β-Siloxy unsaturated nitriles:Stereoselective cyclizations to cis- and trans-decalins

Article abstract of DOI:10.1021/ol990854s

(matrix presented). β-Siloxy unsaturated nitriles are excellent precursors to enolate and nitrile anions that cyclize to cis- and trans-decalins, respectively. The stereoelectronic requirements of endocyclic enolates and exocyclic nitrile anions are compl

Full text of DOI:10.1021/ol990854s

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1547-1550
â-Siloxy Unsaturated Nitriles:
Stereoselective 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,
Pittsburgh, PennsylVania 15282
flemingf@duq.edu
Received July 23, 1999
ABSTRACT
â-Siloxy unsaturated nitriles are excellent precursors to enolate and nitrile anions that cyclize to cis- and trans-decalins, respectively. The
stereoelectronic requirements of endocyclic enolates and exocyclic nitrile anions are complementary, providing cis- and trans-decalins from
a common intermediate. This cyclization allows the synthesis of diastereomeric cis- and trans-decalins containing a contiguous array of
quaternary−tertiary−quaternary stereocenters.
cis- and trans-decalins are among the most prevalent
structural units contained within natural products.1 A long-
standing challenge in decalin synthesis2 is the cyclization of
a single synthetic intermediate common to both cis- and
trans-decalins. Historically, cis-decalins have been particu-
larly common intermediates through their equilibration to
the less accessible trans-decalins,3 although equilibration is
strongly dependent on the substitution pattern4 and neces-
sarily requires an epimerizable ring junction. This indirect
equilibration route to trans-decalins is a direct stereochemical
consequence of intramolecular ketone enolate alkylations that
afford cis-decalones exclusively.
controlled (Scheme 1). Of the three possible transition states
for cyclization, 2a is significantly destabilized by a severe
1,3-diaxial interaction, while 2b, leading to a trans-decalin,
was presumed to be destabilized by steric compression
between the large bromine atom and the adjacent axial proton
(H*). Alkylation therefore occurs through transition state 2c,
affording 3.
Scheme 1
Several cleverly devised cyclizations5 demonstrated that
intramolecular alkylations of ketone enolates are kinetically
(1) (a) Glasby, J. S. In Encyclopedia of the Terpenoids; Wiley:
Chichester, U.K., 1982. For more recent examples, see the following. (b)
For sesquiterpenoids: Fraga, B. M. Nat. Prod. Rep. 1999, 16, 21. (c) For
diterpenoids: Hanson, J. R. Nat. Prod. Rep. 1999, 16, 209. (d) For
triterpenoids: Connolly, J. D.; Hill, R. A. Nat. Prod. Rep. 1999, 16, 221.
(2) For an excellent summary of decalin syntheses see: Vandewalle, M.;
DeClercq, P. Tetrahedron 1985, 41, 1767.
(3) Heathcock, C. H. In The Total Synthesis of Natural Products;
ApSimon, J. Ed.; Wiley: New York, 1973; Vol. 2, pp 197-558.
(4) Thompson, H. W.; Long, D. J. J. Org. Chem. 1988, 53, 4201.
(5) Conia, J.-M.; Rouessac, F. Tetrahedron 1961, 16, 45.
In stark contrast to enolate cyclizations, nitrile anions are
unique in cyclizing to either cis- or trans-decalins,6 depending
on the nature of the metal cation (Scheme 2).7 Unraveling
10.1021/ol990854s CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/14/1999

ether is particularly important in allowing the subsequent
conversion of 8 to a nitrile anion while avoiding a premature
cyclization of enolate 13.
Scheme 2
Scheme 3
Cyclization of 8 to the cis-decalin 9 parallels the known
intramolecular alkylations of ketone enolates.13 Enolate
formation and alkylation of 8 occurs smoothly upon addition
of n-Bu4NF, providing a single cis-decalin 9 whose structure
was secured by X-ray analysis14 (Scheme 4). Attention was
this unprecedented cation effect led to the discovery that the
side chain orientation controls the alkylation stereochemistry,
with equatorially oriented substituents affording trans-
decalins (4 f 6) and axially oriented substituents providing
cis-decalins (4 f 7). This pioneering nitrile anion cyclization
has been underappreciated,8 possibly because of a perceived
substrate specificity and the reversal of stereoselectivity
observed with differing counterions, raising questions about
the predictability and generality of the cyclization.
Scheme 4
Our aim has been to synthesize functionalized â-siloxy
unsaturated nitriles9 (8) for stereoselective cyclizations to cis-
and trans-decalins. Conceptually, â-siloxy unsaturated nitriles
allow generation of either ketone enolates or nitrile anions,
providing a potential means of stereocontrol in alkylations
with an appropriately positioned electrophile. Realizing this
goal would not only facilitate decalin syntheses but contribute
to the fundamental understanding of intramolecular ketone
enolate and nitrile anion alkylations.
then focused on cyclizing the corresponding nitrile anion to
the diastereomeric trans-decalin. The requisite nitrile 15 was
prepared in a one-pot reaction15 involving sequential silyl
ether cleavage, protonation of the intermediate enolate, and
reduction of the resulting ketone (3:2 ratio of â to R nitrile
epimers). Exposing the individual â-hydroxy nitriles 15 to
excess LiNEt2 results in an efficient cyclization to a single
diastereomeric decalin 16. Oxidation16 of 16 provides the
crystalline trans-decalin 10, whose structure was unequivo-
cally determined by X-ray analysis.14
The ketone enolate and nitrile anion cyclizations of 8 and
15 provide diastereomeric cis- and trans-decalins from a
common intermediate. We believe that this complementary
stereoselectivity is caused by different orbital alignments of
ketone enolates and nitrile anions. Endocyclic ketone enolates
The uncatalyzed conjugate addition of Grignard reagents
to the unsaturated oxonitrile 1110 provides an extremely
concise route to â-siloxy unsaturated nitriles.9 Reacting the
chlorobutyl Grignard reagent 1211 with 11 results in a smooth
conjugate addition, affording an intermediate enolate that
reacts with TBDMSCl12 to provide the â-siloxy unsaturated
nitrile 8 (Scheme 3). Interception of the enolate as the silyl
(6) Stork, G.; Gardner, J. O.; Boeckman, R. K., Jr.; Parker, K. A. J. Am.
Chem. Soc. 1973, 95, 2014.
(7) Stork, G.; Boeckman, R. K., Jr. J. Am. Chem. Soc. 1973, 95, 2016.
(8) No examples of trans-selective cyclizations were found from a
Science Citation search of ref 7.
(9) Fleming, F. F.; Pu, Y.; Tercek, F. J. Org. Chem. 1997, 62, 4883.
(10) Fleming, F. F.; Huang, A.; Sharief, V. A.; Pu, Y. J. Org. Chem.
1997, 62, 3036.
(11) Bernady, K. F.; Poletto, J. F.; Nocera, J.; Mirando, P.; Schaub, R.
E.; Weiss, M. J. J. Org. Chem. 1980, 45, 4702.
(14) The authors have deposited atomic coordinates with the Cambridge
Crystallographic Data Center. The coordinates can be obtained, on request,
from the Director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge, CB2 1EZ, U.K.
(12) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462.
(13) Vite, G. D.; Spencer, T. A. J. Org. Chem. 1988, 53, 2560. (b) Piers,
E.; Yeung, B. W. A. J. Org. Chem. 1984, 49, 4567. (c) Posner, G. H.;
Sterling, J. J.; Whitten, C. E.; Lentz, C. M.; Brunelle, D. J. J. Am. Chem.
Soc. 1975, 97, 107.
(15) Rhodes, R. A.; Boykin, D. W. Synth. Commun. 1988, 18, 681.
(16) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(17) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 696-697.
1548
Org. Lett., Vol. 1, No. 10, 1999

can only access two conformations, 17a and 17c, in which
the π-electrons of the enolate are aligned with the electro-
philic chloromethylene carbon for an SN2 displacement
(Scheme 5). This alignment is not possible in 17b, where
orientation of both the chlorobutyl chain and the forming
bond minimizes the syn-axial steric interactions.19 The
stereoselectivity therefore results from the exocyclic nature
of the nitrile anion.20
We have extended this cyclization strategy to the synthesis
of 1,1-gem-dimethyl-substituted decalins that are commonly
found in a large number of terpenoids.1 Installation of the
gem-dimethyl group required access to a novel organome-
tallic reagent (21) that was prepared from 19 by sequential
methylation, iodination,21 and zincation (Scheme 7). Treating
Scheme 5
Scheme 7
the π-electrons of the enolate incline away from the carbon-
chlorine bond, preventing alkylation from conformer 17b,
even though 17b is sterically more favorable than 17c.
Formation of the cis-decalin 9 is therefore stereoelectronically
controlled by the orbital alignment of the endocyclic ketone
enolate.
In contrast to ketone enolates, nitrile anions exhibit unique
stereoselectivities,7 reflecting both the extremely small size
of the nitrile group17 and the exocyclic nature of the anion.
These features are apparent in the conformations 18a-c,
where both six-membered rings can adopt full chair confor-
mations (Scheme 6), unlike the corresponding enolate.18
20 with Rieke zinc22 results in the selective metalation of
the carbon-iodine bond, providing an organozinc reagent
that reacts smoothly with 11 and TBDMSCl to provide the
â-siloxy unsaturated nitrile 23. This conjugate addition
proceeds in excellent yield (71%), particularly considering
the steric bulk of the nucleophile, and represents the first
example of a noncatalyzed, organozinc addition to a â-oxo-
R,â-unsaturated nitrile.23
Scheme 6
Cyclizing the â-siloxy unsaturated nitrile 23 through the
corresponding enolate and nitrile anions selectively provides
either the cis- or trans-dimethyl-substituted decalins. Fluoride-
induced cleavage of 23 generates an intermediate enolate
that cyclizes exclusively to the cis-decalin 24 (Scheme 8).
Formation of the diastereomeric trans-decalin requires cy-
clization of the corresponding nitrile 26, which is prepared
by reduction of 23 with NaBH4.15 Cyclization of 26 occurs
smoothly with excess lithium diethylamide, providing the
trans-decalin 27, regardless of the nitrile orientation in the
Excellent orbital overlap is achieved in all three conforma-
tions, since the nitrile anion is directly oriented toward the
electrophilic chloromethylene carbon. Alkylation preferen-
tially occurs from conformation 18c, in which the equatorial
(20) The equatorial orientation of the alkoxide intermediate has a
profound effect on the stereoselectivity since the cyclization of the
corresponding axial alcohol, obtained as a minor component in the reduction
of 10, affords the cis-decalin. We speculate that an axial alkoxide causes
twisting of the cyclohexane ring, preventing sufficient orbital alignment in
20c and favoring alkylation from 20b. We are currently examining this
stereoselectivity with the des-hydroxy analog.
(21) Olah, G. A.; Husain, A.; Singh, B. P.; Mehrotra, A. K. J. Org. Chem.
1983, 48, 3667.
(22) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56,
1445.
(18) The anion is shown as an sp3-hybridized, inductively stabilized anion
reflecting the product-like character of the transition state. The exact
hybridization of nitrile anions is the subject of considerable discussion. For
leading references see: (a) Strzalko, T.; Seyden-Penne, J.; Wartski, L.;
Corset, J.; Castella-Ventura, M.; Froment, F. J. Org. Chem. 1998, 63, 3287.
(b) Koch, R.; Wiedel, B.; Anders, E. J. Org. Chem. 1996, 61, 2523. (c)
Wiberg, K. B.; Castejon, H. J. Org. Chem. 1995, 60, 6327. (d) Carlier, P.
R.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 11602. (e)
Abbotto, A.; Bradamante, S.; Pagani, G. A. J. Org. Chem. 1993, 58, 449.
(19) A related equatorial alkylation of nitrile anions was recently observed
in a clever double-Michael reaction: Grossman, R. B.; Varner, M. A.;
Skaggs, A. J. J. Org. Chem. 1999, 64, 340.
(23) For the addition of tertiary organozinc bromides to enones see:
Hanson, M. V.; Rieke, R. D. J. Am. Chem. Soc. 1995, 117, 10775.
(24) The identity of the two crystalline decalones was secured by X-ray
analysis.
Org. Lett., Vol. 1, No. 10, 1999
1549

The addition of functionalized Grignard and organozinc
reagents to R,â-unsaturated oxonitriles provides an extremely
simple route to diastereomeric cis- and trans-decalins from
a common â-siloxy unsaturated nitrile. This addition-
cyclization strategy not only allows complementary stereo-
selectivity in intramolecular alkylations but also installs a
contiguous array of quaternary-tertiary-quaternary stereo-
centers commonly found in many terpenoids. Collectively
these cyclizations demonstrate the fundamental stereoelec-
tronic requirements inherent in ketone enolate and nitrile
anion cyclizations.
Scheme 8
Acknowledgment. Financial support from the NIH is
gratefully acknowledged. Shih-Chi Chang is thanked for
assistance with the X-ray structure determinations.
hydroxy nitrile 26. This cyclization leads exclusively to the
trans-decalin 27 and simultaneously installs the hindered
quaternary center with complete stereocontrol. Oxidation16
of 27 provides the trans-decalin 28, that differs from 24 only
in the ring junction stereochemistry.24
Supporting Information Available: X-ray structures of
9 and 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL990854S
1550
Org. Lett., Vol. 1, No. 10, 1999