Diastereoselective heck arylation of spirolactams: An approach to spiroamine-based nicotinic ligands

Article abstract of DOI:10.1055/s-2006-951515

The intermolecular Heck arylations of the cyclopentenyl based spirolactams 6a and 6c are stereoselective leading to adducts 7 and 8 derived by face-selective carbopalladation anti to the lactam carbonyl. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951515

LETTER
3069
Diastereoselective Heck Arylation of Spirolactams: An Approach to
Spiroamine-Based Nicotinic Ligands
D
iastereoselectiv
h
e
H
eckAryl
a
nrolactams itsara Kocharit, Arada Chaiyanurakkul, Timothy Gallagher*
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax +44(117)9298611; E-mail: t.gallagher@bristol.ac.uk
Received 16 June 2006
This paper is dedicated with respect to Professor Richard Heck, whose work represents a fundamental and lasting contribution to the
organic chemistry of palladium.
N
Abstract: The intermolecular Heck arylations of the cyclopentenyl
H
based spirolactams 6a and 6c are stereoselective leading to adducts
7 and 8 derived by face-selective carbopalladation anti to the lactam
carbonyl.
( )n
*
RN
( )n
*
( )n
*
RN
RN
( )m
( )m
( )m
N
Key words: Heck reaction, spirocycles, lactams, metathesis, ste-
reoselectivity
H
N
4a
4b
4c
Figure 2
Natural product leads, such as epibatidine (1)1 and anatox-
in-a (2, Figure 1),2 have attracted interest as leads for se-
lective nicotinic agonists associated with the nicotinic
acetylcholine receptor (nAChR).3
of the basic amine center with respect to the hydrogen
bond acceptor. In addition, this spatial relationship can be
modulated by varying (i) the ring sizes of the bicyclic core
(m vs. n), and (ii) the oxidation level (sp2 vs. sp3) and the
relative stereochemistry associated with the carbon center
carrying the p-moiety (C* in 4a–c, Figure 2). In this way,
a greater proportion of receptor space can be probed than
is normally the case with synthetically less accessible
scaffolds.
Cl
Cl
H
N
N
O
H
N
H
N
N
Me
1
2
3
This paper deals with our initial approach to this putative
class of ligand, with a key feature being use of the Heck
arylation reaction6 as a means of introducing the aryl unit
onto the heterocyclic core.
Figure 1
These ligands incorporate key elements associated with
contemporary nicotinic pharmacophores,4 namely a basic
amine (protonated at physiological pH) and a p-system in-
corporating a hydrogen bond acceptor (the pyridyl ring of
1 and the ketone oxygen of 2). These two pharmacophore
elements must be maintained in the appropriate arrange-
ment to interact with the nAChR, and the rigid bicycle as-
sociated with 1 and 2 provides the scaffold necessary to
achieve optimal orientation. There is an opportunity to ex-
plore alternative frameworks to carry these pharmaco-
phore components, and thereby develop new families of
nicotinic agonists. We have already generated the first
epibatidine–anatoxin-a hybrid, UB-165 (3),5 but there is
an on-going need to define a broader and synthetically
more accessible range of scaffolds.
We targeted the N-methyl variants (i.e. 4, R = Me), which
offer the possibility of access to the corresponding sec-
ondary amines (4, R = H) at a later stage. The core spiro-
cyclic scaffolds based on 4 (m = n = 1, 2) were assembled
in a straightforward fashion as outlined in Scheme 1.
Using N-methyl pyrrolidinone, stepwise enolate alkyla-
tion was carried out to provide the a,a-disubstituted lac-
tams 5a and 5b. Ring-closing metathesis (using the
Grubbs 2nd generation catalyst in toluene) provided spi-
rocyclic alkenes 6a and 6b in 70% and 80% isolated
yields, respectively; these reactions were significantly
slower and less efficient using the Grubbs 1st generation
catalyst. A similar sequence was also applicable to N-
methyl piperidinone leading to 5c,d and 6c,d in compara-
ble yields.7,8
In this paper we report initial results aimed at scaffold as-
semblies based on spirofused bicyclic amines 4 (where
m = n = 1, 2; R = Me, H). These were attractive for a
number of reasons. Spirocyclic arrangements retain a sig-
nificant degree of rigidity thereby controlling the location
The Heck arylation of 6a–d was examined under a variety
of different conditions.9–11 We observed arylation with the
cyclopentene variants 6a and 6c (see below), which repre-
sent a more reactive and stereochemically less complicat-
ed series. However, and despite significant effort,
cyclohexenes 6b and 6d proved to be much less reactive
and with these substrates Heck adducts were produced in
SYNLETT 2006, No. 18, pp 3069–3072
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951515; Art ID: S14306ST
© Georg Thieme Verlag Stuttgart · New York

3070
C. Kocharit et al.
LETTER
O
O
O
O
6
6
i
ii
MeN
MeN
MeN
MeN
( )n
3
3
6a (70%)
6b (80%)
5a n = 1 (68%)
5b n = 2 (47%)
O
O
O
O
1
1
MeN
MeN
MeN
i
MeN
ii
( )n
4
4
6
7
6d (85%)
6c (75%)
5c n = 1 (58%)
5d n = 2 (54%)
Scheme 1 Reagents and conditions (overall yields for the lactam alkylation sequences are shown above): i, 5a and 5c: s-BuLi, THF, –78 °C,
3-bromoprop-1-ene, –78 °C to r.t., then s-BuLi, THF, –78 °C, 3-bromoprop-1-ene, –78 °C to r.t.; i, 5b and 5d: s-BuLi, THF, –78 °C, 4-bromo-
but-1-ene, –78 °C to r.t., then s-BuLi, THF, –78 °C, 3-bromoprop-1-ene, –78 °C to r.t.; ii, RuCl2(=CHPh)(IMes)(PCy3) (1 mol%), PhMe, 70 °C,
1–2 h.
low yields and as inseparable mixtures of regioisomers aided by the rigidity of the spiro framework, and this as-
(see below).
signment was then confirmed by X-ray crystallography
(Figure 3).
With 6a and 6c use of the Larock-modified Jeffery condi-
tions provided the best yields (Scheme 2).10a,b Use of 5- The stereochemical assignment of Heck adducts 7b and
iodo-2-chloropyridine [cf UB-165 (3)] gave the Heck ad- 7c and 8a and 8b was also based on NOE studies and by
ducts 7a12 and 8a12 in 50% and 53% yield, respectively. comparison with the spectroscopic data from 7a.
Heck arylations were also carried using 3-bromopyridine
to give 7b (40%), and 7c (89%) and 8b (85%) were ob-
tained using iodobenzene.
In both spirolactams 6a and 6c, the amide carbonyl ap-
pears to exert a significant influence on the diastereofacial
selectivity of the Heck arylations step, and carbopallada-
While we anticipated (based on mechanistic grounds) that tion step occurred exclusively on the face of the alkene
6a and 6c would lead to formation of the deconjugated ad- moiety opposite to the carbonyl unit of the adjacent lac-
duct (compare e.g. 7a with 9 below) we were surprised tam ring. No direct precedent exists for the process out-
that in all cases studied the Heck adducts 7a–c and 8a and lined in Scheme 2. Intramolecular Heck reactions taking
8b were isolated as single diastereoisomers. No evidence place in close proximity to carbonyl functions (esters and
for the formation of the other diastereomer was seen. The amides) have been reported,13 but the outcomes associated
structure of 7a was established initially by NOE studies, with these reactions are generally determined by other
factors. Recently, Ung and Pyne14 and co-workers have
O
described the intermolecular Heck arylation of cyclopen-
tenyl-based amino acid derivatives. These reactions also
display a high degree of facial selectivity, but in these cas-
es this was attributed to precomplexation of a Cbz-pro-
tected amino function to Pd(II) in order to direct the
carbopalladation step to take place from one face.
O
H
6
i
MeN
1
MeN
7a X = Cl (50%)
7b X = H (40%)
9
2'
4
6a
N
O
H
i
X
MeN
7c (89%)
Ph
O
O
O
H
MeN
1
i
MeN
6
8a (53%)
8
4
2'
6c
N
i
H
Cl
MeN
8b (85%)
Ph
Figure 3 X-ray crystal structure of Heck adduct 7a
Scheme 2 Reagents and conditions: Pd(OAc)2, NaOAc,
n-Bu4NCl·H2O, ArI or ArBr (see text), DMF, 50 °C, 24 h.
Synlett 2006, No. 18, 3069–3072 © Thieme Stuttgart · New York

LETTER
Diastereoselective Heck Arylation of Spirolactams
3071
Such an ‘internal delivery’ option to control delivery of
the aryl moiety is not available with spirocycles 6a and 6c.
However, the extent to which the outcomes reported in
Scheme 2 are driven by electronic vs. steric interactions
during the carbopalladation reaction is not yet clear. Fur-
ther work to elucidate those factors that control this pro-
cess and determine the diastereoselectivity associated
with Heck reactions leading to adducts 7 and 8 is under-
way.
Ph
O
Ph
O
Ph
O
MeN
m( )
i
MeN
NMe
using
10b
n( )
( )n
n( )
10a m = 1, n = 1
10b m = 1, n = 2
10c m = 2, n = 1
10d m = 2, n = 2
11 n = 2
E/Z mixture
O
O
Ph
Ph
MeN
MeN
The formation of the deconjugated adducts 7 and 8 is a
consequence of the stereospecificity of the PdH elimina-
tion step associated with Heck arylation. In order to pro-
vide an entry to conjugated isomers 9 (i.e. precursors to
4a), we explored the applicability of Beller’s conditions11
who has reported the direct formation of conjugated ary-
lated cyclopentenes using Pd2(dba)3⋅dba/PCy3/Na2CO3/
DMA. Attempts to apply these modifications to spirolac-
tam 6a did not, however, provide the desired conjugated
adducts 9 [Ar = 3-(6-chloropyridyl) or Ph]. Furthermore
efforts to isomerize adducts 7a,c under a variety of both
metal- and base-mediated conditions were unsatisfactory
(Scheme 3).15
i or ii
( )n
( )n
12a n = 1 (63%)
12b n = 2 (82%)
12a n = 1 (68%)
12b n = 2 (76%)
Scheme 4 Reagents and conditions: i, RuCl2(=CHPh)(IMes)(PCy3)
(1 mol%), PhMe, 70 °C, 1 h (applicable to 10a and 10c); ii,
RuCl2(=CHPh)(IMes)(PCy3) (1 mol%), CH2Cl2, 40 °C, 4 h (applica-
ble to 10a–d).
the synthesis of a range of spiroamines and their evalua-
tion as nicotinic agonists will be reported in due course.
Acknowledgment
O
We thank Anob Kantacha for the structure determination of 7a, and
the Royal Thai Government for the awards of scholarships to CK
and AC.
MeN
Beller's
conditions11
6a
O
References and Notes
MeN
(1) Badio, B.; Daly, J. W. Mol. Pharmacol. 1994, 45, 563.
(2) (a) Wonnacott, S.; Gallagher, T. In Marine Drugs and Ion
Channels; Arias, H. R., Ed.; MDPI: Basel, 2006, in press.
(b) For an overview of the role of natural products as
nicotinic ligands, see: Daly, J. W. Cell. Mol. Neurobiol.
2005, 25, 513.
(3) (a) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem.
1997, 40, 4169. (b) Jensen, A. A.; Frolund, B.; Lijefors, T.;
Krogsgaard-Larsen, P. J. Med. Chem. 2005, 48, 4705.
(4) (a) Tonder, J. E.; Olesen, P. H. Curr. Med. Chem. 2001, 8,
651. (b) Glennon, R. A.; Dukat, M. Bioorg. Med. Chem.
Lett. 2004, 14, 1841. (c) Glennon, R. A.; Dukat, M.; Liao, L.
Curr. Top. Med. Chem. 2004, 4, 631.
(5) (a) Wright, E.; Gallagher, T.; Sharples, C. G. V.; Wonnacott,
S. Bioorg. Med. Chem. Lett. 1997, 7, 2867. (b) Sharples, C.
G. V.; Kaiser, S.; Soliakov, L.; Marks, M. J.; Collins, A. C.;
Washburn, M.; Wright, E.; Spencer, J. A.; Gallagher, T.;
Whiteaker, P.; Wonnacott, S. J. Neurosci. 2000, 20, 2783.
(c) Sharples, C. G. V.; Karig, G.; Simpson, G. L.; Spencer,
J. A.; Wright, E.; Millar, N. S.; Wonnacott, S.; Gallagher, T.
J. Med. Chem. 2002, 45, 3235. (d) See also: Gohlke, H.;
Gundisch, D.; Schwarz, S.; Seitz, G.; Tilotta, M. C.; Wegge,
T. J. Med. Chem. 2002, 45, 1064.
(6) For reviews covering recent synthetic and mechanistic
aspects of the Heck arylation reaction, see: (a) Amatore, C.;
Jutand, A. Acc. Chem. Res. 2000, 33, 314. (b) Whitcombe,
N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.
(c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009. (d) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945.
O
Ar
H
9
C=C
isomerisation
MeN
Ar
7a,c
Scheme 3
An alternative approach to adducts 9, which also over-
comes the issues associated with arylation of cyclo-
hexenes 6b and 6d, based on ring-closing metathesis is
available, and is exemplified in Scheme 4 for the phenyl-
substituted series. Assembly of the requisite precursors
10a–d was achieved by use of the same lactam alkylation
strategy as used in Scheme 1. While ring closure to gener-
ate the substituted five-membered ring (from 10a,c) pro-
ceeded smoothly in PhMe, application of the same
process to the cyclohexenyl precursor 10b led only to for-
mation of cross metathesis dimer 11. This was solved by
a change of solvent (PhMe to CH2Cl2), which cleanly
gave in all cases the desired conjugated spirolactams 12a–
d in good yields.
In conclusion, the Heck reaction of spirolactams 6a and 6c
leads to the formation of the expected deconjugated Heck
adducts 7 and 8 in a highly diastereoselective fashion. In-
troduction of an aryl substitutent can also be achieved di-
rectly via ring-closing metathesis (leading to 12a–d),16
which complements the Heck arylation sequence. The fur-
ther application of the methodologies described here to
(7) A related sequence aimed at the spirocyclic core of spirolide
marine toxins has been developed. See: Brimble, M. A.;
Trzoss, M. Tetrahedron 2004, 60, 5613.
Synlett 2006, No. 18, 3069–3072 © Thieme Stuttgart · New York

3072
C. Kocharit et al.
LETTER
(8) All compounds reported in this paper are racemic. Nicotinic
activity may only be associated with one enantiomeric series
as is the case with anatoxin-a (2) and UB-165 (3). This is not
the case with epibatidine (1) where both enantiomers are
equipotent. As predicting the biologically active enantiomer
is difficult and subject to pitfalls, our initial targets were
racemates. All novel compounds were characterized by 1H
NMR and 13C NMR, IR, MS, and HRMS or elemental
analysis. The numbering systems used for NMR
(C-5), 124.1 (C-5¢), 135.2 (C-6, C-7), 137.7 (C-4¢), 139.7 (C-
3¢), 148.8 (C-2¢), 149.5 (C-6¢), 176.9 (CO). MS (EI+): m/z
(%) = 264, 262 (100) [M+]. HRMS (EI+): m/z calcd for
C14H1535ClN2O: 262.0873; found: 262.0864. Anal. Calcd for
C14H15ClN2O: C, 64.10; H, 5.77; N, 10.68. Found: C, 64.15;
H, 5.80; N, 10.60.
Compound 8a: mp 89 °C (EtOAc–cyclohexane). IR (neat):
3046, 2970, 2904, 1660, 1580, 1560, 1452, 1273, 1109, 808
cm–1. 1H NMR: (400 MHz, CDCl3): d = 1.44 (1 H, dd,
J = 13.0, 7.5 Hz, H-4), 1.80–1.89 (2 H, m, H-9, H-10), 1.91–
1.99 (2 H, m, H-9, H-10), 2.96 (1 H, dd, J = 13.0, 8.0 Hz, H-
4), 2.97 (3 H, s, -CH3), 3.34 (2 H, t, J = 6.0 Hz, 2 × H-8),
4.35 (1 H, ddt, J = 8.0, 7., 2.0 Hz, H-3), 5.91 (1 H, dd,
J = 5.5, 1.5 Hz, -CH=CH-), 5.93 (1 H, dd, J = 5.5, 2.5 Hz,
-CH=CH-), 7.26 (1 H, d, J = 8.0 Hz, H-5¢), 7.46 (1 H, dd,
assignments are indicated on the relevant structures.
1H NMR and 13C NMR data in CDCl3 for spirolactams 6a–d:
Compound 6a: 1H NMR (300 MHz): d = 2.00 (2 H, t, J = 6.5
Hz, 2 × H-4), 2.26 (2 H, d, J = 14.5 Hz, H-6, H-9), 2.82 (2 H,
d, J = 14.5 Hz, H-6, H-9), 2.88 (3 H, s, CH3), 3.30 (2 H, t,
J = 6.5 Hz, 2 × H-3), 5.65 (2 H, br s, H-7, H-8). 13C NMR
(75.5 MHz): d = 30.0 (CH3), 35.7 (C-4), 43.6 (C-6, C-9),
49.7 (C-5), 46.5 (C-3), 128.4 (C7, C-8), 179.1 (CO).
Compound 6b: 1H NMR (400 MHz): d = 1.42–1.51 (1 H, m,
H-10), 1.76–1.91 (4 H, m, 2 × H-9, 2 × H-4), 2.06–2.16 (2
H, m, H-6, H-10), 2.32–2.42 (1 H, m, H-6), 2.86 (3 H, s,
CH3), 3.30 (2 H, td, J = 7.5, 2.0 Hz, 2 × H-3), 5.61–5.71 (2
H, m). 13C NMR (100 MHz): d = 21.9 (C-10), 28.4 (C-4),
29.2 (C-9), 29.7 (CH3), 32.3 (C-6), 42.8 (C-5), 46.2 (C-3),
126.3 and 124.6 (C-7, C-8), 179.0 (C-1).
J = 8.0, 2.5 Hz, H-4¢), 8.23 (1 H, d, J = 2.5 Hz, H-2¢). 13
C
NMR (100 MHz, CDCl3): d = 20.7 (C-9), 35.5 (-CH3), 35.6
(C-10), 47.3 (C-4), 48.4 (C-3), 50.4 (C-8), 56.9 (C-5), 124.1
(C-5¢), 136.9 and 134.8 (C-1, C-2), 137.7 (C-4¢), 140.1 (C-
6¢), 148.9 (C-2¢), 149.4 (C-3¢), 174.0 (CO). MS (EI+): m/z
(%) = 278, 276 (100) [M+]. HRMS (EI+): m/z calcd for
C15H1735ClN2O: 276.1029; found: 276.1022. Anal. Calcd for
C15H17ClN2O: C, 65.19; H, 6.20; N, 10.14. Found: C, 65.25;
H, 6.11; N, 10.24.
Compound 6c: (300 MHz): d = 1.75–1.89 (4 H, m, 2 × H-9,
2 × H-10), 2.23 (2 H, d, J = 14.5, H-1, H-4), 2.95 (3 H, s,
CH3), 2.99 (2 H, d, J = 14.5, H-1, H-4), 3.31 (2 H, t, J = 6,
2 × H-8), 5.61 (2 H, br s, H-2, H-3). 13C NMR (75.5 MHz):
d = 20.0 (C-9), 35.4 (C-10), 35.3 (CH3), 46.2 (C-1, C-4),
47.8 (C-5), 50.4 (C-8), 128.1 (C-2, C-3), 176.0 (CO).
Compound 6d: 1H NMR (300 MHz): d = 1.55 (1 H, ddt,
J = 12.5, 4.5, 2.0 Hz, H-11), 1.67 (1 H, dd, J = 9.0, 3.5 Hz,
H-5), 1.76–1.85 (4 H, m, 2 × H-10, 1 × H-5, 1 × H-11),
1.89–1.93 (1 H, m, H-7), 2.00–2.07 (1 H, m, H-4), 2.09–2.12
(1 H, m, H-4), 2.64 (1 H, dd, J = 17.0, 13.0 Hz, H-7), 2.93 (3
H, s, CH3), 3.24–3.32 (2 H, m, 2 × H-3), 5.60–5.66 (2 H, m,
CH=CH). 13C NMR (100 MHz): d = 19.1 (C-10), 21.6 (C-4),
29.1 (C-5), 30.5 (C-11), 33.6 (C-7), 35.4 (CH3), 39.9 (C-6),
50.3 (C-3), 125.3 and 125.0 (C-8, C-9), 175.0 (C-1).
(9) Three sets of Heck conditions were used: a) Pd(OAc)2,
NaOAc, n-Bu4NCl, H2O, PhI, DMF, 50 °C, 24 h;10 b)
Herrmann palladacycle catalyst (10 mol%), NaOAc, PhI,
DMA, 100 °C, 24 h;11 c) Pd2(dba)3 (0.1 mol%), 4 PCy3,
Na2CO3, PhI, DMA, 140 °C, 24 h11 (Heck arylation of 6a
and 6c was not observed under these latter conditions). A
number of other conditions, including use of Ag(I) as an
activator, were also evaluated.
(13) (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem.
1989, 54, 4738. (b) Overman, L. E.; Watson, D. A. J. Org.
Chem. 2006, 71, 2600.
(14) Ung, A. T.; Pyne, S. G.; Batenburg-Nguyen, U.; Davis, A.
S.; Sherif, A.; Bischoff, F.; Lesage, A. S. J. Tetrahedron
2005, 61, 1803.
(15) Alkene isomerisation under basic conditions (t-BuOK,
DME, 60 °C) was observed but this could not be controlled
and an inseparable 1:1 mixture of regioisomers was
obtained.
(16) 1H NMR and 13C NMR data for spirolactams 12a–d (all
compounds were characterized by IR, microanalysis and/or
HRMS).
Compound 12a: 1H NMR (300 MHz, CDCl3): d = 2.05 (2 H,
m), 2.39 (1 H, ddd, J = 17.0, 2.5, 2.5 Hz), 2.60 (1 H, d,
J = 16.0 Hz), 3.00 (1 H, dddd, J = 17.0, 2.5, 2.5, 2.5 Hz),
3.25 (1 H, dddd, J = 16.0, 2.5, 2.5, 2.5 Hz), 3.32 (2 H, t,
J = 6.5 Hz), 6.03–6.06 (1 H, m), 7.20–7.41 (5 H, m). 13
C
NMR (100 MHz, CDCl3): d = 30.0, 35.8, 43.8, 43.9, 46.4,
50.1, 123.1, 125.4, 127.0, 128.2, 135.9, 140.1, 178.5.
Compound 12b: 1H NMR (400 MHz, CDCl3): d = 1.54 (1 H,
ddt, J = 13.0, 6.5, 2.5 Hz), 1.88–1.98 (3 H, m), 2.18 (1 H, dt,
J = 17.0, 2.5 Hz), 2.24–2.31 (1 H, m), 2.36–2.45 (1 H, m),
2.82 (1 H, dd, J = 17.0, 2.5 Hz), 2.90 (3 H, s), 3.32–3.34 (2
H, m), 3.34 (1 H, dd, J = 8.0, 2.0 Hz), 6.12 (1 H, dt, J = 5.0,
2.0 Hz), 7.20–7.37 (5 H). 13C NMR (100 MHz, CDCl3): d =
22.5, 27.9, 29.3, 29.7, 34.4, 43.2, 45.9, 122.9, 125.3, 126.6,
128.0, 134.2, 141.8, 178.5
(10) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(b) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667. (c) For the
application of an improved procedure for arylation of simple
cycloalkenes, see: Larock, R. C.; Gong, W. H.; Baker, B. E.
Tetrahedron Lett. 1989, 30, 2603.
(11) Hartung, C. G.; Kohler, K.; Beller, M. Org. Lett. 1999, 1,
709.
(12) Characterization data for Heck adducts 7a and 8a.
Compound 7a: colorless solid; mp 88 °C (EtOAc–
Compound 12c: 1H NMR (400 MHz, CDCl3): d = 1.78–1.92
(4 H, m), 2.42 (1 H, ddd, J = 17.0, 2.5, 2.5 Hz), 2.58 (1 H, d,
J = 15.5 Hz), 3.18 (1 H, dddd, J = 17.0, 2.5, 2.5, 2.5 Hz),
3.35 (2 H, t, J = 6.5 Hz), 3.42 (1 H, dddd, J = 15.5, 2.5, 2.5,
2.5 Hz), 6.02–6.06 (1 H, m), 7.20–7.40 (5 H, m). 13C NMR
(100 MHz, CDCl3): d = 19.9, 35.5, 35.8, 46.3, 48.1, 50.2,
122.5, 125.5, 126.7, 128.2, 136.2, 139.6, 175.7.
cyclohexane). IR (neat): 3060, 3019, 2930, 2870, 1950,
1740, 1660, 1600, 1490, 1654 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.59 (1 H, dd, J = 13.0, 6.5 Hz, H-9), 1.97 (1 H,
ddd, J = 13.0, 8.0, 6.0 Hz, H-4), 2.23 (1 H, ddd, J = 13.0, 8.0,
5.0 Hz, H-4), 2.88 (1 H, dd, J = 13.0, 8.5 Hz, H-9), 2.89 (3
H, s, CH3), 3.31 (1 H, ddd, J = 10.0, 8.0, 5.0, H-3), 3.39 (1
H, ddd, J = 10.0, 8.0, 6.0 Hz, H-3), 4.27 (1 H, ddt, J = 8.5,
6.5, 2.0 Hz, H-8), 5.82 (1 H, dd, J = 5.5, 2.0 Hz, CH=CH),
5.94 (1 H, dd, J = 5.5, 2.0 Hz, CH=CH), 7.26 (1 H, d, J = 8.0
Hz, H-5¢), 7.46 (1 H, dd, J = 8.0, 2.5 Hz, H-4¢), 8.23 (1 H, d,
J = 2.5 Hz, H-2¢). 13C NMR (100 MHz, CDCl3): dC = 30.3
(CH3), 32.9 (C-4), 44.9 (C-9), 46.7 (C-3), 47.7 (C-8), 57.8
Compound 12d: 1H NMR (300 MHz, CDCl3): d = 1.63 (1 H,
dddd, J = 9.0, 4.5, 2.0, 2.0 Hz), 1.67–1.74 (1 H, m), 1.76–
1.85 (3 H, m), 2.15–2.20 (3 H, m), 2.28 (1 H, dt, J = 16.0, 2.0
Hz), 2.97 (3 H, s), 3.08 (1 H, dt, J = 16.0, 2.0 Hz), 3.27–3.32
(2 H, m), 6.07 (1 H, dt, J = 5.0, 2.0 Hz), 7.21–7.38 (5 H, m).
13C NMR (100 MHz, CDCl3): d = 19.2, 22.3, 29.0, 30.1,
35.4, 35.9, 40.5, 50.3, 122.5, 125.0, 126.7, 128.2, 134.7,
142.4, 175.8.
Synlett 2006, No. 18, 3069–3072 © Thieme Stuttgart · New York