Enantiocontrolled synthesis of highly functionalized tropanes via [5 + 2] cycloaddition to eta(3)-pyridinylmolybdenum pi-complexes.

Article abstract of DOI:10.1021/ol000288x

[reaction: see text] A chiral, nonracemic eta(3)-pyridinyl scaffold participates in [5 + 2] cycloaddition with electron-deficient alkenes, an allene, and an alkyne to give eta(3)-allylmolybdenum bicyclic adducts. The adducts can be demetalated, providing a convergent route to highly functionalized tropanes. High enantiocontrol can be achieved throughout the cycloaddition and demetalation sequence.

Full text of DOI:10.1021/ol000288x

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3909-3911
Enantiocontrolled Synthesis of Highly
Functionalized Tropanes via [5 + 2]
Cycloaddition to
η3-Pyridinylmolybdenum π-Complexes
Helena C. Malinakova and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
chemll1@emory.edu
Received September 28, 2000
ABSTRACT
A chiral, nonracemic η3-pyridinyl scaffold participates in [5 + 2] cycloaddition with electron-deficient alkenes, an allene, and an alkyne to give
η3-allylmolybdenum bicyclic adducts. The adducts can be demetalated, providing a convergent route to highly functionalized tropanes. High
enantiocontrol can be achieved throughout the cycloaddition and demetalation sequence.
The psychostimulatory effects of cocaine and related alka-
loids render compounds possessing the azabicyclo [3.2.1]-
octane (tropane) skeleton attractive synthetic targets.1 Al-
though several asymmetric syntheses of tropanes have
recently been reported,2 the regio- and enantiocontrolled
introduction of various substituents around the tropane
skeleton remains a challenging problem.3 An expedient
solution to this problem draws precedence from a previously
described enantiocontrolled construction of oxabicyclo[3.2.1]-
octenes4 and arises from the [5 + 2] attachment of various
unsaturated building blocks to a single face of the chiral,
nonracemic pyridinyl scaffold I (Figure 1). The TpMo(CO)2
auxiliary of I (Tp ) hydridotris(1-pyrazolyl)borate) has been
shown to constitute an ideal metal-ligand set capable of
mediating multiple and sequential regio- and stereoselective
functionalizations of various π-substrates.4-6 Therefore, if
chiral, nonracemic TpMo(CO)2(pyridinyl) complexes I could
be prepared, substituted tropane alkaloids III would result
from demetalation-functionalization of the [5 + 2] adduct
II. Described herein is a general, convergent, and enantio-
controlled synthesis of functionalized tropanes based on the
above outlined strategy. Related cycloadditions of pyridinium
betaines ([5 + 2])7 and racemic furan and pyrrole-derived
π-complexes ([4 + 2]) are known.8
(1) Singh, S. Chem. ReV. 2000, 100(3), 925-1024.
(2) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63(12), 4069-
4078. Araldi, G. L.; Prakash, K. R. C.; George, C.; Kozikowski, A. P. Chem.
Commun. 1997, (19), 1875-1876. Davies, H. M. L.; Matasi, J. J.; Hodges,
L. M.; Huby, N. J. S.; Thornley, C.; Kong, N.; Houser, J. H. J. Org. Chem.
1997, 62(4), 1095-1105. Rigby, J. H.; Pigge, F. C. J. Org. Chem. 1995,
60(23), 7392-7393.
(3) Prakash, K. R. C.; Araldi, G. L.; Smith, M. P.; Ahang, M.; Johnson,
K. M.; Kozikowski, A. P. Med. Chem. Res. 1998, 8(1/2), 43-58. Lomenzo,
S. A.; Bradley, A. L.; Zhu, N.; Klein, C. L.; Trudell, M. L. J. Heterocycl.
Chem. 1997, 34, 1139-1146. Koh, J. S.; Ellman, J. A. J. Org. Chem. 1996,
61, 4494-4495.
Figure 1. Tropane synthetic strategy.
(4) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121(24), 5811-
5812.
10.1021/ol000288x CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/03/2000

Table 1. [5 + 2] Cycloaddition of η3-Pyridinylmolybdenum π-Complexes
entry
alkene
conditionsa
yield, exo:endo
prodt
R1
R2
R3
R4
% ee
1
2
N-methylmaleimide
CH2dCHCOMe
120%, 10 min 68%, 100:0
4
H
-CON(Me)CO-
H
H
COMe
H
H
Me
Me
CHO
H
b
b
b
97c
98c
65d
95c
95c
b
50%, 20 min
50%, 30 min
79%, 82:12
exo-5a
endo-5b
6
H
H
H
H
H
H
H
Et
H
H
H
COMe
H
H
-(CH2)3CO-
CO2Me
CO2Me
CHO
3
4
5
6
2-cyclohexenone
CH2dCHCO2Me
CH2dC(Me)CO2Me
CH2dC(Me)CHO
87%, 100:0, 8% recov 3
180%, 55 min 88%, 100:0, 5% recov 3
7
8
H
H
H
H
H
Et
H
150%, 16 h
20%, 40 min
47%, 100:0, 21% recov 3
74%, 61:39, 21% recov 3
exo-9a
endo-9b
exo-10a
endo-10b
exo-11a
Me
CHO
H
7
8
(E)-EtCHdCHCHO
40%, 40 min
180%, 16 h
74%, 57:43, 14% recov 3
CHO
b
b
86%, 69:31
-CO2(CH2)2-
endo-11b
H
H
-(CH2)2O2C-
b
b
b
9
10
MeO2CCHdCdCHCO2Me 110%, 35 min 57%
HCtCCO2Et 150%, 2.5 h 68%, 11% recov 3
12
13
dCHCO2Me
H
CO2Me
H
C-C bond
CO2Et
a Mol % EtAlCl2, time. b rac-form was used. c (-)-3 of 98% ee was used. d (+)-3 of 96% ee was used.
Racemic and chiral, nonracemic pyridinylmolybdenum
complexes were prepared by the reaction sequence depicted
in Scheme 1. Complex (()-2a, which is readily available
and 7.8 g of pure diastereomers) after two crystallizations.
X-ray crystallographic analysis of (-)-2b permitted the
assignment of absolute configuration for complexes 2b and
all the products later derived from them. While numerous
standard protocols9 failed to cleanly remove the chiral
auxiliary in 2b, SmI2-induced deoxygenation10 of the R-car-
bamyloxy lactone followed by treatment of the free base with
methoxychloroformate furnished both antipodes of 2a (74%
and 80% yields, 98% ee), which were subsequently converted
into (-)-3 (74% yield, 98% ee) and (+)-3 (89% yield, 99%
ee)11 with Ph3CPF6 and Et3N.
Scheme 1. Synthesis of Tp(CO)2Mo(pyridinyl) Scaffolds of
High Enantiopuritya
Unsaturated moieties activated by various electron-
withdrawing groups afforded the [5 + 2] cycloadducts 4-13
shown in Table 1 in good to excellent yields (47%-88%)
and with good exo:endo selectivities (4:3-1:0). As antici-
pated from previous studies,4 Lewis acid (EtAlCl2) was
required to initiate the [5 + 2] cycloaddition. The examples
depicted in Table 1 demonstrate the broad scope of the
(5) Pearson, A. J.; Neagu, I. B. J. Org. Chem. 1999, 64, 2890-2896.
(6) Moretto, A. F.; Liebeskind, L. S. J. Org. Chem. In press.
(7) Dennis, N.; Katritzky, A. R.; Takeuchi, Y. Angew. Chem. 1976, 88(2),
41-44.
a (a) (i) Mo(CO)3(DMF)3, TBDMSCl; (ii) KTp; (iii) TBAF; (iv)
MeI; (b) (i) Ph3CPF6; (ii) TEA; (c) (i) SmI2, HMPA, MeOH; (ii)
ClCO2Me, 3 N aqueous NaOH.
(8) Shiu, L.-H.; Shu, H.-K.; Cheng, D.-H.; Hwang, H.-L.; Wang, S.-L.;
Liao, F.-L.; Liu, R.-S. Organometallics 1998, 17, 4206-4212. Gonzalez,
J.; Koontz, J. I.; Hodges, L. M.; Nilsson, K. R.; Neely, L. K.; Myers, W.
H.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 1995, 117, 3405-3421.
(9) Green, T. W. ProtectiVe Groups in Organic Synthesis; John Wiley
& Sons: New York, 1981.
from (()-1a by following an established procedure,6 was
transformed into racemic (()-3 upon sequential treatment
with Ph3CPF6 and Et3N. An analogous sequence starting with
pyridone 1b afforded complex 2b, armed with an (R)-
pantolactone-derived chiral auxiliary. Although formation of
2b did not proceed with asymmetric induction, diastereo-
merically pure (-)-2b (98% de) and (+)-2b (98% de) were
conveniently obtained in good yields on a large scale (14
(10) Kusuda, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1989,
30(22), 2945-2948.
(11) Partial racemization of (-)-3 (to 94% ee in one case) can be
prevented by limiting all solution manipulations of 3 including chroma-
tography. A brief study revealed (i) slow racemization of ethanolic solutions
of 3 at room temperature exposed to light, (ii) no racemization in the dark,
and (iii) in the dark, racemization was induced by the addition of a Lewis
acid (Sc(OTf)3) to ethanolic solutions of 3.
3910
Org. Lett., Vol. 2, No. 24, 2000

reaction with respect to olefins bearing alkyl substituents on
R- or â-carbons (trisubstituted olefins did not react). Facile
additions to an exocyclic double bond in R-methylene-γ-
butyrolactone (entry 8) and to an allene (entry 9) are
especially notable. Most importantly, cycloadducts can be
prepared in high enantiomeric excess (95-98%). Although
a potential pathway for racemization of 3 is available,4,11 the
cycloaddition is apparently faster than racemization of
complex 3 under the reaction conditions. Only the cycload-
duct 8, derived from a poorly reactive methyl methacrylate
in a slow reaction, was obtained in a low optical purity (entry
5, 65% ee). X-ray crystallographic analysis of complexes
5a, 8, 9b, 10a, 12, and 15 allowed assignment of the
structures and confirmed the anticipated formation of new
C-C bonds from the face opposite the metal-ligand
moiety.12
Table 2. Demetalation of the [5 + 2] Cycloadducts
substrate
prdt (%)
R1
R2
R3
R4
ee%
1
2
3
4
4
16 (52%)
17 (81%)
18 (77%)
19 (77%)
H
H
H
H
-CON(Me)CO-
-(CH2)3CO-
H
H
H
Me
6 or (-)-6
7 or (-)-7
9a
96a
98b
H
CO2Me
H
CHO
a Prepared from (-)-6 of 97% ee. b Prepared from (-)-7 of 98% ee.
The following observations were noteworthy: EtAlCl2
used in excess, as well as prolonged reaction times, lowered
the yields of cycloadducts and decreased the exo:endo
selectivity. The yield of cycloadduct 6 (87%) could not be
further improved, even though unreacted complex 3 was
recovered (entry 3, Table 1). These observations are sug-
gestive of a readily reversible, Lewis acid mediated [5 + 2]
cycloaddition. In fact, when cycloadducts 5a, 6, and 9a
(Table 1) were exposed to EtAlCl2 (50 mol %, 4-6 h, room
temperature), mixtures containing both the exo and endo
cycloadducts and the cycloreversion complex (()-3 were
generated. In contrast, cycloadducts 7 and 8 (Table 1) were
stable (16 h) in the presence of excess EtAlCl2 (150 mol
%). Furthermore, reduction of readily reversible cycloadduct
6 followed by acetylation of alcohol 14 furnished the
modified cycloadduct 15, which was stable in the presence
of excess EtAlCl2 (Scheme 2). Thus, the functional group
Cycloadducts featuring a range of functional groups ef-
ficiently afforded racemic tropanes 16-19 and also tropanes
(+)-17 and (+)-18 in high enantiomeric purity (96 and 98%
ee). The enones 16-19 are well suited for further synthetic
manipulations.1
In conclusion, an enantiocontrolled [5 + 2] cycloaddition
of a pyridinyl-based TpMo(CO)2 scaffold has been described.
The method provides a convergent access to tropanes with
substituent patterns that are difficult to obtain by other
methods. Tropanes of high enantiomeric purity (95-98%
ee) were prepared using this method, and both optical
antipodes are equally accessible. Application of this chem-
istry to the enantiocontrolled synthesis of spirooxindole
alkaloids is currently under investigation. The generation of
tropane diversity libraries is an obvious extension of this new
reaction.
Acknowledgment. This work was supported by Grant
GM43107, awarded by the National Institute of General
Medical Sciences, DHHS. We are most grateful to Dr.
Alessandro F. Moretto for his significant contributions to
early stages of this project. We thank our colleagues, Drs.
Kenneth Hardcastle and Karl Hagen, for their skilled and
efficient assistance with X-ray crystallography.
Scheme 2. Effect of Functional Groups on Cycloadduct
Stability
Supporting Information Available: Complete descrip-
tion of the synthesis and characterization of all compounds
prepared in this study and X-ray crystallographic studies of
adducts (-)-2b, 5a, 8, 9b, 10a, 12, and 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
present in the cycloadducts 4-13 determines the stability,
possibly reflecting the tendency for a Lewis acid induced
C5-C6 bond cleavage leading to a stabilized zwitterionic
intermediate prior to cycloreversion.13 The equilibrium could
not be significantly shifted in favor of products by decreasing
the reaction temperatures (-78 °C).
OL000288X
(13) The analogous reaction leading to oxabicyclo[3.2.1]octenes proceeds
through the zwitterionic intermediate IVa.4 The reversibility of some of
the cycloadditions reported here lend credence to a path proceeding through
zwitterionic intermediate IVb.
Ceric ammonium nitrate (CAN)-mediated oxidative de-
metalation4 concluded the synthetic sequence (Table 2).
(12) Structure assignments for the remaining cycloadducts were based
on 1H NMR spectra. The coupling constants for protons H1 and H5 adjacent
to the bridging nitrogen were indicative of the exo and endo relationships.
The structure of adduct 11a was arbitrarily assigned as exo by relying on
the demonstrated (X-ray) preference for the exo adducts.
Org. Lett., Vol. 2, No. 24, 2000
3911