Intramolecular conjugate displacement: A general route to hexahydroquinolizines, hexahydroindolizines, and related [m,n,0]-bicyclic structures with nitrogen at a bridgehead

Article abstract of DOI:10.1021/jo070664s

(Chemical Equation Presented) N-Protected amino aldehydes can be converted into allylic alcohols by the classical Morita-Baylis-Hillman reaction (cf. 2 → 3) or by condensation with selenium-stabilized carbanions, followed by oxidation (cf. 2 → 8 → 3). The

Full text of DOI:10.1021/jo070664s

Intramolecular Conjugate Displacement: A General Route to
Hexahydroquinolizines, Hexahydroindolizines, and Related
[m,n,0]-Bicyclic Structures with Nitrogen at a Bridgehead
Derrick L. J. Clive,* Zhiyong Li, and Maolin Yu
Chemistry Department, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
derrick.cliVe@ualberta.ca
ReceiVed April 2, 2007
N-Protected amino aldehydes can be converted into allylic alcohols by the classical Morita-Baylis-
Hillman reaction (cf. 2 f 3) or by condensation with selenium-stabilized carbanions, followed by oxidation
(cf. 2 f 8 f 3). The derived acetates undergo cyclization when the nitrogen protecting group is removed,
affording [m,n,0]-bicyclic structures with nitrogen at a bridgehead (cf. 4 f 5 f 6). Formation of bicyclic
structures via the reactions of Schemes 1 and 2 is general, and the stereochemistry of the starting amino
aldehyde is preserved.
Introduction
portant biological properties.4 Our approach,1,5which is sum-
marized in Scheme 1for a generic case with six-membered rings,
is based on formation of Morita-Baylis-Hillman (MBH)
alcohols6 (2 f 3) and their derivatization as acetates (3 f 4),
followed by a type of ring closure (4 f 5 f 6) that resembles
both a Michael addition and an SN2′ displacement. We suggest
the name “intramolecular conjugate displacement” (ICD) for
such processes.7
During work directed at the total synthesis of the marine
alkaloid halichlorine, a stage was reached where it was necessary
to generate ring A of compound 1 from a precursor in which
We describe here full details of this general method, as well
as a route (Scheme 2) to MBH alcohols that is based on
selenides 7; the latter route works even in cases where the
classical MBH procedure fails or is very slow.
C(1) and C(2) were initially part of a linear substituent on ring
B.1 This was achieved1 by a short sequence that constitutes a
new and general method for making [m,n,0]-bicyclic structures
with nitrogen at a bridgehead; such heterocyclic structures are
subunits of many alkaloids,2-4including substances with im-
Results and Discussion
Preparation of Starting Aldehydes for the Classical
Morita-Baylis-Hillman Reaction. The essential starting
(5) (a) For a mechanistically related (and earlier) approach to the
halichlorine system, see: Christie, H. S.; Heathcock, C. H. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 12079-12084. (b) A variant of our approach has
been used in a formal synthesis of halichlorine: Andrade, R. B.; Martin, S.
F. Org. Lett. 2005, 7, 5733-5735.
(6) Reviews on the Morita-Baylis-Hillman reaction: (a) Drewes, S.
E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653-4670. (b) Basavaiah, D.;
Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8011-8062. (c) Ciganek,
E. Org. React. 1997, 51, 201-350. (d) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811-891.
(7) For speculation on the mechanism of related intermolecular processes,
see: Knochel, P.; Seebach, D. Tetrahedron Lett. 1981, 22, 3223-3226.
(1) Preliminary communication: Clive, D. L. J.; Yu, M.; Li, Z. Chem.
Commun. 2005, 906-908.
(2) Indolizidine and quinolizidine alkaloids: Michael, J. P. Nat. Prod.
Rep. 2002, 19, 719-741.
(3) For a recent new approach to quinolizidines, see: Maloney, K. M.;
Danheiser, R. L. Org. Lett. 2005, 7, 3115-3118.
(4) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: New York,
1999; Vol. 13, pp 1-161. (b) Michael, J. P. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 2001; Vol. 55, pp 91-258.
10.1021/jo070664s CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
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J. Org. Chem. 2007, 72, 5608-5617

Intramolecular Conjugate Displacement
TABLE 1. Formation of Morita-Baylis-Hillman Adductse
SCHEME 1a
a Pg ) protecting Group, EWG ) electron-withdrawing group, a )
deprotection of nitrogen.
SCHEME 2 a
a Pg ) protecting Group, EWG ) electron-withdrawing group.
materials are N-protected amino aldehydes (cf. 2); most of those
used in the present research are shown in Table 1, and they are
all readily accessible. Optically pure 98 was made9-11from
N-Boc-(S)-proline by carboxyl reduction (B2H6),9 Parikh-
Doering oxidation (-CH2OH f -CHO),9 Wittig olefination
with Ph3PdCHOMe [-CHO f -CHdCH(OMe)],10,12and enol
ether hydrolysis10 [Hg(OAc)2, KI]. This Wittig homologation
process worked in all cases we tried, except where the formyl
group was attached directly to a four-membered ring (2-
formylazetidine-1-carboxylic acid tert-butyl ester13); in this case
the ring opened during the homologation, possibly by silica-
induced hydrolysis of the intermediate enol ethers.
Commercial (2-hydroxyethyl)piperidine was converted by
N-protection (Boc2O, Et3N) and Dess-Martin oxidation into
aldehyde 12.14
The new aldehyde 18 was made as summarized in Scheme
3.15,16 Application of the Schmidt reaction to ketone 15 generated
lactam 16,15and this was reduced (LiAlH4) to amino alcohol
17,15,16 which was then protected on nitrogen by reaction with
Boc2O16and oxidized under Swern conditions (17 f 18).
(8) Toujas, J.-L.; Jost, E.; Vaultier, M. Bull. Soc. Chim. Fr. 1997, 134,
713-717.
(9) Pettit, G. R.; Singh, S. B.; Herald, D. L.; Lloyd-Williams, P.; Kantoci,
D.; Burkett, D. D.; Barko´czy, J.; Hogan, F.; Wardlaw, T. R. J. Org. Chem.
1994, 59, 6287-6295.
(10) Cf.: Ansell, M. F.; Caton, M. P. L.; Stuttle, K. A. J. J. Chem. Soc.,
Perkin Trans. 1 1984, 1069-1077.
(11) Cf.: Ikeda, M.; Shikaura, J.; Maekawa, N.; Daibuzono, K.; Teranishi,
H.; Teraoka, Y.; Oda, N.; Ishibashi, H. Heterocycles 1999, 31-34.
(12) Racemic enol ethers: Calvet, A. P.; Jacobelli, H.; Junien, J.-L.;
Riviere, P.; Roman, F. J. PCT Int. Appl. WO 9515948 A1, 1995.
(13) Balboni, G.; Marastoni, M.; Merighi, S.; Borea, P. A.; Tomatis, R.
Eur. J. Med. Chem. 2000, 35, 979-988.
(14) Cf.: (a) Rouden, J.; Seitz, T.; Lemoucheux, L.; Lasne, M.-C. J.
Org. Chem. 2004, 69, 3787-3793. (b) Ikeda, M.; Kugo, Y.; Sato, T. J.
Chem. Soc., Perkin Trans. 1 1996, 1819-1824.
(15) Psiorz, M.; Heider, J.; Bomhard, A.; Reiffen, M.; Hauel, N.; Noll,
K.; Narr, B.; Lillie, C.; Kobinger, W.; Dammgen, J. U.S. Patent 5,175,157,
1992.
(16) Cf.: DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.; Fisher, M. H.;
Lo, J.-L.; Yang, Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett.
1999, 9, 2621.
a More polar alcohol. b Less polar alcohol. c We did not establish if the
material is a mixture of isomers or a mixture of rotamers of a single isomer.
d Appears to be a single isomer (13C and 1H NMR). e Reagents and
conditions: (i) methyl acrylate, DABCO; (ii) 3 days; (iii) 5 days; (iv) AcCl,
pyridine, CH2Cl2.
J. Org. Chem, Vol. 72, No. 15, 2007 5609

Clive et al.
SCHEME 3
SCHEME 4
SCHEME 5
SCHEME 6
(Scheme 6), starting from racemic ester 40,22which was made
by methylation (LDA, MeI) of N-Boc-(S)-proline methyl ester.23
Formation of Morita-Baylis-Hillman Adducts. Each of
the aldehydes shown in Table 1 was stirred for several days in
methyl acrylate in the presence of DABCO; condensation
occurred smoothly under these conditions to afford the expected
alcohols in good yield (73-94%). In most cases a separable
mixture of alcohols epimeric at the hydroxyl-bearing carbon
was obtained. Each of the alcohols was readily acetylated by
AcCl in the presence of pyridine, and again the yields are high.
On the basis of one experiment, use of Ac2O in pyridine
appeared to be unsatisfactory.
Formation of Bicyclic and Monocyclic Amines from
Morita-Baylis-Hillman Acetates. The 6-endo cyclization 5
f 6 (Scheme 1) is the crucial step of our sequence.24 While
O-acetates of MBH alcohols are well-known to undergo
intermolecular SN2′ displacement,6d,25the intramolecular 6-endo
pathway requires that it be faster than O f N acetyl transfer or
direct cyclization onto the electron-withdrawing group (see 5)
when that is an ester26 or other group susceptible to nucleophilic
attack. In the event, these conditions are met in all but one of
the examples (i.e., entry 7 of Table 2) we have examined.
Each of the acetates shown in Table 2 was exposed to the
action of CF3CO2H, initially at 0 °C and then at room
temperature. The product was dissolved in MeCN and the
solution was stirred for 30 min with 20% aqueous Na2CO3
solution. In all cases, except that of entry 7, it was then possible
to isolate the desired bicyclic amine, often in more than 90%
yield.
The next homolog (24) was obtained (Scheme 4) by applying
the same sequence of reactions to 21.17
The reported method was used to make aldehyde 27,18except
that the formyl group was generated by DIBAL-H reduction of
the corresponding ethyl ester, rather than by LiAlH4 reduction
and Swern oxidation.
Hydrogenation and DIBAL-H reduction of the known ester
3019 (Scheme 5) provided aldehyde 31.20
Aldehyde 3418 was made as reported, and the known
compound 3721 was obtained from N-Boc-(L)-alanine by a 3-step
literature procedure.21
(22) (a) Racemic ester 40 has been reported: Baldwin, J. J.; McDonald,
E.; Moriarty, K. J.; Sarko, C. R.; Machinaga, N.; Nakayama, A.; Chiba, J.;
Iimura, S.; Yoneda, Y. PCT Int. Appl. WO 2001000206 A1, 2001. (b)
Optically pure ester: Lewis, A.; Wilkie, J.; Rutherford, T. J.; Gani, D. J.
Chem. Soc., Perkin Trans. 1 1998, 3777-3793.
(23) Confalone, P. N.; Huie, E. M.; Ko, S. S.; Cole, G. M. J. Org. Chem.
1988, 53, 482-487.
(24) Cf.: Bode, M. L.; Kaye, P. T. J. Chem. Soc., Perkin Trans. 1 1993,
1809-1813.
Finally, the angularly methylated compound 43 was also
prepared by Wittig homologation of the appropriate aldehyde
(25) E.g.: (a) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett. 2004,
6, 1337-1339. (b) Nilov, D.; Ra¨cher, R.; Reiser, O. Synthesis 2002, 2232-
2242. (c) For sequential inter- and intramolecular SN2′ displacement
(analogous to 5 f 6) to form macrocycles, see: Bauchat, P.; Le Bras, N.;
Rigal, L.; Foucaud, A. Tetrahedron 1994, 50, 7815-7826. (d) Charette,
A. B.; Janes, M. K.; Boezio, A. A. J. Org. Chem. 2001, 66, 2178-2180.
(e) For synthons related to the acetates of MBH alcohols, see, for example:
(i) Brocchini, S. J.; Eberle, M.; Lawton, R. G. J. Am. Chem. Soc. 1988,
110, 5211-5212 and references therein. (ii) Seebach, D.; Knochel, P. HelV.
Chim. Acta 1984, 67, 261-283. (iii) El-Awa, A.; Fuchs, P. Org. Lett. 2006,
8, 2905-2908.
(26) For examples of closure onto an ester: (a) Basavaiah, D.; Reddy,
R. M.; Kumaragurubaran, N.; Sharada, D. S. Tetrahedron 2002, 58, 3693-
3697. (b) Cf.: Familoni, O. B.; Kaye, P. T.; Klaas, P. J. Chem. Commun.
1998, 2563-2564. (c) For a related case, where such closure onto an ester
does not occur: O’Dell, D. K.; Nicholas, K. M. J. Org. Chem. 2003, 68,
6427-6430.
(17) Sinclair, I. W.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1975,
2485-2488.
(18) Sato, T.; Yamazaki, T.; Nakanishi, Y.; Uenishi, J.; Ikeda, M. J.
Chem. Soc., Perkin Trans. 1 2002, 1438-1443.
(19) Bustos, F.; Gorgojo, J. M.; Suero, R.; Aurrecoechea, J. M.
Tetrahedron 2002, 58, 6837-6842.
(20) Costanzo, M. J.; Maryanoff, B. E. U.S. Patent 5,523,308, 1996. Our
sample of 31 had the following: FTIR (CH2Cl2 cast) 1725, 1686 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.32-1.41 (m, 2 H), 1.44 (s, 9 H), 1.47-1.66
(m, 7 H), 1.66-1.80 (m, 1 H), 2.38-2.55 (m, 2 H), 2.72 (t, J ) 13.1 Hz,
1 H), 3.96 (br s, 1 H), 4.22 (br s, 1 H), 9.74 (d, J ) 1.5 Hz, 1 H); 13C NMR
(CDCl3125 MHz) δ 19.0 (t), 21.5 (t), 25.6 (t), 28.5 (q), 29.0 (t), 33.5 (t),
43.6 (t), 79.3 (s), 155.2 (s), 202.4 (d); exact mass m/z calcd for C14H25-
NNaO3 (M + Na) 278.17266, found 278.17267.
(21) McIntosh, J. M.; Acquaah, S. O. Can. J. Chem. 1988, 66, 1752-
1756.
5610 J. Org. Chem., Vol. 72, No. 15, 2007

Intramolecular Conjugate Displacement
TABLE 2. Intramolecular Conjugate Displacementsc
methyl ester carbonyl occurs; this is clearly the major pathway
(61% yield), and we did not search for products of O f N acetyl
transfer.
The examples shown in Table 2 establish that the nitrogen
can originally be in a ring of 5-8 atoms, and rings of 6-8
atoms (but not 5) can be formed by the intramolecular conjugate
displacement. Entries 5 and 6 of Table 2 show that the
intramolecular conjugate displacement pathway leading to 7-
and 8-membered rings is preferred over direct SN2 displacement
of acetate, which would have generated 5- and 6-membered
rings, respectively.7 The reaction can also be used to make
monocyclic amines; in the single case examined (Table 2, entry
8) the product 39c was obtained as a single enantiomer, as
judged by the 1H NMR spectrum of the derived Mosher amide.
Compound 45c probably adopts the conformation shown in
45c′ with transoid ring fusion, on the basis of NOE enhance-
ments of the signals representing Ha and Hb, on irradiation of
the angular methyl group signal.
Selenide Route to Morita-Baylis-Hillman Alcohols. All
of the examples listed in Table 2 are based on the use of methyl
acrylate. Other olefins can be used in the MBH condensation,6
but sometimes, depending on the nature of the electron-
withdrawing group and the degree of substitution of the double
bond, the normal condensation is unacceptably slow or does
not work at all.6 For example, phenyl vinyl sulfone is reported
to react very slowly,27-29as does methyl crotonate.29 The process
summarized in Scheme 2 was used to deal with such cases.
This very simple reaction sequence does not appear to have
been fully appreciated as a effective general route to MBH
alcohols, in spite of the fact that elimination of selenides away
from a hydroxyl-bearing carbon (cf. 8 f 3) has been known
for a long time.30 In the event, the process of Scheme 2 gives
ready access to MBH-like alcohols including members of this
class that are not accessible by the classical MBH procedure.
Compounds such as 46,31 48,32 and 5033 (Scheme 7) have
been reported, as well as their transformation into the MBH-
like alcohols 47, 49, and 51, respectively, but in all these cases
the starting selenides were not made by addition of a selenium-
stabilized carbanion to an aldehyde (cf. Scheme 2, 2 f 8);
instead, they were synthesized by attachment of the PhSe group
to the complete preformed carbon skeleton. Examples of the
condensation of R-(phenylseleno)esters with aldehydes, in which
a Acetate epimers were used as a mixture. b A single isomer (13C and
1H NMR). c Reagents and conditions: (i) CF3CO2H, CH2Cl2, 0 °C to room
temperature; then aq Na2CO3, 30 min.
The acetates 11a and 11b, which were derived from L-proline,
gave 11c with an ee of 99.8% (from a mixture of 11a and 11b),
establishing the important point that the stereochemistry R to
the nitrogen is preserved throughout the sequence. In such cases
there is, in principle, the possibility of retro-Michael reaction
during the initial Baylis-Hillman condensation, followed by
readdition, but this, evidently, does not occur.
The apparent facility of the first few ring closures we studied
prompted us to examine acetate 36 (entry 7); it represents a
demanding test, as the desired pathway is predicted by the
Baldwin rules to be disfavored. In the event, the stereoelectronic
factors on which the rules are based are sufficient to divert the
pathway away from the desired mode, and closure onto the
(27) Weichert, A.; Hoffmann, H. M. R. J. Org. Chem. 1991, 56, 4098-
4112.
(28) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron 1988, 44,
6095-6106.
(29) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68,
692-700.
(30) (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697-
2699. Review: (b) Clive, D. L. J. Tetrahedron 1978, 34, 1049-1132.
(31) Huot, J.-F.; Outurquin, F.; Paulmier, C. Chem. Lett. 1991, 1599-
1991.
(32) Seebach, D.; Calderari, G.; Knochel, P. Tetrahedron 1985, 41,
4861-4872.
(33) Mase, N.; Watanabe, Y.; Toru, T.; Kakumoto, T.; Hagiwara, T. J.
Org. Chem. 2000, 65, 7083-7090.
J. Org. Chem, Vol. 72, No. 15, 2007 5611

Clive et al.
SCHEME 7
not obtain the desired adducts 13a,b, recovering only starting
material, even though, in a test experiment, 59 reacted smoothly
(70%) with PhCHO.
The four selenides 60,3961,4062,41and 6342 were prepared by
conventional means: the two esters by displacement (PhSeNa)
from the corresponding R-bromoesters, the nitrile by alkylation
(MeI) of PhSeCH2CN, and the sulfone by phenylselenation
(PhSeCl) of PhSO2CH2CH3.
SCHEME 8
Each of the selenides 60-63 was deprotonated with LDA in
THF at -78 °C and then allowed to react with the aldehydes
indicated in Table 3. The desired hydroxy selenides (see Table
3) were obtained in yields of 73-90% as isomer mixtures, and
oxidation with H2O2 then caused elimination away from the
hydroxyl-bearing carbon to give the desired alcohols, which
were then acetylated, again using AcCl. With the exception of
66, two acetates were obtained in each case, differing in
stereochemistry at the acetoxy-bearing carbon. In the case of
66 there is the additional complication of Z/E isomerization,
and 1H NMR signals of the crude product at δ 6.92 and δ 6.22
suggest that both double bond geometries were indeed formed.
The acetates were then treated with CF3CO2H to remove the
Boc group (Table 4). In the case of 69a and 69b, deprotection
was slow, and a 12-h reaction period was used; in the other
examples deprotection was complete within 1 h. The resulting
productsspresumably CF3CO2H saltsswere dissolved in MeCN,
and the solution was stirred with saturated aqueous Na2CO3 to
afford the bicyclic amines shown in Table 4. Ring closure is
easy, and even the fully substituted olefins 69a and 69b afforded
cyclized products. The mixture of isomeric trisubstituted olefins
66 gave two isomeric amines 79a,b. These must differ in
stereochemistry at the methyl-bearing carbon [C(6)], but
extensive NOE measurements did not allow us to establish the
conformations.
SCHEME 9
the product was subjected to stannane reduction, are known,34and
more recently selenoxide fragmentation has been used in tandem
with such condensations35to prepare MBH alcohols formally
derived from methyl acrylate. We are aware of three additional
examples36,37 resembling the route to MBH alcohols that
is summarized in Scheme 2; the more complex of these are of
the type 52 f 54 f 55 (R, R′ variable), from studies toward
the synthesis of a natural product (Scheme 8).36 The other
example is the single case summarized in Scheme 9.37
A number of attempts have been made to overcome the low
reaction rate of many MBH condensations,6 and during the
present work we tried one that seemed well-suited to our
needs: we treated aldehyde 12 with the aluminate 59,38but did
Synthesis of (-)-δ-Coniceine. The sulfone 83 derived, as
described above, from L-proline, was hydrogenated over Pd-
C. The hydrogenation step was not facially selective, and the
intermediate sulfone was obtained as a mixture of isomers,
epimeric at C(6). This outcome is inconsequential, as the PhSO2
group was then removed by treatment with W-2 Raney nickel,
affording (-)-δ-coniceine (85) (Scheme 10). Attempts to use
Na(Hg) for desulfonylation led to extensive ring opening,
presumably via an intermediate carbanion.
(38) (a) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem.
Commun. 1999, 1979-1980. (b) Ramachandran, P. V.; Rudd, M. T.;
Burghardt, T. E.; Reddy, M. V. R. J. Org. Chem. 2003, 68, 9310-9316.
(c) Tsuda, T.; Yoshida, T.; Saegusa, T. J. Org. Chem. 1988, 53, 1037-
1040.
(39) Corresponding ethyl ester: Lebarillier, L.; Outurquin, F.; Paulmier,
C. Tetrahedron 2000, 56, 7483-7493.
(40) Cf.: Holmes, A. B.; Nadin, A.; O’Hanlon, P. J.; Pearson, N. D.
Tetrahedron: Asymmetry 1992, 3, 1289-1302.
(41) (a) Masuyama, Y.; Ueno, Y.; Okawara, M. Chem. Lett. 1977, 835-
838. (b) Arrica, M. A.; Wirth, T. Eur. J. Org. Chem. 2005, 395-403.
(42) Cf.: (a) Simpkins, N. S. Tetrahedron 1991, 47, 323-332. (b)
Simpkins, N. S. Tetrahedron Lett. 1988, 29, 6787-6790.
(34) See: (a) Hart, D. J.; Krishnamurthy, R. J. Org. Chem. 1992, 57,
4457-4470. (b) Guindon, Y.; Faucher, A.-M.; Bourque, E.; Caron, V.; Jung,
G.; Landry, S. R. J. Org. Chem. 1997, 62, 9276-9283.
(35) (a) Sheng, S.-R.; Wang, Q.; Wang, Q.-Y.; Guo, L.; Hunag, X. Synlett
2006, 1887-1890. (b) Shiina, I.; Yamai, Y.; Shimazaki, T. J. Org. Chem.
2005, 70, 8103-8106.
(36) (a) Cases, M.; de Turiso, F. G.-L.; Hadjisoteriou, M. S.; Pattenden,
G. Org. Biomol. Chem. 2005, 3, 2786-2804. (b) Cases, M.; de Turiso, F.
G.-L.; Pattenden, G. Synlett 2001, 1869-1872.
(37) Sakakibara, T.; Ikuta, S.; Sudoh, R. Synthesis 1982, 261-263.
5612 J. Org. Chem., Vol. 72, No. 15, 2007

Intramolecular Conjugate Displacement
TABLE 3. Selenium Route to Morita-Baylis-Hillman Adductsp
TABLE 4. Intramolecular Conjugate Displacements
a Isomer mixture was used. b More polar product. c Less polar product.
d Mixture of 78a and 78b was used.
SCHEME 10
a More polar fraction. b We did not establish if the material was a mixture
of isomers or a mixture of rotamers of a single isomer. c Less polar fraction.
d A mixture of both fractions 64a and 64b was used. e Both 65a and 65b
have a single double bond geometry. f A mixture of isomers obtained from
a mixture of 65a and 65b. g Neither fraction was characterized. h A mixture
of 67a and 67b was used. i More polar alcohol. j Single isomer. k Less polar
alcohol. l Alcohol 71a is derived from 70a, while 71b is derived from 70b.
m Alcohol 74a is derived from mixture of 73a and 73b and is a single isomer.
n Alcohol 74b is derived from mixture of 73a and 73b and is a single isomer.
o Alcohol 77a is derived from 76a, while 77b is derived from 76b.
p Reagenst and conditions: (i) the indicated selenide (60, 61, 62 or 63)
was deprotonated with LDA, and then aldehyde 12 was added; (ii) H2O2;
(iii) AcCl, pyridine, CH2Cl2; (iv) the indicated selenide was deprotonated
with LDA and then aldehyde 9 was added.
b
a More polar isomer. Less polar isomer.
alcohols can be prepared by the classical MBH reaction and
also by the general method of Scheme 2, especially in cases
where the conventional MBH reaction is very slow. The key
ring closure (5 f 6) is independent of the degree of substitution
of the double bond, and works, except where the closure would
In our early experiments on this method of making bicyclic
amines, we had shown that the MBH route to 10a and 10b
proceeds with preservation of enantiomeric purity; but in making
(-)-δ-coniceine, we did not check the enantiomeric purity of
83, or its precursors, because the route would not be expected
(43) Reported values: (a) Yoda, H.; Katoh, H.; Ujihara, Y.; Takabe, K.
Tetrahedron Lett. 2001, 42, 2509-2512: [R]23.5 -4.02 (c 2.12, EtOH).
D
(b) Costa, A.; Na´jera, C.; Sansano, J. M. Tetrahedron: Asymmetry 2001,
12, 2205-2211: [R]25D -10.1 (c 1.88, EtOH). (c) Andre´s, J. M.; Herra´iz-
Sierra, I.; Pedrosa, R.; Pe´rez-Encabo, A. Eur. J. Org. Chem. 2000, 1719-
to compromise the ee. Our sample of the alkaloid had [R]20
D
1726: [R]23 -10.1 (c 1.8, EtOH). (d) Sibi, M. P.; Christensen, J. W.
D
-18.27 (c 0.151, EtOH) and [R]20D -12.50 (c 1.00, 95% EtOH);
reported values43cover the range -4 to -20.
Tetrahedron Lett. 1990, 31, 5689-5692: [R]27D -10.8 (c 1.76, EtOH). (e)
Sibi, M. P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434-6442: [R]26
D
-10.8 (c 1.76, EtOH). (f) Waldmann, H.; Braun, M. J. Org. Chem. 1992,
57, 4444-4451: [R]23 -7.9 (c 0.15, EtOH). (g) Waldmann, H.; Braun,
D
M.; Dra¨ger, M. Angew. Chem., Int. Ed. 1990, 29, 1468-1471: [R]22D -7.9
(c 0.15, EtOH). (h) Ringdahl, B.; Pinder, A. R.; Pereira, W. E., Jr.;
Oppenheimer, N. J.; Craig, J. C. J. Chem. Soc., Perkin Trans. 1 1984,
1-4: [R]23D -10.2 (c 1.76, EtOH). (i) Arisawa, M.; Takezawa, E.; Nishida,
Conclusions
The method of Scheme 1 represents a general way of making
bicyclic amines with nitrogen at a ring-fusion position. The
method has been shown to work for a range of ring sizes and
the stereochemistry R to the nitrogen is preserved in the MBH
step (as judged by a test with compound 9). The required
A.; Mori, M.; Nakagawa, M. Synlett 1997, 1179-1180: [R]25 -20.5 (c
D
0.98, EtOH). (j) Arisawa, M.; Takahashi, M.; Takezawa, E.; Yamaguchi,
T.; Torisawa, Y.; Nishida, A.; Nakagawa, M. Chem. Pharm. Bull. 2000,
48, 1593-1596: [R]25 -20.5 (c 0.98, EtOH).
D
J. Org. Chem, Vol. 72, No. 15, 2007 5613

Clive et al.
(8aS)-1,2,3,5,8,8a-Hexahydro-6-indolizinecarboxylic Acid Meth-
yl Ester (11c). CF3CO2H (0.226 mL, 2.93 mmol) was added to a
stirred and cooled (0 °C) solution of esters 11a,b (mixture of esters
from the less polar and more polar alcohols) (100.0 mg, 0.293
mmol) in CH2Cl2 (3 mL). The ice bath was removed and stirring
was continued for 1 h. The solvent was evaporated and the residue
was dissolved in MeCN (3 mL). Aqueous Na2CO3 (20% w/v, 1
mL) was added and the mixture was stirred for 30 min. The aqueous
phase was extracted with EtOAc (3 × 3 mL) and the combined
organic extracts were dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 × 15 cm), using
EtOAc, gave amine 11c (38.0 mg, 72%) as a colorless oil: FTIR
be of the 5-endo trigonal type. The method can be used to make
optically active piperidines (e.g., 39c), and has been used to
make a simple alkaloid [(-)-δ-coniceine]. The method has also
been tested in a far more complex case relevant to the synthesis
of halichlorine.1 The products of the ring closure bear
functionalitysthe electron-withdrawing group and the conju-
gated double bondsthat provide opportunities for further
elaboration.
Experimental Section
(2S)-1-(tert-Butoxycarbonyl)-â-hydroxy-R-methylene-2-pyr-
rolidinebutanoic Acid Methyl Ester (10a,b). DABCO (2.05 g,
18.3 mmol) and methyl acrylate (2.19 mL, 24.4 mmol) were added
to aldehyde 98-11(1.3 g, 6.1 mmol), and the mixture was stirred at
room temperature for 3 days. Evaporation of the solvent and flash
chromatography of the residue over silica gel (2.5 × 20 cm), using
1:3 EtOAc-hexane, gave the less polar isomer 10b (0.62 g, 34%)
and the more polar isomer 10a (0.71 g, 39%) as colorless oils.
More polar isomer 10a: FTIR (CH2Cl2 cast) 3418, 1717, 1693,
(CH2Cl2 cast) 1716, 1650 cm-1; [R]22 +195.9 (c 1.1, CH2Cl2);
D
1H NMR (CDCl3, 400 MHz) δ 1.38-1.47 (m, 1 H), 1.70-1.92
(m, 2 H), 1.95-2.03 (m, 1 H), 2.06-2.15 (m, 2 H), 2.19 (AB q,
∆νAB ) 18.0 Hz, J ) 9.2 Hz, 1 H), 2.38-2.47 (m, 1 H), 2.82-
2.87 (m, 1 H), 3.21 (dt, J ) 2.4, 8.8 Hz, 1 H), 3.71 (s, 3 H), 3.78-
3.83 (m, 1 H), 6.97-7.00 (m, 1 H); 13C NMR (CDCl3, 100 MHz)
δ 21.4 (t), 30.4 (t), 32.8 (t), 51.5 (t), 51.6 (q), 54.1 (t), 58.7 (d),
129.4 (s), 138.3 (d), 166.3 (s); HRMS (ES) exact mass m/z calcd
for C10H15NO2 181.11028, found 181.11019. HPLC analysis
[Chiracel OD-H, 5 µm, 4.6 × 250 mm, 1% EtOH-hexane, flow
) 0.8 mL/min] showed the material to have an enantiomeric purity
of 99.8%.
1
1668 cm-1; H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9 H), 1.64-
2.01 (m, 6 H), 3.26 (t, J ) 5.4 Hz, 2 H), 3.70 (s, 3 H), 3.95-4.02
(m, 1 H), 4.47 (br s, 1 H), 5.92 (br s, 1 H), 6.17 (s, 1 H); 13C NMR
(CDCl3, 100 MHz) δ 23.7 (t), 28.5 (q), 32.0 (t), 43.3 (t), 46.3 (t),
51.7 (q), 55.5 (d), 69.2 (d), 79.6 (s), 124.4 (s), 143.0 (t), 155.3 (s),
166.7 (s); HRMS (ES) exact mass m/z calcd for C15H25NNaO5 (M
+ Na) 322.16249, found 322.16265.
1,6,7,8,9,10,11,11a-Octahydro-4H-pyrido[1,2-a]azocine-3-car-
boxylic Acid Methyl Ester (26c). CF3CO2H (306 mg, 2.66 mmol)
was added to a stirred and cooled (0 °C) solution of acetate 26a
(derived from the more polar alcohol) (102 mg, 0.266 mmol) in
CH2Cl2 (3 mL). The cooling bath was removed and stirring was
continued for 1 h. The solvent was evaporated and the residue was
dissolved in MeCN (3 mL). Aqueous Na2CO3(20% w/v, 1 mL)
was added and the mixture was stirred for 30 min. The organic
phase was separated and the aqueous phase was extracted with
EtOAc (3 × 3 mL). The combined organic extracts were dried
(Na2SO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 15 cm), using EtOAc, gave amine 26c (50 mg, 84%)
as a colorless oil: FTIR (CH2Cl2 cast) 1715, 1664 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.32-1.84 (m, 10 H), 1.96-2.30 (m, 2 H),
2.61-2.80 (m, 2 H), 2.80-2.96 (m, 1 H), 3.32 (d, J ) 17.0 Hz, 1
H), 3.49 (d, J ) 17.0 Hz, 1 H), 3.70 (s, 3 H), 6.94-6.98 (m, 1 H);
13C NMR (CDCl3, 100 MHz) δ 26.0 (t), 26.2 (t), 26.6 (t), 27.6 (t),
31.1 (t), 33.1 (t), 50.0 (t), 51.4 (d), 52.3 (t), 56.2 (q), 129.5 (s),
138.6 (d), 166.5 (s); exact mass m/z calcd for C13H21NO2 223.15723,
found 223.15691.
Less polar isomer 10b: FTIR (CH2Cl2 cast) 3400, 1720, 1693,
1668 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.33-1.43 (m including
singlet at δ 1.43, 10 H in all), 1.54 (br s, 1 H), 1.80-2.00 (m, 4
H), 3.32-3.34 (m, 2 H), 3.71 (s, 3 H), 4.16 (br s, 1 H), 4.43 (d, J
) 10.3 Hz, 1 H), 5.42 (br s, 1 H), 6.00 (s, 1 H), 6.22 (s, 1 H); 13
C
NMR (CDCl3, 100 MHz) δ 23.5 (t), 28.4 (q), 31.2 (t), 43.0 (t),
46.4 (t), 51.6 (q), 53.8 (d), 66.4 (d), 80.0 (s), 124.3 (s), 142.7 (t),
156.7 (s), 166.7 (s); HRMS (ES) exact mass m/z calcd for C15H25-
NNaO5 (M + Na) 322.16249, found 322.16263.
(2S)-â-(Acetoxy)-1-(tert-butoxycarbonyl)-R-methylene-2-pyr-
rolidinebutanoic Acid Methyl Ester (11a,b). Pyridine (0.281 mL,
3.48 mmol) and AcCl (0.247 mL, 3.48 mmol) were added
successively dropwise to a stirred and cooled (0 °C) solution of
the less polar alcohol 10b (520 mg, 1.74 mmol) in CH2Cl2 (15
mL). Stirring was continued for 2 h, the ice bath was removed,
and stirring was continued for 1 h. Evaporation of the solvent and
flash chromatography of the residue over silica gel (2.5 × 18 cm),
using 1:3 EtOAc-hexane, gave acetate 11b (501 mg, 85%) as a
colorless oil.
Under similar conditions, acetate 26b (derived from the less polar
alcohol) (51 mg, 0.13, mmol) gave amine 26c (27 mg, 93%) as a
colorless oil.
Under similar conditions, the more polar alcohol 10a (500 mg,
1.67 mmol) gave the corresponding acetate 11a (507 mg, 89%) as
a colorless oil.
1,2,3,4,6,9,10,10a-Octahydropyrido[1,2-a]azepine-7-carboxyl-
ic Acid Methyl Ester (29c). CF3CO2H (237 mg, 2.06 mmol) was
added to a stirred and cooled (0 °C) solution of acetate 29 (76 mg,
0.206 mmol) in CH2Cl2 (5 mL). The cooling bath was removed
and stirring was continued for 1 h. The solvent was evaporated
and the residue was dissolved in MeCN (3 mL). Aqueous Na2CO3
(20% w/v, 1 mL) was added and the mixture was stirred for 30
min. The aqueous phase was extracted with EtOAc (3 × 3 mL)
and the combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (1
× 15 cm), using EtOAc, gave amine 29c (41 mg, 95%) as a
Acetate 11a from the more polar alcohol: FTIR (CH2Cl2 cast)
1746, 1719, 1693 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.38 (s, 9
H), 1.53-1.60 (m, 1 H), 1.73-1.93 (m, 4 H), 1.95-2.19 (m
including singlet at δ 2.03, 4 H in all), 3.21-3.32 (m, 2 H), 3.52-
3.78 (m including singlet at δ 3.70, 4 H in all), 5.53 (d, J ) 10.0
Hz, 1 H), 5.72 (s, 1 H), 6.19 (s, 1 H); 13C NMR (CDCl3, 100 MHz)
δ 21.0 (q), 23.0 (t), 28.5 (q), 29.8 (t), 46.2 (t), 51.9 (q), 54.3 (d),
69.6 (d), 79.0 (s), 124.4 (s), 140.1 (t), 154.2 (s), 165.5 (s), 169.9
(s); HRMS (ES) exact mass m/z calcd for C17H27NNaO6 (M + Na)
364.17306, found 364.17329.
colorless oil: FTIR (CH2Cl2 cast) 1709, 1265 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.20-1.38 (m, 1 H), 1.38-1.75 (m, 6 H),
1.75-1.89 (m, 1 H), 2.17-2.58 (m, 4 H), 2.89 (d, J ) 11.3 Hz, 1
H), 3.28 (d, J ) 16.2 Hz, 1 H), 3.65 (s, 1 H), 3.70 (s, 3 H), 7.11-
7.23 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 23.7 (t), 23.8 (t),
25.8 (t), 32.1 (t), 32.6 (t), 51.7 (q), 54.4 (t), 56.6 (t), 64.9 (d), 128.3
(s), 145.8 (d), 167.4 (s); exact mass m/z calcd for C12H19NO2
209.14159, found 209.14172.
1,3,4,6,9,10,11,11a-Octahydro-2H-pyrido[1,2-a]azocine-7-car-
boxylic Acid Methyl Ester (33c). CF3CO2H (253 mg, 2.20 mmol)
was added to a stirred and cooled (0 °C) solution of acetate 33 (85
Acetate 11b from the less polar alcohol: FTIR (CH2Cl2 cast)
1
1745, 1693 cm-1; H NMR (CDCl3, 500 MHz) δ 1.42 (s, 9 H),
1.72-1.95 (m, 5 H), 2.02 (s, 3 H), 2.07-2.15 (m, 1 H), 3.21-
3.26 (m, 1 H), 3.32 (br s, 1 H), 3.70-3.81 (m including singlet at
δ 3.74, 4 H in all), 5.58 (t, J ) 6.6 Hz, 1 H), 5.87 (br s, 1 H), 6.29
(s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 21.1 (q), 23.4 (t), 28.5
(q), 31.2 (t), 46.3 (t), 52.0 (q), 54.6 (d), 70.0 (d), 79.2 (s), 126.0
(s), 139.9 (t), 154.4 (s), 165.7 (s), 169.8 (s); HRMS (ES) exact
mass m/z calcd for C17H27NNaO6 (M + Na) 364.17306, found
364.17318.
5614 J. Org. Chem., Vol. 72, No. 15, 2007

Intramolecular Conjugate Displacement
mg, 0.22 mmol) in CH2Cl2 (5 mL). The ice bath was removed and
stirring was continued for 1 h. The solvent was evaporated and the
residue was dissolved in MeCN (3 mL). Aqueous Na2CO3 (20%
w/v, 1 mL) was added and the mixture was stirred for 30 min. The
aqueous phase was extracted with EtOAc (3 × 3 mL) and the
combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (1 × 20 cm),
using EtOAc, gave amine 33c (45 mg, 92%) as a colorless oil:
FTIR (CH2Cl2 cast) 1710, 1264 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.08-1.32 (m, 1 H), 1.32-1.78 (m, 8 H), 1.78-1.97 (m, 1 H),
2.02-2.40 (m, 3 H), 2.68 (br s, 1 H), 2.95 (d, J ) 11.4, Hz, 1 H),
3.50-4.01 (m, 5 H), 7.21 (t, J ) 8.4, Hz, 1 H); 13C NMR (CDCl3,
100 MHz) δ 22.1 (t), 24.1 (t), 25.3 (t), 25.8 (t), 27.5 (t), 33.7 (t),
51.9 (q), 55.4 (t), 57.2 (t), 61.7 (d), 129.1 (s), 144.1 (d), 168.1 (s);
exact mass m/z calcd for C13H21NO2 223.15723, found 223.15707.
8a-Methyl-1,2,3,5,8,8a-hexahydroindolizine-6-carboxylic Acid
Methyl Ester (45c). CF3CO2H (0.33 mL, 4.23 mmol) was added
to a stirred and cooled (0 °C) solution of acetates 45a,b (mixture
of both acetates) (150 mg, 0.42 mmol) in CH2Cl2 (5 mL). The
cooling bath was removed and stirring was continued for 2 h. The
solvent was evaporated and the residue was dissolved in MeCN (3
mL). Aqueous Na2CO3 (20% w/v, 1 mL) was added and the mixture
was stirred for 30 min. The aqueous phase was extracted with
CH2Cl2 (3 × 5 mL) and the combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 20 cm), using EtOAc, gave amine 45c (79 mg,
96%) as a colorless oil: FTIR (CH2Cl2 cast) 1716, 1258 cm-1; 1H
NMR (CDCl3, 500 MHz) δ 0.86 (s, 3 H), 1.54-1.62 (m, 1 H),
1.64-1.73 (m, 1 H), 1.74-1.82 (m, 2 H), 2.04-2.12 (m, 1 H),
2.17-2.26 (m, 1 H), 2.61-2.69 (m, 1 H), 2.83-2.91 (m, 1 H),
3.17-3.25 (m, 1 H), 3.52-3.60 (m, 1 H), 3.69 (s, 3 H), 6.94 (m,
1 H); 13C NMR (CDCl3, 125 MHz) δ 17.3 (q), 19.9 (t), 35.7 (t),
38.4 (t), 45.0 (t), 50.0 (t), 51.4 (q), 56.4 (s), 127.6 (s), 137.7 (d),
166.5 (s); exact mass m/z calcd for C11H17NO2 195.12593, found
195.12554.
2-[2-Hydroxy-3-(methoxycarbonyl)-4-methyl-3-(phenylseleno-
)pentyl]piperidine-1-carboxylic Acid tert-Butyl Ester (67a,b).
BuLi (2.5 M in hexane, 0.15 mL, 0.37 mmol) was added to a stirred
and cooled (-78 °C) solution of i-Pr2NH (40.5 mg, 0.40 mmol) in
THF (10 mL). Stirring was continued for 20 min and a solution of
phenylseleno ester 6140(101 mg, 0.37 mmol) in THF (1 mL) was
then added dropwise. Stirring at -78 °C was continued for 20 min,
and a solution of aldehyde 1214 (79 mg, 0.35 mmol) in THF (1
mL) was added dropwise. Stirring at -78 °C was continued for 1
h and the mixture was quenched with saturated aqueous NH4Cl
(10 mL) and extracted with Et2O (10 mL). The organic extract was
dried (MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (1 × 20 cm), using 8:1 hexane-EtOAc, gave a less
polar phenylseleno alcohol fraction 67b (54 mg, 31%) and a more
polar phenylseleno alcohol fraction 67a (73 mg, 42%) as colorless
oils. The individual fractions had broad 1H NMR spectra, and were
not characterized.
2-[(3-Benzenesulfonyl)-2-hydroxy-3-(phenylseleno)butyl]pip-
eridine-1-carboxylic Acid tert-Butyl Ester (73a,b). BuLi (2.5 M
in hexane, 0.08 mL, 0.21 mmol) was added to a stirred and cooled
(-78 °C) solution of i-Pr2NH (23.3 mg, 0.23 mmol) in THF (3
mL). The cold bath was replaced by a bath at -20 °C, stirring was
continued for 10 min, and then the cold bath at -78 °C was
replaced. Phenylseleno sulfone 6342 (93 mg, 0.29 mmol) in THF
(2 mL) was added dropwise and stirring was continued for 30 min.
Aldehyde 1214 (47.7 mg, 0.21 mmol) in THF (1 mL) was added
dropwise and stirring was continued for 10 min. The mixture was
quenched with saturated aqueous NH4Cl (5 mL) and extracted with
Et2O (10 mL). The organic extract was dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (1
× 10 cm), using 3:1 hexane-EtOAc, gave a more polar phenyl-
seleno alcohol fraction 73a (41 mg, 30%) and a less polar
phenylseleno alcohol fraction 73b (63 mg, 46%). We did not
establish if each fraction was a single isomer or a mixture of
isomers; the material was used without characterization.
2-[3-(Benzenesulfonyl)-2-hydroxybut-3-enyl]piperidine-1-car-
boxylic Acid tert-Butyl Ester (74a,b). H2O2 (30%, 0.20 mL) was
added to a stirred and cooled (0 °C) solution of phenylseleno
alcohols 73a,b (mixture of more polar and less polar fractions) (110
mg, 0.20 mmol) in THF (3 mL). Stirring was continued for 2 h
and then water (5 mL) and Et2O (10 mL) were added. The ether
phase was dried (MgSO4) and evaporated. Flash chromatography
of the residue over silica gel (1 × 10 cm), using 3:1 hexane-
EtOAc, gave the less polar alcohol 74b (31 mg, 39%) and the more
polar alcohol 74a (32 mg, 41%) as colorless oils.
More polar alcohol 74a: FTIR (CH2Cl2 cast) 3401, 1686, 1660
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34-1.48 (m, 11 H), 1.48-
1.63 (m, 4 H), 1.71-1.85 (m, 1 H), 1.92-2.09 (m, 1 H), 2.75 (t,
J ) 12.1 Hz, 1 H), 3.24-3.68 (br s, 1 H), 3.86 (d, J ) 13.3 Hz, 1
H), 4.24 (d, J ) 4.4 Hz, 1 H), 4.36 (dd, J ) 8.9, 2.6 Hz, 1 H), 6.17
(s, 1 H), 6.39 (s, 1 H), 7.49-7.65 (m, 3 H), 7.84-7.90 (m, 2 H);
13C NMR (CDCl3, 100 MHz) δ 18.9 (t), 25.2 (t), 28.4 (q), 29.1 (t),
39.1 (t), 39.9 (t), 48.5 (d), 68.0 (d), 80.1 (s), 125.1 (s), 128.0 (d),
129.2 (d), 133.6 (d), 139.6 (s), 153.2 (t), 155.8 (s); exact mass m/z
calcd for C20H29NO5S 395.17664, found 395.176674.
Less polar alcohol 74b: FTIR (CH2Cl2 cast) 3386, 1717, 1683
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.18-1.53 (m, 13 H), 1.54-
1.76 (m, 3 H), 2.43 (t, J ) 14.4 Hz, 1 H), 2.96 (t, J ) 12.0 Hz, 1
H), 3.92 (d, J ) 13.1 Hz, 1 H), 4.01 (d, J ) 10.6 Hz, 1 H), 4.40
(m, 1 H), 6.24 (s, 1 H), 6.47 (d, J ) 0.9 Hz, 1 H), 7.44-7.69 (m,
3 H), 7.74-7.88 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 19.3
(t), 25.5 (t), 28.6 (q), 29.2 (t), 38.4 (t), 45.0 (t), 46.6 (d), 65.2 (d),
80.6 (s), 125.2 (s), 128.0 (d), 129.3 (d), 133.7 (d), 139.9 (s), 152.9
(t), 161.5 (s); exact mass m/z calcd for C20H29NO5S 395.17664,
found 395.17540.
(2S)-2-[3-(Benzenesulfonyl)-2-hydroxy-3-(phenylseleno)butyl]-
pyrrolidine-1-carboxylic Acid tert-Butyl Ester (76a,b). BuLi (2.5
M in hexane, 0.31 mL, 0.79 mmol) was added dropwise to a stirred
and cooled (-78 °C) solution of i-Pr2NH (0.11 mL, 0.79 mmol) in
2-[2-Hydroxy-3-methoxycarbonyl-3-(phenylseleno)pentyl]pi-
peridine-1-carboxylic Acid tert-Butyl Ester (64a,b). BuLi (2.5
M in hexane, 0.28 mL, 0.7 mmol) was added dropwise to a stirred
and cooled (-78 °C) solution of i-Pr2NH (0.13 mL, 0.9 mmol) in
THF (10 mL). The solution was stirred at -78 °C for 20 min and
a solution of ester 6039(116 mg, 0.45 mol) in THF (1 mL) was
added dropwise. The mixture was stirred at -78 °C for 20 min,
and then a solution of aldehyde 1214(93 mg, 0.412 mmol) in THF
(1 mL) was added dropwise. The mixture was stirred at -78 °C
for 1 h, quenched with saturated aqueous NH4Cl (10 mL), and
extracted with Et2O (15 mL). The organic extract was dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 15 cm), using 8:1 hexane-EtOAc, gave the less
polar phenylseleno alcohol fraction 64b (86 mg, 43%) and the more
polar phenylseleno alcohol fraction 64a (73 mg, 47%) as colorless
oils; both were used without full characterization and we did not
establish if each fraction was a single isomer or a mixture of
isomers.
2-[2-Hydroxy-3-(methoxycarbonyl)pent-3-enyl]piperidine-1-
carboxylic Acid tert-Butyl Ester (65a,b). H2O2 (30%, 0.15 mL)
was added to a stirred solution of phenylseleno alcohols 64a,b (a
mixture of the less polar and more polar phenylseleno alcohol
fractions) (86 mg, 0.18 mmol) in a mixture of THF (5 mL) and
water (1 mL). Stirring was continued for 2 h and then water (10
mL) and Et2O (20 mL) were added. The organic phase was dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 10 cm), using 5:1 hexane-EtOAc, gave a less polar
alcohol fraction 65b (32 mg, 54%) and a more polar alcohol fraction
65a (26 mg, 44%), both as colorless oils. Each fraction was
composed of material having a single double bond geometry. The
vinyl H signal of the less polar fraction had δ 6.43 and the signal
for the more polar fraction had δ 6.89, suggesting that the former
has a Z double bond and the later an E double bond. Both fractions
were used without full characterization.
J. Org. Chem, Vol. 72, No. 15, 2007 5615

Clive et al.
Less polar amine 79b: FTIR (CH2Cl2 cast) 1716, 1256 cm-1
THF (10 mL). The solution was stirred at -78 °C for 20 min and
a solution of phenylseleno sulfone 6342 (258 mg, 0.79 mmol) in
THF (5 mL) was added dropwise. The mixture was stirred at -78
°C for 1 h, and then a solution of aldehyde 98 (168 mg, 0.79 mmol)
in THF (5 mL) was added dropwise. The mixture was stirred at
-78 °C for 1 h, quenched with saturated aqueous NH4Cl (10 mL),
and extracted with Et2O (20 mL). The organic extract was dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (2 × 15 cm), using 2:1 hexane-EtOAc, gave a less polar
phenylseleno alcohol fraction 76b (149 mg, 35%) and a more polar
phenylseleno alcohol fraction 76a (166 mg, 39%) as colorless oils.
We did not establish if each fraction is a mixture of isomers or a
mixture of rotamers of a single isomer. Each fraction was used
without characterization.
(2S)-2-[3-(Benzenesulfonyl)-2-hydroxybut-3-enyl]pyrrolidine-
1-carboxylic Acid tert-Butyl Ester (77a,b). Water (1 mL),
NaHCO3 (34 mg, 0.40 mmol), and NaIO4 (171 mg, 0.80 mmol)
were added to a stirred solution of the less polar phenylseleno
alcohol fraction 76b (188 mg, 0.35 mmol) in MeOH (5 mL), and
stirring was continued for 24 h. The mixture was poured into 3:17
Et2O-pentane (10 mL) and saturated aqueous NaHCO3 (10 mL).
The organic phase was washed with water (5 mL) and brine (5
mL), dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (2 × 10 cm), using 3:1 hexane-EtOAc, gave
alcohol 77b (113 mg, 85%) as a colorless oil that was a single
isomer.
;
1H NMR (CDCl3, 300 MHz) δ 1.12-1.40 (m, 5 H), 1.42-1.80
(m, 4 H), 1.95 (dt, J ) 2,6, 11.7 Hz, 1 H), 2.06 (d, J ) 2.6 Hz, 3
H), 3.02-3.18 (m, 1 H), 3.25 (d, J ) 11.9 Hz, 1 H), 3.70 (s, 3 H),
6.84-6.92 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 19.9 (q), 24.2
(t), 26.0 (t), 33.3 (t), 33.4 (t), 51.4 (q), 53.3 (t), 56.0 (d), 57.1 (d),
134.0 (s), 136.0 (d), 167.4 (s); exact mass m/z calcd for C12H19NO2
209.14159, found 209.14115.
(8aS)-6-(Benzenesulfonyl)-1,2,3,5,8,8a-hexahydroindolizine (83).
CF3CO2H (0.13 mL, 1.65 mmol) was added to a stirred and cooled
(0 °C) solution of acetates 78a,b (mixture of more polar and less
polar isomers) (70 mg, 0.17 mmol) in CH2Cl2 (5 mL). The ice bath
was removed and stirring was continued for 2 h. The solvent was
evaporated and the residue was dissolved in MeCN (3 mL).
Aqueous Na2CO3 (20% w/v, 1 mL) was added and the mixture
was stirred for 30 min. The aqueous phase was extracted with
CH2Cl2 (3 × 5 mL) and the combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 20 cm), using EtOAc, gave amine 83 (41 mg, 94%)
as a colorless oil: FTIR (CH2Cl2 cast) 2791 cm-1; 1H NMR (CDCl3,
500 MHz) δ 1.36-1.47 (m, 1 H), 1.70-1.90 (m, 2 H), 1.95-2.06
(m, 1 H), 2.09-2.23 (m, 3 H), 2.55 (ddd, J ) 14.6, 5.6, 2.9 Hz, 1
H), 2.93-3.03 (m, 1 H), 3.11 (dt, J ) 2.4, 8.8 Hz, 1 H), 3.55 (d,
J ) 15.8 Hz, 1 H), 7.06-7.11 (m, 1 H), 7.49-7.63 (m, 3 H), 7.84-
7.89 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 21.4 (t), 30.1 (t),
32.3 (t), 50.1 (t), 53.8 (t), 58.5 (d), 127.9 (d), 129.2 (d), 133.3 (d),
137.6 (d), 139.2 (s), 139.4 (s); exact mass m/z calcd for C14H17-
NO2S 263.09799, found 263.09785.
Under similar conditions the more polar phenylseleno alcohol
fraction 76a (107 mg, 0.20 mmol) gave alcohol 77a (68 mg, 90%)
as a colorless oil, which was a single isomer and was more polar
than the isomer obtained from the other fraction.
(8aS)-6-(Benzenesulfonyl)octahydroindolizine (84a,b). Pd-C
(10% Pd on C, 50 mg) was added to a solution of amine 83 (500
mg, 1.90 mmol) in dry EtOH (20 mL) and the mixture was
hydrogenated at room temperature in a Parr shaker (initial pressure
58 psi) for 48 h. The mixture was filtered and the filtrate was
evaporated. Flash chromatography of the residue over silica gel (2
× 20 cm), using 5% MeOH-CH2Cl2, gave the less polar saturated
sulfone 84b (312 mg, 62%) and the more polar sulfone 84a (173
mg, 34%) as colorless oils.
Alcohol 77a derived from the more polar phenylseleno alcohol:
FTIR (CH2Cl2 cast) 3395, 1667 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.42 (s, 9 H), 1.56-169 (m, 1 H), 1.72-2.04 (m, 5 H), 3.28 (t,
J ) 6.9 Hz, 2 H), 3.87-3.96 (m, 1 H), 4.34-4.41 (m, 1 H), 6.21
(s, 1 H), 6.38 (s, 1 H), 7.48-7.64 (m, 3 H), 7.83-7.90 (m, 2 H);
13C NMR (CDCl3, 400 MHz) δ 23.7 (t), 28.5 (q), 32.5 (t), 44.4 (t),
46.3 (t), 55.5 (d), 67.9 (d), 80.0 (s), 124.6 (s), 128.0 (d), 129.2 (d),
133.5 (d), 139.6 (t), 153.6 (s), 155.9 (s); exact mass m/z calcd for
C19H27NNaO5S (M + Na) 404.15022, found 404.15049.
Alcohol 77b derived from the less polar phenylseleno alcohol:
FTIR (CH2Cl2 cast) 3366, 1665 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.40 (s, 9 H), 1.51-1.61 (m, 2 H), 1.77-1.98 (m, 4 H), 3.26-
3.36 (m, 2 H), 4.01-4.15 (m, 1 H), 4.28 (d, J ) 9.9 Hz, 1 H),
5.01-5.60 (br s, 1 H), 6.21 (s, 1 H), 6.46 (s, 1 H), 7.55-7.63 (m,
3 H), 7.82-7.89 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 23.4
(t), 28.3 (q), 31.1 (t), 43.5 (t), 46.5 (t), 53.5 (d), 65.3 (d), 80.1 (s),
124.7 (s), 128.2 (d), 129.0 (d), 133.3 (d), 139.6 (t), 152.9 (t), 156.7
(s); exact mass m/z calcd for C19H27NNaO5S (M + Na) 404.15022,
found 404.15006.
More polar sulfone 84a: FTIR (CH2Cl2 cast) 2790, 2730 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.48-1.60 (m, 1 H), 1.62-1.71
(m, 1 H), 1.72-1.92 (m, 5 H), 1.97-2.10 (m, 1 H), 2.67-2.80
(m, 2 H), 2.80-2.93 (m, 2 H), 3.11 (dd, J ) 12.0, 7.7 Hz, 1 H),
3.40-3.49 (m, 1 H), 7.49-7.67 (m, 3 H), 7.86-7.92 (m, 2 H);
13C NMR (CDCl3, 125 MHz) δ 19.9 (t), 20.8 (t), 24.4 (t), 27.2 (t),
47.2 (t), 53.9 (t), 59.3 (d), 60.3 (d), 128.9 (d), 129.1 (d), 133.9 (d),
138.0 (s); exact m/z calcd for C14H19NO2S 265.11365, found
265.11295.
Less polar sulfone 84b: FTIR (CH2Cl2 cast) 2791, 2730 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.018-1.45 (m, 3 H), 1.55-1.98
(m, 5 H), 2.11-2.29 (m, 3 H), 3.03 (dt, J ) 2.3, 9.0 Hz, 1 H),
3.30-3.41 (m, 2 H), 7.51-7.69 (m, 3 H), 7.82-7.89 (m, 2 H);
13C NMR (CDCl3, 125 MHz) δ 20.9 (t), 23.9 (t), 28.6 (t), 29.5 (t),
50.8 (t), 53.4 (t), 60.6 (d), 63.5 (d), 128.7 (d), 129.2 (d), 133.8 (d),
137.5 (s); exact mass m/z calcd for C14H19NO2S 265.11365, found
265.11295.
6-Methyl-1,3,4,6,9,9a-hexahydro-2H-quinolizine-7-carboxyl-
ic Acid Methyl Ester (79a,b). CF3CO2H (93.2 mg, 0.81 mmol)
was added to a stirred and cooled (0 °C) solution of acetates 66
(30 mg, 0.081 mmol) in CH2Cl2 (2 mL). The cooling bath was
removed and stirring was continued for 1 h. The solvent was
evaporated and residue was dissolved in MeCN (2 mL) and aqueous
Na2CO3 (20% w/v, 0.5 mL) was added. The mixture was stirred
for 30 min then extracted with EtOAc (3 × 2 mL). The combined
organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (1 × 8 cm), using
EtOAc, gave the less polar amine 79b (10 mg, 59%) and the more
polar amine 79a (6 mg, 35%) as colorless oils.
(8aR)-Octahydroindolizine [(-)-δ-Coniceine] (85).43 Sulfone
84a,b (mixture of more polar and less polar sulfones) (200 mg,
0.75 mmol) in EtOH (30 mL) was refluxed with freshly activated
W-2 Raney-Nickel catalyst44in water (2.08 g of the moist solid)
under Ar. After 3 h, the mixture was filtered and the filtrate was
evaporated. Flash chromatography of the residue over silica gel (1
× 25 cm), using 10:1 CH2Cl2-MeOH, gave δ-coniceine 85 (85
mg, 91%) as a colorless oil: [R]20D -18.27 (c 0.151, EtOH), [R]20
More polar amine 79a: FTIR (CH2Cl2 cast) 1715 1257 cm-1
;
D
-12.50 (c 1.0, EtOH);43 1H NMR (CDCl3, 400 MHz) δ 1.07-1.24
(m, 2 H), 1.26-1.39 (m, 1 H), 1.41-1.82 (m, 8 H), 1.89 (dt, J )
3.3, 11.5 Hz, 1 H), 1.99 (q, J ) 8.9 Hz, 1 H), 2.94-3.07 (m, 2 H);
13C NMR (CDCl3, 100 MHz) δ 20.6 (t), 24.5 (t), 25.5 (t), 30.5 (t),
31.1 (t), 53.1 (t), 54.3 (t), 64.3 (d).
1H NMR (CDCl3, 300 MHz) δ 1.16 (d, J ) 6.6 Hz, 2 H), 1.22-
1.45 (m, 3 H), 1.48-1.92 (m, 4 H), 2.16-2.34 (m, 2 H), 2.48-
2.66 (m, 1 H), 2.69-2.90 (m, 2 H), 3.68-3.84 (m, 4 H), 6.94 (t,
J ) 3.9, Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 13.9 (q), 22.8
(t), 25.8 (t), 31.3 (t), 32.9 (t), 47.5 (d), 50.4 (t), 51.4 (q), 54.1 (d),
133.7 (s), 136.5 (d), 166.1 (s); exact mass m/z calcd for C12H19NO2
209.14159, found 209.14109.
(44) Pavlic, A. A.; Adkins, H. J. Am. Chem. Soc. 1946, 68, 1471.
5616 J. Org. Chem., Vol. 72, No. 15, 2007

Intramolecular Conjugate Displacement
70a,b; 71a,b; 72a,b; 75a,b; 78a,b; 80; 81; 82 and NMR spectra of
10a,b; 11a,b,c; 13a,b; 14a,b,c; 18, 19a,b; 20a,b,c; 23; precursor
to 24; 24; 25a,b; 26a,b,c; 28; 29; 29c, hydrogenation product of
30, 32; 33; 33c; 35; 36; 36c; 38a,b; 39a,b,c; 41; 43, 44a,b; 45a,b,c;
60; 61; 68a,b; 69a,b; 70a,b; 71a,b; 72a,b; 74a,b; 75a,b; 77a,b;
78a,b; 79a,b; 80-83, 84a,b; 85. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank NSERC for financial support
and C. Boucher [Boehringer Ingelheim (Canada)] for ee
measurements. M.Y. held a Province of Alberta Graduate
Fellowship.
Supporting Information Available: Experimental procedures
for 13a,b; 14a,b,c; 18; 19a,b; 20a,b,c; 22; 23; precursor to 24; 24;
25a,b; 26a,b; 28; 29; precursor to 31; 32; 33; 35; 36; 36c; 38a,b;
39a,b,c; 40; 41; 42; 43; 44a,b; 45a,b; 60; 61; 66; 68a,b; 69a,b;
JO070664S
J. Org. Chem, Vol. 72, No. 15, 2007 5617