β-siloxy unsaturated nitriles: Stereodivergent cyclizations to cis- and trans-decalins

Article abstract of DOI:10.1016/S0040-4020(02)01615-0

Nitrile and enolate anions exhibit divergent intramolecular cyclization stereoselectivities. Enolates cyclize to cis-decalones, whereas nitrile anions are predisposed to pyramidalize, cyclizing instead through a less-congested conformation to trans-decali

Full text of DOI:10.1016/S0040-4020(02)01615-0

Tetrahedron 59 (2003) 737–745
b-Siloxy unsaturated nitriles: stereodivergent cyclizations to
cis- and trans-decalins
*
Fraser F. Fleming, Brian C. Shook, Tao Jiang and Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne University, Mellon Hall, Pittsburgh, PA 15282-1530, USA
Received 9 September 2002; revised 12 December 2002; accepted 12 December 2002
Abstract—Nitrile and enolate anions exhibit divergent intramolecular cyclization stereoselectivities. Enolates cyclize to cis-decalones,
whereas nitrile anions are predisposed to pyramidalize, cyclizing instead through a less-congested conformation to trans-decalins.
Conjugation of nitrile anions with adjacent sp2 centers prevents pyramidalization, and redirects cyclization through a planar-delocalized
anion to cis-decalins. Collectively these cyclizations allow conversion of a single b-siloxynitrile to either cis- or trans-decalins that are
ideally suited for elaboration into terpenoid natural products. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
equilibration of cis-decalones often furnished both stereo-
chemical series, although the equilibration is strongly
dependent on the substitution pattern6 and necessarily
requires an epimerizable ring junction. Diterpenoids 1 and
2 exemplify the challenge in devising efficient, stereo-
divergent syntheses of cis- and trans-decalins varying only
in the non-epimerizable ring junction stereochemistry.
The decalin ring system is one of the most prevalent
structural motifs contained within terpenoid natural
products.1 Decalin-containing terpenoids are broadly par-
titioned into two stereochemical groups reflecting different
stereochemical orientations of the two sp3 bridgehead
carbons; trans-decalin-containing terpenoids and the less
common, but numerically significant, cis-decalin
terpenoids.2 Highlighting the two decalin series are the
diastereomeric clerodane terpenoids 1 and 23 (Fig. 1) that
differ at a single stereocenter and yet co-occur in the same
plant!
The prevalence of cis-decalone intermediates stems from
the stereoselectivity of intramolecular ketone enolate
alkylations. Pioneering enolate cyclizations7 with confor-
mationally-biased decalones demonstrates that the stereo-
chemistry is kinetically controlled (Scheme 1).
Cyclization of the enolate 4 clearly identifies the reactive
conformation as 4c since the gem-dimethyl substituent
causes a severe diaxial interaction that effectively precludes
cyclization from conformer 4a. Exclusive formation of the
cis-decalone 5 therefore occurs from conformation 4c since
cyclization from 4b would evolve to a trans-decalin.
Originally2 the preference for enolate cyclizations through
conformation 4c, rather than 4b, was presumed to stem from
Figure 1. Diastereomeric clerodane diterpenoids.
The widespread occurrence of biologically important4 cis-
and trans-decalins has stimulated numerous syntheses of
this ubiquitous ring system.5 Conceptually, the most
attractive route to diastereomeric cis- and trans-decalins is
through a stereodivergent cyclization of a single inter-
mediate to either a cis- or trans-decalin. Historically,
Keywords: decalin; stereoselectivity; terpenoids; nitrile anions.
*
Corresponding author. Tel.: þ1-412-396-6031; fax: þ1-412-396-5683;
Scheme 1. cis-Selective enolate cyclizations.
e-mail: flemingf@duq.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01615-0

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F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
a destabilizing steric compression between the large
bromine atom and the adjacent axial proton (Hp) in
conformer 4b. A comparative stereoelectronic analysis of
conformers 4b and 4c reveals a more subtle reason for the
stereoselectivity—the orbital alignment between the
nucleophilic and electrophilic centers. Conformations 4b
and 4c differ primarily in the orientation of the p-electrons,
with the nucleophilic enolate orbitals of 4b being tilted
away from the electrophilic carbon–bromine bond, whereas
the p-orbitals of 4c are ideally aligned for an SN2
displacement. Formation of the cis-fused decalin 5 is
therefore stereoelectronically controlled by the orientation
of the p-orbitals in the endocyclic enolate.
Figure 2. Stereoelectronically controlled cyclizations.
side chain in 4b positions the electrophilic tether closer to
the ‘equator’ of the half-chair, allowing the bromo-
methylene carbon to more easily approach the nucleophilic
carbon than in the corresponding chair conformation of the
nitrile anion 8 (408 versus 608).11 Despite the apparent
geometric proclivity for enolate cyclization to a trans-
decalin, 4 cyclizes exclusively to the cis-decalin 5 whereas
the nitrile anion 8 selectively cyclizes to the trans-decalin
9—consistent with orbital alignment being the determining
factor rather than folding of the electrophilic side chain. The
complementary orbital alignments account for the
selectivity differences of endocyclic enolate and exocyclic
nitrile anion cyclizations and establish the fundamental
stereoelectronic requirements for a general strategy to cis-
and trans-decalins.
Contrasting with the cis-selective enolate cyclizations are a
seminal series of nitrile anion cyclizations to trans-
decalins.8 The reversed stereoselectivity stems from the
propensity of nitrile anions to pyramidalize,9 fulfilling an
inherent stereoelectronic requirement for a nucleophilic
orbital oriented directly towards the electrophilic carbon
(Scheme 2). Cyclization therefore occurs through the least
sterically congested conformation10 8 resulting in the
predominant formation of the trans-decalin 9.
b-Siloxy unsaturated nitriles are uniquely poised for
stereodivergent cyclizations to cis- and trans-decalins
through selective unmasking of the latent nitrile and enolate
anion moieties.12 The b-siloxy unsaturated nitriles 15 are
ideal prototypes for developing stereodivergent cyclizations
to cis- and trans-decalins since 15 are rapidly synthesized in
two synthetic operations (Scheme 3). Ozonolysis of 10, and
addition of Me2S, triggers a domino ozonolysis–aldol
cyclization13 providing ketonitrile 11 for a facile conjugate
addition with 4-chlorobutylmagnesium bromide14 (12) or
the gem-dimethyl organozinc reagent 13.15 Intercepting the
intermediate enolate 14 with TBSCl effectively prevents a
premature enolate cyclization16 and provides the
unsaturated b-siloxy-nitriles 1517 for stereoselective
cyclizations.
Scheme 2. trans-Selective nitrile anion cyclizations.
2. Results and discussion
Unmasking the enolates 16 with n-Bu4NF results in a
smooth cyclization to the cis-decalins 17 (Scheme 3). Facile
cyclization of the ammonium enolate contrasts with
minimal cyclization16 of the magnesium or zinc enolates
14, presumably reflecting the greater enolate nucleophilicity
Comparative conformational analyses of the half-chair
enolate 4b and the chair nitrile anion 8 corroborate the
stereoelectronic control in the stereodivergent cyclizations
(Fig. 2). The pseudo-equatorial orientation of the enolate
Scheme 3.

F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
739
Scheme 4. Influence of b-alkoxy and sp2 centers on nitrile anion cyclizations.
that results from minimal complexation with the tetra-n-
butylammonium cation. NMR analysis of the crude product
clearly shows only one diastereomer with the cis-decalin
stereochemistry being unequivocally determined by X-ray
diffraction.18
planar anion 22 where cyclization to the trans-decalin is
prevented through 22a, redirecting the stereoelectronically
controlled cyclization through 22b to the cis-decalin 23.
Although undesired, the cyclization of 22 establishes that
two adjacent sp2 centers are sufficient to abrogate the
propensity of the nitrile anion to pyramidalize.9
Cyclizing 15a and 15b to trans-decalins requires conversion
to a pyramidalized nitrile anion.10 Forming a pyramidalized
anion from the b-siloxy nitrile requires temporary masking
of the adjacent sp2 centers since related benzylic nitrile
anions favor a planar geometry, implying that delocalization
overcomes the propensity of nitrile anions to pyramidalize.9
Attempted masking of the sp2 hybridized enol silyl ether
15a by methanol-induced ketalization triggers sequential
enol ether hydrolysis, nitrile methanolysis and retro-Claisen
fragmentation,19 whereas ethylene glycol effectively installs
the cyclic acetal to afford 18 (Scheme 4).
A potential solution to overcome alkoxide elimination is to
install an equatorial oxygen substituent since a diaxial
elimination is retarded by virtue of proceeding through a
high-energy twist conformation. Selective formation of the
requisite equatorial alcohols 25 occurs readily upon
borohydride reduction in a pyridine–methanol solvent
mixture,25 (Scheme 5). Performing the reduction at
2208C, rather than at ambient temperature, allows identi-
fication of the keto-nitrile 24 as a transient intermediate,
presumably formed through methoxide-induced26 silyl ether
cleavage, that is subsequently reduced with excess NaBH4.
Similarly, borohydride reduction of 15b affords primarily
the equatorial b-hydroxynitriles 25b accompanied by the
axial b-hydroxy nitrile 26b (11%) and a small amount of the
cis-decalins 27 (Scheme 5). Formation of cis-decalins 27
requires rapid cyclization of the enolate intermediate prior
to protonation, that is likely facilitated by the close
proximity27 of the electrophilic side-chain induced by the
gem-dimethyl group.28 The cis-stereochemistry was deter-
mined by oxidation of 27 to cis-decalone 17b.
Deprotonating 18 was anticipated to trigger cyclization via
the pyramidal nitrile anion 19 (Scheme 4). LDA indeed
deprotonates 18 but triggers alkoxide ejection to form 20,20
presumably reflecting a facile anion inversion followed by a
rapid anti-periplanar elimination.21 Repeating the cycliza-
tion in neat HMPA was envisaged to render the alkoxide
elimination reversible,22 providing the requisite pyramidal
nitrile anion 19 by equilibration. The dramatic effect of
HMPA was immediately apparent in efficiently forming a
single decalin 23 (Scheme 4), although the successful
cyclization was tempered in finding the decalin stereo-
chemistry to be cis.23 Presumably, deprotonation initiates an
elimination to the alkoxide 21 followed by inter- or
intramolecular deprotonation24 to generate the conjugated,
Access to the alcohols 25a and 25b affords potential
cyclization precursors with equatorial oxygenation.29
Silylation of 25b and exposure to LiNEt2 generates
alkenenitrile 30 despite requiring a twist conformation for
Scheme 5. (a) a:b, 1:2; (b) a:b, 1:1; (c) a:b, 1:3; (d) a:b, 0:1; (e) a:b, 1:1.

740
F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
an E2 alkoxide elimination (Scheme 6). An alternative
strategy to circumvent alkoxide ejection is the double
deprotonation of a b-hydroxy nitrile that, although
unknown,12 is precedented by analogous enolate alkyl-
ations30 of aldol dianions. Initial cyclizations of 25b (b-CN)
explored MeMgCl as the base since magnesium alkoxides
are highly covalent31 thereby facilitating formal dianion
formation. Surprisingly, the dimagnesiated intermediate is
completely unreactive at room temperature, requiring
refluxing THF to coax a modest 47% yield of the trans-
decalin 29b in addition to 17% of the alkenenitrile 30
(Scheme 7). The remarkable formation of 30 through the
elimination of MgO stimulated the development of a
general alkenenitrile synthesis by MgO ejection,21 and
provided insight for cleanly cyclizing nitrile dianions by
changing the metal cation.
two syn-axial interactions between the axial nitrile and Ha
and Hb in 31c. The latter conformation, 31c, avoids one syn-
axial interaction, with a more profound stabilization
(,2 kcal mol21 32
)
resulting from the axial orientation of
the small nitrile rather than the larger ring methylene groups
(the A-value for a nitrile is 0.1 kcal mol21 compared to
0.85 kcal mol21 for a methylene group).33 Interestingly, the
b-hydroxynitriles 25b cyclize at 2788C, whereas the des-
methyl analogs 25a require warming to room temperature,
suggesting a beneficial orientation of the chloroalkyl
electrophile induced by buttressing of the gem-dimethyl
substituents,27 analogous to the effect observed on reducing
15b with borohydride (Scheme 5). TPAP oxidation34 of the
resulting hydroxy decalins 29a and 29b afford single,
crystalline13 trans-decalones 32a and 32b.
Conceivably the exquisite stereoselectivity in the cycliza-
tions of 25 could stem from a facile ‘retro-aldol’
equilibration from the cis-decalin 27 (Scheme 8). Mechan-
istically, formation of the alkoxide 33, retro-aldol fragmen-
tation to 34, and recyclization through conformer 34,
conceivably equilibrates 27 to the equatorially-oriented
trans-nitrile 29b (Scheme 8). Evidence against the equi-
libration was garnered by individually subjecting the cis-
decalins 27, a and b OH, to the same cyclization conditions
with complete recovery of the cis-nitriles 27.
Nitrile and enolate anions cyclize with divergent
stereoselectivities. The inherent orbital alignment of sp2-
hybridized enolates favor stereoelectronically-controlled
cyclizations to cis-decalones, whereas nitrile anions are
predisposed to pyramidalize, and cyclize with comple-
mentary stereoselectivity to trans-decalins. Adjacent sp2
Scheme 6.
Scheme 7. trans-Selective nitrile anion cyclizations.
Lithium diethylamide-induced cyclization of the b-hydroxy
nitriles 25a and 25b proceed with exquisite stereocontrol—
with no detectable elimination (Scheme 7). Both sets of
nitrile epimers (R¼H and Me) cyclize in virtually identical
yield, and within the same time period, indicating alkylation
through a single dianion 31. The stereoselectivity reflects an
exclusive preference for cyclization through conformation
31c. Severe 1,3-diaxial interactions in 31a effectively
prevent cyclization from this conformation whereas the
primary difference between 31b and 31c are the three
destabilizing syn-axial interactions between the axial
methylenes ( p ) and Ha and Hb in 31b, compared with
Scheme 8.

F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
741
centers diminish the nitrile anion pyramidalization,
redirecting cyclization through a planar-delocalized anion
to cis-decalins, analogous to enolate cyclizations. Delineat-
ing the fundamental stereoelectronic features of nitrile anion
and enolate cyclizations permits controlled, stereodivergent
cyclizations of b-siloxy unsaturated nitriles to either cis- or
trans-decalones through selective unmasking of the
respective enolate and nitrile anion intermediates. Collec-
tively these cyclization strategies rapidly assemble a variety
of decalin precursors ideally suited for elaboration into
terpenoid natural products.
27.6, 29.1, 40.8, 45.5, 70.4; MS m/e 119 (M2OH). Neat
5-chloro-2-methyl-pentan-2-ol (2.08 g, 15.2 mmol) and
MeSiCl3 (1.37 g, 9.2 mmol) were sequentially added to a
room temperature, acetonitrile solution (23 mL) of NaI
(6.88 g, 45.9 mmol). After 15 min water was added and the
crude product was extracted with ethyl acetate. The extracts
were successively washed with saturated aqueous sodium
thiosulfate, water, and brine. The crude material was
purified by vacuum distillation (4 mm Hg, 60–708C) to
afford 2.79 g (74%) of iv as a caramel colored liquid: IR
1
(film) 1102 cm21; H NMR d1.72–1.78 (m, 2H), 1.94 (s,
6H), 1.98–2.08 (m, 2H), 3.60 (t, J¼6.3 Hz, 2H); 13C NMR
d: 31.9, 38.1, 44.5, 47.6, 50.1; MS m/e 246 (MþH).
3. Experimental35
3.1.4. 2-(tert-Butyldimethylsiloxy)-6-((2-methyl-5-
chloro)-2-pentyl)-1-cyclohexenyl-1-carbonitrile (15b). A
THF solution (40 mL) of ZnCl2 (3.32 g, 24.39 mmol) was
slowly added (45 min) to a refluxing dark green, THF
solution (20 mL) formed by the addition of finely cut Li
metal (339 mg, 48.78 mmol) to naphthalene (666 mg,
5.20 mmol). The solution was refluxed for an additional
1.25 h and then the Zn metal was allowed to settle
overnight. The supernatant was removed by syringe and
the Zn metal was washed with THF (15 mL). The Zn was
suspended in THF (40 mL), iv (4.0 g, 16.26 mmol) was
added, and then the resultant mixture was heated to reflux
for 2 h. The solution was allowed to cool (1.5–2 h) during
which time the excess zinc metal settled on the bottom of
the flask. The organozinc iodide was removed by syringe
and added to a cold (2788C), THF solution (100 mL) of 11
(2.0 g, 16.26 mmol) over 30 min. After 4 h solid TBDMSCl
(3.68 g, 24.39 mmol) was added and the solution was
allowed to warm to room temperature over a 12 h period.
Saturated, aqueous NH4Cl was then added and the crude
product was extracted with EtOAc. Concentration of the
crude material and purification by column chromatography
(5:95 EtOAc–hexanes) gave 4.51 g (78%) of 15b as a clear,
viscous liquid: IR (film) 2203, 1614 cm21; 1H NMR d 0.23
(s, 3H), 0.25 (s, 3H), 0.99 (s, 12H), 1.03 (s, 3H), 1.41–1.91
(m, 8H), 2.10–2.15 (m, 2H), 2.33–2.38 (m, 1H), 3.51 (ddd,
J¼17, 10.5, 6.9 Hz, 1H), 3.56 (ddd, J¼17, 10.5, 6.4 Hz,
1H); 13C NMR: d 23.7, 18.2, 21.2, 24.0, 25.6, 25.8, 26.0,
27.6, 31.2, 37.0, 38.0, 43.1, 45.7, 92.8, 120.3, 168.8; MS m/e
355 (MþH).
3.1. Data for compounds
3.1.1. 2-(tert-Butyldimethylsilyloxy)-6-(4-chloro-butyl)-
1-cyclohexenyl-1-carbonitrile (15a). A THF solution
(20 mL) of 4-chlorobutylmagnesium bromide14 (12) was
prepared by the addition of 30 mL of 1-bromo-4-chloro-
butane to magnesium metal (237 mg, 9.76 mmol) at room
temperature. The solution was sonicated until cloudy,
cooled to 08C, and then neat 1-bromo-4-chlorobutane
(1.0 mL, 8.94 mmol total) was slowly added. After 2 h the
solution was briefly warmed to room temperature and was
then added to a 2788C, THF solution (40 mL) of 1113
(1.00 g, 8.13 mmol). After 45 min the solution was allowed
to warm to room temperature, solid TBDMSCl (1.84 g,
12.20 mmol) was added, and stirring was continued for a
further 15 h. The resultant mixture was quenched by the
addition of saturated, aqueous NH4Cl, extracted with
EtOAc, dried (MgSO4), and concentrated. The crude
product was purified by radial chromatography (4 mm
plate, 1:19 EtOAc–hexanes) to afford 1.97 g (74%) of 15a
as an oil: IR (film) 2208, 1626 cm21; H NMR d: 0.21
1
(s, 3H), 0.22 (s, 3H), 0.96 (s, 9H), 1.26–1.81 (m, 10H),
2.10–2.31 (m, 3H), 3.53 (br t, J¼7 Hz, 2H); 13C NMR
d: 23.8, 18, 19.9, 23.8, 25.4, 26.5, 30.9, 32.5, 33.6, 35.1,
44.8, 95.5, 118.3, 165.6; MS m/e 327 (M); HRMS (ESI)
calcd for (MþNaþ) C17H30NOSiNa 350.1677, found
350.1661.
3.1.2. 6-{4-[2-Cyano-3-(1,1,2,2-tetramethyl-2-silapro-
poxy)cyclohex-2-enyl]butyl}-2-(1,1,2,2-tetramethyl-1-
silapropoxy)cyclohex-1-enecarbonitrile (i). An experi-
ment performed as above without slow formation of 12
afforded 66% of 15a and 14% of i as a crystalline, X-ray
diffracting,18 solid: IR (film) 2206, 1622 cm21; 1H NMR d:
0.22 (s, 6H), 0.23 (s, 6H), 0.98 (s, 18H), 1.26–1.78 (m,
16H), 2.10–2.14 (m, 4H), 2.29 (br s, 2H); 13C NMR d:
23.7, 18.1, 19.9 25.5, 26.6, 26.7, 31.0, 34.5, 35.2, 95.9,
118.5, 165.4.
3.1.5. cis-10-Cyano-decahydro-1-naphthalenone (17a). A
THF solution (6 mL) of 15a (90 mg, 0.275 mmol) and
n-Bu4NF (1.0 M, 0.33 mmol) was refluxed for 3 h and then
allowed to cool to room temperature, overnight. The
resultant mixture was concentrated and the crude product
was purified by radial chromatography (2 mm plate, 1:9
EtOAc–hexanes) to afford 44 mg (90%) of 17a as an oil.
Careful dissolution in EtOAc–hexanes afforded white
crystals (mp 88–898C) suitable for X-ray crystallography:18
IR (film) 2237, 1714 cm21; 1H NMR d: 1.40–1.48 (m, 2H),
1.60–2.06 (m, 9H), 2.25–2.50 (m, 3H), 2.60–2.69 (m, 1H);
13C NMR d: 21.9, 22.6, 23.3, 26.7, 27.4, 29.5, 38.1, 42.7,
51.7, 120.4, 203.2; MS m/e 177 (M).
3.1.3. 5-Chloro-2-iodo-2-methylpentane (iv). An ethereal
solution of MeLi (41.7 mmol) was added to a 2788C, THF
solution (40 mL) of 5-chloropentanone (2.28 g, 18.9 mmol)
and, after 10 min, saturated aqueous NH4Cl was added. The
crude mixture was extracted with ethyl acetate to afford
2.08 g of 5-chloro-2-methyl-pentan-2-ol as a clear, analyti-
cally pure, viscous liquid (81%): IR (film) 3389 cm21; H
NMR d 1.23 (s, 6H), 1.56–1.62 (m, 2H), 1.82–1.92 (m,
2H), 2.17 (br s, 1H), 3.56 (t, J¼6.6 Hz, 2H); 13C NMR d
3.1.6. 8ab-Cyano-5a,5b-dimethyl-3,4,4ab,5,6,7,8,8a-
octahydro-1(2H)-naphthalenone (17b). A THF solution
(2 mL) of n-Bu4NF (0.583 mmol) was added to a room
temperature, THF solution (3 mL) of 15b (0.10 g,
1

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F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
0.29 mmol). After 2 h water was added and the reaction
mixture was extracted with ethyl acetate. The crude material
was concentrated and was then purified by radial chroma-
tography (1 mm plate, 3:7 EtOAc–hexanes) to afford 0.50 g
(83%) of the cis-decalin 17b as white, X-ray diffracting,18
1.88 (m, 11H), 2.26–2.30 (m, 3H), 3.56 (t, J¼6 Hz, 2H),
3.85 (br t, J¼4 Hz, 2H), 4.08 (t, J¼4 Hz, 2H); 13C NMR d:
19.7, 23.9, 26.3, 26.5, 32.5, 33.6, 35.0, 44.9, 61.4, 69.7,
92.6, 123.2, 168.0; MS m/e 258 (MþH).
1
crystals (mp 57–588C): IR (KBr) 2239, 1710 cm21; H
3.1.10. cis-1-(2-Hydroxyethoxy)-10-cyano-3,4,5,6,7,8-
octahydronaphthalene (23). A hexane solution (0.19 mL)
of n-BuLi (1.06 M, 0.20 mmol) was added to a 2408C,
HMPA solution (6 mL) of i-Pr2NH (28 mL, 0.20 mmol).
After 30 min a THF solution (1 mL) of 18, as a 5:1 ratio of
epimers, (20 mg, 0.1 mmol) was added. After 1.5 h at
2408C, the solution was allowed to warm to room
temperature and stirred for a further 3.5 h. Aqueous HCl
(10%) was added until a pH of 7, the reaction mixture was
extracted with EtOAc, and then the combined extracts were
dried (MgSO4) and concentrated. The crude product was
purified by radial chromatography (2 mm plate, 1:4–3:7
EtOAc–hexanes) to afford 15 mg (75%) of 23 as an oil: IR
NMR d 0.91 (s, 3H), 1.26 (s, 3H), 1.29–1.33 (m, 1H), 1.45
(ddd, J¼14, 11, 3.7 Hz, 1H), 1.60–1.83 (m, 5H), 1.98–2.09
(m, 4H), 2.42–2.59 (m, 2H); 13C NMR d 19.1, 22.6, 24.0,
29.3, 29.5, 29.8, 33.6, 35.6, 37.0, 50.2, 51.9, 121.7, 204.1;
HRMS (ESI) calcd for (MþNaþ) C13H19NONa 228.1359,
found 228.1364.
3.1.7. Dimethyl 3-(chlorobutyl)-heptanedioate (iii). A
methanolic solution (20 mL) of 15a (224 mg, 1.05 mmol)
and p-TsOH (100 mg, 0.53 mmol) was heated to reflux for
5 h and then allowed to cool to room temperature. The crude
mixture was filtered through a short silica column
(10£10 mm), concentrated, and purified by radial chroma-
tography (1 mm plate, 1:9–1:4 EtOAc–hexanes) to afford
1
(film) 3439, 2234, 1664 cm21; H NMR d: 1.48–1.98 (m,
11H), 2.09–2.18 (m, 3H), 3.73–3.88 (m, 4H), 4.76 (t,
J¼4.0 Hz, 1H); MS m/e 222 (MþH). Upon standing 22
(20 mg, 0.1 mmol) in CDCl3 at room temperature for 2 days
cis-9-cyano-1-naphthalenone ethyl ketal was obtained
1
170 mg (58%) of iii as an oil: IR (film): 1738 cm21; H
NMR d: 1.25–1.81 (m, 11H), 2.28–2.40 (m, 2H), 2.31 (br t,
J¼7 Hz, 2H), 3.51 (t, J¼6.6 Hz, 2H), 3.66 (s, 3H), 3.68 (s,
3H); 13C NMR d: 22.7, 24.4, 24.7, 31.5, 31.7, 32.4, 33.8,
44.6, 45.1, 51.5 (coincident methyl signals), 173.6, 176.2;
HRMS (ESI) calcd for (MþNaþ) C13H23ClO4Na 301.1177,
found 301.1183.
1
20 mg (100%) as an oil: IR (film) 2866, 2236 cm21; H
NMR d: 1.37–1.94 (m, 14H), 2.21–2.23 (br s, 1H), 3.95–
4.03 (m, 2H), 4.17–4.26 (m, 2H); 13C NMR d: 19.7, 21.9,
23.0, 24.3, 25.5, 28.3, 30.2, 37.2, 49.4, 65.5, 65.6, 109.8,
122.6; MS m/e 221 (M). Acid hydrolysis (10% aqueous HCl
in THF, 1:1) afforded 17a spectrally identical to material
isolated previously.
3.1.8. trans- and cis-2-Cyano-3-(4-chloro-butyl)-cyclo-
hexanone ethylene ketal (18). A benzene solution (20 mL)
of 15a (224.0 mg, 0.68 mmol), ethylene glycol (44 mL,
0.79 mmol) and a trace of p-toluenesulfonic acid (5 mg) was
heated to reflux for 4 h. The resultant mixture was
concentrated and the crude product was then purified by
radial chromatography (2 mm plate, 1:1 hexanes–CH2Cl2)
to afford 128 mg (72%) of 18 as a 5:1 ratio of trans and cis
3.1.11. 6-(4-Chlorobutyl)-2-hydroxycyclohexanecarbo-
nitrile (25a,26a). Incremental portions of solid NaBH4
(195 mg 5.16 mmol) were added over 25 min to a stirred,
room temperature, solution (16 mL, 3:1 pyridine–metha-
nol) of the b-siloxy nitrile 15a (1.53 g 4.30 mmol). After
10 h saturated, aqueous NH4Cl was added and the aqueous
phase extracted with EtOAc (3£50 mL). The organic
extracts were combined, washed succesively with 10%
aqueous HCl, and brine, dried (MgSO4), and concentrated.
The crude mixture of alcohols were separated by radial
chromatography (4 mm plate, 3:7 EtOAc–hexanes) to
afford 431 mg (43%) of 25a (b-CN), 210 mg (21%) of
25a (a-CN), 90 mg (9%) of 26a (b-CN) and 80 mg (8%) of
26a (a-CN) as clear oils. For 25a (a-CN): IR (film) 3426,
2240 cm21; 1H NMR d 0.77–0.92 (m, 1H), 1.15–1.68 (m,
6H), 1.71–1.89 (m, 5H), 2.05–2.18 (m, 2H), 2.48 (d,
J¼4.4 Hz, 1H), 3.55 (t, J¼6.4 Hz, 2H), 3.71 (ddd, J¼14.6,
10, 4 Hz, 1H); 13C NMR d 23.0, 23.6, 29.7, 32.4, 33.7, 33.9,
39.0, 44.8, 44.9, 71.3, 120.7; MS m/e 216 (MþH). For 25a
(b-CN): IR (film) 3426, 2240 cm21; 1H NMR d 1.18–1.37
(m, 2H), 1.49–1.68 (m, 7H), 1.73–1.88 (m, 3H), 1.94–2.00
(m, 2H), 3.16 (br s, 1H), 3.55 (t, J¼6.5 Hz, 2H), 3.66 (dt,
J¼11.5, 4.4 Hz, 1H); 13C NMR d 23.3, 24.0, 27.7, 31.6,
32.3, 33.4, 38.0, 42.2, 44.7, 70.0, 118.1; MS m/e 216
1
isomers (ratio determined by H NMR). Repeated chroma-
tography gave pure samples of each isomer with the
transisomer being obtained as an oil: IR (film)
1
2243 cm21; H NMR d: 0.85 (br qd, J¼13, 3 Hz, 1H),
1.22–1.93 (m, 12H), 2.47 (d, J¼11.7 Hz, 1H), 3.55 (t,
J¼6.5 Hz, 2H), 3.93–4.07 (m, 2H), 4.18–4.28 (m, 2H); 13C
NMR d: 22.1, 23.5, 29.6, 32.4, 33.7, 34.9, 38.5, 44.8, 45.8,
65.6, 65.9, 107.9, 119.3; MS m/e 258 (MþH). The cis
isomer 17 was obtained as an oil: IR (film) 2239 cm21; 1H
NMR d: 1.25–1.93 (m, 13H), 2.78 (br s, 1H), 3.55 (t,
J¼6.5 Hz, 2H), 3.93–4.06 (m, 4H); 13C NMR d: 22.1, 24.0,
27.5, 32.1, 32.4, 33.2, 37.1, 42.6, 44.8, 64.8, 65.0, 107.6,
118.1; MS m/e 258 (MþH).
3.1.9. 2-(2-Hydroxyethoxy)-6-(4-chlorobutyl)-1-cyclo-
hexene-1-carbonitrile (20). A hexane solution (0.25 mL)
of BuLi (1.06 M, 0.27 mmol) was added to a THF solution
(3 mL) of i-Pr2NH (32 mL, 0.23 mmol) followed by cooling
to 2788C. After 10 min, a THF solution (1 mL) of 18, as a
5:1 mixture of isomers, (26 mg, 0.10 mmol) was added. The
solution was allowed to warm to room temperature, stirred
for 5 h, and then aqueous HCl (10%) was added until a pH
of 7. The reaction mixture was extracted with EtOAc, the
combined extracts were dried (MgSO4), concentrated, and
the crude product purified by radial chromatography (1 mm
plate, 3:7 EtOAc–hexanes) to afford 20 mg (77%) of 20 as
an oil: IR (film) 3434, 2206, 1626 cm21; 1H NMR d: 1.30–
1
(MþH). For 26a (a-CN): IR (film) 3452, 2242 cm21; H
NMR d 0.85–0.98 (m, 2H), 1.25–2.04 (m, 12H), 2.86 (br t,
J¼4.1 Hz, 1H), 3.55 (t, J¼6.6 Hz, 2H), 4.23 (br s, 1H); 13C
NMR d 19.0, 24.0, 28.0, 30.0, 32.4, 32.6, 32.8, 39.6, 44.8,
67.1, 119.0; MS m/e 216 (MþH). For 26a (b-CN): IR
1
(film) 3452, 2242 cm21; H NMR d 0.88–1.05 (m, 2H),
1.22–2.06 (m, 12H), 2.44 (dd, J¼10.3, 2.5 Hz, 1H), 3.55 (t,
J¼6.4 Hz, 2H), 4.21 (br s, 1H); 13C NMR d 18.9, 23.6, 29.5,

F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
743
31.7, 32.4, 33.4, 34.2, 41.7, 44.8, 66.5, 120.7; MS m/e 216
(MþH).
general procedure afforded only 30, spectrally identical to a
previously characterized sample.16
3.1.12. 6-(4-Chloro-1,1-dimethylbutyl)-2-hydroxycyclo-
hexanecarbonitrile (25b), (26b), and (27). Following the
procedure for the reduction of 15a the b-siloxy nitrile 15b
(2.49 g, 6.99 mmol) was reduced with NaBH4 to afford
934 mg (55%) of 25b (b-CN), 238 mg (14%) of 25b
(a-CN), 187 mg (11%) of 26b (b-CN), 43 mg (3%) of 27
(a-CN), and 29 mg (2%) of 27 (b-CN)as oils. For 25b
(b-CN): IR (film) 3432, 2235 cm21; 1H NMR d 1.00 (s, 3H),
1.09 (s, 3H), 1.15–1.29 (m, 2H), 1.50–1.92 (m, 8H), 2.04–
2.11 (m, 2H), 2.25 (dd, J¼11, 9.8 Hz, 1H), 3.49 (dt, J¼13,
6 Hz, 1H), 3.58 (dt, J¼13, 7 Hz, 1H) 3.68–3.75 (dt, J¼10,
4 Hz, 1H); 13C NMR d 23.0, 25.9, 26.0, 27.3, 33.6, 35.7,
38.1, 38.4, 40.3, 45.5, 60.4, 72.7, 122.4; MS m/e 244
3.1.14. (1R p,2R p)-2-Hydroxy-7,7-dimethylbicyclo-
[4.4.0]decanecarbonitrile (29b) by cyclization with
MeMgCl. A THF solution (3 M) of MeMgCl (55 mL,
0.163 mmol) was added to a cold, 2788C, THF solution
(1 mL) of 25b (b-CN) (18 mg, 0.074 mmol). After 3 h at
2788C only starting material was observed by TLC and
consequently the reaction was allowed to warm to room
temperature overnight. TLC analysis showed only starting
material and therefore the reaction was heated to reflux.
After 5 h the reaction mixture was allowed to cool to room
temperature, saturated aqueous NH4Cl was added and the
aqueous phase was extracted with EtOAc. The combined
organics were washed with water and brine, dried (Na2SO4),
concentrated, and purified via radial chromatography (1 mm
plate, 1:9–3:10 EtOAc–hexanes) to give 7 mg (47%) of
29b and 3 mg (17%) of 30.
1
(MþH). For 25b (a-CN): IR (film) 3415, 2235 cm21; H
NMR d 0.99 (s, 3H), 1.00 (s, 3H), 1.06–1.76 (m, 10H),
1.87–2.04 (m, 2H), 3.21 (br s, 1H), 3.52 (t, J¼6.6 Hz, 2H),
3.65 (br dt, J¼11, 4 Hz, 1H); 13C NMR d 22.7, 23.9, 24.7,
25.2, 27.3, 31.7, 35.1, 38.1, 45.5, 46.9, 71.5, 119.6; MS m/e
244 (MþH). For 26b: IR (film) 3439, 2235 cm21; 1H NMR
d 0.94 (s, 3H), 0.95 (s, 3H), 1.23–1.59 (m, 4H), 1.61–1.88
(m, 8H), 2.92 (br s, 1H), 3.51 (br t, J¼6.6 Hz, 2H), 4.24 (br
dd, J¼5.6, 2.8 Hz, 1H); 13C NMR d 20.4, 23.5, 24.5, 25.2,
25.8, 27.2, 29.2, 34.7, 38.0, 40.1, 45.7, 68.5, 120.5; MS m/e
244 (MþH). For 27 (a-CN): (mp 88–908C); IR (KBr) 3435,
3.2. General procedure for cyclizing b-hydroxy nitriles
A THF solution of LiNEt2 (2.5 equiv.) was prepared by
addition of a BuLi solution (hexanes, 2.5 equiv.) to a
2788C, THF solution (1 M) of Et2NH (2.7 equiv.). The
resulting pale yellow solution was allowed to stir at 2788C
for 15 min. A THF solution (1 M) of the b-hydroxy nitrile
(1 equiv.) was added and the resulting mixture allowed to
warm slowly (,4 h) to room temperature and stirred an
additional 8 h at room temperature. Saturated, aqueous
NH4Cl was added and the aqueous phase extracted with
EtOAc. The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated. The resulting
material was purified by radial chromatography to yield the
hydroxy nitrile.
1
2959, 2930, 2242 cm21; H NMR d 0.91 (s, 3H), 1.04 (s,
3H), 1.15–1.28 (m, 2H), 1.33–1.52 (m, 3H), 1.54–1.92 (m,
8H), 1.98–2.10 (m, 1H), 3.83 (t, J¼2.8 Hz, 1H); 13C NMR d
19.4, 20.2, 20.4, 23.8, 30.6, 31.7, 33.2, 33.2, 41.2, 43.9,
44.0, 71.9, 123.7; MS m/e 208 (MþH); HRMS (ESI) calcd
for (MþNaþ) C13H21NONa 230.1515, found 230.1523.
Oxidation of 27 (a-CN)(6 mg, 29 mmol), following the
procedure for 31a, afforded, after radial chromatography
(1 mm plate, 1:9 EtOAc–hexanes), 5 mg (83%) of 17b as a
white crystalline solid. For 27 (b-CN): (mp 94–968C); IR
3.2.1. (1R p,2R p)-2-Hydroxybicyclo[4.4.0]decanecarbo-
nitrile (29a). The general procedure was employed with
25a (b-CN) (22 mg, 0.102 mmol) to afford, after radial
chromatography (1 mm plate, 3:7 EtOAc–hexanes), 15 mg
(78%) of 29a as a white crystalline solid (mp 87–898C): IR
1
(KBr) 3450, 2952, 2872, 2235 cm21; H NMR d 0.89 (s,
3H), 1.20–1.98 (m, 13H), 1.36 (s, 3H), 2.21 (br s, 1H), 3.80
(dd, J¼11, 4 Hz, 1H); 13C NMR d 19.6, 22.0, 22.3, 23.0,
27.9, 28.7, 31.4, 34.2, 34.3, 44.4, 47.4, 75.6, 126.7; MS m/e
208 (MþH). Oxidation of 27 (b-CN) (7 mg, 34 mmol),
following the procedure for 31a, afforded, after radial
chromatography (1 mm plate, 1:9 EtOAc–hexanes), 6 mg
(86%) of 17b as a white crystalline solid.
1
(KBr) 3434, 2234 cm21; H NMR d1.16–1.49 (m, 7H),
1.57–2.03 (m, 8H), 2.41–2.46 (m, 1H), 3.31 (br dd, J¼11,
3 Hz, 1H); 13C NMR d 22.9, 23.5, 25.5, 29.6, 29.7, 32.6,
33.0, 43.0, 50.2, 75.2, 120.5; MS m/e 180 (MþH). The
general procedure was employed with 25a (a-CN) (20 mg,
0.093 mmol) to afford, after radial chromatography (1 mm
plate, 3:7 EtOAc–hexanes), 13 mg (83%) of 29a as a white
crystalline solid.
3.1.13. 6-(4-Chloro-1,1-dimethylbutyl)cyclohex-1-eniso-
cyanide (30). Neat TBSOTf (24 mL, 0.103 mmol) was
added to a CH2Cl2 solution (1.5 mL) of 25b (b-CN) (20 mg,
0.082 mmol) and pyridine (13 mL, 0.164 mmol). After 3 h
water was added and the aqueous phase extracted with
EtOAc. The extracts were combined, washed successively
with NaHCO3 and brine, dried (MgSO4), concentrated, and
purified by radial chromatography (1 mm plate, 1:19
EtOAc–hexanes) to afford 27 mg (92%) of (1R p,2R p)-6-
(4-chloro-1,1-dimethylbutyl)-2-(1,1,2,2-tetramethyl-1-sila-
propoxy)cyclohexanecarbonitrile (v) as a colorless oil: IR
(film) 2237 cm21; 1H NMR d 0.06 (s, 3H), 0.07 (s, 3H), 0.90
(s, 9H), 0.98 (s, 3H), 0.99 (s, 3H), 1.10–1.88 (m, 12H), 2.99
(br s, 1H), 3.51(td, J¼6, 2.3 Hz, 2H), 3.54–3.61 (m, 1H);
13C NMR d 24.8, 18.0, 22.7, 23.8, 24.7, 25.2, 25.7, 27.3,
32.1, 34.9, 38.1, 38.6, 45.5, 46.7, 72.0, 119.6; MS m/e 300
(M2 t-Bu). Cyclization of the silyl ether v following the
3.2.2. (1R p)-2-Oxobicyclo[4.4.0]decanecarbonitrile
(32a). Solid TPAP (0.05 equiv.) was added in one portion
to a room temperature, CH2Cl2 solution (0.05 M) of 29a
(23 mg, 0.128 mmol, 1 equiv.), NMO (1.5 equiv.) and
˚
powdered 4 A molecular sieves (500 mg/mmol). After 8 h
the suspension was filtered through a short pad of silica,
eluting with CH2Cl2, the filtrate was concentrated and then
purified by radial chromatography (1 mm plate 1:9,
EtOAc–hexanes) to afford 22 mg (97%) of 32a as a white
crystalline, X-ray diffracting,18 solid (mp 55–568C): IR
1
(KBr) 2227, 1731 cm21; H NMR d 1.54–1.64 (m, 2H),
1.74–2.34 (m, 10H), 2.41–2.52 (m, 1H), 2.63–2.73 (m,
1H), 3.19 (ddd, J¼14, 7, 2 Hz, 1H); 13C NMR d 23.8, 26.9,

744
F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
2001, 18, 88. (d) For triterpenoids see: Connolly, J. D.; Hill,
R. A. Nat. Prod. Rep. 2001, 18, 131.
28.2, 30.8, 31.1, 31.6, 39.7, 49.0, 54.3, 118.7, 201.6; MS m/e
178 (MþH).
2. The stereochemical features of decalin-containing terpenoids
are encapsulated in the diverse clerodane diterpenoids:
Merritt, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243.
3. McCrindle, R.; Nakamura, E.; Anderson, A. B. J. Chem. Soc.
Perkin Trans. 1 1976, 1590.
3.2.3. (1R p,2R p)-2-Hydroxy-7,7-dimethylbicyclo[4.4.0]-
decanecarbonitrile (29b). The general cyclization pro-
cedure was employed with 25b (b-CN) (261 mg,
1.074 mmol), with the modification of maintaining the
solution at 2788C for 4 h before adding saturated, aqueous
NH4Cl. Radial chromatography (1 mm plate, 3:7 EtOAc–
hexanes) afforded 189 mg (85%) of 29b as a white,
crystalline, X-ray diffracting,18 solid (mp 104–1068C): IR
(KBr) 3460, 2238 cm21; 1H NMR d 0.90 (s, 3H), 0.97 (dd,
J¼12, 3 Hz, 1H) 1.05 (s, 3H), 1.11–1.44 (m, 5H), 1.50 (ddd,
J¼13, 5, 3 Hz, 1H), 1.59–2.00 (m, 5H), 2.48 (ddd, J¼13.4,
5, 3 Hz, 2H), 3.28 (dd, J¼11.4, 4.2 Hz, 1H); 13C NMR d
19.2, 20.5, 23.2, 23.7, 32.0, 32.5, 33.2, 34.3, 41.2, 47.2,
50.8, 76.6, 122.2; MS m/e 207 (Mþ). Repeating the general
procedure with 25b (a-CN) (22 mg, 0.091 mmol), with the
modification of maintaining the solution at 2788C for 4 h
before adding saturated, aqueous NH4Cl. Radial chroma-
tography (1 mm plate, 3:7 EtOAc–hexanes) afforded 16 mg
(84%) of 29b as a white crystalline solid.
4. (a) Buchbauer, G.; Spreitzer, H.; Supp, B. Chem.-Ztg. 1988,
112, 319. (b) Sarma, A. S. J. Sci. Ind. Res. 1987, 46, 492.
5. For reviews see: (a) Tokoroyama, T. Synthesis 2000, 611.
(b) Varner, M. A.; Grossman, R. B. Tetrahedron 1999, 55,
13867. (c) d’Angelo, J.; Desmaele, D.; Dumas, F.; Guingant,
A. Tetrahedron: Asymmetry 1992, 3, 459. (d) Jansen, B. J. M.;
de Groot, A. Nat. Prod. Rep. 1991, 319. (e) Sutherland, J. K.
Comprehensive Organic Synthesis, Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 341–377.
(f) Vandewalle, M.; De Clercq, P. Tetrahedron 1985, 41, 1767.
6. Thompson, H. W.; Long, J. Org. Chem. 1988, 53, 4201.
7. Conia, J.-M.; Rouessac, F. Tetrahedron 1961, 16, 45.
8. (a) Stork, G.; Gardner, J. O.; Boeckman, Jr. R. K.; Parker, K. A.
J. Am. Chem. Soc. 1973, 95, 2014. (b) Stork, G.; Boeckman, Jr.
R. K. J. Am. Chem. Soc. 1973, 95, 2016.
9. Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
10. Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
11. These figures were calculated with MOPAC using the
minimized bond angles of cyclohexene and cyclohexane.
12. For a preliminary account see: Fleming, F. F.; Shook, B. C.;
Jiang, T.; Steward, O. W. Org. Lett. 1999, 1, 1547.
3.2.4. (1R p)-7,7-Dimethyl-2-oxobicyclo[4.4.0]decane-
carbonitrile (32b). Oxidation of 29b (87 mg,
0.420 mmol), following the procedure for 29a, afforded,
after radial chromatography (1 mm plate, 1:9 EtOAc–
hexanes), 86 mg (100%) of 32b as a white, X-ray
diffracting,13 crystalline solid (mp 59–618C): IR (KBr)
13. Fleming, F. F.; Shook, B. C. Org. Synth. 2001, 77, 254.
14. Bernady, K. F.; Poletto, J. F.; Nocera, J.; Mirando, P.; Schaub,
R. E.; Weiss, M. J. J. Org. Chem. 1980, 45, 4702.
1
2224, 1723 cm21; H NMR d 0.91 (s, 3H), 1.12 (s, 3H),
1.13–1.24 (m, 2H), 1.43–2.06 (m, 8H), 2.17 (dddd, J¼13,
7, 6, 3 Hz, 1H), 2.37–2.44 (m, 1H), 2.93 (dt, J¼13.6,
6.8 Hz, 1H); 13C NMR d 18.4, 20.3, 23.5, 26.4, 30.3,
31.9, 34.5, 38.6, 40.5, 51.6, 54.8, 120.4, 203.1; MS m/e 205
(M).
15. Prepared from 5-chloro-2-pentanone by sequential methyl-
ation with MeLi, iodination with MeSiCla3–c and zincationd:
(a) Olah, G. A.; Husain, A.; Singh, B. P.; Mehrotra, A. K.
J. Org. Chem. 1983, 48, 3667. (b) Olah, G. A.; Gupta, B. G. B.;
Malhotra, R.; Narang, S. C. J. Org. Chem. 1980, 45, 1638.
(c) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247. (d) Zhu, L.; Wehmeyer, R. M.;
Rieke, R. D. J. Org. Chem. 1991, 56, 1445.
3.3. Attempted equilibration of 27
Employing the general cyclization procedure with
1.5 equiv. of LiNEt2, the cis-decalin 27 (a-OH, 14 mg,
0.068 mmol) for 3 h at 2788C, followed by the addition of
saturated aqueous NH4Cl and extractive isolation gave
12 mg (86%) of recovered cis-decalin 27 (a-OH). An
analogous deprotonation of 27 (b-OH) (11 mg,
0.053 mmol) afforded 8 mg (73%) of recovered 27
(b-OH).
16. Cyclization of the intermediate enolate 14a occurs on
warming, affording decalone 17a and an epimeric mixture of
monocyclic ketones in equilibrium with the enol tautomer.
17. Optimization experiments revealed the need for slow
formation of 12 at 2108C to minimize formation of the
corresponding bis-Grignard reagent that otherwise generates
the bis-addition product i. The stereochemical assignment was
determined by X-ray crystallography18 of the sole
diastereomer isolated in 14% yield.
Acknowledgements
Financial support from NIH is gratefully acknowledged. We
are particularly grateful to Drs Jeffry Madura, Gernot
Boche, and Paul Carlier for discussions concerning the
structure of nitrile anions.
18. The supplementary crystallographic data for all of the crystal
structures (i CCDC# 183551, 17b CCDC# 183548, 29b
CCDC# 183549, 32b CCDC# 183550) can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: þ44-1223-336033; or
deposit@ccdc.cam.ac.uk).
References
1. (a) Glasby, J. S. Encyclopedia of the Terpenoids. Wiley:
Chichester, 1982. For more recent examples (b) For
sesquiterpenoids see: Fraga, B. M. Nat. Prod. Rep. 2001, 18,
650. (c) For diterpenoids see: Hanson, J. R. Nat. Prod. Rep.

F. F. Fleming et al. / Tetrahedron 59 (2003) 737–745
745
19.
25. Rhodes, R. A.; Boykin, D. W. Synth. Commun. 1988, 18, 681.
26. Hurst, D. T.; McInnes, A. G. Can. J. Chem. 1965, 43, 2004.
27. Jung, M. E. Synlett 1990, 186.
28. No decalins were detected from the borohydride reduction of
the corresponding des-methyl nitrile 15a.
29. Probing the role of the proximal hydroxyl group led to an
extensive series of cyclizations with the des-hydroxy analog of
25a.10
30. Martin, V. A.; Murray, D. H.; Pratt, N. E.; Zhao, Y.; Albizati,
K. F. J. Am. Chem. Soc. 1990, 112, 6965.
31. Simanek, E.; Huang, N. L. Phys. Rev. Lett. 1966, 17, 699.
32. Assuming a full syn-axial interaction between the CH2Cl and
Ha and Hb, the steric interactions present in 31b are
3£0.85 kcal mol21, compared to 2£0.1 kcal mol21 for the
axially oriented nitrile in 31c.
33. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds. Wiley: New York, 1994; pp 696–697.
The syn-axial interactions between the nitrile and the axial
protons in the forming ring are the same in conformers 31b and
31c, and therefore do not need to be considered in this
comparative analysis.
20. For an analogous reaction of esters see: (a) Chitkul, B.;
Pinyopronpanich, Y.; Thebtaranonth, C.; Thebtaranonth, Y.
Tetrahedron Lett. 1994, 35, 1099. (b) Tanaka, M.; Oba, M.;
Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667.
21. Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 3668.
22. Related sulfenylate and selenolate additions occur smoothly in
HMPA but not in THF: Fleming, F. F.; Pak, J. J. J. Org. Chem.
1995, 60, 4299.
34. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
35. For general experimental procedures see: Fleming, F. F.;
Hussain, Z.; Weaver, D.; Norman, R. E. J. Org. Chem. 1997,
62, 1305. All 1H NMR spectra were recorded at 300 MHz and
13C spectra at 75 MHz. The high-resolution mass spectra were
recorded at The Ohio State University Campus Chemical
Instrumentation Center.
23. Facile ketalization of 23 occurs in CDCla3 which, followed by
acid hydrolysis, converges 23 to the cis-decalone 17a. Lu, T. J.;
Cheng, S. M.; Sheu, L. J. J. Org. Chem. 1998, 63, 2738.
24. A pKa of 21 is estimated for analogous b,g-unsaturated
nitriles: Walters, E. A.; Long, F. A. J. Am. Chem. Soc. 1969,
91, 3733.