Synthesis of carbocycles via intramolecular conjugate additions: Total syntheses of axane sesquiterpenoids

Article abstract of DOI:10.1021/jo951532e

Syntheses of (±)-axamide-1 (2) and (±)-axisonitrile-1 (1) are described. The syntheses require 12 steps and 13 steps, respectively, from vinylogous ester 8 and feature the diastereoselective cyclization of unsaturated ester 7 to perhydroindan 5. Some interesting reactions of the organometallic derived from [(trimethylsilyl)methyl]magnesium chloride and cerium trichloride are also described.

Full text of DOI:10.1021/jo951532e

J . Org. Chem. 1996, 61, 473-479
473
Syn th esis of Ca r bocycles via In tr a m olecu la r Con ju ga te Ad d ition s:
Tota l Syn th eses of Axa n e Sesqu iter p en oid s
Alyx-Caroline Guevel and David J . Hart*
Department of Chemistry, The Ohio State University, 120 W. 18th Avenue, Columbus, Ohio 43210
Received August 18, 1995X
Syntheses of (()-axamide-1 (2) and (()-axisonitrile-1 (1) are described. The syntheses require 12
steps and 13 steps, respectively, from vinylogous ester 8 and feature the diastereoselective cyclization
of unsaturated ester 7 to perhydroindan 5. Some interesting reactions of the organometallic derived
from [(trimethylsilyl)methyl]magnesium chloride and cerium trichloride are also described.
Sch em e 1
A variety of sesquiterpenoid isonitriles have been
isolated from marine sponges.1,2 These compounds are
often found, along with their isothiocyanate and forma-
mide counterparts, in nudibranchs that feed on these
sponges. The axanes are one family of such sesquiter-
penoids, first isolated from the sponge Axinella canna-
bina in the mid 1970s.3,4 During studies on the chemical
defense systems of Mediterranean nudibranchs, axisoni-
trile-1 (1) was found to be a potent ichthyotoxin toward
the marine fish Chromis chromis and the fresh water fish
Carassius carassius.5,6 Indeed, at a concentration as low
as 8 ppm, ingestion by the fish was followed by sedation
and death occurred within 24 h. Moreover, axisonitrile-1
was also present in ethereal extracts of the digestive
glands, mantles, and secretion of the nudibranch Phyl-
lidia pulitzeri which feeds on Axinella cannabina. This
led to the suggestion that the nudibranch uses the sponge
as its source of a chemical substance used as a form of
defense against predators.
is the presence of a side chain appended to the perhy-
droindan by a stereogenic carbon. This article describes
total syntheses of racemic axanes 1-3 using an intramo-
lecular conjugate addition to establish the four contiguous
stereogenic centers in these natural products.8,9,10
Our approach revolved around preparation of an
R-amino acid derivative such as 4 or 5 via cyclization of
an unsaturated ester such as 6 or 7 (Scheme 1). The
carbethoxy group was to serve as a functional handle for
construction of the side chain isopropyl group, and the
stereochemical course of the cyclization was predicted on
the basis of earlier studies in our laboratory.11 The
preparation of cyclization substrates 6 and 7 is outlined
in Scheme 2. Addition of (4-methyl-3-pentenyl)magne-
sium bromide12 to vinylogous ester 8 was followed by an
acidic workup to provide cyclohexenone 9 in 70% yield.
Treatment of 9 with lithium dimethylcuprate gave 10 in
89% yield.13 Protection of the ketone and ozonolysis of
the olefin gave aldehyde 11 (87%). Treatment of 11 with
ethyl R-acetamidomalonate gave 12 (64%), and ketal
hydrolysis provided cyclization substrate 6 in 82% yield.14
In a similar manner, 11 was converted to 13 (80%) and
ketal hydrolysis provided 7 in 94% yield.15 The olefin
geometry in 6 and 7 was assigned on the basis of the
chemical shift of their vinyl protons.16
Along with these interesting biological properties, the
rather unusual skeleton of the axane family of sesqui-
terpenoids has attracted some attention and only a few
other compounds having the same perhydroindan skel-
eton have been discovered.7 From the standpoint of
synthesis, a challenging feature of axisonitrile-1 (1), and
its congeners axamide-1 (2) and axisothiocyanate-1 (3),
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) For relevant reviews, see: Minale, L. In Marine Natural
Products, Chemical and Biological Perspectives; Scheuer, P. J ., Ed.;
Academic Press: New York, 1978; Vol. 1, p 175. Edenborough, M. S.;
Herbert, R. B. Nat. Prod. Rep. 1988, 229.
(2) Also see: Burreson, B J .; Christophersen, C.; Scheuer, P. J .
Tetrahedron 1975, 31, 2015. Ciminiello, P.; Magno, S.; Mayol, L.;
Piccialli, V. J . Nat. Prod. 1987, 50, 217. Ciminiello, P.; Fattorusso,
E.; Magno, S.; Mayol, L. J . Nat. Prod. 1985, 48, 64.
(3) For the axane-1 sesquiterpenoids, see: Cafieri, F.; Fattoruso, E.;
Magno, S.; Santacroce, C.; Sica, D. Tetrahedron 1973, 29, 4259.
Fattoruso, E.; Magno, S.; Mayol, L.; Santacroce, C.; Sica, D. Tetrahe-
dron 1974, 30, 3911. Adinolfi, M.; DeNapoli, L.; DiBlasio, B.; Iengo,
A.; Pedone, C.; Santacroce, C. Tetrahedron Lett. 1977, 2815.
(4) For other axanes, see: Fattoruso, E.; Magno, S.; Mayol, L.;
Santacroce, C.; Sica, D. Tetrahedron 1975, 31, 269. Iengo, A.; Mayol,
L.; Santacroce, C. Experientia 1977, 33, 11. Iengo, A.; Santacroce, C.;
Sodano, G. Experientia 1979, 35, 10.
(8) For a communication that describes a portion of this research,
see: Guevel, A.-C.; Hart, D. J . Synlett 1994, 169.
(9) For another synthesis of these natural products, see: Piers, E.;
Yeung, B. W. A. Can. J . Chem. 1986, 64, 2475. Piers, E.; Yeung, B.
W. A.; Rettig, S. J . Tetrahedron 1987, 43, 5521.
(10) For syntheses of the stereochemically less complex axane-4
family of sesquiterpenoids, see: Hart, D. J .; Lai, C.-S. Synlett 1989,
49. Chenera, B.; Chuang, C.-P.; Hart, D. J .; Lai, C.-S. J . Org. Chem.
1992, 57, 2018. Ohkubo, T.; Akino, H.; Asaoka, M.; Takei, H.
Tetrahedron Lett. 1995, 36, 3365.
(5) For a review of marine invertebrate chemical defenses, see:
Pawlik, J . R. Chem. Rev. 1993, 93, 1911.
(6) Cimino, G.; De Rosa, S.; De Stefano, S.; Sodano, G. Comp.
Biochem. Physiol. 1982, 73B, 471.
(7) For examples, see: Hall, S. S.; Faulkner, D. J .; Fayos, J .; Clardy,
J . J . Am. Chem. Soc. 1973, 95, 7187. Shizuri, Y.; Yamaguchi, S.;
Terada, Y.; Yamamura, S. Tetrahedron Lett. 1986, 27, 57. Fukuzawa,
A.; Sato, H.; Masamune, T. Tetrahedron Lett. 1987, 28, 4303. Howard,
B. M.; Fenical, W.; Donovan, S. F.; Clardy, J . Tetrahedron Lett. 1982,
23, 3847. Fusetani, N.; Wolstenholme, H. J .; Shinoda, K.; Asai, N.;
Matsunaga, S.; Onuki, H.; Hirota, H. Tetrahedron Lett. 1992, 33, 6823.
Weyerstahl, P.; Marschall, H.; Schneider, K. Liebigs Ann. Chem. 1995,
231.
(11) Guevel, A.-C.; Hart, D. J . J . Org. Chem. 1996, 61, 465-472.
(12) Prepared from the bromide: Biernacki, W.; Gdula, A. Synthesis
1979, 37.
(13) Posner, G. H. In Organic Reactions; Dauben, W. G., Ed.;
Wiley: New York, 1972; Vol. 19, pp 1-113.
(14) Hellmann, H.; Piechota, H. J ustus Liebigs Ann. Chem. 1960,
631, 175. Hengartner, U.; Valentine, D., J r.; J ohnson, K. K.; Larscheid,
M. E.; Pigott, F.; Scheidl, F.; Scott, J . W.; Sun, R. C.; Townsend, J . M.;
Williams, T. H. J . Org. Chem. 1979, 44, 3741.
0022-3263/96/1961-0473$12.00/0 © 1996 American Chemical Society

474 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
Sch em e 2
Sch em e 4
in the presence of triethylamine gave ketone 19 (54%),21
and subsequent Wittig olefination gave 18 in 95% yield.
Finally, selective hydrogenation of 18 using Crabtree’s
catalyst gave 20 (64%) along with 5% of its ∆1,2-isomer.22
Unfortunately, numerous attempts to hydrolyze aceta-
mide 20 met with failure and we eventually prepared
perhydroindan 5 (vide supra) and examined its conver-
sion to the target structures.23 As will be seen, this was
also not without problems.
Sch em e 3
The first problem was encountered during the Wittig
olefination of 5. Although this could be accomplished in
83% yield, the product was a 2:1 mixture of 21 and its
C10 isomer. Thus, the R-formamido ester was more
susceptible to base-promoted isomerization than the
R-acetamido ester. It was eventually found that 5 reacted
with the reagent prepared from [(trimethylsilyl)methyl]-
magnesium chloride and cerium trichloride to afford
olefinic acid 22 (71%) (Scheme 5).24 The acid could then
be converted to ester 21 (85%) using iodoethane and
cesium fluoride.25 The production of acid 22 was actually
a surprise as we had anticipated that the reaction of 5
would give an allylsilane which, upon protonolysis, would
give diene 24. Apparently the intermediate ketone
addition product reacts with the neighboring ester,
ultimately leading to the carboxylic acid. We next hoped
to convert 21 to diene 24 using a Peterson olefination
procedure.24,26 Again we were surprised to find that the
reaction of [(trimethylsilyl)methyl]magnesium chloride-
On the basis of results obtained with related sub-
strates, cyclization of 6 and 7 was expected to provide 4
and 5, respectively, with excellent stereoselectivity at
each stereogenic center.11 This proved to be the case
(Scheme 3). Treatment of 6 and 7 with pyrrolidine and
acetic acid in tetrahydrofuran afforded 4 and 5 in 85%
and 86% yields, respectively. The structure of 5 was
determined by X-ray crystallographic analysis while the
structure of 4 was assigned by analogy.17
As will be seen, converting perhydroindans 4 and 5 to
the target sesquiterpenoids was challenging. Our efforts
began with 4 as this was the first perhydroindan we had
prepared (Scheme 4). Wittig olefination of 4 gave 14
(88%), which reacted with methylmagnesium bromide to
afford tertiary alcohol 15 (84%). Attempts to convert the
tertiary alcohol to a halide for subsequent reduction, not
surprisingly, met with failure. For example, treatment
of 15 with conditions known to accomplish such trans-
formations gave electrophile-initiated cyclization prod-
ucts such as 16 and 17.18,19 It was possible to dehydrate
15 to diene 18 in 75% yield using Martin’s sulfurane.20
An alternate route from 14 to 18 was also developed.
Thus, treatment of 14 with methylmagnesium bromide
(20) Martin, J . C.; Arhart, R. J . J . Am. Chem. Soc. 1971, 93, 4327.
Arhart, R. J .; Martin, J . C. J . Am. Chem. Soc. 1972, 94, 5003. Martin,
J . C.; Arhart, R. J . J . Am. Chem. Soc. 1974, 96, 4604.
(21) Kikkawa, I.; Yorifugi, T. Synthesis 1980, 877.
(22) Crabtree, R. H.; Felkin, H.; Fillebeen-Kahn, T.; Morris, G. E.
J . Organomet. Chem. 1979, 168, 183. For amide-directed hydrogena-
tions using this catalyst, see: Schultz, A. G.; McCloskey, P. J . J . Org.
Chem. 1985, 50, 5905.
(15) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863. Schmidt,
U.; Lieberknecht, A.; Schanbacher, U.; Beuttler, T.; Wild, J . Angew.
Chem., Int. Ed. Engl. 1982, 21, 776. Schmidt, U.; Lieberknecht, A.;
Wild, J . Synthesis 1984, 53. Schmidt, U.; Griesser, H.; Leitenberger,
A.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992,
487.
(16) Keith, D. D.; Tortora, J . A.; Yang, R. J . Org. Chem. 1978, 43,
3711.
(17) We thank Dr. J udith C. Gallucci for performing the X-ray
crystallographic analysis of 5 at The Ohio State University Crystal-
lography Facility.
(23) Acidic conditions were not investigated due to the known acid
sensitivity of the exocyclic methylene. Conditions that failed included
hydrolysis with potassium hydroxide (Pearson, A. J .; Rees, D. C. J .
Am. Chem. Soc. 1982, 104, 1118), hydrazinolysis (Fujinaga, M.;
Matsuhima, Y. Bull. Chem. Soc. J pn. 1964, 37, 468), an amide
exchange procedure (Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org.
Chem. 1983, 48, 2424), and activation with Meerwein’s reagent
followed by hydrolysis with dilute acid or base (Muxfeldt, H.; Rogalski,
W. J . Am. Chem. Soc. 1965, 87, 933). The last procedure gave the
desired imidate, but attempts to hydrolyze this material failed.
(24) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
6261.
(18) Olah, G. A.; Balaram Gupta, B. G.; Malhotra, R.; Narang, S.
C. J . Org. Chem. 1980, 45, 1638.
(19) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra,
R. J . Org. Chem. 1979, 44, 1247.
(25) Sato, T.; Otera, J .; Nozaki, H. J . Org. Chem. 1992, 57, 2166.

Carbocycles via Intramolecular Conjugate Additions
J . Org. Chem., Vol. 61, No. 2, 1996 475
mixture maintained a gentle reflux. After the addition was
complete, the dark grey reaction mixture was heated under
reflux for 50 min and then cooled to rt. A solution of 3.5 g (25
mmol) of 3-ethoxycyclohex-2-en-1-one31 in 15 mL of dry Et2O
was then added dropwise over a 15 min period, at a rate such
that the mixture maintained a gentle reflux. The resulting
olive green mixture was heated under reflux for another 1.3 h
and then cooled to rt. A 10% aqueous H2SO4 solution (30 mL)
was added to 0 °C with stirring, and the mixture turned deep
red, then orange, and then dark yellow. The organic phase
was separated, and the aqueous layer was extracted with three
30 mL portions of ether. The organic layers were combined,
washed with four 15 mL portions of brine and 25 mL of
saturated aqueous NaHCO3, dried (MgSO4), and concentrated
in vacuo to afford 4.2 g of 9 as a pale yellow oil, a 4 g portion
of which was distilled to give 3.0 g (70%) of enone 9 as a clear
colorlesss liquid: bp 80 °C at 0.3 mmHg; IR (neat) 1671, 1625
cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.59 (s, 3H, CH3), 1.67 (s,
3H, CH3), 1.89-2.02 (m, 2H), 2.12-2.37 (m, 8H), 5.05 (m, 1H,
dCH), 5.86 (t, J ) 1.1 Hz, 1H, dCH); 13C NMR (CDCl3, 62.9
MHz) δ 17.6 (q), 22.7 (t), 25.5 (t), 25.6 (q), 29.7 (t), 37.3 (t),
38.0 (t), 122.7 (d), 125.8 (d), 132.7 (s), 166.0 (s), 199.8 (s); exact
mass calcd for C12H18O m/e 178.1357, found m/e 178.1374.
(()-3-Met h yl-3-(4-m et h yl-3-p en t en yl)cycloh exa n on e
(10). To a suspension of 21.5 g (113 mmol) of CuI in 150 mL
of dry Et2O at 0 °C was slowly added 125 mL (175 mmol) of
1.4 M ethereal methyllithium. The resulting straw yellow
mixture was cooled to -78 °C and allowed to stir at that
temperature for 35 min. To this mixture was added dropwise
via syringe pump 11.0 g (61.8 mmol) of enone 9 in 35 mL of
dry Et2O over a 15 min period. The resulting mixture was
allowed to warm to -30 °C and stir for 2.6 h between -30
and -10 °C. The reaction mixture was then poured into 500
mL of chilled 10% aqueous NH4Cl. The resulting mixture was
stirred for 2.8 h, and the organic layer was separated and
washed with two 120 mL portions of saturated aqueous NH4-
Cl. The combined dark blue aqueous phases were extracted
with two 250 mL portions of ether. The combined organic
phases were washed with two 200 mL portions of brine, dried
(MgSO4), and concentrated in vacuo to afford 10.6 g (88%) of
Sch em e 5
cerium trichloride with 21 stopped at the stage of methyl
ketone 23 (78%). Apparently enolization of the presumed
intermediate R-trimethylsilyl ketone, or desilylation of
that intermediate, prevents addition of the second mole
of organometallic.27 Fortunately, treatment of 23 with
the same Peterson olefination reagent finally delivered
diene 24 in 70% yield.24,26
All that remained was to selectively hydrogenate the
isopropenyl group of 24 using Crabtree’s catalyst.22 Once
again the formamide behaved differently from the acet-
amide as the isolated yield of axamide-1 (2) was only 39%.
Other products that could be detected in the 1H-NMR
spectrum of the crude reaction mixture included (()-
axamide-410 and perhydroindans in which the exocyclic
olefin had isomerized into the ring. One clear difference
between acetamide 18 and formamide 24 is amide
geometrical isomerism. Whereas 18 appears to exist as
a single geometrical isomer, 24 is clearly a 2.5:1 mixture
of isomers at room temperature in chloroform by NMR.
This geometrical difference may translate into the ob-
served difference in behavior because acetamide 18
should populate a conformation that can undergo a
directed hydrogenation of the isopropenyl group, while
the E-isomer of formamide 24 cannot.28 Whatever the
reason for the disappointing yield in the hydrogenation,
we subjected (()-axamide-1 (2) to p-toluenesulfonyl
chloride to obtain (()-axisonitrile-1 (1) in 87% yield.29
Since 1 has previously been converted to axisothiocyan-
ate-1 (3),9 this also constitutes a formal total synthesis
of the third member of this triad of sesquiterpenoids.
In summary, syntheses of racemic 1-3 have been
achieved. The route to 1 requires 13 steps from vinylo-
gous ester 8 and proceeds in 4% overall yield. Key steps
involve a highly diastereoselective intramolecular Michael
addition and a series of cerium-mediated olefinations.
ketone 10 as a pale yellow oil: IR (neat) 3071, 1714, 1640 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.91 (s, 3H, CH3), 1.26 (bt, J )
8.6 Hz, 2H, CH2), 1.48-1.67 (m, 2H), 1.57 (s, 3H, dCCH3),
1.65 (d, J ) 1.0 Hz, 3H, dCCH3), 1.80-1.95 (m, 4H), 2.08 (d,
J ) 12.9 Hz, 1H, CHC(O)), 2.18 (d, J ) 13.4 Hz, 1H, CHC(O)),
2.25 (t, J ) 6.8 Hz, 2H, CH2), 5.05 (bt, J ) 7.1 Hz, 1H, dCH);
13C NMR (CDCl3, 62.9 MHz) δ 17.5 (q), 22.1 (t, two carbons),
24.9 (q), 25.6 (q), 35.8 (t), 38.5 (s), 41.0 (t), 41.6 (t), 53.6 (t),
124.3 (d), 131.5 (s), 212.1 (s); exact mass calcd for C13H22O m/e
194.1670, found m/e 194.1718.
7-Me t h yl-1,4-d ioxa sp ir o[4.5]d e ca n e -7-p r op ion a ld e -
h yd e (11). A solution of 10.6 g (54.7 mmol) of ketone 10, 16
mL (287 mmol) of ethylene glycol, 27 mL of dry benzene, 16
mL (146 mmol) of trimethyl orthoformate, and 133 mg (699
mmol) of p-toluenesulfonic acid monohydrate was stirred at
rt for 3.25 h, and the reaction was quenched by addition of 25
mL of saturated aqueous NaHCO3. The organic phase was
separated and concentrated in vacuo, and the residue was
diluted with 200 mL of ether. The solution was washed with
two 50 mL portions of brine, dried (Na2SO4), and concentrated
in vacuo. The residual liquid (13.0 g) was chromatographed
over 200 g of silica gel (eluted with petroleum ether-EtOAc,
24:1) to give 12.4 g (95%) of (()-7-methyl-7-(4-methyl-3-
pentenyl)-1,4-dioxaspiro[4.5]decane as a clear colorless liquid;
IR (neat) 1673 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.96 (s, 3H,
CH3), 1.18-1.40 (m, 4H), 1.46 (d, J ) 7.0 Hz, 1H, CH), 1.49-
1.64 (m, 5H), 1.59 (s, 3H, dCCH3), 1.67 (s, 3H, dCCH3), 1.90
(m, 2H), 3.90 (m, 4H, (OCH2)2), 5.10 (tt, J ) 7.1, 1.4 Hz, 1H,
dCH); 13C NMR (CDCl3, 62.9 MHz) δ 17.5 (q), 19.7 (t), 22.3
(t), 25.4 (q), 25.7 (q), 34.5 (s), 35.1 (t), 37.2 (t), 42.8 (t), 44.7 (t),
63.9 (t), 64.1 (t), 109.5 (s), 125.2 (d), 130.8 (s); exact mass calcd
for C15H26O2 m/e 238.1934, found m/e 238.1941.
Exp er im en ta l Section 30
3-(4-Meth yl-3-pen ten yl)-2-cycloh exen -1-on e (9). To 1.03
g (42.3 mmol) of magnesium turnings were added with stirring
a few drops of a solution of 6.16 g (37.8 mmol) of 1-bromo-4-
methyl-3-pentene12 in 25 mL of dry Et2O. After the onset of
Grignard formation, the remaining ethereal solution of bro-
mide was added over a 20 min period, at a rate such that the
(26) Hudrlik, P. F.; Peterson, D. J . Am. Chem. Soc. 1975, 97, 1464.
J ohnson, C. R.; Tait, B. D. J . Org. Chem. 1987, 52, 281. For overviews
of the Peterson olefination, see: Kelly, S. E. In Comprehensive Organic
Synthesis, Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol.
1, p 729. Chan, T.-H. Acc. Chem. Res. 1977, 10, 442.
(27) Demuth, M. Helv. Chim. Acta 1978, 61, 3136.
Through a stirred solution of 7.02 g (29.5 mmol) of the ketal
and a spatula tipful of NaHCO3 in 60 mL of CH2Cl2 and 15
mL of methanol at -78 °C was passed a stream of ozone
(28) Brown, J . M.; Cutting, I.; J ames, A. P. Bull. Soc. Chim. Fr. 1988,
211.
(29) This transformation has also been reported by Piers.9 Spectral
data for 1 and 2 were in accord with those reported by Piers.
(30) General experimental considerations were the same as those
presented in the preceding article (ref 11).
(31) Gannon, W. F.; House, H. O. Org. Synth. 1973, 5, 539.

476 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
(Welsbach ozone generator) at a flow rate of 1.0 mmol min-1
.
12 in 165 mL of THF was added 225 mL of 0.3 N aqueous
HCl. The reaction mixture was stirred for rt for 11 h, diluted
with 500 mL of Et2O, and neutralized with two 250 mL
portions of saturated aqueous NaHCO3. The combined washes
were extracted with 300 mL of Et2O, and the combined organic
phases were washed with two 250 mL portions of saturated
brine, dried (Na2SO4), and concentrated to afford 6.74 g (82%
crude) of 6 as a pale yellow heavy oil: IR (CDCl3) 3412, 1701,
When the reaction mixture maintained a blue color for 1 min,
the stream of ozone was replaced by argon and the solution
was stirred until the color dissipated (1.5 h). To the resulting
clear reaction mixture was added 22 mL of dimethyl sulfide.
The reaction mixture was stirred at -78 °C for 45 min, then
the dry ice-acetone bath was removed, and the mixture was
stirred overnight for another 12.7 h. The solvent was removed
in vacuo, and the residual crude liquid (9.55 g) was chromato-
graphed over 100 g of silica gel (eluted with hexane-EtOAc,
5:1) to give 5.77 g (92%) of aldehyde 11 as a clear colorless oil.
Spectral data of 11 were consistent with data published in the
literature:10 1H NMR (CDCl3, 250 MHz) δ 0.94 (s, 3H, CH3),
1.23-1.30 (m, 2H, CH2), 1.45 (d, J ) 3.8 Hz, 2H, CH2), 1.51-
1.78 (m, 6H), 2.36 (m, 2H, CH2CHO), 3.89 (bs, 4H, (OCH2)2),
9.76 (t, J 2.0 Hz, 1H, CHO).
1
1492 cm-1; H NMR (CDCl3, 300 MHz) δ 0.92 ( s, 3H, CH3),
1.28 (t, J ) 7.1 Hz, 3H, OCH2CH3), 1.23-1.32 (m, 1H), 1.36-
1.47 (m, 2H, CH2), 1.52-1.67 (m, 2H, CH2), 1.85 (td, J ) 13,
6.5 Hz, 2H, CH2CH2CdO), 2.05-2.17 (m, 3H), 2.12 (s, 3H,
CH3CdO), 2.22-2.28 (m, 2H, CH2CdO), 4.20 (q, J ) 7.1 Hz,
2H, OCH2CH3), 6.61 (t, J ) 7.3 Hz, 1H, dCH), 6.96 (s, 1H,
NH); 13C NMR (CDCl3, 62.9 MHz) δ 14.1 (q), 22.1 (t), 23.4 (t),
23.4 (q), 24.8 (q), 35.8 (t), 38.6 (s), 39.6 (t), 40.9 (t), 53.3 (t),
61.5 (t), 125.0 (s), 137.7 (d), 164.6 (s), 168.3 (s), 212.0 (s); exact
mass calcd for C16H25NO4 m/e 295.1783, found m/e 295.1787.
Eth yl (()-(Z)-2-F or m a m id o-5-(1-m eth yl-3-oxocycloh ex-
yl)-2-p en ten oa te (7). To a solution of 6.20 g (19.0 mmol) of
ketal 13 in 120 mL of THF was added 150 mL of 0.3 N aqueous
HCl. The reaction mixture was stirred at rt for 2.5 h, diluted
with 225 mL of Et2O, and neutralized with 110 mL of
saturated aqueous NaHCO3. The organic layer was separated,
and the aqueous phase was extracted with 120 mL of Et2O.
The combined organic phases were washed with 100 mL brine,
dried (Na2SO4), and concentrated in vacuo to afford 6.74 g
(95%) of crude 7 as a pale yellow heavy oil. This material was
a 1.5:1 mixture of geometrical isomers by integration of
Eth yl (()-(Z)-2-Aceta m id o-5-(7-m eth yl-1,4-d ioxa sp ir o-
[4.5]d ec-7-yl)-2-p en ten oa te (12). To 380 mg (2.01 mmol) of
neat ethyl 2-acetamidomalonate at rt was added a solution of
421 mg (1.99 mmol) of aldehyde 11 in 1.6 mL (19.6 mmol) of
pyridine. The resulting mixture was cooled to about 13 °C
using an ice bath, and 0.58 mL (6.40 mmol) of acetic anhydride
was added dropwise over a 2 min period. The resulting yellow-
orange solution was stirred at rt for 3.8 h, and another 112
mg (0.592 mmol) portion of ethyl 2-acetamidomalonate was
added. The resulting mixture was stirred at rt for 1.8 h, the
reaction was quenched by addition of 2.3 g of crushed ice, and
the solution was stirred for another 1.5 h. The mixture was
then diluted with 26 mL of water and extracted with two 50
mL portions of ether. The combined organic phases were dried
(Na2SO4) and concentrated in vacuo to afford 1.13 g of an
orange oil. The residue was chromatographed over 45 g of
silica gel (eluted with EtOAc-hexane, 2:1) to afford 389 mg
1
selected peaks in the H NMR spectrum of the mixture. The
13C NMR of this mixture also showed two isomers: IR (CDCl3)
3400, 1701, 1655, 1489 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
0.94 (bs, 3H, CH3), 1.31 (t, J ) 7.1 Hz, 3H, OCH2CH3), 1.40-
1.49 (m, 2H), 1.52-1.65 (m, 2H), 1.86 (m, 2H), 2.10-2.30 (m,
6H), 4.23 (q, J ) 7.0 Hz, 2H, (OCH2)2), 6.56 (t, J ) 7.6 Hz,
0.4H, dCH), 6.67 (t, J ) 7.3 Hz, 0.6H, dCH), 7.00 (bs, 0.4H,
NH), 7.01 (bs, 0.6H, NH), 8.18 (d, J ) 11.4 Hz, 0.4H, CHO),
8.25 (s, 0.6H, CHO); 13C NMR (CDCl3, 62.9 MHz, for major
isomer) δ 14.1 (q), 22.0 (t), 23.8 (t), 24.8 (q), 35.6 (t), 38.5 (s),
39.6 (t), 40.9 (t), 53.4 (t), 61.6 (t), 123.4 (s), 138.2 (d), 158.8
(d), 163.7 (s), 211.9 (s); exact mass calcd for C15H23NO4 m/e
281.1627, found m/e 281.1621.
(64%) of 12 as a heavy oil: IR (CDCl3) 3416, 1691, 1096 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 0.95 (s, 3H, CH3), 1.30 (t, J )
7.1 Hz, 3H, OCH2CH3), 1.21-1.59 (m, 10H), 2.12 (s, 3H, CH3-
CO), 2.01-2.21 (m, 2H, CH2Cd), 3.91 (s, 4H, (OCH2)2), 4.21
(q, J ) 7.1 Hz, 2H, OCH2CH3), 6.69 (t, J ) 7.2 Hz, 1H, dCH),
6.80 (bs, 1H, NH); 13C NMR (CDCl3, 62.9 MHz) δ 14.2 (q), 19.6
(t), 23.4 (q), 23.7 (t), 25.7 (q), 34.6 (s), 34.9 (t), 37.1 (t), 40.4 (t),
44.6 (t), 61.4 (t), 64.0 (t, 2 carbons), 109.4 (s), 124.7 (s), 139.4
(d), 164.8 (s), 168.2 (s); exact mass calcd for C18H29NO5 m/e
339.2046, found m/e 339.2044.
Eth yl (()-(rR*,1R*,3a R*,7a S*)-r-rceta m id oh exa h yd r o-
3a -m eth yl-7-oxo-1-in d a n a ceta te (4). To a solution of 6.73
g (22.8 mmol) of 6 in 100 mL of THF was added 2.10 mL (25.2
mmol) of pyrrolidine followed by 3.2 mL (55.8 mmol) of glacial
acetic acid. The resulting mixture was heated under reflux
for 3 h, diluted with 250 mL of Et2O, and washed with a
solution of 50 mL of saturated aqueous NaHCO3 in 50 mL of
water. The aqueous phase was extracted with two 100 mL
portions of Et2O, and the combined organic phases were
washed with two 100 mL portions of saturated brine, dried
(Na2SO4), and concentrated in vacuo to afford 6.16 g (91%) of
perhydroindan 4 as a pale yellow solid. This material was
used directly in subsequent reactions without further purifica-
tion. Recrystallization of a sample from hexane-carbon
tetrachloride, however, gave pure 4 as a white solid (snow
flakes): mp 123-125 °C; IR (CDCl3) 3426, 1736, 1677, 1514
Eth yl (()-(Z)-2-F or m a m id o-5-(7-m eth yl-1,4-d ioxa sp ir o-
[4.5]d ec-7-yl)-2-p en ten oa te (13). To a solution of 9.77 g
(36.6 mmol) of ethyl formamido(diethylphosphono)acetate in
40 mL of dry CH2Cl2 at -30 °C was added dropwise 4.5 mL
(30.1 mmol) of DBU. The resulting solution was stirred for
1.2 h between -30 and -13 °C and then cooled to -30 °C. A
solution of 5.08 g (23.9 mmol) of aldehyde 11 in 35 mL of dry
CH2Cl2 was added dropwise over a 20 min period. The
resulting mixture was stirred for 1.7 h at -30 °C and for an
additional 2.5 h at rt and diluted with 300 mL of EtOAc. The
resulting solution was washed with 100 mL of saturated
aqueous NH4Cl. The organic layer was separated, and the
aqueous phase was extracted with two 100 mL portions of
EtOAc. The combined organic phases was dried (Na2SO4) and
concentrated in vacuo. The residual yellow oil (11 g) was
chromatographed over 200 g of silica gel (eluted with hexane-
EtOAc, 1:1) to give 6.2 g (80%) of 13 as a pale yellow oil. This
material was a 1:1 mixture of geometrical isomers by integra-
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.12 (s, 3H, CH3), 1.26 (t,
J ) 7.1 Hz, 3H, OCH2CH3), 1.44-1.90 (m, 8H), 1.99 (s, 3H,
CH3CO), 2.02 (bd, J ) 7.8 Hz, 1H, CHCO), 2.23-2.47 (m, 2H),
2.71 (p, J ) 8.5 Hz, 1H, CH), 4.16 (q, J ) 7.1 Hz, 2H, OCH2-
CH3), 4.29 (dd, J ) 8.7, 6.7 Hz, 1H, CHNHAc), 6.68 (bd, J )
6.5 Hz, 1H, NH); 13C NMR (CDCl3, 62.9 MHz) δ 14.1 (q), 20.8
(t), 23.0 (q), 27.1 (t), 27.8 (q), 35.0 (t), 39.0 (t), 39.7 (t), 43.8
(d), 46.1 (s), 56.8 (d), 61.2 (t), 62.0 (d), 170.3 (s), 171.7 (s), 215.2
(s); exact mass calcd for C16H25NO4 m/e 295.1783, found m/e
295.1787.
1
tion of selected peaks in the H NMR spectrum of the mixture.
The 13C NMR of this mixture also showed two geometrical
isomers: IR (CDCl3) 3400, 1698, 1654, 1489 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 0.95 (s, 3H, CH3), 1.25-1.68 (m, 13H),
2.08-2.22 (m, 2H), 3.91 (s, 4H, (OCH2)2), 4.25 (m, 2H, OCH2-
CH3), 6.61 (t, J ) 7.84 Hz, 0.5H, dCH), 6.73 (t, J ) 7.24 Hz,
0.5H, dCH), 6.97 (bs, 1H, NH), 8.22-8.26 (m, 1H, CHO); 13C
NMR (CDCl3, 62.9 MHz) δ 14.2 (q), 18.2 (s), 19.5 (t) and 19.6
(t), 22.7 (t) and 24.0 (t), 25.8 (q) and 26.9 (q), 34.5 (t) and 34.9
(t), 37.1 (t) and 37.8 (t), 39.3 (t) and 40.1 (t), 44.1 (t) and 44.5
(t), 61.5 (t) and 61.7 (t), 63.8 (t) and 63.9 (t), 64.0 (t) and 64.2
(t), 109.2 (s) and 109.4 (s), 123.2 (s) and 125.5 (s), 134.9 (d)
and 139.7 (d), 158.8 (d) and 163.9 (d), 164.3 (s); exact mass
calcd for C17H27NO5 m/e 325.1889, found m/e 325.1893.
Anal. Calcd for C16H25NO4: C, 65.06; H, 8.53. Found: C,
64.90; H, 8.55.
Eth yl (()-(rR*,1R*,3a R*,7a S*)-r-F or m a m id oh exa h y-
d r o-3a -m eth yl-7-oxo-1-in d a n a ceta te (5). To a solution of
5.00 g (17.8 mmol) of 7 in 80 mL of dry THF was added 1.65
mL (19.8 mmol) of pyrrolidine followed by 2.6 mL (45 mmol)
of glacial acetic acid. The resulting mixture was heated under
reflux for 1.7 h, diluted with 200 mL of ether, and washed
with a solution of 40 mL of saturated aqueous NaHCO3 in 40
Eth yl (()-(Z)-2-Acetam ido-5-(1-m eth yl-3-oxocycloh exyl)-
2-p en ten oa te (6). To a solution of 9.55 g (28.2 mmol) of ketal

Carbocycles via Intramolecular Conjugate Additions
J . Org. Chem., Vol. 61, No. 2, 1996 477
mL of water. The organic layer was separated, and the
aqueous phase was extracted with two 75 mL portions of ether.
The combined organic phases were washed with 100 mL of
brine, dried (Na2SO4), and concentrated in vacuo to afford 4.53
g (91%) of perhydroindan 5 as a pale yellow solid. Recrystal-
lization of a sample from hexane-carbon tetrachloride gave
pure 5 (86% recovery) as colorless crystals. This material was
a 14:1 mixture of geometrical isomers by integration of selected
(()-N-[(3R*,3a R*,5a R*,8a R*,8bS*)-8a -(Br om om eth yl)-
decah ydr o-2,2,5a-tr im eth yl-2H-cyclopen ta[de]-1-ben zopy-
r a n -3-yl]a cet a m id e (16). To a suspension of 50 mg (0.16
mmol) of pyridinium bromide perbromide in 0.4 mL of chlo-
roform was added under argon 33.8 mg (0.121 mmol) of alcohol
15, followed by 31 µL (0.15 mmol) of hexamethyldisilane. The
resulting pale orange solution was stirred at rt for 50 min,
dissolved in 20 mL of ether, washed with three 15 mL portions
of water, dried (Na2SO4), and concentrated in vacuo to afford
47 mg of a pale yellow solid. Purification by column chroma-
tography (eluted with EtOAc-hexane, 2:1) yielded 30 mg (69%)
of 16 as a white solid: mp 188-189 °C dec; IR (CDCl3) 3417,
1
peaks in the H NMR spectrum of the mixture. The 13C NMR
of this mixture also showed one major isomer and one minor
isomer: mp 82-84 °C; IR (CDCl3) 3416, 3352, 1737, 1690, 1506
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.13 (s, 3H, CH3), 1.27 (t,
1665, 1514 cm-1 1H NMR (CDCl3, 200 MHz) δ 1.14 (s, 3H,
;
J ) 7.1 Hz, 3H, OCH2CH3), 1.47-1.92 (m, 8H), 2.03 (d, J )
7.9 Hz, 1H, CHCdO), 2.23-2.46 (m, 2H, CH2CdO), 2.78 (p, J
) 8.5 Hz, 1H, CH), 4.18 (q, J ) 7.1 Hz, 2H, OCH2CH3), 4.42
(t, J ) 8.0 Hz, 1H, CHCO2Et), 6.75 (bs, 1H, NH), 8.18 (s, 1H,
CHO); 13C NMR (CDCl3, 62.9 MHz, for major isomer) δ 14.1
(q), 20.8 (t), 27.1 (t), 27.8 (q), 35.1 (t), 39.0 (t), 39.7 (t), 43.6
(d), 46.1 (s), 55.2 (d), 61.5 (t), 61.7 (d), 161.1 (d), 171.1 (s), 215.2
(s); exact mass calcd for C15H23NO4 m/e 281.1627, found m/e
281.1636. The structure of 5 was confirmed by X-ray crystal-
lography.
CH3), 1.22-1.83 (m, 16H), 2.06 (s, 3H, CH3CdO), 1.97-2.14
(m, 1H, CH), 2.49 (m, 1H, CH), 3.47 (d, J ) 10.6 Hz, 1H,
CH(H)Br), 3.79 (d, J ) 10.6 Hz, 1H, C(H)HBr), 4.04 (dd, J )
10.1, 2.4 Hz, 1H, CHNH), 5.91 (bd, J ) 10.3 Hz, 1H, NH); 13
C
NMR (CDCl3, 62.9 MHz) δ 21.6 (t), 23.4 (q), 25.1 (t), 26.8 (q),
28.3 (q), 28.5 (q), 33.1 (t), 36.0 (t), 36.9 (d), 39.9 (t), 40.2 (s),
45.0 (d), 46.3 (t), 52.8 (d), 75.4 (s), 76.4 (s), 170.1 (s); exact mass
calcd for C17H29NO2Br + H m/e 358.1382, found m/e 358.1380.
(()-N-[(3R*,3a R*,5a R*,8a R*,8b S*)-Deca h yd r o-2,2,5a ,-
8a -t et r a m et h yl-2H -cyclop en t a [d e]-1-b en zop yr a n -3-yl]-
a ceta m id e (17). To a solution of 30 mg (0.11 mmol) of alcohol
15 and 16.1 mg (0.107 mmol) of sodium iodide in 0.4 mL of
acetonitrile was added dropwise under argon 15 µL (0.12
mmol) of trimethylsilyl chloride. The resulting solution was
stirred for 55 min, and 20 mL of ether was added, which
resulted in darkening of the solution. After successively
washing with 15 mL of water, 15 mL of 10% aqueous sodium
thiosulfate, and 15 mL of brine, the organic layer was dried
(Na2SO4) and concentrated in vacuo to afford 48 mg of crude
product. This material was purified by column chromatogra-
phy to yield 22 mg (73%) of 17 as a whilte solid: mp 209-211
Anal. Calcd for C15H23NO4: C, 64.03; H, 8.24. Found: C,
63.94; H, 8.27.
Eth yl (()-(rR*,1R*,3aR*,7aR*)-r-Acetam idoh exah ydr o-
3a -m eth yl-7-m eth ylen e-1-in d a n a ceta te (14). A mixture of
1.88 g (5.26 mmol) of methyltriphenylphosphonium bromide
and 393 mg (3.51 mmol) of potassium tert-butoxide in 8 mL of
toluene was stirred at rt for 3.7 h followed by the addition of
a solution of 689 mg (2.34 mmol) of 4 in 20 mL of toluene
dropwise over a 15 min period. The reaction mixture was
stirred at rt for 1.8 h, neutralized with 15 mL of saturated
aqueous NH4Cl in 60 mL of water, and diluted with 100 mL
of ether. The organic phase was separated, and the aqueous
layer was extracted with three 50 mL portions of ether. The
combined organic phases were washed with 100 mL of brine,
dried (Na2SO4), and concentrated in vacuo. The residue was
chromatographed over 80 g of silica gel (eluted with hexane-
EtOAc, 1:2) to give 601 mg (88%) of olefin 14 as a white solid:
1
°C dec; IR (CDCl3) 3446, 1665, 1509 cm-1; H NMR (CDCl3,
200 MHz) δ 1.12 (s, 6H, CH3), 1.15-1.99 (m, 11H), 1.30 (s,
3H, CH3), 1.40 (s, 3H, CH3), 2.05 (s, 3H, CH3CdO), 2.51 (m,
1H, CH), 4.03 (bd, J ) 10.2, 3.1 Hz, 1H, CHN), 5.55 (bd, J )
9.1 Hz, 1H, NH); 13C NMR (CDCl3, 62.9 MHz) δ 21.9 (t), 23.4
(q), 24.7 (t), 28.0 (q), 29.0 (q), 29.4 (q), 30.2 (q), 34.1 (t), 35.8
(t), 37.1 (d), 39.9 (t), 41.0 (s), 51.7 (d), 52.9 (d), 74.6 (s), 77.1
(s), 170.0 (s); exact mass calcd for C17H29NO2 + H m/e 280.2276,
found m/e 280.2254.
1
mp 122-125 °C; IR (CDCl3) 3434, 1731, 1673, 1510 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.94 (s, 3H, CH3), 1.26 (t, J ) 7.1
Hz, 3H, OCH2CH3), 0.97-1.66 (m, 8H), 1.99 (s, 3H, CH3CO),
1.87-2.14 (m, 3H), 2.64 (m, 1H, CH), 4.12 (q, J ) 7.1 Hz, 2H,
OCH2CH3), 4.54 (dd, J ) 7.9, 6.5 Hz, 1H, CHNHAc), 4.66 (d,
J ) 2.5 Hz, 1H, dCH), 4.79 (d, J ) 2.5 Hz, 1H, dCH), 6.00
(bd, J ) 7.6 Hz, 1H, NH); 13C NMR (CDCl3, 75.5 MHz) δ 14.1
(q), 23.1 (q), 24.0 (t), 24.5 (q), 25.3 (t), 30.7 (t), 32.8 (t), 40.0
(t), 42.3 (d), 44.5 (s), 55.5 (d), 57.3 (d), 61.0 (t), 111.3 (t), 148.3
(s), 170.0 (s), 171.9 (s); exact mass calcd for C17H27NO3 m/e
293.1991, found m/e 293.1985.
(()-N-[(1R*)-1-[(1R*,3a R*,7a R*)-Hexa h yd r o-3a -m eth yl-
7-m eth ylen e-1-in d a n yl]-2-m eth yla llyl]a ceta m id e (18). A.
P r ep a r a tion by Deh yd r a tion of Alcoh ol 15. To a solution
of 175 mg (0.63 mmol) of alcohol 15 in 5 mL of CH2Cl2 was
added a solution of 687 mg (1.02 mmol) of Martin’s sulfurane
[Ph2S(OC(CF3)2Ph)2] in 5 mL of CH2Cl2 in one portion. The
mixture was stirred at rt for 25 min and concentrated in vacuo.
The residue was chromatographed over 50 g of silica gel (eluted
with hexane-EtOAc, 2:1) to give 124 mg (75%) of diene 18 as
a pale yellow oil. B. P r ep a r a tion by Olefin a tion of Keton e
19. A mixture of 1.32 g (3.70 mmol) of methyltriphenylphos-
phonium bromide and 282 mg (2.52 mmol) of potassium tert-
butoxide in 4 mL of toluene was stirred at rt for 3.2 h followed
by the addition via cannula of a solution of 251 mg (0.95 mmol)
of 19 in 10 mL of toluene over a 5 min period. The reaction
mixture was stirred at rt for 2 h, neutralized with 20 mL of
saturated aqueous NH4Cl in 40 mL of water, and diluted with
100 mL of ether. The organic phase was separated, and the
aqueous layer was extracted with two 50 mL portions of ether.
The combined organic phases were washed with 100 mL of
brine, dried (Na2SO4), and concentrated in vacuo. The residue
was chromatographed over 75 g of silica gel (eluted with
hexane-EtOAc, 1:2) to give 235 mg (95%) of olefin 18 as a
pale yellow solid. The material was used directly in subse-
quent reactions without further purification. Recrystallization
of a sample from hexane, however, afforded 18 as a white
Anal. Calcd for C17H27NO3: C, 69.59; H, 9.28. Found: C,
69.47; H, 9.35.
(()-N-[(1R*)-1-[(1R*,3a R*,7a R)-Hexa h yd r o-3a -m eth yl-
7-m e t h yle n e -1-in d a n yl]-2-h yd r oxy-2-m e t h ylp r op yl]-
a ceta m id e (15). To an ice-cooled solution of 174 mg (0.59
mmol) of 14 in 5.4 mL of dry THF was added dropwise with
stirring 1.20 mL (2.04 mmol) of 1.7 M ethereal methylmag-
nesium bromide. The resulting mixture was stirred at 5 °C
for 1.5 h, the reaction was quenched with 7 mL of saturated
aqueous NH4Cl in 30 mL of water, and the solution was diluted
with 100 mL of ether. The organic layer was separated, and
the aqueous phase was extracted with three 50 mL portions
of ether. The combined organic phases were washed with 130
mL brine, dried (Na2SO4), and concentrated in vacuo to afford
the crude alcohol as a pale yellow solid. Recrystallization from
hexane-CH2Cl2 afforded 140 mg (84%) of 15 as a white solid:
1
mp 142-145 °C; IR (CDCl3) 3500, 3433, 1662, 1506 cm-1; H
NMR (CDCl3, 200 MHz) δ 0.93 (s, 3H, CH3), 1.16 (d, J ) 6.9
Hz, 6H, (CH3)2), 1.00-1.80 (m, 8H), 2.04 (s, 3H, CH3CO), 1.90-
2.20 (m, 4H), 2.59 (tt, J ) 10.4, 5.2 Hz, 1H, CH), 3.97 (dd, J )
9.9, 5.2 Hz, 1H, CH), 4.74 (d, J ) 2.5 Hz, 1H, dCH), 4.94 (bd,
J ) 2.1 Hz, 1H, dCH), 6.01 (bd, J ) 9.6 Hz, 1H, NH); 13C
NMR (CDCl3, 62.9 MHz) δ 23.3 (q), 24.2 (q), 24.8 (t), 27.3 (q),
27.9 (q), 30.1 (t), 31.2 (t), 32.2 (t), 40.2 (t), 40.3 (d), 45.8 (s),
56.9 (d), 60.9 (d), 73.3 (s), 111.3 (t), 152.4 (s), 170.6 (s); exact
mass calcd for C17H29NO2 m/e 280.2276, found m/e 280.2276.
1
solid: mp 98-100 °C; IR (CDCl3) 1665, 1509 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.93 (s, 3H, CH3) 1.20 (bd, J ) 10 Hz, 1H,
CH), 1.35-1.70 (m, 6H), 1.65 (bs, 3H, dCCH3), 1.87 (s, 3H,
CH3CO), 1.81-2.29 (m, 5H), 4.22 (dd, J ) 10.7, 8.0 Hz, 1H,
CHNHAc), 4.69 (bd, J ) 2.0 Hz, 1H, dCH), 4.80 (bd, J ) 2.0
Hz, 1H, dCH), 4.85 (bs, 1H, dCH), 4.95 (bs, 1H, dCH), 5.47
(bs, 1H, NH); 13C NMR (CDCl3, 62.9 MHz) δ 18.5 (q), 23.3 (q),
24.3 (q), 24.4 (t), 27.1 (t), 31.3 (t), 32.7 (t), 39.9 (t), 41.5 (d),

478 J . Org. Chem., Vol. 61, No. 2, 1996
Guevel and Hart
45.5 (s), 59.7 (d), 61.7 (d), 110.6 (t), 113.5 (t), 144.3 (s), 150.6
(s), 169.3 (s); exact mass calcd for C17H27NO m/e 261.2094,
found m/e 261.2080.
Anal. Calcd for C17H27NO: C, 78.11; H, 10.41. Found: C,
78.02; H, 10.32.
263.1885, found m/e 263.1873. Anal. Calcd for C16H25NO2:
C, 72.96; H, 9.57. Found: C, 73.08; H, 9.55.
(()-(rR*,1R*,3a R*,7a R*)-r-F or m a m id oh exa h yd r o-3a -
m et h yl-7-m et h ylen e-1-in d a n a cet ic Acid (22). Cerium
trichloride (3.61 g, 14.6 mmol) was dried at 145 °C and 0.1
mmHg for 6 h. The flask was cooled to rt and vented to a
dry-argon atmosphere. Dry THF was added (35 mL), and the
suspension was stirred at rt under argon for 14 h. The light
grey slurry was then cooled to -78 °C, and a solution of t-BuLi
(3.0 M in hexanes) was added until an orange color was
obtained. A 12 mL solution (12 mmol) of (trimethylsilyl)-
methylmagnesium chloride (1.0 M in Et2O) was added drop-
wise, and the resulting suspension was stirred at -78 °C for
3.5 h, at which time 564 mg (2.00 mmol) of ester 5 in 7 mL of
dry THF was added dropwise. The resulting mixture was
allowed to stir overnight (21 h) and warm to rt. The reaction
was quenched by addition of 70 mL of 1 N aqueous HCl
solution. The organic layer was separated, and the aqueous
phase was extracted with three 50 mL portions of CH2Cl2. The
combined organic phases were dried (MgSO4) and concentrated
in vacuo to afford 533 mg of a beige solid. Trituration with
CH2Cl2-hexane afforded several crops which overall accounted
for 358 mg (71%) of acid 22 as a white solid: mp 178-180 °C
(()-N-[(1R*)-1-[(1R*,3a R*,7a R*)-Hexa h yd r o-3a -m eth yl-
7-m eth ylen e-1-in d a n yl]-2-m eth ylp r op yl]a ceta m id e (20)
a n d (()-N-[(1R*)-2-Meth yl-1-[(1S*,3a S*,7a R*)-3a ,4,5,7a -
tetr a h yd r o-3a ,7-d im eth yl-1-in d a n yl]p r op yl]a ceta m id e. A
solution of 130 mg (0.5 mmol) of 18 in 15 mL of CH2Cl2 was
purged with argon for 10 min. To this solution was added in
one portion under argon 19 mg (0.024 mmol) of Crabtree’s
catalyst [Ir(COD)P(Cy)3(py)]PF6. The resulting bright orange
solution was placed under 1 atm of hydrogen and stirred until
about 12 mL (0.5 mmol) of hydrogen had been absorbed (the
color became faint as soon as stirring began). The solution
was filtered through Celite, and the filter cake was washed
with CH2Cl2. The combined layers were dried (Na2SO4) and
concentrated in vacuo. The residue was chromatographed over
silica gel (eluted with hexane-EtOAc, 2:1) to afford 84 mg
(64%) of 20 (which was further recrystallized from CH2Cl2-
hexane to afford 20 as a clear solid (cubes)) and 55 mg of a
mixed fraction which was purified by MPLC to give a product,
which after recrystallization afforded 7 mg (5%) of (()-N-
[(1R*)-2-methyl-1-[1S*,3aS*,7aR*)-3a,4,5,7a-tetrahydro-3a,7-
dimethyl-1-indanyl]propyl]acetamide as white needles. Amide
20: mp 124-125 °C; IR (CCl4) 3450, 3070, 1682, 1386, 1368
dec; IR (KBr pellet) 3327, 3300-2500, 3070, 1726, 1617 cm-1
;
1H NMR (DMSO-d6, 300 MHz) δ 0.89 (s, 3H, CH3), 1.10-1.19
(m, 1H, CH), 1.24-1.50 (m, 5H), 1.54-1.60 (m, 1H, CH), 1.82-
2.11 (m, 4H), 2.57-2.64 (m, 1H, CH), 4.38 (dd, J ) 9.1, 4.3
Hz, 1H, CHN), 4.65-4.70 (m, 2H, dCH2), 8.03 (d, J ) 1.0 Hz,
1H, CHO), 8.29 (bd, J ) 9.2 Hz, 1H, NH), 12.5 (bs, 1H, CO2H);
13C NMR (DMSO-d6, 75.5 MHz) δ 23.6 (t), 24.6 (q), 25.1 (t),
30.2 (t), 32.6 (t), 39.6 (t), 41.8 (d), 43.8 (s), 52.0 (d), 55.3 (d),
111.3 (t), 147.2 (s), 161.3 (d), 172.0 (s); exact mass calcd for
C14H21NO3 m/e 251.1521, found m/e 251.1522.
1
cm-1; H NMR (CDCl3, 250 MHz) δ 0.77 (d, J ) 6.8 Hz, 3H,
CH(CH3)CH3), 0.88 (d, J ) 6.8 Hz, 3H, CH(CH3)CH3), 0.92 (s,
3H, CH3), 1.17 (bd, J ) 12.2 Hz, 1H, CH), 1.35-1.69 (m, 6H),
1.80-2.11 (m, 5H), 1.91 (s, 3H, CH3CO), 2.24 (qd, J ) 9.9, 5.2
Hz, 1H, CH), 3.84 (td, J ) 10.0, 3.6 Hz, 1H, CHNHAc), 4.63
(d, J ) 2.8 Hz, 1H, dCH), 4.75 (bs, 1H, dCH), 5.02 (bd, J )
9.0 Hz, 1H, NH); 13C NMR (CDCl3, 62.9 MHz) δ 15.9 (q), 20.5
(q), 23.5 (q), 24.3 (q), 24.6 (t), 27.8 (t), 30.6 (d), 31.1 (t), 32.9
(t), 39.8 (t), 42.0 (d), 45.1 (s), 59.3 (d), 59.3 (d), 109.9 (t), 150.2
(s), 170.0 (s); exact mass calcd for C17H29NO m/e 263.2249,
found m/e 263.2243. Anal. Calcd for C17H29NO: C, 77.51; H,
11.10. Found: C, 77.62; H, 11.15. (()-N-[(1R*)-2-Methyl-1-
[1S*,3aS*,7aR*)-3a,4,5,7a-tetrahydro-3a,7-dimethyl-1-indanyl]-
propyl]acetamide: mp 198-200 °C; IR (CDCl3) 3446, 1664,
Anal. Calcd for C14H21NO3: C, 66.90; H, 8.42. Found: C,
66.26; H, 8.44.
Eth yl (()-(rR*,1R*,3a R*,7a R*)-r-F or m a m id oh exa h y-
d r o-3a -m eth yl-7-m eth ylen e-1-in d a n a ceta te (21). A mix-
ture of 237 mg (0.94 mmol) of acid 22, 0.16 mL (2.0 mmol) of
iodoethane, and 287 mg (1.89 mmol) of cesium fluoride in 5
mL of dry N,N-dimethylformamide was stirred at 13 °C under
argon for 24 h. The reaction mixture was combined with 35
mL of saturated aqueous NaHCO3 and extracted with two 50
mL portions of EtOAc. The combined organic phases were
dried (Na2SO4) and concentrated in vacuo. The residual oil
(271 mg) was purified by flash chromatography over 25 g of
silica gel (eluted with hexane-EtOAc, 2:1) to afford 223 mg
(85%) of ester 21 as a clear colorless oil. This material was a
3.5:1 mixture of geometrical isomers by integration of selected
1
1511, 1371 cm-1; H NMR (CDCl3, 250 MHz) δ 0.81 (d, J )
6.9 Hz, 3H, CH(CH3)CH3), 0.92 (d, J ) 6.8 Hz, 3H, CH(CH3)-
CH3), 1.03 (s, 3H, CH3), 1.23-1.37 (m, 2H), 1.41-1.60 (m, 3H),
1.65 (d, J ) 1.4 Hz, 3H, dCCH3), 1.72-2.04 (m, 6H), 2.02 (s,
3H, CH3CO), 3.89 (dt, J ) 10.5, 2.8 Hz, 1H, CHN), 5.15 (bd, J
) 11.0 Hz, 1H, NH), 5.39 (bs, 1H, dCH); 13C NMR (CDCl3,
62.9 MHz) δ 14.9 (q), 21.0 (q), 22.1 (t), 23.1 (q), 23.8 (q), 28.0
(t), 28.1 (q), 29.2 (d), 32.2 (t), 36.2 (t), 41.2 (s), 46.6 (d), 51.8
(d), 58.7 (d), 122.0 (d), 135.8 (s), 169.1 (s); exact mass calcd for
C17H29NO m/e 263.2249, found m/e 263.2245.
1
peaks in the H NMR spectrum of the mixture. The 13C NMR
of this mixture also showed one major isomer and one minor
isomer: IR (CDCl3) 3424, 3072, 1733, 1690, 1645 cm-1 1H
;
NMR (CDCl3, 250 MHz) δ 0.95 (s, 3H, CH3), 1.26 (t, J ) 7.16
Hz, 3H, CH2CH3), 1.23-1.68 (m, 7H), 1.89-2.16 (m, 4H), 2.67-
2.80 (m, 1H, CHCN), 4.12 (q, J ) 7.15 Hz, 2H, OCH2CH3),
4.62-4.65 (m, 1H, dCH), 4.70 (dd, J ) 8.4, 5.4 Hz, 1H, CHCO2-
Et), 4.78-4.80 (m, 1H, dCH), 6.15 (bd, J ) 6.0 Hz, 1H, NH),
(()-N-[(1R*)-1-[(1R*,3a R*,7a R)-Hexa h yd r o-3a -m eth yl-
7-m eth ylen e-1-in d a n yl]a ceton yl]a ceta m id e (19). To an
ice-cooled mixture of 1.55 mL (2.63 mmol) of 1.7 M ethereal
methylmagnesium bromide and 0.72 mL (5.16 mmol) of
triethylamine in 5 mL of toluene was added dropwise via
syringe pump a solution of 238 mg (0.81 mmol) of 14 in 8 mL
of THF over a 45 min period. The resulting mixture was
stirred at a temperature ranging from 5 to 10 °C for 4 h,
acidified with 10 mL of 5% aqueous HCl in 60 mL of water
(pH 3), and diluted with 100 mL of ether. The organic layer
was separated, and the aqueous phase was extracted with two
50 mL portions of ether. The combined organic phases were
dried (Na2SO4) and concentrated in vacuo. The residue was
chromatographed over 50 g of silica gel (eluted with EtOAc-
hexane, 2:1) to afford 81 mg (34%) of recovered ester 14, along
with 22 mg (9%) of alcohol 15 and 115 mg (54%) of 19.
Recrystallization of a 45 mg sample from CH2Cl2-hexane
afforded 43 mg of pure 19: mp 116-117 °C; IR (CDCl3) 3420,
8.00 (d, J ) 11.7 Hz, 0.23 H, CHO), 8.22 (s, 0.77 H, CHO); 13
C
NMR (CDCl3, 75.5 MHz, for major isomer) δ 14.3 (q), 24.2 (t),
24.8 (q), 25.5 (t), 30.8 (t), 33.0 (t), 40.1 (t), 42.5 (d), 44.6 (s),
53.5 (d), 56.8 (d), 61.4 (t), 111.8 (t), 147.8 (s), 161.3 (d), 171.4
(s); exact mass calcd for C16H25NO3 m/e 279.1834, found m/e
279.1837.
(()-N-[(1R*)-1-[(1R*,3a R*,7a R*)-Hexa h yd r o-3a -m eth yl-
7-m eth ylen e-1-in d a n yl]a ceton yl]for m a m id e (23). Cerium
trichloride (1.12 g, 4.54 mmol) was dried at 145 °C and 0.1
mmHg for 8 h. The flask was cooled to rt and vented to a
dry-argon atmosphere. Dry THF was added (20 mL), and the
suspension was stirred at rt under argon for 12 h. The light
grey slurry was then cooled to -78 °C, and a solution of t-BuLi
(3.0 M in hexanes) was added until an orange color was
obtained. A 3.8 mL solution (3.8 mmol) of (trimethylsilyl)-
methylmagnesium chloride (1.0 M in Et2O) was added drop-
wise, and the resulting suspension was stirred at -78 °C for
5 h, at which time 223 mg (0.80 mmol) of ester 21 in 3 mL of
dry THF was added dropwise. The resulting mixture was
allowed to stir overnight (19 h) and warm to rt. The reaction
was quenched by addition of 15 mL of a 1 N aqueous HCl
1
1716, 1671, 1505 cm-1; H NMR (CDCl3, 250 MHz) δ 0.94 (s,
3H, CH3), 1.18-1.74 (m, 7H), 1.88-2.22 (m, 4H), 1.99 (s, 3H,
CH3CdO), 2.17 (s, 3H, CH3CdO), 2.60 (m, 1H, CH), 4.56 (t, J
) 7.1 Hz, 1H, CHAc), 4.62 (d, J ) 2.4 Hz, 1H, dCH), 4.81 (s,
1H, dCH), 6.14 (bs, 1H, NH); 13C NMR (CDCl3, 62.9 MHz) δ
23.0 (q), 24.1 (t), 24.4 (q), 26.4 (t), 28.4 (q), 30.8 (t), 32.7 (t),
40.1 (t), 40.7 (d), 44.8 (s), 57.5 (d), 62.6 (d), 112.0 (t), 148.7 (s),
170.3 (s), 206.7 (s); exact mass calcd for C16H25NO2 m/e

Carbocycles via Intramolecular Conjugate Additions
J . Org. Chem., Vol. 61, No. 2, 1996 479
solution. The organic layer was separated, and the aqueous
phase was extracted with three 25 mL portions of CH2Cl2. The
combined organic phases were dried (MgSO4) and concentrated
in vacuo. The residual yellow oil (218 mg) was purified by
flash chromatography over 25 g of silica gel (eluted with
hexane-EtOAc, 5:1, then 2:1) to afford 155 mg (78%) of ketone
23 as a white solid. The material was used directly in
subsequent reactions without further purification. Recrystal-
lization of a sample from CH2Cl2-hexane, however, afforded
23 as white needles. This material was a 9:1 mixture of
A solution of 62.6 mg (0.25 mmol) of diene 24 in 5 mL of CH2-
Cl2 was purged with argon for 10 min. To this solution was
added in one portion under argon 6 mg (7 µmol) of [Ir(COD)P-
(Cy)3(py)]PF6. The resulting bright orange solution was
hydrogenated at 1 atm for 2 h (although no clear sign of
hydrogen uptake was detected). The solution was filtered
through Celite, and the filter cake was washed with CH2Cl2.
The combined layers were dried (Na2SO4) and concentrated
in vacuo. The residue was chromatographed over silica gel
(eluted with hexane-EtOAc, 2:1) to afford 76 mg of material
which, after chromatography over silica gel (eluted with
petroleum ether-Et2O, 2:1), afforded 24 mg (39%) of axamide-1
(2) along with 23 mg of a mixture of products containing
material with the endocyclic methylene and 16 mg of a mixture
containing the epimer of axamide-1 at the position R to the
formamide group. Spectral data of amide 2 were consistent
with data published in the literature for (()-axamide-1.9 After
a few weeks on the bench top and/or in the freezer, amide 2
crystallized as a white solid without any change in the spectral
data. This material was a 1.8:1 mixture of geometrical isomers
by integration of selected peaks in the 1H NMR spectrum of
the mixture. The 13C NMR of this mixture also showed one
major isomer and one minor isomer: mp 71-74 °C; IR (neat)
3278, 1660, 890 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.79 (d, J
) 6.8 Hz, 1.92H, CH(CH3)(CH3)), 0.80 (d, J ) 6.8 Hz, 1.08H,
CH(CH3)(CH3)), 0.89 (d, J ) 6.8 Hz, 1.92H, CH(CH3)(CH3)),
0.90 (d, J ) 6.8 Hz, 1.08H, CH(CH3)(CH3)), 0.92 (s, 1.92H,
CH3), 0.95 (s, 1.08H, CH3), 1.19-1.53 (m, 6H), 1.60-1.71 (m,
1H), 1.84-2.42 (m, 5H), 2.95 (ddd, J ) 12.5, 8.4, 4.2 Hz, 0.36H,
CH), 3.91 (td, J ) 9.9, 4.1 Hz, 0.64 H, CH), 4.65 (bs, 0.36H,
dCH), 4.68 (d, J ) 2.6 Hz, 0.64H, dCH), 4.75 (t, J ) 1.8 Hz,
0.64H, dCH), 4.82 (t, J ) 2.0Hz, 0.36H, dCH), 5.12 (bs, 0.64H,
NH), 5.28 (bs, 0.36H, NH), 7.90 (d, J ) 11.8 Hz, 0.36H, CHO),
8.15 (d, J ) 2.1 Hz, 0.64H, CHO); 13C NMR (CDCl3, 75.5 MHz,
major isomer) δ 16.2 (q), 20.5 (q), 24.3 (q), 24.5 (t), 27.8 (t),
30.4 (d), 31.1 (t), 32.8 (t), 39.7 (t), 40.8 (d), 45.1 (s), 58.9 (d),
63.9 (d), 110.7 (t), 149.9 (s), 161.7 (d); 13C NMR (CDCl3, 75.5
MHz, minor isomer) δ 16.3 (q), 20.5 (q), 24.3 (q), 24.4 (t), 27.7
(t), 29.7 (d), 31.1 (t), 32.1 (t), 39.7 (t), 42.2 (d), 44.8 (s), 58.1
(d), 59.4 (d), 111.7 (t), 148.2 (s), 164.2 (d); exact mass calcd for
C16H27NO m/e 249.2092, found m/e 249.2091.
1
geometrical isomers by integration of selected peaks in the H
NMR spectrum of the mixture. The 13C NMR of this mixture
also showed one major isomer and one minor isomer: mp 75-
77 °C; IR (CDCl3) 3409, 1716, 1675, 1644 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 0.94 (s, 3H, CH3), 1.21 (bd, J ) 10.3 Hz,
1H, CH), 1.32-1.54 (m, 4H), 1.57-1.70 (m, 2H, CH), 1.88 (d,
J ) 10.3 Hz, 1H, CH), 1.95-2.13 (m, 3H), 2.17 (s, 3H, COCH3),
2.70 (m, 1H, CH), 4.60 (bs, 1H, dCH), 4.70 (dd, J ) 7.9, 5.9
Hz, 1H, CHNCHO), 4.80 (t, J ) 1.8 Hz 1H, dCH), 6.33 (bs,
1H, NH), 8.2 (s, 1H, CHO); 13C NMR (CDCl3, 75.5 MHz) δ 24.0
(t), 24.4 (q), 26.4 (t), 28.1 (q), 30.8 (t), 32.7 (t), 40.0 (t), 40.6
(d), 44.7 (s), 56.7 (d), 60.7 (d), 112.6 (t), 147.8 (s), 161.3 (d),
205.6 (s); exact mass calcd for C15H23NO2 m/e 249.1728, found
m/e 249.1743.
Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30. Found: C,
72.25; H, 9.32.
(()-N-[(1R*)-1-[(1R*,3a R*,7a R*)-Hexa h yd r o-3a -m eth yl-
7-m eth ylen e-1-in dan yl]-2-m eth ylallyl]for m am ide (24). Ce-
rium trichloride (877 mg, 3.56 mmol) was dried at 145 °C and
0.1 mmHg for 8 h. The flask was cooled to rt and vented to a
dry-argon atmosphere. Dry THF was added (18 mL), and the
suspension was stirred at rt under argon for 11 h. The light
grey slurry was then cooled to -78 °C, and a solution of t-BuLi
(3.0 M in hexane) was added until an orange color was
obtained. A 2.8 mL solution (2.8 mmol) of (trimethylsilyl)-
methylmagnesium chloride (1.0 M in Et2O) was added drop-
wise, and the resultng suspension was stirred at -78 °C for 4
h, at which time 146 mg (0.58 mmol) of ketone 23 in 7 mL of
dry THF was added dropwise. The resulting mixture was
allowed to stir overnight (20 h) and warm up to rt. The
reaction was quenched by addition of 25 mL of a 1 N aqueous
HCl solution. The organic layer was separated, and the
aqueous phase was extracted with three 35 mL portions of
CH2Cl2. The combined organic phases were dried (MgSO4) and
concentrated in vacuo to afford 164 mg of hydroxysilane as
an off-white solid. Potassium hydride (35% oil dispersion, 5.23
mmol) was washed with three 2 mL portions of hexane, and 5
mL of dry THF was added by syringe. A solution of 163 mg
(0.48 mmol) of the hydroxysilane in 5 mL of dry THF was
added dropwise. The mixture was stirred for 2.5 h at rt and
neutralized with 25 mL of saturated aqueous NH4Cl. The
organic layer was separated, and the aqueous phase was
extracted with three 30 mL portions of pentane-ether (1:2).
The combined organic phases were washed with 20 mL brine,
dried (Na2SO4), and concentrated in vacuo. The residual oil
was chromatographed over 25 g of silica gel (eluted with
hexane-EtOAc, 2:1) to give 93 mg (69% from ketone) of diene
24. This material was a 2.5:1 mixture of geometrical isomers
by integration of selected peaks in the 1H NMR spectrum of
the mixture. The 13C NMR of this mixture also showed one
major isomer and one minor isomer: IR (CDCl3) 3427, 3155,
(()-(1R*)-1-[(1S*,3a S*,7a S*)-H exa h yd r o-3a -m et h yl-7-
m eth ylen e-1-in d a n yl]-2-m eth ylp r op yl Isocya n id e (1). To
a stirred solution of 17.1 mg (0.068 mmol) of (()-axamide-1
(2) in 1 mL of pyridine was added under an argon atmosphere
46 mg (0.24 mmol) of p-toluenesulfonyl chloride, and the
mixture was stirred at rt for 2.5 h. A few chips of ice were
added, and the mixture was poured into 10 mL of ice-cooled
water and then extracted with two 10 mL portions of pentane.
The combined extracts were washed with two 5 mL portions
of water, dried (MgSO4), and concentrated in vacuo to afford
13.7 mg (87%) of (()-axisonitrile-1 (1) as a white solid.
Spectral data of isonitrile 1 were consistent with data pub-
lished in the literature for (()-axisonitrile-1: mp 45-46 °C;
IR (CCl4) 3072, 2135, 1637, 1390, 1375, 898 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 0.88 (d, J ) 6.7 Hz, 3H, CH(CH3)(CH3)),
0.99 (s, 3H, CH3), 1.01 (d, J ) 6.6 Hz, 3H, CH(CH3)(CH3)),
1.20-1.26 (m, 1H), 1.43-1.66 (m, 6H), 1.98-2.19 (m, 5H), 2.48
(m, 1H, CH), 3.23 (tt, J ) 5.6, 1.8 Hz, 1H, CHNdC), 4.82 (bs,
2H, dCH2); 13C NMR (CDCl3, 75.5 MHz) δ 18.9 (q), 19.7 (q),
24.2 (q), 24.2 (t), 27.6 (t), 29.6 (d), 31.2 (t), 33.2 (t), 39.5 (t),
40.1 (d), 45.0 (s), 57.1 (d), 67.6 (td, J CNC ) 5.3 Hz), 111.5 (t),
148.5 (s), the isonitrile carbon singlet was not detected; exact
mass calcd for C16H25N m/e 231.1987, found m/e 231.1988.
1
3073, 1672 cm-1; H NMR (CDCl3, 300 MHz) δ 0.91 (s, 2.1H,
CH3), 0.92 (s, 0.9H, CH3), 1.15-1.46 (m, 6H), 1.50-1.85 (m,
1H), 1.63 (bs, 3H, dCCH3), 1.87-2.30 (m, 5H), 3.68 (dd, J )
9.6, 6.8 Hz, 0.28H, CHNHCHO), 4.29 (t, J ) 9.2 Hz, 0.72 H,
CHNHCHO), 4.68-4.94 (m, 4H, dCH), 5.80 (bs, 0.71H, NH),
6.10 (bs, 0.28H, NH), 7.95 (d, J ) 12 Hz, 0.28H, CHO), 8.02
(bs, 0.72H, CHO); 13C NMR (CDCl3, 75.5 MHz, major isomer)
δ 18.7 (q), 24.6 (q), 24.5 (t), 27.2 (t), 31.5 (t), 32.9 (t), 40.0 (t),
41.0 (d), 45.7 (s), 59.7 (d), 60.6 (d), 111.6 (t), 114.1 (t), 144.0
(s), 150.3 (s), 161.0 (d); 13C NMR (CDCl3, 75.5 MHz, minor
isomer) δ 17.7 (q), 24.4 (t), 24.7 (q), 26.7 (t), 31.3 (t), 33.1 (t),
39.9 (t), 41.9 (d), 45.6 (s), 60.5 (d), 65.5 (d), 112.7 (t), 114.9 (t),
144.6 (s), 149.1 (s), 164.4 (d); exact mass calcd for C16H25NO
m/e 247.1936, found m/e 247.1934.
Ack n ow led gm en t. We thank the National Science
Foundation for generous support of this research and
Dr. Kurt Loening for help with nomenclature.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra for compounds prepared (50 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(()-N-[(1R*)-1-[(1S*,3a S*,7a S*)-Hexa h yd r o-3a -m eth yl-
7-m eth ylen e-1-in d a n yl]-2-m eth ylp r op yl]for m a m id e (2).
J O951532E