participates with π-nucleophiles in a Lewis acid-
promoted intramolecular Friedel-Crafts alkylation,5 lead-
ing to enantiomerically pure eight-membered carbo- and
heterocyclic carboxylic acids.
Dihydroxycrenulide, pachylactone, and acetoxycrenulide
are members of the crenulide family, a small but impor-
tant group of natural diterpenoids that contain an
unusual bicyclo[6.1.0]nonane skeleton fused to a buteno-
lide (Scheme 1).1 Acetoxycrenulide, isolated from the sea
hare Aplysia vaccaria, has been postulated to act as a
chemical defense against herbivorous reef-dwelling fish
as a result of its high toxicity at very low concentrations
(10 µg/mL).2 The most synthetically challenging feature
of the crenulide diterpenoids is the highly substituted
eight-membered carbocyclic central core that contains up
to five stereocenters. Synthetic efforts reported by Paquette
and co-workers have resulted in the enantioselective total
synthesis of acetoxycrenulide in 1995.3 The eight-
membered carbocyclic framework was accessed via a
Claisen ring-expansion rearrangement. Formation of the
medium-sized ring proceeded in modest yield mainly due
to the instability of the Claisen precursor, a vinyl ether,
and the forceful conditions required to promote the [3.3]
sigmatropic rearrangement. A highly stereoselective
SCHEME 2. Gen er a l Str a tegy
The viability and scope of the proposed strategy to
efficiently assemble bicyclo[6.1.0]nonanes were estab-
lished by the synthesis of 3-oxabicyclo[3.1.0]hexan-2-one
cyclization precursors with varied nucleophilic moieties
and substituents at the 6-position. π-Nucleophiles were
rationally selected for their tolerance to strong Lewis
acidic conditions required to promote the Friedel-Crafts
alkylation reaction. The synthesis of the substrates
bearing a methyl group at the 6-position is illustrated in
Scheme 3.
Neryl acetate was first transformed to alcohol 1 in
three steps (Scheme 3).6 The monoacetylated diol 1 was
brominated and the acetate subsequently removed and
then replaced by a TIPS protecting group yielding
(1) (a) Ko¨nig, G. M.; Wright, A. D.; Sticher, O. Tetrahedron 1991,
47, 1399-1410. (b) Tringali, C.; Oriente, G.; Piattelli, M.; Geraci, C.;
Nicolosi, G.; Breitmaier, E. Can. J . Chem. 1988, 66, 2799-2802. (c)
Kusumi, T.; Muanza-Nkongolo, D.; Gota, M.; Ishitsuka, M.; Iwashita,
T.; Kakisawa, H. J . Org. Chem. 1986, 51, 384-387. (d) Ishitsuka, M.;
Kusumi, T.; Kakisawa, H.; Kawakami, Y.; Nagai, Y.; Sato, T. Tetra-
hedron Lett. 1983, 24, 5117-5120.
(2) (a) Sun, H. H.; McEnroe, F. J .; Fenical, W. J . Org. Chem. 1983,
48, 1903-1906. (b) Midland, S. L.; Wing, R. M.; Sims, J . J . J . Org.
Chem. 1983, 48, 1906-1909.
(4) For an excellent review, see: Petasis, N. A.; Patane, M. A.
Tetrahedron 1992, 48, 5757-5821.
(5) For reviews on the Friedel-Crafts alkylation reaction, see: (a)
Olah, G. A.; Krishnamurti, A. R.; Prakash, G. K. S. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon Press:
Oxford, 1991; Vol. 3, pp 293-339. (b) Roberts, R. M.; Khalaf, A. A.
Friedel-Crafts Alkylation Chemistry: A Century of Discovery; Marcel
Dekker: New York, 1984.
(3) (a) Wang, T.-Z.; Pinard, E.; Paquette, L. A. J . Am. Chem. Soc.
1996, 118, 1309-1318. (b) Paquette, L. A.; Wang, T.-Z.; Pinard, E. J .
Am. Chem. Soc. 1995, 117, 1455-1456. (c) Paquette, L. A.; Ezquerra,
J .; He, W. J . Org. Chem. 1995, 60, 1435-1447.
(6) (a) Germain, J .; Deslongchamps, P. J . Org. Chem. 2002, 67,
5269-5278. (b) For a similar transformation of geraniol acetate, see:
Tago, K.; Arai, M.; Kogen, H. J . Chem. Soc., Perkin Trans. 1 2000,
2073-2078.
10.1021/jo0351419 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/29/2003
J . Org. Chem. 2003, 68, 9485-9488
9485

bromide 2. Alkylation of 2-lithiofuran with bromide 2
followed by removal of the silyl group provided the allylic
alcohol 3a . Diazoacetate 4a was prepared from glyoxylic
acid chloride p-toluenesulfonylhydrazone7 in accordance
with a modification of the Corey and Myers procedure.8
An optimal yield was obtained when freshly prepared
acid chloride was added to a solution of the allylic alcohol
and freshly distilled N,N-dimethylaniline. Most impor-
tant was the removal of the excess glyoxylic acid chloride
p-toluenesulfonylhydrazone by filtration over a pad of
silica gel following the extraction and prior to the in vacuo
removal of the solvent. When the filtration was omitted,
the excess acid chloride reacted with the π-nucleophile
upon concentration and resulted in yield erosion.
azoacetate 4a was cyclopropanated using Rh2(5S-MEPY)4
catalyst (0.5 mol %) providing bicycle 5a in 65% yield for
two steps starting from the allylic alcohol 3a .9,10 An
enantiomeric excess of 94% was obtained for 5a , and
consequently, the absolute stereochemistry of the cyclo-
propane was assumed by comparison to Doyle’s results
obtained on similar models.9a The preparation of sub-
strates 5b-d followed the same sequence of steps, and
the yields and enantiomeric excesses for the acylation/
cyclopropanation are reported in Scheme 3. The enanti-
oselectivity of the cyclopropanation was not affected by
the pyrrole moiety and 5b obtained in 97%ee (Scheme
3). The ee’s for compounds 5c and 5d were not deter-
mined.
SCHEME 3. Syn th esis of Cycliza tion P r ecu r sor s
5a -d
SCHEME 4. P r ep a r a tion of Cycliza tion
P r ecu r sor s 8a ,b
a
Determined by 1H NMR using Eu(hfc)3. bDetermined by HPLC
using chiral OD columns.
Bicyclic substrates bearing a hydrogen atom at the
6-position in place of a methyl group were prepared from
ethyl 4-bromobutyrate (Scheme 4). Ester reduction to the
aldehyde11 using DIBAL-H at -78 °C and subsequent
Horner-Emmons reaction under Ando’s conditions led
to an R,â-unsaturated ester.12 Reduction of the resulting
ester provided allylic alcohol 6 as an inseparable mixture
of isomers (95:5 Z/E) that was carried over the entire
sequence of steps. Protection of alcohol 6 followed by
alkylation with 2-lithiofuran and deprotection yielded the
allylic alcohol 7a in good yield. Preparation of the
diazoacetate was carried out as before, and the purifica-
tion problems described above were encountered. Cyclo-
a
Determined by HPLC using chiral OD columns.
A second problem encountered in the preparation of
the allylic diazoacetate was the well-known competitive
formation of p-toluenesulfinate ester that arises from
Et3N-induced decomposition of glyoxylic acid chloride
p-toluenesulfonylhydrazone. The p-toluenesulfinate ester
byproduct could be tediously separated from the allylic
diazoacetate by chromatography, but it was found that
its presence had a negligible effect on the efficiency of
the cyclopropanation reaction and the overall yield for
the two steps was unaffected. An operationally simple
two-step protocol for the formation of the 3-oxabicyclo-
[3.1.0]hexan-2-ones starting from allylic alcohols was
therefore adopted in which the crude allylic diazoacetates
were directly cyclopropanated. The contaminated di-
(9) (a) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C.
J .; Pieters, R. J .; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou,
Q.-L.; Martin, S. F. J . Am. Chem. Soc. 1995, 117, 5763-5775. For
reviews on asymmetric cyclopropanation, see: (b) Lebel, H.; Marcoux,
J .-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977-1050.
(c) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946.
(d) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911-935. (e) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; J ohn Wiley & Sons: New York,
1998.
(10) For the preparation of the MEPY catalyst, see: (a) Doyle, M.
P.; Winchester, W. R.; Protopopova, M. N.; Kazala, A. P.; Westrum, L.
J . Org. Synth. 1996, 73, 13-24. (b) Doyle, M. P.; Winchester, W. R.;
Hoorn, J . A. A.; Lynch, V.; Simonsen, S. H.; Ghosh, R. J . Am. Chem.
Soc. 1993, 115, 9968-9978.
(11) Lautens, M.; Paquin, J .-F.; Piguel, S.; Dahlmann, M. J . Org.
Chem. 2001, 66, 8127-8134.
(12) Ando, K. J . Org. Chem. 1997, 62, 1934-1939.
(7) Blankley, C. J .; Sauter, F. J .; House, H. O. Organic Syntheses;
Wiley: New York, 1973; Collect. Vol. V, pp 258-263.
(8) Corey, E. J .; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559-
3562.
9486 J . Org. Chem., Vol. 68, No. 24, 2003

propanation of the contaminated diazoacetate gave cy-
clopropane 8a in good yield and enantioselectivity as
shown in Scheme 4. Cyclopropane 8b was prepared from
the allylic alcohol 7b in 97% ee, but with a modest yield
overall (Scheme 4).
and 8b. Lewis acid-promoted intramolecular Friedel-
Crafts alkylation yielded the desired eight-membered-
ring carboxylic acids that proved difficult to purify. In
1
addition, some signals in the H and 13C NMR spectra
were unresolved due to slow conformer interconversion.
The purification of the bicyclo[6.1.0]nonanes was simpli-
fied by treating the crude carboxylic acids with
TMSCHN2 to provide the corresponding methyl esters
9c and 9d in 78% and 81% yield, respectively, from the
cyclopropane substrates (Scheme 5).16 The 1H and 13C
NMR spectra of carboxylic ester 9c were well-resolved
at rt, but 9d still required high-temperature NMR
experiments.
Studies of the intramolecular Friedel-Crafts alkyla-
tion were initiated with substrate 5a . A wide variety of
reaction conditions and Lewis acids (EtAlCl2, Et2AlCl,
SnCl4, TiCl4, BF3‚OEt2, Mg(OTf)2, TMSOTf, Sc(OTf)3, Yb-
(OTf)3, and Dy(OTf)3) were investigated to induce the
cyclization. Et2AlCl promoted the Friedel-Crafts alky-
lation yielding the desired eight-membered carbocycle,
but Me2AlOTf in ClCH2CH2Cl was a superior Lewis acid
with respect to yield and reproducibility.13 The operation-
ally simple and optimized protocol did not require high
dilution or slow substrate addition. A Me2AlOTf solution
in ClCH2CH2Cl was freshly prepared in a resealable
Schlenk tube from Me3Al and TfOH, to which the
substrate was added. Four equivalents of Me2AlOTf was
required for the reaction to proceed to completion. The
resulting cloudy solution was heated at 85 °C for 24 h,
and the final product was purified by HPLC on a normal-
phase semipreparative column. As illustrated in Scheme
5, cyclopropane 5a gave the desired eight-membered
carbocycle 9a in an excellent 83% yield under these
conditions.14 The structure of 9a was confirmed by COSY
and NOESY NMR experiments on the corresponding
primary alcohol, prepared by LiAlH4 reduction.15
The π-nucleophilicity of the tethered heterocycle is
crucial for the success of the intramolecular Friedel-
Crafts alkylation. Substrates 5c and 5d , bearing the
weak 2-thienyl and 2,3-dimethoxybenzene π-nucleophiles,
did not undergo cyclization to form the eight-membered
carbocycles.17 Under the standard reaction conditions, the
starting material was recovered for these two substrates.
When the reaction was run at higher temperatures (85-
130 °C) and prolonged reaction time (12-72 h), complex
mixtures of dienes identified as cyclopropane-opening
products were exclusively isolated.
Two plausible mechanisms may rationalize the reac-
tivity of 3-oxabicyclo[3.1.0]hexan-2-one in the Me2AlOTf-
promoted Friedel-Crafts alkylation.18 Childs has re-
ported that cyclopropylcarbinyl cations have a minimum
energy conformation, which is bisected or close to bisected
as a result of the involvement of the cyclopropane in
charge delocalization.19 This observation suggests that
complexation of the Lewis acid with the carbonyl group
of the lactone moiety promotes the formation of a loosely
associated ion pair that is stabilized by the adjacent
cyclopropane. The π-nucleophile then undergoes cycliza-
tion with the primary carbocation to provide the corre-
sponding eight-membered ring.20 Concurrently, the re-
action may proceed via a concerted displacement21 in
which the cyclopropane plays a significant role in the
stabilization of the transition state, decreasing the energy
of activation and thus favoring the unprecedented σ-C-O
bond cleavage of 3-oxabicyclo[3.1.0]hexan-2-ones to yield
aluminum cyclopropanecarboxylate products.22 The SN2
pathway, illustrated in Scheme 6, shows that the meth-
ylene bearing a partial positive charge (δ+) is in a bisected
orientation relative to the cyclopropane ring. In addition,
the template effect provided by the conformationally rigid
bicyclic substrate facilitates the intramolecular Friedel-
SCHEME 5. Scop e of th e Bicyclo[6.1.0]n on a n e
Syn th esis
The optimized reaction conditions were applied to other
substrates. It was essential to determine if the intra-
molecular Friedel-Crafts alkylation would proceed for
substrates having a hydrogen substituent at the 6-posi-
tion instead of a methyl group since the crenulane
natural products possess hydrogens at the bicyclo[6.1.0]-
nonane ring junction. Comparison of cyclopropanes 5a
and 8a reveals that the nature of the substituent on the
cyclopropane (Me vs H) does not affect the cyclization
process, and good yields are obtained in both cases
(Scheme 5). Eight-membered heterocycles were prepared
from π-nucleophilic N-substituted pyrrole precursors 5b
(16) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475-1478.
(17) For an excellent review on π-nucleophilicity, see: Mayr, H.;
Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-77.
(18) Brauman, J . I.; Pandell, A. J . J . Am. Chem. Soc. 1967, 89,
5421-5424.
(19) (a) Childs, R. F.; Kostyk, M. D.; Lock, C. J . L.; Mahendran, M.
J . Am. Chem. Soc. 1990, 112, 8912-8920. (b) Childs, R. F.; Faggiani,
R.; Lock, C. J . L.; Mahendran, M.; Zweep, S. D. J . Am. Chem. Soc.
1986, 108, 1692-1693.
(20) Numerous examples of Lewis acid-promoted intermolecular
lactone-opening by π-nucleophiles via σ-C-O bond cleavage have been
reported in the literature. In most cases, the carbinol carbon is
substituted by alkyl groups or benzylic, favoring the formation of a
secondary, tertiary, or benzylic carbocation and the SN1 pathway. See
ref 5.
(13) Sakane, S.; Fujiwara, J .; Maruoka, K.; Yamamoto, H. Tetra-
hedron 1986, 42, 2193-2201.
(14) Stork reported the intramolecular opening of acylcyclopropanes
via homologous Michael addition of π-nucleophiles. That opening mode
was not observed in our systems, see: (a) Stork, G.; Gregson, M. J .
Am. Chem. Soc. 1969, 91, 2373-2374. (b) Stork, G.; Marx, M. J . Am.
Chem. Soc. 1969, 91, 2371-2373.
(21) Ghatak, U. R.; Chatterjee, N. R.; Sanyal, B. J . Org. Chem. 1979,
44, 1992-1999.
(15) See the Supporting Information for details.
J . Org. Chem, Vol. 68, No. 24, 2003 9487

lecular Friedel-Crafts alkylation using cyclopropane 8a (150
mg, 0.727 mmol), AlMe3 (1.5 mL, 2.0 M solution in hexanes, 2.9
mmol), TfOH (257 µL, 2.91 mmol), and ClCH2CH2Cl (2 mL).
Purification by HPLC (retention time ) 23.0 min) provided 9b
SCHEME 6. F r ied el-Cr a fts Alk yla tion Mech a n ism
(129 mg, 86%) as a clear colorless oil: [R]22 +73.1 (c 0.25,
D
CHCl3); IR (neat, cm-1) 2928, 2860, 2687, 2543, 1689, 1511, 1444,
1
1348, 1300, 1213; H NMR (300 MHz, CDCl3) δ 11.1 (1H, brs),
7.15 (1H, d, J ) 1.8 Hz), 6.17 (1H, d, J ) 1.6 Hz), 3.01 (1H, dd,
J ) 16.4, 10.7 Hz), 2.94 (1H, m), 2.68 (1H, m), 2.64 (1H, dd, J )
16.1, 4.9 Hz), 1.90 (3H, m), 1.80 (1H, m), 1.73 (1H, m), 1.62 (1H,
m), 1.39 (1H, m); 13C NMR (75 MHz, CDCl3) δ 179.1, 151.5,
138.8, 118.1, 112.8, 27.5, 26.5, 25.7, 25.4, 22.1, 21.4, 19.2; HRMS
(EI) m/z calcd for C12H14O3 (M+) 206.0943, found 206.0942.
Meth yl (1R,1a R,9a R)-1a -Meth yl-1a ,2,3,4,9,9a -h exa h yd r o-
1H-cyclop r op a [f]p yr r olo[1,2-a ]a zocin e-1-ca r boxyla te (9c).
The Friedel-Crafts reaction was carried out as in the general
procedure for the intramolecular Friedel-Crafts alkylation using
cyclopropane 5b (20 mg, 0.091 mmol), AlMe3 (182 µL, 2.0 M in
hexanes, 365 mmol), TfOH (32.3 µL, 365 mmol), and ClCH2CH2-
Cl (2 mL). The crude oil was filtered through a pad of silica gel,
eluted with Et2O, and concentrated. The oil was then dissolved
in MeOH/PhH (0.5 mL/1.5 mL), treated with TMSCHN2 (60 µL,
2.0 M solution in hexanes, 0.119 mmol), and stirred for 30 min
at rt. The solvent was removed in vacuo and the residue purified
by HPLC (retention time ) 24.6 min) to provide 9c (16.5 mg,
Crafts alkylation. The requirement of excess Lewis acid
is attributed to the likely formation of a complex ag-
gregate of the substrate and Lewis acid in the activation
stage that is common for aluminum Lewis acids.23 When
weak π-nucleophiles such as thiophene and veratrol are
involved, activation of the lactone moiety by the Lewis
acid induces the σ-C-O bond cleavage and formation of
the associated ion pair but rearrangement of the cyclo-
propane is probably faster than Friedel-Crafts alkyla-
tion.
In summary, an efficient method for the synthesis of
enantiomerically pure bicyclo[6.1.0]nonane-9-carboxylic
acid derivatives from 3-oxabicyclo[3.1.0]hexan-2-ones has
been described. Efforts are currently directed at the
application of this methodology to the synthesis of
crenulide natural products. These results will be reported
in due course.
78%) as a clear colorless oil: [R]22 +68.7 (c 0.12, CHCl3); IR
D
(neat, cm-1) 3100, 2952, 2917, 2856, 1718, 1485, 1466, 1439,
1369, 1301, 1274, 1234; 1H NMR (500 MHz, CDCl3) δ 6.51 (1H,
t, J ) 2.0 Hz), 5.99 (1H, t, J ) 3.0 Hz), 5.91 (1H, brs), 4.04 (1H,
dd, J ) 14.9, 6.3 Hz), 3.84 (1H, dd, J ) 14.5, 10.8 Hz), 3.66 (3H,
s), 3.13 (1H, dd, J ) 15.0, 11.9 Hz), 2.81 (1H, m), 2.47 (1H, m),
1.86 (2H, m), 1.71 (1H, dd, J ) 14.8, 7.5 Hz), 1.49 (1H, d, J )
8.2 Hz), 1.34 (1H, ddd, J ) 12.1, 8.6, 3.7 Hz), 1.05 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 172.5, 133.2, 121.7, 106.5, 106.1, 51.5,
51.3, 50.9, 36.6, 29.7, 29.1, 28.0, 26.4, 21.9; HRMS (EI) m/z calcd
for C14H19NO2 (M+) 233.1416, found 233.1412.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e In tr a m olecu la r F r ied el-
Cr a fts Alk yla tion . (6a R,7R,7a R)-6a -Meth yl-5,6,6a ,7,7a ,8-
h exa h yd r o-4H-cyclop r op a [4,5]cycloocta [b]fu r a n -7-ca r box-
ylic Acid (9a ). To a solution of AlMe3 (1.4 mL, 2.0 M solution
in hexanes, 2.7 mmol) in ClCH2CH2Cl (2 mL) at 0 °C in a
resealable Schlenk tube was added TfOH (241 µL, 2.72 mmol)
dropwise. After the addition was complete, the cloudy white
solution was stirred for 30 min at 0 °C. A solution of 3-oxabicyclo-
[3.1.0]hexan-2-one 5a (150 mg, 0.681 mmol) in ClCH2CH2Cl (2
mL) was cannulated into the Schlenk tube. After warming to
rt, the sealed tube was placed into an 85 °C oil bath and stirred
for 24 h. The reaction was quenched with cold 5% HCl (50 mL)
and the aqueous layer extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated. Purification by
HPLC on a normal-phase semipreparative column (100% hex-
anes for 15 min followed by 98:2 hexanes/i-PrOH, flow rate 7.0
mL/min, retention time ) 25.4 min) provided 9a (125 mg, 83%)
Meth yl (1S,1a R,9a S)-1a ,2,3,4,9,9a -Hexa h yd r o-1H-cyclo-
p r op a [f]p yr r olo[1,2-a ]a zocin e-1-ca r b oxyla t e (9d ). The
Friedel-Crafts reaction was carried out as in the general
procedure for the intramolecular Friedel-Crafts alkylation using
cyclopropane 8b (20 mg, 0.097 mmol), AlMe3 (195 µL, 2.0 M
solution in hexanes, 0.390 mmol), TfOH (34.5 µL, 0.390 mmol),
and ClCH2CH2Cl (2 mL). The crude oil was filtered through a
pad of silica gel, eluted with Et2O, and concentrated. The oil
was then dissolved in MeOH/PhH (0.5 mL/1.5 mL), treated with
TMSCHN2 (63 µL, 2.0 M solution in hexanes, 0.127 mmol), and
stirred for 30 min at rt. The solvent was removed in vacuo and
the residue purified by HPLC (retention time ) 24.8 min) to
provide 9d (17.3 mg, 81%) as a clear colorless oil: [R]22 +26.6
D
(c 0.33, CHCl3); IR (neat, cm-1) 2920, 2848, 1721, 1637, 1487,
1447, 1374, 1447, 1374, 1349, 1320, 1302, 1283, 1269, 1232; 1H
NMR (500 MHz, 363K, DMSO-d6) δ 6.55 (1H, t, J ) 2.1 Hz),
5.88 (1H, t, J ) 3.0 Hz), 5.80 (1H, m), 4.07 (1H, ddd, J ) 14.4,
9.4, 3.4 Hz), 3.81 (1H, ddd, J ) 14.5, 5.9, 4.1 Hz), 3.59 (3H, s),
3.14 (1H, dd, J ) 15.3, 4.8 Hz), 2.68 (1H, dd, J ) 15.1, 7.0 Hz),
2.06 (1H, m), 1.84 (1H, m), 1.55 (2H, m), 1.35 (1H, dddd, J )
as a clear colorless oil: [R]22 +45.6 (c 0.45, CHCl3); IR (neat,
D
cm-1) 2930, 2865, 1689, 1506, 1441, 1384, 1348, 1311, 1287,
1
1226; H NMR (300 MHz, CDCl3) δ 10.7 (1H, brs), 7.12 (1H, d,
J ) 1.7 Hz), 6.18 (1H, d, J ) 1.7 Hz), 3.04 (1H, dddd, J ) 15.4,
10.1, 5.0, 4.5 Hz), 2.86 (1H, ddd, J ) 15.5, 8.0, 3.1 Hz), 2.64
(1H, ddd, J ) 15.1, 8.5, 3.4 Hz), 2.55 (1H, dd, J ) 15.8, 3.9 Hz),
2.24 (1H, m), 1.77 (3H, m), 1.54 (2H, q, J ) 3.9 Hz), 1.11 (3H,
s); 13C NMR (75 MHz, CDCl3) δ 178.4, 152.4, 138.7, 118.7, 112.5,
36.4, 30.5, 29.9, 27.6, 27.2, 26.2, 24.9, 20.0; HRMS (EI) m/z calcd
for C13H16O3 (M+) 220.1099, found 220.1094.
15.9, 5.0, 4.9, 4.8 Hz), 1.23 (1H, t, J ) 4.7 Hz), 0.60 (1H, m); 13
C
NMR (125 MHz, 363 K, DMSO-d6) δ 172.8, 130.1, 120.8, 106.2,
106.1, 50.6, 45.9, 29.5, 27.8, 25.7, 25.2, 24.8, 23.9; HRMS (EI)
m/z calcd for C13H17NO2 (M+) 219.1259, found 219.1255.
Ack n ow led gm en t. The Natural Science and Engi-
neering Research Council of Canada (NSERC) and the
University of Waterloo are thanked for financial sup-
port. R.L.B. thanks NSERC for a PGS A fellowship.
(6a R,7R,7a S)-5,6,6a ,7,7a ,8-H exa h yd r o-4H -cyclop r op a -
[4,5]cycloocta [b]fu r a n -7-ca r boxylic Acid (9b). The reaction
was carried out as in the general procedure for the intramo-
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and full characterization data for com-
pounds 1, 2, 3a -d , 5a -d , 6, 7a ,b, 8a ,b and NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) No experimental evidence is available to determine if the triflate
dissociates in the complexation process of Me2AlOTf with the lactone.
In addition, no attempts were made to identify likely side products
such as methane or TfOH generated in the course of the Friedel-Crafts
alkylation.
(23) Beal, R. B.; Dombroski, M. A.; Snider, B. B. J . Org. Chem. 1986,
51, 4391-4399.
J O0351419
9488 J . Org. Chem., Vol. 68, No. 24, 2003