Electrocyclic ring-opening/π-allyl cation cyclization reaction sequences involving gem-dihalocyclopropanes as substrates: Application to syntheses of (±)-, (+)-, and (-)-γ-lycorane

Article abstract of DOI:10.1021/jo991791u

The readily prepared gem-dibromocyclopropanes (±)-13 and (±)-19 each engage in a silver(I)-promoted electrocyclic ring-opening/π-allyl cation cyclization sequence to deliver the hexahydroindole (±)-20, which participates in a Suzuki cross-coupling reaction with arylboronic acid 3 to give the tetracyclic compound (±)-21. Catalytic hydrogenation of this last compound proceeds in a completely stereoselective manner to give the saturated analogue (±)-24, which undergoes Bischler-Napieralski cyclization on reaction with phosphorus oxychloride. The resulting lactam (±)-25 is then reduced with lithium aluminum hydride to give (±)-γ-lycorane [(±)-1]. By using (-)-menthyl-derived carbamates 27 and 28, this chemistry has been extended to the synthesis of the (+)- and (-)-modifications of the title compound.

Full text of DOI:10.1021/jo991791u

J . Org. Chem. 2000, 65, 4241-4250
4241
Electr ocyclic Rin g-Op en in g/π-Allyl Ca tion Cycliza tion Rea ction
Sequ en ces In volvin g gem -Dih a locyclop r op a n es a s Su bstr a tes:
Ap p lica tion to Syn th eses of (()-, (+)-, a n d (-)-γ-Lycor a n e
Martin G. Banwell,* J oanne E. Harvey, and David C. R. Hockless
Research School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 0200, Australia
Angela W. Wu
School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia
Received November 18, 1999
The readily prepared gem-dibromocyclopropanes (()-13 and (()-19 each engage in a silver(I)-
promoted electrocyclic ring-opening/π-allyl cation cyclization sequence to deliver the hexahydroindole
(()-20, which participates in a Suzuki cross-coupling reaction with arylboronic acid 3 to give the
tetracyclic compound (()-21. Catalytic hydrogenation of this last compound proceeds in a completely
stereoselective manner to give the saturated analogue (()-24, which undergoes Bischler-Napieralski
cyclization on reaction with phosphorus oxychloride. The resulting lactam (()-25 is then reduced
with lithium aluminum hydride to give (()-γ-lycorane [(()-1]. By using (-)-menthyl-derived
carbamates 27 and 28, this chemistry has been extended to the synthesis of the (+)- and
(-)-modifications of the title compound.
In tr od u ction
corane, but the ee obtained in this case was only 46%.
More recently Ishibashi and co-workers3d have exploited
1-arylethylamine-based chiral auxiliaries in developing
a synthesis of (-)-γ-lycorane. It is against this back-
ground that we now report short and efficient syntheses
of the (()-, (+)-, and (-)-modifications of the title
compound.4 The work reported herein derives from a
general program underway within our laboratories5 that
is designed to exploit electrocyclic ring-opening reactions
of readily available halocyclopropanes for the purposes
of natural product synthesis.
Many of the lycorine-type Amaryllidaceae alkaloids,
which are characterized by the presence of the galanthan
ring system,1 display potentially useful biological proper-
ties including antiviral, insect antifeedant, and antin-
eoplastic activity, while others are known to inhibit plant
growth and/or disrupt the formation of peptide bonds
during protein synthesis.1 As a consequence of such
features, considerable effort has been directed toward the
total synthesis of these compounds.1 Unlike many of its
congeners, γ-lycorane (1), which was obtained in both
enantiomeric forms by Kotera during his degradation
studies2 of lycorine, does not appear to possess any useful
pharmacological properties. Nevertheless, it has been a
popular synthetic target3 primarily because its pentacy-
clic structure provides a means to demonstrate the utility
of new synthetic strategies. The racemic modification of
compound 1 has been prepared a number of times.3 Mori
has described3e an asymmetric synthesis of (+)-γ-ly-
Our retrosynthetic analysis of the target molecule 1 is
shown in Scheme 1 and involves, inter alia, disconnection
at the C7-C7a bond, which would be established via
Bischler-Napieralski cyclization of carbamate 2. Com-
pound 2 would, in turn, be constructed via installation
of the C12a-C12b bond (lycorane numbering) using a
Suzuki cross-coupling reaction between boronic acid 3
and hexahydroindole 4. It was anticipated that interme-
diate 4 could be prepared by subjecting the gem-dibro-
mocyclopropane 5 to silver(I)-promoted electrocyclic ring
opening and intramolecular nucleophilic capture of the
incipient π-allyl cation by the nitrogen of the tethered
carbamate so as to give the target hexahydroindole.6,7
Establishing the required all-cis stereochemical rela-
tionship between the three mutually fused and saturated
rings of γ-lycorane would rely on preferential formation
of the cis-isomer of hexahydroindole 4 during the cycliza-
tion step just mentioned. As a consequence of establishing
(1) For general reviews on lycorine-type alkaloids see: (a) Hoshino,
O. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York,
1998; Vol. 51, p 323-424. (b) Lewis, J . R. Nat. Prod. Rep. 1998, 107-
110.
(2) (a) Takeda, K.; Kotera, K.; Mizukami, S.; Kobayashi, M. Chem.
Pharm. Bull. 1960, 8, 483-486. (b) Kotera, K. Tetrahedron 1961, 12,
240-247. (c) Kotera, K. Tetrahedron 1961, 12, 248-261.
(3) For previous syntheses of γ-lycorane see: (a) Cassayre, J .; Zard,
S. Z. Synlett. 1999, 501-503. (b) Hoang-Cong, X.; Quiclet-Sire, B.; Zard,
S. Z. Tetrahedron Lett. 1999, 40, 2125-2126. (c) Cossy, J .; Tresnard,
L.; Pardo, D. G. Eur. J . Org. Chem. 1999, 1925-1933. (d) Ikeda, M.;
Ohtani, S.; Sato, T.; Ishibashi, H. Synthesis 1998, 1803-1806. (e)
Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.: Shibasaki, M.; Mori, M.
J . Org. Chem. 1995, 60, 2016-2021. (f) Angle, S. R.; Boyce, J . P.
Tetrahedron Lett. 1995, 36, 6185-6188. (g) Grothjahn, D. B.; Vollhardt,
K. P. C. Synthesis 1993, 579-605. (h) Pearson, W. H.; Schkeryantz, J .
M. J . Org. Chem. 1992, 57, 6783-6789. (i) Ba¨ckvall, J .-E.; Andersson,
P. G.; Stone, G. B.; Gogoll, A. J . Org. Chem. 1991, 56, 2988-2993. (j)
Sugiyama, N.; Narimiya, M.; Iida, H.; Kikuchi, T. J . Heterocycl. Chem.
1988, 25, 1455-1457. (k) Umezawa, B.; Hoshino, O.; Sawaki, S.;
Sashida, H.: Mori, K.; Hamada, Y.; Kotera, K.; Iitaka, Y.; Tetrahedron
1984, 40, 1783-1790 and references therein. (l) Higashiyama, H.;
Honda, T.; Otomasu, H.; Kametani, T. Planta Med. 1983, 48, 268-
271. (m) Iida, H.; Yuasa, Y.; Kibayashi, C. J . Org. Chem. 1979, 44,
1074-1080.
(4) Aspects of this work have been described previously in com-
munication form: Banwell, M. G.; Wu, A. W. J . Chem. Soc., Perkin
Trans. 1 1994, 2671-2672.
(5) See: (a) Banwell, M. G.; Berak, M.; Hockless, D. C. R. J . Chem.
Soc., Perkin Trans. 1 1996, 2217-2219. (b) Banwell, M. G.; Gable, R.
W.; Peters, S. C.; Phyland, J . R. J . Chem. Soc., Chem. Commun. 1995,
1395-1397. (c) Banwell, M. G.; Cowden, C. J .; Gable, R. W. J . Chem.
Soc., Perkin Trans. 1 1994, 3515-3518. (d) Banwell, M. G.; Cowden,
C. J . Aust. J . Chem. 1994, 47, 2235-2254. (e) Banwell, M. G.; Lambert,
J . N.; Gulbis, J . M.; Mackay, M. F. J . Chem. Soc., Chem. Commun.
1990, 1450-1452. (f) Banwell, M. G.; Onrust, R. Tetrahedron Lett.
1985, 26, 4543-4546.
10.1021/jo991791u CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/14/2000

4242 J . Org. Chem., Vol. 65, No. 14, 2000
Banwell et al.
Sch em e 1
bene addition reaction, compound (()-7 was converted
into acetate (()-8.
Reaction of compound (()-8 with dibromocarbene,
generated from bromoform and aqueous sodium hydrox-
ide with triethylbenzylammonium chloride (TEBAC) as
phase-transfer catalyst,9 gave an inseparable and ca. 3:1
mixture of compound (()-9 and its C2-epimer. The
assignment of compound (()-9 as the major product of
this reaction was based on the reasonable assumption
that dibromocarbene would add, preferentially, to the less
hindered face of the double bond within precursor (()-8.
Hydrolysis of the mixture of compound (()-9 and its C2-
epimer was readily effected with potassium carbonate in
methanol, and the ensuing alcohols [(()-10 and C2-epi-
(()-10] were converted into the corresponding mesylates,
(()-11 and C2-epi-(()-11, using conditions developed by
Crossland and Servis.10 The major mesylate was readily
separated from its less abundant and unstable counter-
part by flash chromatography. Reaction of compound
(()-11 with sodium azide in DMF at 18 °C for 24 h then
gave the azide (()-12. Reduction of this latter material
to the corresponding amine could be achieved under
Staudinger conditions (triphenylphosphine/water) or,
preferably, via hydrogenolysis using hydrogen with 10%
Pd on C as catalyst. Since the product amine was a labile
material, it was reacted in situ with methyl chlorofor-
mate. In this manner the target carbamate (()-13 was
obtained as an oil and characterized by standard spec-
troscopic methods.
A stereoselective route to the C2-epimer of carbamate
(()-13, viz., compound (()-19, is shown in Scheme 3 and
starts with the allylic acetate (()-14, which is readily
prepared in large quantity from cyclopentadiene.11 Thus,
dibromocarbene addition to compound (()-14 afforded a
ca. 4:1 mixture of the expected adducts (()-15 and C2-
epi-(()-15, which were hydrolyzed to the corresponding
alcohols (()-16 and C2-epi-(()-16 with potassium hy-
droxide in methanol. Oxidation of the latter compounds
with pyridinium chlorochromate (PCC)12 then gave the
previously reported ketone (()-17,13 which was reacted
with the anion derived from diethyl cyanomethylphos-
phonate,14 and in this manner a ca. 2:1 mixture of the
(E)- and (Z)-isomers of R,â-unsaturated nitrile (()-18 was
obtained. Subjection of this mixture to reaction with
hydrogen in the presence of PtO2 and chloroform15
resulted in formation of the hydrochloride salt of the
target amine. This material was immediately subjected
to reaction with methyl chloroformate in the presence of
pyridine, and the carbamate (()-19 was thereby obtained
[ca. 32% overall yield from the starting alkene (()-14].
Like isomer (()-13, carbamate (()-19 was obtained as
an oil and fully characterized by standard spectroscopic
methods. While rigorous proof of the stereochemical
relationship between the cyclopropane ring and the C2
side chain within this compound could not be obtained,
it is reasonable to assume that hydrogenation of the
the latter stereochemical feature, it was anticipated that
hydrogenation of the derived 7-arylhexahydroindole 2
should proceed with the desired facial selectivity and
thereby allow for installation of the correct (relative)
stereochemistry at C12b. The successful implementation
of this plan is outlined below.
Resu lts a n d Discu ssion
Syn th esis of (()-γ-Lycor a n e. To establish whether
the crucial π-allyl cation cyclization reaction 5 f 4 had
any specific stereochemical requirements, both diastere-
oisomers represented by structure 5 were sought. The
synthesis of a relevant congener, compound (()-13, is
outlined in Scheme 2 and starts with the commercially
available carboxylic acid (()-6. Thus, reduction of the
latter compound to the corresponding and previously
reported8 alcohol (()-7 was achieved using lithium
aluminum hydride. To reduce the possibility of O-H and
C-H insertion reactions in the subsequent dibromocar-
(6) For some earlier examples of cationic cyclizations initiated by
electrocyclic cleavage of gem-dibromocyclopropanes see: (a) Gassman,
P. G.; Tan, L.; Hoye, T. R. Tetrahedron Lett. 1996, 37, 439-442. (b)
Hemmingsen, T. H.; Svendsen, J . S.; Sydnes, L. K. Acta Chem. Scand.
1988, B42, 651-661. (c) Brocksom, T. J .; Canevarolo, E. T.; Lopes, F.
T. An. Acad. Bras. Cienc. 1985, 57, 165-168; Chem. Abs. 1986, 105,
191422. (d) Danheiser, R. L.; Morin, J . M.; Salaski, E. J . J . Am. Chem.
Soc. 1985, 107, 8066-8073. (e) Danheiser, R. L.; Morin, J . M.; Yu, M.;
Basak, A. Tetrahedron Lett. 1981, 22, 4205-4208.
(9) Banwell, M. G. J . Chem. Soc., Chem. Commun. 1983, 1453-
1454.
(10) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35, 3195-
3196.
(11) Alder, K.; Flock, F. H. Chem. Ber. 1956, 89, 1732-1737.
(12) Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis 1982, 245-
258.
(13) Washburn, W. N.; Zahler, R.; Chen, I. J . Am. Chem. Soc. 1978,
100, 5863-5874.
(14) Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis; J ohn
Wiley and Sons: New York, 1974; Vol. 4, p 150 and references therein.
(15) Secrist, J . A.; Logue, M. W. J . Org. Chem. 1972, 37, 335-336.
(7) For other examples of intramolecular alkylation at carbamate
nitrogen see: (a) see ref 3i. (b) Abelman, M. M.; Overman, L. E.; Tran,
V. D. J . Am. Chem. Soc. 1990, 112, 6959-6964. (c) Knapp, S.; Kukkola,
P. J .; Sharma, S.; Murali Dhar, T. G.; Naughton, A. B. J . J . Org. Chem.
1990, 55, 5700-5710 and references therein. For an excellent recent
review on “the tethered nitrogen in natural product synthesis” see:
Knapp, S. Chem. Soc. Rev. 1999, 28, 61-72.
(8) Balme, G.; Bouyssi, D.; Faure, R.; Gore, J .; Van Hemelryck, B.
Tetrahedron 1992, 48, 3891-3902.

Syntheses of (()-, (+)- and (-)-γ-Lycorane
J . Org. Chem., Vol. 65, No. 14, 2000 4243
Sch em e 2
Sch em e 3
the tether linking the reacting centers in precursors
(()-13 and (()-19.
With the pivotal hexahydroindole (()-20 in hand,
completion of the synthesis of the racemic modification
of γ-lycorane proved relatively straightforward. Thus,
Suzuki cross-coupling of this compound with the readily
available arylboronic acid 35d proceeded uneventfully to
give the 7-arylated hexahydroindole (()-21 in 87% yield.
When this latter compound was subjected to a Bischler-
Napieralski reaction with POCl3 at 80 °C for 30 h, the
previously reported16 cyclization product (()-23, contain-
ing a rearranged double bond, was obtained in 56% yield.
When the same reaction was conducted for 16 h, a 1:1
mixture of cyclization products (()-22 and (()-23 was
obtained in a combined yield of 92%, thus suggesting that
the double-bond isomerization process leading to the
latter product occurs after the cyclization reaction. While
compound (()-22 was readily hydrogenated, in excellent
yield, to give the known lactam (()-25,3i isomer (()-23
was quite resistant to such a conversion even when ionic
hydrogenation conditions were employed. The difficulties
created by the double-bond migration process accompa-
nying the POCl3-promoted cyclization reaction could be
overcome by using a combination of triflic anhydride
(Tf2O)/N,N-(dimethylamino)pyridine (DMAP)17 to effect
this conversion, and under appropriate conditions lactam
(()-22 was the exclusive product of reaction. Another
serviceable route to compound (()-25, a proven precursor3i
to the target γ-lycorane, involved reversing the order of
hydrogenation and Bischler-Napieralski cyclization steps.
Thus, compound (()-21 was readily hydrogenated under
standard conditions, and the resulting product (()-24
(95%) underwent a smooth reaction with POCl3 to give
lactam (()-25 in 79% yield. Using the conditions reported
by Ba¨ckvall,3i this last compound was reduced with
LiAlH4 to give (()-γ-lycorane [(()-1] in 84% yield. The
1H and 13 C NMR spectra of this material matched those
derived from an authentic sample kindly provided by
Professor W. Pearson (University of Michigan).
carbon-carbon double bond within precursors (()-18
should occur from the less hindered R-face and thereby
establish the illustrated syn-relationship between the
cyclopropane ring and the side chain.
The critical π-allyl cation cyclization reaction foreshad-
owed in Scheme 1 proved to be a rather facile process
and was initially effected using trifluoroethanol (TFE)
as solvent and silver acetate to promote electrocyclic ring
opening of the halocyclopropane unit (Scheme 4). Under
such conditions, substrate (()-19 was readily converted
into desired hexahydroindole (()-20, which was obtained
in 87% yield. Under the same conditions, the isomeric
gem-dihalocyclopropane (()-13 also gave compound
(()-20 (44%). However, the reaction was not as clean, and
1H NMR and MS analysis of the reaction products
suggested formation of uncyclized products, each incor-
porating either an acetate or trifluoroethoxy group. The
formation of such byproducts could be suppressed dra-
matically by using silver perchlorate in TFE at 18 °C to
effect the π-allyl cation cyclization, and under such
conditions substrates (()-13 and (()-19 gave product
(()-20 in yields of 95% and 91%, respectively.
These results clearly suggest that, under optimal
conditions, the stereochemical relationship between the
gem-dihalocyclopropane and the tethered nucleophile is
not important in determining the success of this type of
electrocyclic ring-opening/cyclization process. Indeed, on
the basis of the latter observations it could be argued that
the conversions described here are not concerted but
involve a common cationic intermediate. The exclusive
formation of the cis-fused cyclization product (()-20, the
structure of which follows from its successful conversion
into target (()-1, is a consequence of the short length of
Syn th esis of (+)- a n d (-)-γ-Lycor a n e. Previous
work from our laboratories5d suggested that replacing,
in the synthetic sequences outlined in Scheme 4, methyl
carbamates such as (()-13 and (()-19 with the corre-
sponding (-)-menthyl carbamates should enable prepa-
ration of the (+)- and (-)-forms of γ-lycorane. This could
be done without any need to increase the number of
synthetic steps, since the use of such a chiral auxiliary
would only entail a separation of diastereoisomers at an
appropriate stage. To these ends, the E/Z mixture of R,â-
(16) Iida, H.; Aoyagi, S.; Kibayashi, C. J . Chem. Soc., Perkin Trans.
1 1975, 2502-2506.
(17) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J .;
Hockless, D. C. R.; Holman, J . W.; Read, R. W.; Wu, A. W. J . Chem.
Soc., Chem. Commun. 1995, 2551-2553.

4244 J . Org. Chem., Vol. 65, No. 14, 2000
Banwell et al.
Sch em e 4
Sch em e 5
route to these compounds, methyl carbamate (()-20 was
treated with potassium hydroxide and hydrazine hydrate
in ethylene glycol, and the resulting (racemic) amine was
reacted with (-)-menthyl carbamate. As with precursors
27 and 28, compounds 29 and 30 could not be separated
from one another by conventional means, so the mixture
was subjected to palladium-catalyzed Suzuki cross-
coupling with the boronic acid 3. The products 31 and
32 so formed were now easily separated by HPLC
techniques, and each was obtained as an oil in 49% yield.
The absolute stereochemistry of these compounds follows
from their successful conversions into (+)- and (-)-γ-
lycorane. Thus, each was converted, quantitatively, into
the corresponding saturated analogues, 33 and 34, under
1
standard hydrogenation conditions. The H and {1H}13C
NMR spectra of diastereoisomers 33 and 34 were in stark
contrast to those of their unsaturated precursors. Thus,
the extensive line broadening observed in the precursors
was no longer as severe, with the result that the signals
(in both spectra) were sharper. The removal of the double
bond seemingly results in more ready interconversion of
the carbamate rotamers.18Compounds 33 and 34 were
each subjected to Bischler-Napieralski cyclization with
POCl3, and the lactams (-)-25 and (+)-25, respectively,
were thereby obtained (95% in each case). Each of these
products had identical physical and spectroscopic proper-
ties save for the fact that the specific rotations were of
opposite sign (although of equal magnitude). Compound
(+)-25 was subjected to single-crystal X-ray analysis, and
the resulting structure is shown in Figure 1.19
Lithium aluminum hydride promoted reduction of
compounds (+)- and (-)-25 then gave the corresponding
(+)- and (-)-forms of γ-lycorane, and the physical and
spectroscopic properties of each of these materials matched
those reported previously. The enantiomeric purity of
unsaturated nitriles (()-18 was hydrogenated under the
previously described conditions, and the resulting amine
was reacted with (-)-menthyl chloroformate.
The ensuing 1:1 mixture of diastereoisomeric carba-
mates 27 and 28 was subjected to reaction with silver
acetate in TFE. Under such conditions the expected
hexahydroindoles 29 and 30 were formed in 94% com-
bined yield. In an alternate and equally high yielding
(18) Cox, C.; Lectka, T. J . Org. Chem. 1998, 63, 2426-2427.
(19) Crystal data for compound (+)-25: C16H17NO3
) 411.38,
orthorhombic, P212121 (no. 19) with a ) 7.006(2), b ) 12.782(2), c )
29.395(2) Å, V ) 2632.4(8) Å3, Z ) 8, Dc ) 1.038 g cm-1, R ) 0.027
and Rw ) 0.030 with 2062 reflections having I > 3σ(I) (from a total of
2305 reflections).

Syntheses of (()-, (+)- and (-)-γ-Lycorane
J . Org. Chem., Vol. 65, No. 14, 2000 4245
2-Cyclop en ten e-1-eth a n ol [(()-7]. LiAlH4 (13.3 mL of a
1.0 M solution in THF, 13.3 mmol) was slowly added to a
magnetically stirred solution of acid 6 (2.0 mL, 16.6 mmol,
Aldrich) in anhydrous THF (5.0 mL) at such a rate so as to
maintain gentle reflux. The resulting mixture was allowed to
cool to 18 °C, stirred at this temperature for 21 h, cooled on
an ice-water bath, and treated, dropwise, with ethyl acetate
(1.1 mL), NaOH (1.2 mL of a 15% w/v aqueous solution), and
water (3.0 mL). The resulting suspension was stirred at 0 °C
for 3 h and then filtered through a no. 3 porosity sintered-
glass funnel. The solids thus retained were washed with
diethyl ether (20 mL), and the combined filtrates were
concentrated under reduced pressure. The residue was cooled
on an ice-water bath and treated with HCI (120 mL of a 2 M
aqueous solution), and the resulting mixture was extracted
with diethyl ether. The combined organic phases were dried
(MgSO4), filtered, and concentrated under reduced pressure
to give alcohol (()-78 (1.80 g, 97%) as a pungent yellow liquid,
which was immediately used in the next step of the reaction
sequence. A spectroscopically pure sample of this material was
obtained by vacuum distillation (bp 79 °C, 2 mmHg) of the
crude material: found (M - H)+ 111.0809, C7H12O requires
(M - H)+ 111.0810; IR (KBr) 3326, 1613 cm-1; 1H NMR δ 5.73
(m, 1H), 5.68 (m, 1H), 3.69 (m, 2H), 2.76 (m, 1H), 2.42-2.21
(complex m, 2H), 2.06 (m, 1H), 1.69 (m, 1H), 1.58 (s, 1H), 1.58
(partially obscured m, 1H), 1.43 (m, 1H); 13C NMR δ 134.6
(CH), 130.7 (CH), 61.8 (CH2), 42.1 (CH), 38.9 (CH2), 31.9 (CH2),
29.8 (CH2); MS (EI, 70 eV) m/z (rel intensity) 111 [(M - H+,
25], 95 [(M - OH)+, 100].
F igu r e 1. CS Chem3D Pro drawing of compound (+)-25
generated using data derived from an X-ray crystallographic
study (hydrogen atoms omitted for clarity).
2-Cyclop en ten e-1-eth a n ol Aceta te [(()-8]. A magneti-
cally stirred solution of alcohol (()-7 (1.83 g, 16.3 mmol) in
anhydrous pyridine (2.65 mL, 32.8 mmol) maintained under
a nitrogen atmosphere at 18 °C was treated with acetic
anhydride (3.10 mL, 32.9 mmol). The reaction mixture was
stirred at 18 °C for 20 h and then subjected to flash chroma-
tography (silica, 1:19 EtOAc/hexane elution). Concentration
of the appropriate fractions (Rf ) 0.3) gave a pale-yellow oil,
which was subjected to short path distillation under reduced
pressure. Collection of the appropriate fractions then gave the
title compound (()-821 (2.30 g, 92%) as a clear colorless oil (bp
89 °C, 3 mmHg): IR (KBr) 1745 cm-1; 1H NMR δ 5.72 (m, 1H),
5.64 (m, 1H), 4.09 (m, 2H), 2.71 (m, 1H), 2.38-2.19 (complex
m, 2H), 2.05 (m, 1H), 2.02 (s, 3H), 1.74 (m, 1H), 1.58 (m, 1H),
1.46-1.35 (complex m, 1H); 13C NMR δ 171.1 (CO), 134.1 (CH),
130.9 (CH), 63.4 (CH2), 42.3 (CH), 34.6 (CH2), 31.8 (CH2), 29.7
(CH2), 21.0 (CH3); MS (EI, 70 eV) m/z (rel intensity) 94 (75)
[(M - CH3CO2H)+], 79 (100).
F igu r e 2. Chiral HPLC analysis of (i) (()-(1), (ii) (+)-(1), and
(iii) (-)-(1). Analyses conducted using a Chiralcel OD analyti-
cal column (4.6 cm × 25 cm) with 1:9 EtOH/hexane as eluting
solvent and a flow rate of 1 mL/min; limits of detection, (5%.
these compounds was confirmed using a chiral HPLC
column, and under appropriate conditions baseline sepa-
ration of the two enantiomers could be achieved (Figure
2).
Con clu sion
[1r,2r,5r]-6,6-Dibr om o-2-(2′-h ydr oxyeth yl)bicyclo[3.1.0]-
h exa n e Aceta te [(()-9] a n d [1r,2â,5r]-6,6-Dibr om o-2-(2′-
h yd r oxyeth yl)bicyclo[3.1.0]h exa n e Aceta te [C2-epi-(()-
9]. NaOH (5.5 g of a 44% w/w aqueous solution) was added
dropwise to a magnetically stirred solution of alkene (()-8 (409
mg, 2.65 mmol), bromoform (2.60 mL, 29.8 mmol), and TEBAC
(64 mg, 0.28 mmol) in benzene (7.2 mL) maintained at 0 °C
(ice bath). The resulting two-phase mixture was allowed to
warm to 18 °C, stirred vigorously for 66 h, and then poured
into a mixture of hexane (40 mL) and water (40 mL). The
separated aqueous phase was extracted with hexane, and the
combined organic fractions were washed with brine, dried
(MgSO4), filtered, and concentrated under reduced pressure
to a pale-yellow oil. This material was subjected to flash
chromatography (silica, 1:24 EtOAc/hexane elution), and after
concentration of the appropriate fractions (Rf ) 0.2), a ca. 3:1
mixture of compound (()-9 and C2-epi-(()-9 (606 mg, 70%)
was obtained as a pale-yellow oil: found (M + H+) 326.9417;
The concise syntheses of the (()-, (+)-, and
(-)-modifications of γ-lycorane outlined above serve to
highlight the potential utility of the title reaction se-
quences for the synthesis of polycyclic frameworks,
including those associated with alkaloids. The capacity
to vary the internal nucleophile, which captures the
pivotal π-allyl cation intermediate, and the length of the
tether connecting such reacting centers would seem to
offer considerable potential for the synthesis of a wide
range of carbo- and heterocyclic frameworks. This po-
tential is further enhanced by the ease of production of
the requisite gem-dihalocyclopropane-containing sub-
strates via phase-transfer generated dihalocarbene ad-
dition to the corresponding alkene. Work aimed at
extending this type of chemistry is currently underway
in our laboratories and the results will be reported in
due course.
C
10H1479Br81BrO2 requires (M + H+) 326.9418; IR (KBr) 1740
1
cm-1; H NMR δ [(()-9] 4.11 (m, 2H), 2.29-2.21 (complex m,
2H), 2.15-1.60 (complex m, 6H), 2.06 (s, 3H), 1.47 (m, 1H); δ
[C2-epi-(()-9] 4.21 (m, 2H), 2.53 (broad m, 1H), 2.12-1.60
(complex m, 7H), 2.09 (s, 3H), 1.47 (m, 1H); 13C NMR δ [(()-9]
Exp er im en ta l Section
(20) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J . Org. Chem. 1998,
63, 9139-9144.
(21) Adam, W.; Carballeira, N.; Gillaspey, W. D. Tetrahedron Lett.
1983, 24, 5473-5476.
Unless otherwise specified, all NMR spectra were recorded
in CDCl3 on
a Varian Unity 300 spectrometer. General
experimental procedures have been described elsewhere.5d,20

4246 J . Org. Chem., Vol. 65, No. 14, 2000
Banwell et al.
δ 171.1 (CO), 62.8 (CH2), 44.1 (CH), 40.0 (CH), 39.4 (CH), 38.6
(CBr2), 34.5 (CH2), 32.9 (CH2), 28.3 (CH2), 21.0 (CH3); δ [C2-
epi-(()-9] 171.2 (CO), 63.9 (CH2), 41.9 (CH), 41.3 (CH), 36.2
(CH), 29.4 (CH2), 28.7 (CH2) (three signals obscured/overlap-
ping); MS m/z (EI, 70 eV) (rel intensity) 329 (1.5) 327 (2.7)
325 (1.4) (M + H+), 149 (100).
Meth yl (1′r,2′r,5′r)-{2-(6′,6′-Dibr om obicyclo[3.1.0]h ex-
2′-yl)eth yl}ca r ba m a te [(()-13]. Meth od A. A solution of
triphenylphosphine (51 mg, 0.19 mmol) in THF (250 µL)
maintained under a nitrogen atmosphere was treated with a
solution of azide (()-12 (52 mg, 0.168 mmol) in THF (400 µL).
The reaction mixture was protected from light and stirred at
18 °C for 1.5 h and then treated with water (30 mg, 1.67 mmol).
The resulting two-phase mixture was stirred at 18 °C for a
further 6.5 h and then concentrated under reduced pressure.
The residue was dissolved in anhydrous dichloromethane (0.80
mL), and the resulting magnetically stirred solution was cooled
to 0 °C and treated, dropwise, with pyridine (61 µL, 0.754
mmol) and methyl chloroformate (147 µL, 1.90 mmol). Stirring
was continued for 2 h at 0 °C followed by 14 h at 18 °C, and
then the reaction mixture was diluted with dichloromethane
(5 mL) and washed with water followed by brine. The
separated organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure to a pale-yellow oil,
which was subjected to flash chromatography (silica, 1:4
EtOAc/hexane elution). Concentration of the appropriate frac-
tions (Rf ) 0.2) then gave the title carbamate (()-13 (25 mg,
43%) as a pale-yellow oil: found M+ 338.9466; C10H1579Br2NO2
[1r,2r,5r]-6,6-Dibr om o-2-(2′-h ydr oxyeth yl)bicyclo[3.1.0]-
h exan e [(()-10] an d [1r,2â,5r]-6,6-Dibr om o-2-(2′-h ydr oxy-
eth yl)bicyclo[3.1.0]h exa n e [C2-epi-(()-10]. A solution of a
ca. 3:1 mixture of compound (()-9 and its C2-epimer (606 mg,
1.86 mmol) in methanol (4.0 mL) was treated with potassium
carbonate (688 mg, 4.98 mmol), and the resulting suspension
was stirred at 18 °C for 24 h and then poured into brine (100
mL). The ensuing mixture was extracted with dichloromethane,
and the combined organic layers were then washed with water
before being dried (MgSO4), filtered, and concentrated under
reduced pressure to a pale-yellow oil. Subjection of this
material to flash chromatography (silica, 1:4 EtOAc/hexane
elution) and concentration of the appropriate fractions (Rf )
0.2) afforded a ca. 3:1 mixture of alcohol (()-10 and its C2-
epi-(()-10 (329 mg, 62%) as a clear, colorless oil: found (M -
H2O)+ 263.9153; C8H1279Br2O requires (M - H2O)+ 263.9149;
IR (KBr) 3332 cm-1; 1H NMR δ [(()-10] 3.70 (m, 2H), 2.26 (m,
2H), 2.17-1.72 (complex m, 6H), 1.62 (m, 1 H), 1.50-1.40
(complex m,1H); δ [C2-epi-(()-10] 3.75 (m, 2H), 2.60 (broad
m, 1H), 2.26 (m, 2H), 2.17-1.72 (complex m, 6H), 1.62 (m, 1
H); 13C NMR δ [(()-10] 61.2 (CH2), 44.3 (CH), 39.8 (CH), 39.7
(CBr2), 39.3 (CH), 38.6 (CH2), 33.0 (CH2), 28.3 (CH2); δ [C2-
epi-(()-10] 62.2 (CH2), 42.0 (CH), 40.7 (CH), 38.4 (CH), 36.6
(CBr2), 33.5 (CH2), 29.3 (CH2), 28.8 (CH2); MS m/z (EI, 70 eV)
(rel intensity) 286 (0.2) 284 (0.5) 282 (0.3) (M+), 105 (100).
[1r,2r,5r]-6,6-Dibr om o-2-(2′-h ydr oxyeth yl)bicyclo[3.1.0]-
h exa n e Meth a n esu lfon a te [(()-11]. A chilled (0 °C) and
magnetically stirred mixture of a solution of a ca. 3:1 mixture
of compound (()-10 and C2-epi-(()-10 (88 mg, 0.31 mmol) in
anhydrous dichloromethane (400 µL) maintained under a
nitrogen atmosphere was treated, dropwise, with triethyl-
amine (60 µL, 0.43 mmol) and then methanesulfonyl chloride
(30 µL, 0.338 mmol). The resulting solution was stirred at 0
°C for 10 h and then at 18 °C for 14 h before being poured
into brine (20 mL) and extracted with dichloromethane. The
combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure to give a ca. 3:1 mixture
of compound (()-11 and C2-epi-(()-11 as a pale-yellow oil.
Subjection of this mixture of mesylates to flash chromatogra-
phy (silica, 1:4 EtOAc/hexane elution) afforded, after concen-
tration of the appropriate fractions (Rf ) 0.2), the mesylate
(()-11 (80 mg, 72%) as a pale-yellow oil: IR (KBr) 1354, 1175
cm-1; 1H NMR δ 4.27 (m, 2H), 3.04 (s, 3H), 2.29 (m, 2H), 2.17-
1.93 (m, 4H), 1.88-1.77 (m, 2H), 1.52-1.44 (m, 1H); 13C NMR
δ 68.0 (CH2), 43.8 (CH), 39.6 (CH or CH3), 39.4 (CH or CH3),
39.0 (CBr2), 37.5 (CH or CH3), 34.9 (CH2), 33.1 (CH2), 28.3
(CH2).
1
requires M+ 338.9470; IR (KBr) 3332, 1701 cm-1; H NMR δ
4.74 (s, 1H, NH), 3.67 (s, 3H), 3.21 (m, 2H), 2.27 (m, 1H), 2.22-
1.77 (complex m, 5H), 1.71 (m, 1H), 1.62-1.41 (complex m,
2H); 13C NMR δ 157.0 (CO), 52.1 (CH), 44.1 (CH or CH3), 40.6
(CH or CH3), 39.5 (CH2), 39.3 (CH or CH3), 36.1 (CH2), 32.9
(CH2), 28.4 (CH2) (one signal obscured/overlapping); MS m/z
(EI, 70 eV) (rel intensity) 343 (0.4) 341 (0.8) 339 (0.4) (M+), 88
(100) [(CH2NHCO2CH3)+].
Meth od B. A chilled (0 °C) and magnetically stirred solution
of azide (()-12 (65 mg, 0.21 mmol) in THF (5.0 mL) was treated
with 10% palladium on charcoal (67 mg), and an atmosphere
of hydrogen was established above the reaction mixture. After
0.66 h methyl chloroformate (81 µL, 1.1 mmol) and then
triethylamine (58 µL, 0.42 mmol) were introduced, and stirring
was continued under a hydrogen atmosphere at 0 °C for 2 h.
The reaction mixture was then filtered through a 1 cm deep
pad of Celite contained in a sintered-glass funnel. The pad was
washed with EtOAc (30 mL), and the combined filtrates were
concentrated under reduced pressure to give a light-yellow oil,
which was subjected to flash chromatography (silica, 1:4
EtOAc/hexane elution). Concentration of the appropriate frac-
tions (Rf ) 0.3) then gave the title carbamate (()-13 (61 mg,
85%) as a clear colorless oil, which was identical, in all
respects, with the material obtained via Method A (above).
(1r,2r,5r)-6,6-Dibr om obicyclo[3.1.0]h exa n -2-ol a ceta te
[(()-15] a n d (1r,2â,5r)-6,6-d ibr om obicyclo[3.1.0]h exa n -
2-ol a ceta te [C2-epi-(()-15]. NaOH (85 mL of a 50% w/v
aqueous solution) was added in portions to a magnetically
stirred solution of 3-acetoxycyclopentene (()-1411 (8.0 g, 63.5
mmol), bromoform (55 mL, 0.698 mol), and TEBAC (170 mg,
0.75 mmol) in benzene (150 mL), which was maintained at 0
°C on an ice bath. After addition was complete the resulting
mixture was allowed to stir vigorously for a further 16 h at 18
°C and then poured into water (200 mL) and hexane (200 mL).
The aqueous layer was extracted with hexane, and the
combined organic fractions were washed with brine before
being dried (MgSO4), filtered, and concentrated under reduced
pressure to give a brown oil. This material was subjected to
dry-column flash chromatography (silica, 1:19 EtOAc/hexane
elution) to give a ca. 4:1 mixture of diastereoisomeric adducts
(()-15 and C2-epi-(()-15 (15.2 g, 81%) as a pale-yellow oil. For
the purposes of spectroscopic characterization a small amount
of this material was resubjected to dry-column flash chroma-
tography (silica, 1:19 EtOAc/hexane elution) to afford two
fractions, A and B.
[1r,2r,5r]-2-(2′-Azid oe t h yl)-6,6-d ib r om ob icycloh e x-
a n e [(()-12]. A magnetically stirred solution of mesylate
(()-11 (110 mg, 0.30 mmol) in anhydrous DMF (3.0 mL)
maintained under a nitrogen atmosphere was treated, in one
portion, with NaN3 (398 mg, 6.12 mmol). The resulting mixture
was protected from light and stirred at 18 °C for 24 h, and
then the DMF was removed under reduced pressure. The white
solid thus obtained was partitioned between hexane (60 mL)
and water (60 mL), and the separated aqueous layer was
extracted with hexane. The combined organic phases were
dried (MgSO4), filtered, and concentrated under reduced
pressure to a pale-yellow oil, which was subjected to flash
chromatography (silica, 1:19 CH2Cl2/hexane elution). Concen-
tration of the appropriate fractions (Rf ) 0.3) gave the title
azide (()-12 (72 mg, 77%) as a clear, colorless oil: found (M -
N2 - H)+ 281.9142; C8H1181Br2N3 requires (M - N2 - H)+
Concentration of fraction A (Rf ) 0.3) afforded (()-15 as a
clear colorless oil: found M+ 295.9058; C8H1079Br2 O2 requires
1
1
281.9139; IR (KBr) 2095 cm-1; H NMR δ 3.33 (m, 2H), 2.25
M+ 295.9047; IR (NaCl) 1733 cm-1; H NMR δ 5.16 (m, 1H),
(m, 2H), 2.15-1.75 (complex m, 5H), 1.64 (m, 1H), 1.44 (m,
1H); 13C NMR δ 49.8 (CH2), 44.0 (CH), 40.5 (CH), 39.3 (CH),
39.1 (CBr2), 34.7 (CH2), 32.9 (CH2), 28.3 (CH2); MS m/z (EI,
70 eV) (rel intensity) 283 (0.2) 281 (0.6) 279 (0.3) [(M - N2)+],
55 (100).
2.41 (m, 2H), 2.31-2.16 (complex m, 2H), 2.06 (s, 3H), 1.92
(m, 1H), 1.72 (m, 1H); 13C NMR δ 170.0, 77.9, 42.8, 39.0, 33.7,
32.8, 27.5, 21.1; MS m/z (EI, 70 eV) (rel intensity) 300 (3) 298
(5) 296 (3) (M+), 77 (100). Concentration of fraction B (Rf )
0.25) afforded C2-epi-(()-15 as a clear colorless oil: found M+

Syntheses of (()-, (+)- and (-)-γ-Lycorane
J . Org. Chem., Vol. 65, No. 14, 2000 4247
295.9052; C8H1079Br2O2 requires M+ 295.9047; IR (NaCl) 1733
a ca. 2:1 mixture of the title compounds (E)-(()-18 and (Z)-
(()-18 (7.86 g, 100%) as a clear, colorless oil, which could be
used without purification in the next step of the reaction
sequence. For the purposes of spectroscopic characterization
a portion of this mixture was resubjected to flash column
chromatography (silica gel, 1:9 EtOAc/hexane elution) to afford
two fractions, A and B.
1
cm-1; H NMR δ 5.45 (dd, J ) 9.3 and 5.9 Hz, 1H), 2.57 (dd,
J ) 7.4 and 5.9 Hz, 1H), 2.27 (m, 1H), 2.17-2.11 (complex m,
1H), 2.10 (s, 3H), 2.09-2.03 (complex m, 2H), 1.90-1.80
(complex m, 1H); 13C NMR δ 171.0, 77.8, 40.0, 38.3, 32.5, 28.6,
26.6, 21.1; MS m/z (EI, 70 eV) (rel intensity) 300 (3) 298 (7)
296 (4) (M+), 77 (100).
(1r,2r,5r)-6,6-Dibr om obicyclo[3.1.0]h exa n -2-ol [(()-16]
a n d (1r,2â,5r)-6,6-d ibr om obicyclo[3.1.0]h exa n -2-ol [C2-
epi-(()-16]. The ca. 4:1 mixture of acetates (()-15 and C2-
epi-(()-15 (9.10 g, 30.7 mmol), prepared as described above,
was added dropwise to a magnetically stirred solution of KOH
(20.0 g, 0.357 mol) in MeOH (100 mL) maintained at 0 °C.
After addition was complete the resulting mixture was allowed
to warm to 18 °C, and stirring was continued for a further 16
h. The reaction mixture was then poured into brine (200 mL)
and extracted with CH2Cl2. The combined organic fractions
were washed with water before being dried (MgSO4), filtered,
and concentrated under reduced pressure to give a yellow
residue. Subjection of this material to dry-column flash chro-
matography (silica gel, 1:4 EtOAc/hexane elution) afforded a
ca. 4:1 mixture of diastereoisomeric alcohols (()-16 and C2-
epi-(()-16 (7.5 g, 96%) as a clear, colorless oil, which could be
used in the next step of the reaction sequence. For the purposes
Concentration of fraction A (Rf ) 0.4) gave a white solid,
which was recrystallized (diethyl ether/hexane) to give com-
pound (E)-(()-18 as white prisms, mp 72-73 °C: found C, 34.8;
H, 2.2; N, 5.1; Br, 57.6; M+ 274.8936; C8H779Br2N requires C,
34.7; H, 2.5; N, 5.1; Br, 57.7; M+ 274.8945; IR (KBr) 2210, 1604
cm-1; 1H NMR δ 5.50 (t, J ) 2.7 Hz, 1H), 2.90 (d, J ) 6.8 Hz,
1H), 2.84-2.75 (complex m, 1H), 2.70 (dt, J ) 6.8 and 0.7 Hz,
1H), 2.65-2.55 (complex m, 1H), 2.37-2.67 (complex m, 1H),
2.14-2.07 (complex m, 1H); 13C NMR δ 167.8, 116.5, 94.7, 45.1,
42.8, 33.7, 33.1, 27.3; MS m/z (EI, 70 eV) (rel intensity) 278
(0.6) 276 (1) 274 (0.5) [(M - H)+], 117 (100), 116 (54).
Concentration of fraction B (Rf ) 0.3) gave compound (Z)-(()-
18 as a clear, colorless oil: found M+ 274.8947; C8H779Br2N
requires M+ 274.8945; IR (NaCl) 2216, 1630 cm-1; 1H NMR δ
5.37 (t, J ) 2.3 Hz, 1H), 3.18 (d, J ) 6.6 Hz, 1H), 2.70 (t, J )
6.7 Hz, 1H), 2.59-2.54 (m, 2H), 2.34-2.25 (m, 1H), 2.11-2.04
(m, 1H); 13C NMR δ 167.5, 116.8, 94.6, 44.3, 42.5, 33.6, 33.2,
27.5; MS m/z (EI, 70 eV) (rel intensity) 278 (1) 276 (2) 274 (1)
[(M - H)+], 198 (97) 196 (100) [M - Br)+].
of spectroscopic characterization
a small amount of this
material was resubjected to dry-column flash chromatography
to afford two fractions, A and B.
Meth yl (1′r,2′â,5′r)-{2-(6′,6′-Dibr om obicyclo[3.1.0]h ex-
2′-yl)eth yl}ca r ba m a te [(()-19]. A solution of a ca. 2:1
mixture of compounds (E)-(()-18 and (Z)-(()-18 (550 mg, 2.0
mmol) and CHCl3 (1.0 mL) in EtOH (40 mL) containing PtO2
(50 mg) was placed in a Parr apparatus, which was pressurized
to 3 atm with hydrogen. The vessel was shaken for 3 h at 18
°C, the pressure was released, and the reaction mixture was
filtered through a pad of Celite. The solids thus retained were
washed with EtOAc (80 mL), and the combined filtrates were
concentrated under reduced pressure to give a white crystal-
line solid (amine salt). This material was partitioned between
HCl (30 mL of a 1 M aqueous solution) and CH2Cl2 (30 mL),
and the separated aqueous layer was basified with NaHCO3
(saturated aqueous solution) to pH 12 and then extracted with
CH2Cl2. The organic fractions were dried (MgSO4), filtered, and
concentrated under reduced pressure to give a light-yellow oil
(free amine), which was immediately dissolved in CH2Cl2 (30
mL) containing pyridine (0.5 mL, 6.18 mmol). The resulting
solution was cooled to 0 °C and while being magnetically
stirred and maintained under a nitrogen atmosphere was
treated, dropwise, with methyl chloroformate (0.46 mL, 5.95
mmol). The resulting yellow solution was warmed to 18 °C,
stirred for a further 12 h, diluted with CH2Cl2 (20 mL), and
washed with water and then brine. The organic phase was
dried (MgSO4), filtered, and concentrated under reduced
pressure to give a yellow oil. Subjection of this material to dry-
column flash chromatography (silica gel, 3:7 EtOAc/hexane
elution) and concentration of the appropriate fractions (Rf )
0.4) afforded the title compound (()-19 (529 mg, 78%) as a
clear, colorless oil: found (M - H)+ 337.9394; C10H1579Br2NO2
requires (M - H)+ 337.9391; IR (NaCl) 1696 cm-1; 1H NMR δ
4.72 (broad s, 1H), 3.67 (s, 3H), 3.27 (m, 2H), 2.51 (m, 1H),
2.21 (m, 2H), 2.07-1.92 (complex m, 3H), 1.85-1.70 (complex
m, 2H), 1.67-1.45 (complex m, 1H); 13C NMR δ 157.1, 52.0,
41.9, 41.7, 40.5, 38.6, 36.3, 31.0, 29.3, 28.8; MS m/z (EI, 70
eV) (rel intensity) 340 (0.3) 338 (0.2) [(M - H)+], 88 (100).
π-Allyl Ca tion Cycliza tion Rea ction s of Com p ou n d s
(()-13 a n d (()-19. F or m a tion of Meth yl cis-7-Br om o-2,3,-
3a ,4,5,7a -h exa h yd r o-1H-in d ole-1-ca r boxyla te [(()-20]. A
magnetically stirred solution of carbamate (()-13 (28 mg, 0.082
mmol) in 2,2,2-trifluoroethanol (TFE) (1.0 mL), maintained
under a nitrogen atmosphere and protected from light, was
treated with AgClO4 (38 mg, 0.18 mmol). The resulting
suspension was stirred at 18 °C for 5 h and then filtered
through a pad of Celite, which was washed with EtOAc (10
mL). The combined filtrates were concentrated under reduced
pressure, and the resulting yellow solid was subjected to flash
chromatography (silica, 1:4 EtOAc/hexane elution). Concentra-
tion of the appropriate fractions (Rf ) 0.3) afforded a solid,
Concentration of fraction A (Rf ) 0.5) afforded alcohol
(()-1613 as a clear colorless oil: found (M - HO)+ 236.8920;
C6H879Br2O requires (M - HO)+ 236.8914; IR (NaCl) 3333
cm-1 1H NMR δ 4.35 (m, 1H), 2.42-2.12 (complex m, 4H),
;
1.92-1.63 (complex m, 3H); 13C NMR δ 76.0, 45.6, 39.0, 36.4,
33.9, 27.3; MS m/z (EI, 70 eV) (rel intensity) 240 (0.3) 238 (0.5)
236 (0.3) (M - HO)+, 214 (39) 212 (80) 210 (42) [(M - H2O -
C2H2)+], 67 (100). Concentration of fraction B (Rf ) 0.35)
afforded alcohol C2-epi-(()-1613 as a clear colorless oil: found
(M - H)+ 252.8868; C6H879Br2O requires (M - H)+ 252.8864;
1
IR (NaCl) 3366 cm-1; H NMR δ 4.78 (broad s, 1H), 2.46 (dd,
J ) 7.3 and 5.9 Hz, 1H), 2.26-2.00 (complex m, 4H), 1.81-
1.71 (complex m, 1H), 1.54 (broad s, 1H); 13C NMR δ 77.7, 42.1,
38.8, 33.8, 32.2, 27.0; MS m/z (EI, 70 eV) (rel intensity) 255
(0.3) 253 (0.2) [(M - H)+], 67 (100).
(1r,5r)-6,6-Dibr om obicyclo[3.1.0]h exa n -2-on e [(()-17].
Pyridinium chlorochromate (12.0 g, 55.7 mmol) was added, in
portions, to a magnetically stirred solution of a ca. 4:1 mixture
of alcohols (()-16 and C2-epi-(()-16 (7.70 g, 30.3 mmol) in CH2-
Cl2 (200 mL) maintained at 0 °C under a nitrogen atmosphere.
The resulting mixture was stirred in the dark for 8 h and then
filtered through a 2 cm deep pad of TLC-grade silica gel, which
was eluted with ether (400 mL). The combined filtrates were
concentrated under reduced pressure to give a brown oil, which
was subjected to dry-column flash chromatography (silica gel,
1:9 EtOAc/hexane elution). Concentration of the appropriate
fractions (Rf ) 0.3) afforded the title ketone (()-1713 (6.88 g,
90%) as a pale-yellow and low melting solid: found M+
251.8782; C6H679Br2O requires M+ 251.8785; IR (NaCl) 1727
1
cm-1; H NMR δ 2.77 (m, 1H), 2.71 (dd, J ) 6.4 and 0.5 Hz,
1H), 2.42-2.12 (complex m, 4H); 13C NMR δ 207.9, 45.5, 39.8,
36.3, 28.1, 22.8; MS m/z (EI, 70 eV) (rel intensity) 256 (0.4)
254 (0.8) 252 (0.5) (M+), 214 (49) 212 (100) 210 (52).
(E)-(1′r,5′r)-{6′,6′-Dibr om obicyclo[3.1.0]h ex-2′-yliden e}-
aceton itr ile [(E)-(()-18]an d (Z)-(1′r,5′r)-{6′,6′-Dibr om obicy-
clo[3.1.0]h ex-2′-ylid en e}a ceton itr ile [(Z)-(()-18]. A mag-
netically stirred suspension of NaH (822 mg, 34.3 mmol) in
anhydrous 1,2-dimethoxyethane (DME) (80 mL) maintained
under a nitrogen atmosphere at 0 °C was treated with diethyl
cyanomethylphosphonate (6.07 g, 34.3 mmol, Aldrich). After
the evolution of hydrogen had ceased (ca. 20 min) a solution
of ketone (()-17 (7.2 g, 28.6 mmol) in anhydrous DME (15 mL)
was added dropwise, and the resulting mixture was allowed
to stir at 0 °C for 1.5 h. The reaction mixture was then filtered
through a 2 cm deep pad of TLC-grade silica gel, which was
eluted with ether (400 mL). Concentration of the combined
filtrates gave a yellow oil, which was subjected to flash
chromatography (silica gel, 1:9 EtOAc/hexane elution) to afford

4248 J . Org. Chem., Vol. 65, No. 14, 2000
Banwell et al.
which was recrystallized (diethyl ether/hexane) to give the title
compound (()-20 (20 mg, 95%) as a white crystalline solid,
yellow oil on workup. Subjection of this material to dry-column
flash chromatography (silica gel, EtOAc elution) afforded two
fractions, A and B.
mp 55-56 °C: found C, 46.2; H, 5.5; N, 5.5; Br, 30.6; C10H14
-
BrNO2 requires C, 46.2; H, 5.4; N, 5.4; Br, 30.7; IR (KBr) 1696,
Concentration of fraction A (Rf ) 0.4) gave a white solid
which was recrystallized (CH2Cl2/hexane) to afford compound
(()-22 (10 mg, 46%) as colorless prisms, mp 149-151 °C (lit.22
145-147 °C): found M+ 269.1037; C16H15NO3 requires M+
1
1638 cm-1; H NMR δ 6.12 (m, 1H), 4.61 (broad s, 1H), 3.73
(s, 3H), 3.53 (broad s, 1H), 3.38 (m, 1H), 2.51 (broad s, 1H),
2.21-2.00 (complex m, 2H), 1.94-1.73 (complex m, 4H); 13C
NMR δ 156.3 (CO), 131.2 (CH), 124.1 (C), 60.2 (CH or CH3),
52.4 (CH or CH3), 44.9 (CH2), 38.6 (CH, broad), 25.7 (CH2,
broad), 22.8 (CH2), 21.5 (CH2); MS m/z (EI, 70 eV) (rel
intensity) 261 (0.3) 259 (0.3) (M+), 180 (100) [(M - Br)+].
Subjection of carbamate (()-19 (42 mg, 0.12 mmol) to the
same conditions afforded compound (()-20 (29 mg, 91%), which
was identical, in all respects, to the material obtained as
described above.
1
269.1052; IR (KBr) 1639, 1610 cm-1; H NMR δ 7.46 (s, 1H),
6.82 (s, 1H), 6.11 (dt, J ) 6.6 and 2.4 Hz, 1H), 5.98 (dd, J )
1.5 and 1.2 Hz, 2H), 4.10 (d, J ) 7.1 Hz, 1H), 3.68 (m, 2H),
2.50 (m, 1H), 2.35-1.99 (complex m, 3H), 1.87-1.72 (complex
m, 2H), 1.32-1.18 (complex m, 1H); 13C NMR δ 162.6, 150.5,
147.4, 134.1, 132.2, 125.9, 124.0, 107.5, 102.5, 101.5, 56.5, 43.3,
37.4, 29.3, 25.5, 24.6; MS m/z (EI, 70 eV) (rel intensity) 269
(100) (M+).
Meth yl cis-7-(1′,3′-Ben zod ioxol-5′-yl)-2,3,3a ,4,5,7a -h exa -
h yd r o-1H-in d ole-1-ca r boxyla te [(()-21]. A magnetically
stirred mixture of hexahydroindole (()-20 (287 mg, 1.11 mmol),
boronic acid 35d (204 mg, 1.23 mmol), benzene (25 mL), EtOH
(3.0 mL), Na2CO3 (7.0 mL of a 2 M aqueous solution), and Pd-
(PPh3)4 (128 mg, 0.111 mmol) was heated at reflux for 6 h while
being maintained under a nitrogen atmosphere and protected
from light. The cooled reaction mixture was diluted with
diethyl ether (40 mL) and NaHCO3 (40 mL of a saturated
aqueous solution), and the separated aqueous layer was
extracted with diethyl ether. The combined organic fractions
were washed with NaHCO3 (saturated aqueous solution) and
brine before being dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil. Subjection of this
material to dry-column flash chromatography (silica gel, 3:7
EtOAc/hexane elution) afforded, after concentration of the
appropriate fractions (Rf ) 0.3), a white solid. Recrystallization
(diethyl ether/hexane) of this material gave the title compound
(()-21 (307 mg, 92%) as white prisms, mp 81-83 °C: found
C, 67.9; H, 6.4; N, 4.7; C17H19NO4 requires C, 67.8; H, 6.4; N,
Concentration of fraction B (Rf ) 0.3) afforded compound
(()-23 (10 mg, 46%), which was identical in all respects with
the material obtained by Method A detailed above.
Meth od C. A solution of Tf2O (210 µL, 1.25 mmol) in
anhydrous CH2Cl2 (2.0 mL) was added, dropwise, to a mag-
netically stirred solution of compound (()-21 (74 mg, 0.25
mmol) and DMAP (95 mg, 0.78 mmol) in anhydrous CH2Cl2
(10 mL) maintained at 0 °C under a nitrogen atmosphere. The
resulting yellow mixture was stirred for a further 2 h at 0 °C
and then diluted with ether (20 mL). The organic layer was
washed with Na2CO3 (saturated aqueous solution) and HCl
(1 M aqueous solution), dried (MgSO4), filtered, and concen-
trated under reduced pressure to give a pale-yellow oil.
Subjection of this material to dry-column flash chromatogra-
phy (silica gel, EtOAc elution) afforded, after concentration of
the appropriate fractions (Rf ) 0.4), a white solid. This solid
was recrystallized (CH2Cl2/hexane) to give compound (()-22
(56 mg, 85%), which was identical in all respects with the
material obtained by Method B detailed above.
Meth yl (3a r,7â,7a r)-7-(1′,3′-ben zod ioxol-5′-yl)octa h y-
d r o-1H-in d ole-1-ca r boxyla te [(()-24]. A solution of com-
pound (()-21 (66 mg, 0.22 mmol) in EtOAc (5.0 mL) containing
10% Pd on C (15 mg) and maintained at 18 °C was stirred
under an atmosphere of hydrogen for 16 h. The catalyst was
then removed by filtration through a pad of Celite, and the
solids thus retained were washed with EtOAc (15 mL). The
combined filtrates were concentrated under reduced pressure
to give a yellow oil, which was subjected to dry-column flash
chromatography (silica gel, 3:7 EtOAc/hexane elution). Con-
centration of the appropriate fractions (Rf ) 0.4) then afforded
the title compound (()-24 (66 mg, 100%) as a clear, colorless
oil: found M+ 303.1474, C17H21NO4 requires M+ 303.1470; IR
1
4.7; IR (KBr) 1692 cm-1; H NMR δ 6.75-6.69 (m, 3H), 5.90
(t, J ) 1.7 Hz, 2H), 5.69 (broad s, 1H), 4.84 (broad s, 1H), 3.51
(m, 1H), 3.44 (broad s, 3H), 3.23 (m, 1H), 2.47 (m, 1H), 2.28-
2.07 (complex m, 2H), 2.01-1.74 (complex m, 4H); 13C NMR δ
156.0, 146.7, 146.1, 138.5, 135.8, 127.6, 121.1, 108.6, 107.4,
100.7, 57.5, 52.0, 44.6, 36.6, 25.4, 22.0, 20.8; MS m/z (EI, 70
eV) (rel intensity) 301 (100) (M+).
1,15-Did eh yd r o-9,10-[m eth ylen ebis(oxy)]-ga la n th a n -7-
on e [(()-22] a n d 1,2,3,3a ,4,5-Hexa h yd r o-7H-[1,3]d ioxolo-
[4,5-j]p yr r olo[3,2,1-d e]p h en a n th r id in -7-on e [(()-23]. Me-
th od A. A solution of compound (()-21 (50 mg, 0.166 mmol)
in freshly distilled POCl3 (4.0 mL, 0.043 mol) was placed in
an Ace Glass pressure tube (Aldrich) containing a magnetic
stirring bar. The tube was sealed and then placed in an oil
bath maintained at 80 °C, and the contents were stirred
magnetically for 30 h while being protected from light. The
resulting yellow reaction mixture was cooled to 0 °C and
basified (CAUTION) to pH 12 using NaOH (2 M aqueous
solution). Water (15 mL) was then added, and the resulting
mixture was extracted with EtOAc. The combined organic
fractions were washed with water and brine and then dried
(MgSO4), filtered, and concentrated under reduced pressure
to provide a yellow oil. Subjection of this material to dry-
column flash chromatography (silica gel, EtOAc elution) af-
forded, after concentration of the appropriate fractions (Rf )
0.3), a white solid which was recrystallized (acetone/hexane)
to give the title compound (()-23 (25 mg, 56%) as colorless
plates, mp 170-172 °C (lit.16 mp 166-168 °C): found M+
269.1042; C16H15NO3 requires M+ 269.1052; IR (KBr) 1673,
1
(NaCl) 1693 cm-1; H NMR δ 6.75 (s, 1H), 6.69 (s, 2H), 5.89
(q, J ) 1.3 Hz, 2H), 4.12 (t, J ) 7.1 Hz, 1H), 3.42 (s, 3H), 3.13
(m, 1H), 3.05-2.97 (complex m, 1H), 2.42-2.34 (complex m,
1H), 1.96-1.52 (m, 9H); 13C NMR δ 156.3, 147.0, 145.4, 138.3,
121.4, 108.9, 107.6, 100.6, 59.7, 52.0, 46.5, 41.2, 37.4, 29.1, 26.2,
25.1, 19.3; MS m/z (EI, 70 eV) (rel intensity) 303 (65) (M+),
140 (100).
(15r)-(()-9,10-[Me t h yle n e b is(oxy)]ga la n t h a n -7-on e
[(()-25]. Meth od A. Treatment of compound (()-24 (95
mg, 0.08 mmol) with POCl3 (3.0 mL, 0.043 mol) under the
conditions defined for the conversion (()-21 f (()-22 (but
using a reaction time of 22 h) afforded a light-yellow oil on
workup. Subjection of this material to dry-column flash
chromatography (silica gel, EtOAc elution) and concentration
of the appropriate fractions (Rf ) 0.4) gave a white solid.
Recrystallization (EtOAc/diethyl ether) of this material then
afforded the title compound (()-25 (69 mg, 81%) as colorless
prisms, mp 125-126 °C (lit.3h 126-127 °C): found M+ 271.1214;
1
1602 cm-1; H NMR δ 7.82 (s, 1H), 6.89 (s, 1H), 6.06 (s, 2H),
4.37 (dd, J ) 12.2 and 8.5 Hz, 1H), 3.82 (td, J ) 11.9, 11.9
and 5.8 Hz, 1H), 3.00 (m, 1H), 2.72 (dd, J ) 16.1 and 6.9 Hz,
1H), 2.52-2.43 (complex m, 1H), 2.43-2.33 (complex m, 1H),
2.26-2.16 (complex m, 1H), 1.84-1.63 (complex m, 3H), 1.40-
1.28 (complex m, 1H); 13C NMR δ 160.0, 151.7, 146.6, 141.2,
135.1, 121.1, 106.5, 106.0, 101.6, 99.9, 46.8, 40.3, 31.1, 28.1,
22.8, 22.1; MS m/z (EI, 70 eV) (rel intensity) 269 (100) (M+).
Meth od B. Treatment of compound (()-21 (25 mg, 0.08
mmol) with POCl3 (4.0 mL, 0.043 mol) under the conditions
defined above but using a reaction time of 16 h afforded a light
C
16H17NO3 requires M+ 271.1208; IR (NaCl) 1647, 1605 cm-1
;
1H NMR δ 7.52 (s, 1H), 6.61 (s, 1H), 5.98 (d, J ) 2.2 Hz, 2H),
3.84 (t, J ) 4.7 Hz, 1H), 3.75 (m, 1H), 3.62 (dt, J ) 11.5 and
7.6 Hz, 1H), 2.79 (dt, J ) 12.0 and 4.9 Hz, 1H), 2.26 (sextet, J
) 5.6 Hz, 1H), 2.00-1.87 (complex m, 1H), 1.78-1.60 (complex
m, 4H), 1.37-1.02 (complex m, 3H); 13C NMR δ 162.7, 150.2,
(22) Hwang, G.; Magnus, P. J . Chem. Soc., Chem. Commun. 1983,
693-694.

Syntheses of (()-, (+)- and (-)-γ-Lycorane
J . Org. Chem., Vol. 65, No. 14, 2000 4249
146.7, 138.5, 122.9, 107.5, 106.9, 101.4, 57.9, 42.7, 39.1, 38.1,
29.9, 28.9, 26.2, 23.7; MS m/z (EI, 70 eV) (rel intensity) 271
(37) (M+), 83 (100).
384.1538; IR (NaCl) 1685 cm-1; 1H NMR δ 4.54 (m, 2H), 3.31-
3.17 (complex m, 2H), 2.55-2.47 (complex m, 1H), 2.25-2.17
(complex m, 2H), 2.07-1.42 (complex m, 13H), 1.37-1.25
(complex m, 1H), 1.12-0.94 (complex m, 2H), 0.89 (d, J ) 6.5
Hz, 6H), 0.79 (d, J ) 7.1 Hz, 3H); 13C NMR δ 156.5, 74.4, 47.4,
42.0, 41.5, 40.5, 38.5, 34.3, 33.2, 32.4, 31.4, 31.1, 29.4, 28.8,
27.8, 26.5, 26.3, 25.7, 23.5, 22.1, 20.8, 16.5 (sixteen signals
obscured/overlapping); MS m/z (EI, 70 eV) (rel intensity) 386
(0.3) 384 (0.3) [(M - Br)+], 166 (100).
Meth od B. Treatment of compound (()-22 (25 mg, 0.093
mmol) with hydrogen (1 atm) under the conditions defined for
the conversion (()-2 f (()-24 afforded a light-yellow oil on
workup. Subjection of this material to dry-column flash
chromatography (silica gel, EtOAc elution) and concentration
of the appropriate fractions (Rf ) 0.4) gave a white solid.
Recrystallization (EtOAc/diethyl ether) of this material then
afforded compound 22 (24 mg, 95%), which was identical in
all respects with the material prepared via Method A.
(15r)-(()-9,10[Meth ylen ebis(oxy)]ga la n th a n [(()-γ-ly-
cor a n e, (()-1]. LiAlH4 (34 mg, 0.89 mmol) in anhydrous THF
(1.0 mL) was added to a magnetically stirred solution of lactam
(()-25 (40 mg, 0.15 mmol) in anhydrous THF (6.0 mL)
[1r(R*),2â,5r]-5-Meth yl-2-(1′-m eth yleth yl)cycloh exyl-
(3a S,7a R)-7-br om o-2,3,3a ,4,5,7a -h exa h yd r o-1H-in d ole-1-
ca r boxyla te (29) a n d [1r(R*),2â,5r]-5-Meth yl-2-(1′-m eth -
y le t h y l)c y c lo h e x y l-(3a R ,7a S )-7-b r o m o -2,3,3a ,4,5,7a -
h exah ydr o-1H-in dole-1-car boxylate (30). Meth od A. Silver
acetate (80 mg, 0.479 mmol) was added to a magnetically
stirred solution of a 1:1 mixture of carbamates 27 and 28 (150
mg, 0.324 mmol) in anhydrous TFE (50 mL). The resulting
mixture was protected from light and allowed to stir, under
an atmosphere of nitrogen, at 18 °C for 10 h. The precipitated
silver salts were then removed by filtration through a plug of
Celite, and the solids thus retained were washed with EtOAc
(60 mL). Concentration of the combined filtrates afforded a
pale-yellow oil, which was subjected to dry-column flash
chromatography (silica gel, 1:4 EtOAc/hexane elution). Con-
centration of the appropriate fractions (Rf ) 0.4) gave an
inseparable 1:1 mixture of the diastereoisomeric hexahydroin-
doles 29 and 30 (116 mg, 94%) as a clear, colorless oil: found
(M - Br)+ 304.2265; C19H30BrNO2 requires (M - Br)+ 304.2276;
IR (NaCl) 1687 cm-1; 1H NMR δ 6.09 (broad s, 1H), 4.64-4.55
(complex m, 2H), 3.61-3.36 (complex m, 2H), 2.50 (m, 1H),
2.13-1.95 (complex m, 4H), 1.93-1.73 (complex m, 5H), 1.66-
1.61 (complex m, 2H), 1.47-1.32 (complex m, 2H), 1.11-0.94
(complex m, 2H), 0.87 (d, J ) 6.9 Hz, 6H), 0.76 (d, J ) 7.1 Hz,
3H); 13C NMR δ 155.7, 130.8, 124.5, 75.0, 60.1, 59.8, 47.3, 44.7-
(4), 44.6(6), 41.8, 38.0, 34.4, 34.3, 31.4, 26.5, 25.7, 24.8, 23.9,
22.8, 22.0, 21.5, 21.0, 20.7, 16.8 (fourteen signals obscured/
overlapping; MS m/z (EI, 70 eV) (rel intensity) 304 (9) [(M -
Br)+], 166 (100).
Meth od B. A solution of carbamate (()-20 (500 mg, 1.93
mmol), KOH (2.7 g, 48.2 mmol) and hydrazine hydrate (0.6
mL, 19.3 mmol) in ethylene glycol (30 mL) was heated at reflux
under a nitrogen atmosphere for 2 h. The cooled reaction
mixture was poured into water (100 mL) and extracted with
CH2Cl2. The combined organic fractions were acidified with
HCl (40 mL of a 2 M aqueous solution), and the separated
aqueous phase was basified to pH 12 using NaOH (2 M
aqueous solution) and then extracted with CH2Cl2. The
combined organic fractions were dried (MgSO4), filtered, and
concentrated under reduced pressure to give cis-(()-7-bromo-
2,3,3a,4,5,7a-hexahydro-1H-indole (380 mg, 98%) as an un-
stable, volatile and colorless oil. 1H NMR δ 6.17 (t, J ) 4.3
Hz, 1H), 3.59 (d, J ) 6.3 Hz, 1H), 3.07-2.99 (complex m, 1H),
3.95-2.87 (complex m, 1H), 2.44-2.32 (complex m, 1H), 2.18-
1.90 (complex m, 4H), 1.75-1.65 (complex m, 1H), 1.63-1.45
(complex m, 2H); 13C NMR δ 131.1, 125.9, 62.5, 44.2, 38.0, 30.2,
25.6, 24.3.
maintained under
a nitrogen atmosphere. The resulting
mixture was heated at reflux for 3 h then cooled to room
temperature and treated (CAUTION) with water (0.15 mL).
The resulting slurry was filtered through a plug of Celite, and
the filtrate was concentrated under reduced pressure to afford
a yellow oil. Subjection of this material to dry-column flash
chromatography (silica gel, EtOAc elution) and concentration
of the appropriate fractions (Rf ) 0.4) afforded (()-γ-lycorane
[(()-1] (32 mg, 84%) as white prisms, mp 98-99 °C (lit.2c 101-
102 °C): found (M - H)+ 256.1341; C16H19NO2 requires (M -
1
H)+ 256.1337; H NMR δ 6.61 (s, 1H), 6.49 (s, 1H), 5.89 (q, J
)1.5 Hz, 2H), 4.02 (d, J ) 14.4 Hz, 1H), 3.38 (dt, J ) 9.2 and
3.9 Hz, 1H), 3.21 (d, J ) 14.4 Hz, 1H), 2.74 (dt, J ) 11.7 and
5.3 Hz, 1H), 2.37 (t, J ) 4.8 Hz, 1H), 2.23-2.08 (complex m,
2H), 2.07-1.95 (complex m, 1H), 1.78-1.60 (complex m, 3H),
1.53-1.21 (complex m, 4H); 13C NMR δ 146.0, 145.6, 133.2,
127.3, 108.3, 106.2, 100.6, 62.9, 57.2, 53.7, 39.5, 37.4, 31.7, 30.4,
29.3, 25.2; MS m/z (EI, 70 eV) (rel intensity) 257 (35) (M+),
256 (100) [M - H]+.
A small sample of amine (()-1 was dissolved in HCl (1 M
aqueous solution), and the resulting mixture was concentrated
under reduced pressure to give a white solid. This material
recrystallized (water) to give (()-γ-lycorane hydrochloride as
white needles, mp 255-256 °C (dec) [lit.2c 255-256 °C (dec)].
[1r(R*),2â,5r]-5-Meth yl-2-(1′-m eth yleth yl)cycloh exyl-
(1′R,2′S,5′S)-(()-{2-(6′,6′-d ibr om obicyclo[3.1.0]h ex-2′-yl)-
eth yl}ca r ba m a te (27) a n d [1r(R*),2â,5r]-5-Meth yl-2-(1′-
m e t h y le t h y l)c y c lo h e x y l-(1′S ,2′R ,5′R )-(()-{2-(6′,6′-
d ibr om obicyclo[3.1.0]h ex-2′-yl)eth yl}ca r ba m a te (28). A
ca. 2:1 mixture of nitriles (E)-(()-18 and (Z)-(()-18 (400 mg,
1.45 mmol), anhydrous CHCl3 (1.0 mL), and PtO2 (50 mg) were
added to absolute EtOH (50 mL), and the resulting mixture
was hydrogenated, with continuous agitation, in
a Parr
apparatus at 3 atm and 18 °C for 3 h.15 The reaction mixture
was then filtered through a pad of Celite, and the solids thus
retained were washed with EtOAc (80 mL). Concentration of
the combined filtrates gave a white crystalline solid, which
was treated with HCl (30 mL of a 1 M aqueous solution) and
CH2Cl2 (30 mL). The organic layer was discarded, and the
aqueous layer basified to pH 12 with NaHCO3 (saturated
aqueous solution) and then extracted with CH2Cl2. The
combined organic fractions were dried (MgSO4), filtered, and
concentrated under reduced pressure to give an unstable
yellow oil (free amine), which was immediately dissolved in
anhydrous CH2Cl2 (15 mL) containing pyridine (0.234 mL, 2.90
mmol). The resulting solution was stirred magnetically, cooled
to 0 °C, and then treated dropwise with (-)-menthyl chloro-
formate (620 µL, 2.90 mmol). The resulting clear yellow
solution was allowed to warm to 18 °C, stirred for a further
16 h, and then diluted with CH2Cl2 (20 mL) and water (20
mL). The separated aqueous phase was extracted with CH2-
Cl2, and the combined organic fractions were washed with
water and brine before being dried (MgSO4), filtered, and
concentrated under reduced pressure. The yellow oil obtained
in this manner was subjected to dry-column flash chromatog-
raphy (silica gel, 3:17 EtOAc/hexane elution). Concentration
of the appropriate fractions (Rf ) 0.4) gave a 1:1 mixture of
compounds 27 and 28 (430 mg, 64%) as a clear, colorless oil:
found (M - Br)+ 384.1534; C19H3179Br2NO2 requires (M - Br)+
A magnetically stirred solution of cis-(()-7-bromo-2,3,-
3a,4,5,7a-hexahydro-1H-indole (380 mg, mmol) and pyridine
(320 µL, 3.96 mmol) in anhydrous CH2Cl2 (25 mL) maintained
at 0 °C was treated, dropwise, with (-)-menthyl chloroformate
(830 µL, 3.87 mmol). The resulting mixture was stirred at room
temperature for 10 h and then diluted with CH2Cl2 (25 mL)
and water (30 mL). The separated aqueous phase was ex-
tracted with CH2Cl2, and the combined organic fractions were
washed with water and then brine before being dried (MgSO4),
filtered, and concentrated under reduced pressure. The result-
ing oil was subjected to dry-column flash chromatography
(silica gel, 1:4 EtOAc/hexane elution), and concentration of the
appropriate fractions (Rf ) 0.4) gave an inseparable 1:1
mixture of the carbamates 29 and 30 (665 mg, 92%) as a clear,
colorless oil. This material was identical, in all respects, with
that obtained by Method A as described above.
[1r(R*),2â,5r]-5-Meth yl-2-(1′-m eth yleth yl)cycloh exyl-
[3a S,7a R]-7-(1′,3′-ben zod ioxol-5′-yl)-2,3,3a ,4,5,7a -h exa h y-
d r o-1H-in d ole-1-ca r boxyla te (31) a n d [1r(R*),2â,5r]-5-

4250 J . Org. Chem., Vol. 65, No. 14, 2000
Banwell et al.
Met h yl-2-(1′-m et h ylet h yl)cycloh exyl-[3a R,7a S]-7-(1′,3′-
b en zod ioxol-5′-yl)-2,3,3a ,4,5,7a -h exa h yd r o-1H -in d ole-1-
ca r boxyla te (32). A solution of a 1:1 mixture of carbamates
29 and 30 (374 mg, 0.98 mmol) and boronic acid 35d (205 mg,
1.23 mmol) in EtOH (6.0 mL) and benzene (50 mL) was treated
with Na2CO3 (14 mL of a 2 M aqueous solution) and Pd(PPh3)4
(113 mg, 0.098 mmol). The resulting mixture was heated at
reflux for 16 h under a nitrogen atmosphere while being
protected from light. The cooled reaction mixture was then
diluted with diethyl ether (40 mL) and washed with NaHCO3
(saturated aqueous solution) and then brine. The separated
organic phase was dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil, which was
subjected to dry-column flash chromatography (silica gel, 3:17
EtOAc/hexane elution). Concentration of the appropriate frac-
tions (Rf ) 0.4) then gave a clear, colorless oil, which was
subjected to semipreparative HPLC (Waters µ-Porasil column,
3:17 EtOAc/hexane elution, flow rate 2 mL/min), and in this
manner two fractions, A and B, were obtained.
Concentration of fraction A (Rt ) 9.6 min) afforded carba-
mate 31 (203 mg, 49%) as a clear, colorless oil: found M+
425.2555; C26H35NO4 requires M+ 425.2566; IR (NaCl) 1688
cm-1; 1H NMR δ 6.70 (m, 3H), 5.89 (s, 2H), 5.67 (broad s, 1H),
4.85 (broad s, 1H), 4.40-4.34 (complex m, 1H), 3.51 (broad s,
1H), 3.27-3.19 (complex m, 1H), 2.45 (broad s, 1H), 2.27-2.06
(complex m, 2H), 1.98-1.56 (complex m, 8H), 1.46-1.31
(complex m, 1H), 1.23 (broad s, 1H), 1.04-0.60 (complex m,
6H), 0.84 (d, J ) 6.8 Hz, 6H); 13C NMR δ 155.6 146.7, 146.2,
138.5, 135.9, 127.0, 121.2, 108.7, 107.5, 100.6, 74.6, 57.5, 47.0,
44.4, 41.3, 36.4, 34.3, 31.2, 25.7, 23.3, 22.0, 20.9(1), 20.8(6),
16.2, (two signals obscured/overlapping); MS m/z (EI, 70 eV)
(rel intensity) 425 (5) (M+), 54 (100).
chromatography (silica gel, 3:17 EtOAc/hexane elution, Rf )
0.5), the title compound 34 (72 mg, 100%) as a clear, colorless
oil: found M+ 427.2699; C26H37NO4 requires M+ 427.2722; IR
(NaCl) 1688 cm-1; 1H NMR δ 6.77-6.64 (complex m, 3H), 5.89
(s, 2H), 4.44 (dt, J ) 10.7 and 4.2 Hz, 1H), 4.16 (t, J ) 8.3 Hz,
1H), 3.29 (broad s, 1H), 3.22 (broad s, 1H), 2.94 (broad s, 1H),
2.37 (broad s, 1H), 2.01-1.50 (complex m, 12H), 1.46 (broad
s, 1H), 1.28-1.21 (complex m, 1H), 1.09-0.66 (complex m, 3H),
0.89 (d, J ) 7.4 Hz, 3H), 0.87 (d, J ) 7.5 Hz, 3H), 0.78 (d, J )
6.9 Hz, 3H); 13C NMR δ 155.5, 147.1, 145.5, 138.2, 121.8, 109.3,
107.6, 100.6, 74.4, 59.5, 47.2, 46.2, 41.4, 40.3, 37.4, 34.4, 31.3,
29.0, 26.4, 26.3, 25.0, 23.6, 22.1, 20.9, 18.7, 16.5; MS m/z (EI,
70 eV) (rel intensity) 427 (17) (M+), 83 (100).
(12r,15r,16r)-9,10-[Met h ylen eb is(oxy)]ga la n t h a n -7-
on e [(-)-25]. Treatment of compound 33 (50 mg, 0.08 mmol)
with POCl3 (8.0 mL, 0.043 mol) under the conditions defined
for the conversion (()-24 f (()-25 above but using a reaction
time of 24 h afforded a light-yellow oil on workup. Subjection
of this material to dry-column flash chromatography (silica,
EtOAc elution) and concentration of the appropriate fractions
(Rf ) 0.4) gave a white solid, which was recrystallized (EtOAc/
diethyl ether) to afford the title compound (-)-25 (30 mg, 95%)
as colorless prisms, mp 152-153 °C: found C, 70.4; H, 6.3; N,
5.1; C16H17NO3 requires C, 70.8; H, 6.3; N, 5.2; [R]D -41.5 (c
0.2). This material was identical, by IR, 1H NMR, and 13C NMR
spectroscopy, with the racemic modification obtained earlier.
(12r,15r,16r)-9,10-[Met h ylen eb is(oxy)]ga la n t h a n -7-
on e [(+)-25]. Treatment of compound 34 (48 mg, 0.08 mmol)
with POCl3 (8.0 mL, 0.043 mol) under the conditions defined
for the conversion (()-24 f (()-25 above but using a reaction
time of 24 h afforded a light-yellow oil on workup. Subjection
of this material to dry-column flash chromatography (silica,
EtOAc elution) and concentration of the appropriate fractions
(Rf ) 0.4) gave a white solid, which was recrystallized (EtOAc/
diethyl ether) to afford the title compound (+)-25 (29 mg, 95%)
as colorless prisms, mp 152-153 °C: found C, 70.7; H, 6.0; N,
5.2; C16H17NO3 requires C, 70.8; H, 6.3; N, 5.2; [R]D +41.5 (c
0.2). This material was identical, by IR, 1H NMR, and 13C NMR
spectroscopy, with the racemic modification obtained earlier.
(12r,15r,16r)-9,10-[Me t h y le n e b is (o x y )]g a la n t h a n
[(-)-γ-lycor a n e, (-)-1]. Treatment of compound (-)-25 (30
mg, 0.11 mmol) with LiAlH4 (26 mg, 0.684 mol) in THF (1 mL)
under the conditions defined for the conversion (()-25 f (()-1
afforded, after workup and flash chromatography (silica,
EtOAc elution, Rf ) 0.4), the title compound (-)-1 (24.5 mg,
86%) as a clear colorless oil, [R]D -16.7 (c 1.2) {lit.2 [R]D -17.0
(c 0.25)}. This material was identical, by IR, 1H NMR, and
13C NMR spectroscopy, with the racemic modification obtained
earlier.
Concentration of fraction B (Rt ) 10.3 min) gave carbamate
32 (203 mg, 49%) as a colorless oil: found (M - H)+ 424.2468;
C
26H35NO4 requires (M - H)+ 424.2488; IR (NaCl) 1688 cm-1
;
1H NMR δ 6.78-6.56 (complex m, 3H), 5.88 (s, 2H), 5.65 (broad
s, 1H), 4.92-4.73 (complex m, 1H), 4.39-4.30 (dt, J ) 10.8
and 4.0 Hz, 1H), 3.61-3.45 (complex m, 1H), 3.22 (broad s,
1H), 2.52-2.41 (complex m, 1H), 2.31-2.07 (complex m, 2H),
2.00-1.71 (complex m, 6H), 1.62-1.58 (complex m, 3H), 1.37
(broad s, 1H), 1.27-1.21 (complex m, 1H), 1.18-0.74 (complex
m, 10H), 0.56 (broad s, 1H); 13C NMR δ 155.3, 146.6, 146.2,
138.7, 136.2, 127.9, 121.2, 108.9, 107.6, 100.6, 74.5, 57.5, 47.1,
44.5, 41.7, 40.2, 36.9, 36.1, 34.3, 31.1, 26.0, 25.2, 23.8, 22.0,
20.8, 16.8; MS m/z (EI, 70 eV) (rel intensity) 425 (1) (M+), 174
(100).
[1r(R*),2â,5r]-5-Meth yl-2-(1′-m eth yleth yl)cycloh exyl-
[3a S,7S,7a R]-7-(1′,3′-ben zod ioxol-5′-yl)octa h yd r o-1H-in -
d ole-1-ca r boxyla te (33). A magnetically stirred solution of
compound 31 (72 mg, 0.17 mmol) in EtOAc (10 mL) containing
10% Pd on C (15 mg) maintained at 18 °C was stirred under
an atmosphere of hydrogen for 16 h. The catalyst was then
removed by filtration through a pad of Celite, and the solids
thus retained were washed with EtOAc (15 mL). The combined
filtrates were concentrated under reduced pressure to give a
yellow oil, which was subjected to dry-column flash chroma-
tography (silica, 3:17 EtOAc/hexane elution). Concentration
of the appropriate fractions (Rf ) 0.5) afforded the title
compound 33 (72 mg, 100%) as a clear, colorless oil: found
M+ 427.2703; C26H37NO4 requires M+ 427.2722; IR (NaCl) 1688
(12â,15â,16â)-9,10-[Meth ylen ebis(oxy)]ga la n th a n [(+)-
γ-lycor a n e, (+)-1]. Treatment of compound (+)-25 (28 mg,
0.103 mmol) with LiAlH4 (25 mg, 0.658 mol) under the
conditions defined for the conversion (()-25 f (()-1 afforded,
after workup and flash chromatography (silica, EtOAc elution,
Rf ) 0.4), the title compound (+)-1 (22.5 mg, 85%) as a clear
colorless oil, [R]D +17.0 (c 1.2) {lit.2 [R]D ) +16.3 (c 0.30)}. This
material was identical, by IR, 1H NMR, and 13C NMR
spectroscopy, with the racemic and levorotatory modifications
obtained earlier.
1
cm-1; H NMR δ 6.81-6.75 (complex m, 2H), 6.67 (d, J ) 8.0
Ack n ow led gm en t. We thank the Australian Re-
search Council and the Institute of Advanced Studies
for financial support. A.W.W. is the grateful recipient
of a University of Melbourne PhD Scholarship, and
J .E.H. thanks the ANU for a post-Graduate Research
Scholarship.
Hz, 1H), 5.89 (s, 2H), 4.48 (dt, J ) 10.7 and 4.1 Hz, 1H), 4.17
(t, J ) 7.1 Hz, 1H), 3.36-3.22 (complex m, 2H), 2.85 (m, 1H),
2.35 (m, 1H), 2.10-1.40 (complex m, 12H), 1.37-1.28 (complex
m, 1H), 1.10-0.80 (complex m, 4H), 0.91 (d, J ) 6.4 Hz, 3H),
0.86 (d, J ) 7.0 Hz, 3H), 0.76 (d, J ) 6.9 Hz, 3H); 13C NMR δ
155.3, 147.1, 145.4, 138.1, 121.8, 109.3, 107.6, 100.6, 74.5, 59.3,
47.2, 45.9, 41.6, 39.9, 37.2, 34.4, 31.3, 28.8, 26.7, 26.2, 25.2,
23.3, 22.1, 20.9, 18.7, 16.2; MS m/z (EI, 70 eV) (rel intensity)
427 (32) (M+), 289 (100).
Su p p or tin g In for m a tion Ava ila ble: 1H or 13C NMR
spectra for the mixtures of compounds (+)-9/C2-epi-(+)-9,
1
(+)-10/C2-epi-(+)-10, 27/28, 29/30 and H or 13C NMR spectra
[1r(R*),2â,5r]-5-Meth yl-2-(1′-m eth yleth yl)cycloh exyl-
[3a R,7R,7a S]-7-(1′,3′-ben zod ioxol-5′-yl)octa h yd r o-1H-in -
d ole-1-ca r boxyla te (34). Hydrogenation of the unsaturated
carbamate 32 (72 mg, 0.17 mmol) under the same conditions
as used for isomer 31 gave, after work up and dry-column flash
for compounds (()-11, (()-12, (()-13, (()-15, C2-epi-(()-15,
(Z)-(()-18, (()-19, (()-24, 31, 32, 33 and 34. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O991791U