Asymmetric synthesis of piperidines and octahydroindolizines

Article abstract of DOI:10.1055/S-0029-1219346

The conjugate addition of a homochiral lithium amide to a ξ-hydroxy-α,β-unsaturated ester, followed by a one-pot, ring-closure-N-debenzylation protocol has been used in the asymmetric syntheses of (S)-coniine and (R)-δ-coniceine (isolated as the corresponding hydrochloride salts) and the bicyclic core of stellettamide A. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1219346

LETTER
567
Asymmetric Synthesis of Piperidines and Octahydroindolizines
A
symmetric
S
t
ynthesi
e
s
of Piperid
p
ines hen G. Davies,* Deri G. Hughes, Paul D. Price, Paul M. Roberts, Angela J. Russell, Andrew D. Smith,
James E. Thomson, Oliver M. H. Williams
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
E-mail: steve.davies@chem.ox.ac.uk
Received 30 November 2009
Dedicated to Professor Gerry Pattenden on the occasion of his 70th birthday in recognition of his efforts to ensure UK chemistry is where it
is today.
ed that iodoamination of 6 upon treatment with I2 occurs
Abstract: The conjugate addition of a homochiral lithium amide to
with in situ loss of the N-a-methylbenzyl protecting
a x-hydroxy-a,b-unsaturated ester, followed by a one-pot, ring-
group. The reaction proceeds via quaternary ammonium
closure–N-debenzylation protocol has been used in the asymmetric
ion 7 that undergoes preferential loss of the N-a-methyl-
syntheses of (S)-coniine and (R)-d-coniceine (isolated as the corre-
sponding hydrochloride salts) and the bicyclic core of stellettamide benzyl cation, which is then trapped by acetonitrile in a
A.
Ritter reaction to give racemic N-a-methylbenzylacet-
amide in 72% yield in addition to pyrrolidine 8 which was
Key words: asymmetric synthesis, lithium amides, piperidines,
coniine, d-coniceine
isolated in 63% yield and >99:1 dr (Scheme 2).8
Ph
Ph
Ph
Ph
CO2t-Bu
I
COt-Bu
Enantiopure piperidines are common structural motifs
present in a range of natural products and biologically sig-
nificant molecules,1 and as such there has been a great
deal of interest in their synthesis. These syntheses have
employed a vast range of synthetic methods, including
manipulation of the chiral pool,2 chiral-auxiliary-based
approaches,3 asymmetric catalysis,4 and the conjugate ad-
dition of homochiral lithium amides. For example,
O’Brien et al. have shown that addition of lithium amide
(S)-1 to a,b-unsaturated ester 2 gives the corresponding x-
chloro-b-amino ester 3 which may then be cyclised, after
oxidative N-debenzylation, via an intramolecular SN2-
type displacement to give piperidine 5 (Scheme 1).5
N
N
Ph
N
(i)
I
O
O
O
O
CO2t-Bu
O
O
6 >99:1 dr
7
8 63%, >99:1 dr
Scheme 2 Reagents and conditions: (i) I2, NaHCO3, MeCN, r.t., 20 h.
We envisaged that a similar one-pot procedure may be
employed in the synthesis of homochiral piperidine scaf-
folds 9 from the corresponding x-halo-b-amino esters 10
via an intramolecular SN2-type displacement of the halide
by the amino substituent with concomitant loss of the N-
a-methylbenzyl group. It was anticipated that the cyclisa-
tion precursors 10 could either be accessed directly from
the conjugate addition of enantiopure lithium amides 11 to
x-halo-a,b-unsaturated esters 12 or via the intermediacy
of the known x-hydroxy-b-amino esters 149 which can be
readily produced via the addition of a lithium amide 11 to
x-hydroxy-a,b-unsaturated ester 13, which in turn is de-
rived from commercially available d-valerolactone
(Scheme 3).
PMB
Ph
N
R
(S)-1
Li
Ph
N
CO2Et
Cl
(i)
(iii)
CO2Et
N
Ph
R = H
CO2Et
Cl
2
3 R = PMB, 88%, >97:3 dr
4 R = H, 70%
5 70%
(ii)
Scheme 1 Reagents and conditions: (i) (S)-N-(a-methylbenzyl)-N-
(p-methoxybenzyl)amine, BuLi, THF, –78 °C, 30 min; (ii) CAN,
MeCN–H2O (5:1), 0 °C, 30 min; (iii) K2CO3, NaI, EtOH, reflux, 16 h.
x-Iodo-, x-bromo-, and x-chloro-a,b-unsaturated esters
16–18 were synthesized from tert-butyl 7-hydroxyhept-2-
enoate 1310 via standard procedures.11 Addition of lithium
amide (R)-15 to x-iodo substituted 16 gave exclusively the
known transhexacin derivative 19,12 resulting from in situ
cyclisation of the intermediate lithium b-amino enolate
onto the pendant x-iodo functionality,13 in 58% isolated
yield and >99:1 dr. Conjugate addition of (R)-15 to x-bro-
mo-substituted 17 resulted in an inseparable 56:44 mix-
ture of 19 and x-bromo-b-amino ester 20, respectively,
both as single diastereomers (>99:1 dr), consistent with
the decreased reactivity of the x-bromo group towards SN2
displacement. However, addition of (R)-15 to x-chloro-
As part of our ongoing research program concerning the
application of enantiopure lithium amides6 as homochiral
ammonia equivalents in total synthesis7 we became inter-
ested in developing methodology for one-pot processes
involving cyclisation with concomitant N-debenzylation
of a b-amino ester. For example, we have recently report-
SYNLETT 2010, No. 4, pp 0567–0570
0
1.
0
3.
2
0
1
0
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219346; Art ID: D34409ST
© Georg Thieme Verlag Stuttgart · New York

568
S. G. Davies et al.
LETTER
Ph
lents of AgBF4 resulted in complete consumption of start-
ing material, giving a 63:37 mixture of 9 and 24,
respectively, in addition to 25. Purification of this mixture
enabled isolation of 9 in 55% yield, 24 in 33% yield and
>99:1 dr, and (RS)-25 in 49% yield (Scheme 5). The for-
mation of 24 in this case is consistent with silver-promot-
ed elimination of HI from 23.
Ar
N
NBn
CO2t-Bu
X
CO2t-Bu
9
10 X = Cl, Br, I
Ph
N
Ar
11
Ph
Ph
Li
Ph
N
+
Ph
N
Ph
N
Ar
CO2t-Bu
OH
CO2t-Bu
I
CO2t-Bu
(i)
CO2t-Bu
X
OH
12 X = Cl, Br, I
13 X = OH
23 85%, >99:1 dr
22 >99:1 dr
14
Ph
(ii)
Scheme 3 Retrosynthetic analysis of enantiopure piperidine 9
Ph
+
N
O
CO2t-Bu
NBn
substituted 18 gave exclusively x-chloro-b-amino ester 21
in >99:1 dr, which was isolated in 76% yield and >99:1 dr
after purification (Scheme 4). Attempted cyclisation and
in situ N-debenzylation by heating 21 in MeCN at 80 °C
for 16 hours unfortunately returned only starting material,
even in the presence of 1.5 equivalents of AgBF4.
+
Ph
N
Me
CO2t-Bu
(R)-9 55%, >99:1 er
H
(RS)-25 49%
24 33%, >99:1 dr
Scheme 5 Reagents and conditions: (i) Ph3P, imidazole, I2, PhMe–
MeCN (4:1), 65 °C, 2 h; (ii) AgBF4, MeCN, 80 °C, 16 h.
Since it was probable that loss of the benzylic cation could
be rate-limiting, the corresponding N-(p-methoxy-a-
methylbenzyl)-substituted analogue 27, which was pro-
duced in 76% yield and >99:1 dr from the conjugate addi-
tion of (R)-26 to 13, was also investigated. Iodination11c of
27 gave x-iodo-b-amino ester 28 in 91% yield and >99:1
dr. Subsequent treatment of 28 under the AgBF4-promot-
ed cyclisation conditions gave an 86:14 mixture of 9 and
a compound which was tentatively assigned as w-unsatur-
ated b-amino ester 29, although only 9 was isolated in
84% yield after purification. Interestingly, heating a solu-
tion of 28 in MeCN at reflux for 16 hours (in the absence
of AgBF4) caused complete consumption of starting ma-
terial, to give 9 and p-methoxystyrene 30 which were iso-
lated in 94% and 65% yield, respectively. The one-pot
conversion of x-hydroxy-b-amino ester 27 into 9 was next
attempted by heating a solution of 27 in MeCN in the pres-
ence of I2, Ph3P, and imidazole. Under these conditions
cyclisation and in situ N-debenzylation gave piperidine 9
in 75% isolated yield (in 3 steps and 31% overall yield
from d-valerolactone) and 30 in 33% isolated yield
(Scheme 6).
Ph
Ph
Ph
N
Ph
N
Li
CO2t-Bu
CO2t-Bu
(i)
(R)-15
I
16 (94% from 13)
19 58%, >99:1 dr
Ph
Ph
Ph
N
Ph
CO2t-Bu
N
CO2t-Bu
CO2t-Bu
Br
(i)
+
Br
17 (92% from 13)
19 >99:1 dr
20 >99:1 dr
19/20 = 56:44
Ph
Ph
N
CO2t-Bu
CO2t-Bu
(i)
Cl
Cl
21 76%, >99:1 dr
18 (88% from 13)
Scheme 4 Reagents and conditions: (i) (R)-15, THF, –78 °C, 2 h.
With methodology for the synthesis of piperidine 9 estab-
lished, attention was turned towards the conversion of 9
into the Hemlock alkaloids (S)-coniine 34 and (R)-d-coni-
ceine 37. Reduction of 9 with DIBAL-H gave the corre-
sponding alcohol 31 in 99% yield. Subsequent oxidation
of 31 under Swern conditions gave aldehyde 32 in quanti-
tative yield.14 Wittig reaction of b-amino aldehyde 32
gave olefin 33 in 52% yield which, when subjected to tan-
dem hydrogenation–hydrogenolysis conditions gave 34,
which was isolated as the corresponding hydrochloride
salt, in 82% yield (Scheme 7).15
Attention next turned towards our second strategy involv-
ing the synthesis of x-iodo-b-amino ester 23 from the cor-
responding known x-hydroxy-b-amino ester 22. Thus,
iodination11c of 229 (>99:1 dr) gave 23 in 85% isolated
yield as a single diastereomer. Heating a solution of 23 in
MeCN for 16 hours at reflux resulted in a 48:49:3 mixture
of starting material 23, the desired piperidine 9 and w-
unsaturated b-amino ester 24, respectively, in addition to
racemic N-a-methylbenzylacetamide 25 (resulting from
Ritter reaction of the a-methylbenzyl cation). However,
repetition of this reaction in the presence of 1.5 equiva-
Synlett 2010, No. 4, 567–570 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Piperidines
569
Ph
(i)
NBn
NBn
PMP
N
Ph
Ph
(R)-26
O
OMe
Li
35 81%, 52:48 dr
32
PMP
N
PMP
CO2t-Bu
(ii)
N
(ii)
CO2t-Bu
I
CO2t-Bu
OH
H
(i)
Cl
(iii)
N
NBn
OH
O
28 91%, >99:1 dr
13
27 76%, >99:1 dr
37⋅HCl, 94%
36 quant
(v)
(iii) or (iv)
(R)-δ-coniceine hydrochloride
Ph
OMe
Scheme 8 Reagents and conditions: (i) MeOCH2PPh3Br, KOt-Bu,
THF, 0 °C to r.t., 16 h; (ii) HCO2H, CH2Cl2, r.t., 16 h; (iii) Pd(OH)2/
C (20 wt%), H2 (1 atm), MeOH, r.t., 48 h then HCl.
NBn
PMP
N
+
+
CO2t-Bu
(R)-9 >99:1 er
Conditions
CO2t-Bu
29 >99:1 dr (not isolated)
Ratio 9/29 Yield of 9 Yield of 30
30
required to promote cyclisation to give hexahydroindoli-
zin-3-one 39.19 Subsequent purification enabled isolation
of 39 in 53% yield and >99:1 dr. The relative configura-
tion within 39 was confirmed by 1H NMR NOE analysis
which showed strong reciprocal enhancements between
the C(1)H and C(8a)H protons. Subsequent treatment of
39 with LiAlH4 gave (1R,8aR)-1-(hydroxymethyl)-octa-
hydroindolizine 40 in 95% yield and >99:1 dr
(Scheme 9).21–23
(iii) from 28
(iv) from 28
(v) from 27
86:14
100:0
100:0
84%
94%
75%
--
65%
33%
Scheme 6 Reagents and conditions: (i) THF, –78 °C, 2 h; (ii) Ph3P,
imidazole, I2, PhMe–MeCN (4:1), 65 °C, 2 h; (iii) AgBF4, MeCN,
80 °C, 16 h; (iv) MeCN, 80 °C, 16 h; (v) Ph3P, imidazole, I2, MeCN,
80 °C, 16 h.
(i)
NBn
NBn
NBn
CO2t-Bu
CO2t-Bu
(i)
NBn
OH
31 99%
9
70% conv.
90:10 dr
CO2t-Bu
CO2Me
38
(ii)
9
Cl
NH2
(ii), (iii)
(iv)
NBn
O
4
N
5
8
X
(iv)
3
1
N
6
7
2
32 X = O, quant
33 X = CH2, 52%
34⋅HCl, 82%
(iii)
8a
(S)-coniine hydrochloride
CO2t-Bu
OH
40 95%, >99:1 dr
Scheme 7 Reagents and conditions: (i) DIBAL-H, THF, 0 °C to r.t.,
6 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to r.t.; (iii)
MePPh3Br, KOt-Bu, THF, 0 °C to r.t., 16 h; (iv) Pd(OH)2/C (20 wt%),
H2 (1 atm), MeOH, r.t., 48 h then HCl.
39 53% (2 steps), >99:1 dr
Scheme 9 Reagents and conditions: (i) LiTMP, THF, –78 °C then
BrCH2CO2Me, –78 °C to r.t., 16 h; (ii) Pd(OH)2/C (20 wt%), H2 (1
atm), MeOH, r.t., 48 h; (iii) CHCl3, reflux, 16 h; (ix) LiAlH4, THF,
reflux, 16 h.
For the synthesis of (R)-d-coniceine 37, chain extension of
aldehyde 32 gave enol ether 35 in 81% yield as a 52:48
mixture of geometric isomers. Hydrolysis of this mixture
gave g-amino aldehyde 36 in quantitative yield, which
upon treatment with Pd(OH)2/C under 1 atm of H2 under-
went one-pot hydrogenolysis, imine formation, and in situ
reduction to give (R)-d-coniceine 37, which was isolated
as the corresponding hydrochloride salt, in 94% yield
(Scheme 8).17
In conclusion, a one-pot ring closure with concomitant N-
debenzylation protocol for the synthesis of tert-butyl (R)-
(N-benzylpiperidin-2¢-yl)acetate has been developed and
subsequently employed in the total asymmetric syntheses
of (S)-coniine and (R)-d-coniceine (as the corresponding
hydrochloride salts), and the bicyclic core of stellettamide
A.
Further efforts focused upon the elaboration of 9 to give
40 (the bicyclic core of stellettamide A).18 Thus, alkyla-
tion of 9 with 2.0 equivalents of LiTMP and 3.0 equiva-
lents of methyl bromoacetate proceeded to 70%
conversion giving 38 in 90:10 dr.19,20 Attempted purifica-
tion of the crude reaction mixture gave a 77:23 mixture of
38 (98:2 dr) and recovered starting material 9, respective-
ly. Treating this mixture under hydrogenolysis conditions
led to successful N-debenzylation, although heating the
crude reaction mixture at reflux in CHCl3 for 16 hours was
References and Notes
(1) (a) Shin, J.; Seo, Y.; Cho, K. W.; Rho, J.-R.; Sim, C. J.
J. Nat. Prod. 1997, 60, 611. (b) Saporito, R. A.; Garraffo,
H. M.; Donnelly, M. A.; Edwards, A. L.; Longino, J. T.;
Daly, J. W. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8045.
(c) Daly, J. W.; McNeal, E.; Gusovsky, F.; Ito, F.; Overman,
L. E. J. Med. Chem. 1988, 31, 477. (d) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645. (e) Karpas, A.; Fleet, G. W. J.;
Dwek, R. A.; Petursson, S.; Namgoong, S. K.; Ramsden,
Synlett 2010, No. 4, 567–570 © Thieme Stuttgart · New York

570
S. G. Davies et al.
LETTER
{lit.16 [a]D23 +9.4 (c 0.3 in EtOH)}. 1H NMR (400 MHz,
N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 9229. (f) Goss, P. E.; Baptiste, J.;
Fernandes, B.; Baker, M.; Dennis, J. W. Cancer Res. 1994,
54, 1450.
CDCl3): d = 0.94 [3 H, t, J = 7.3 Hz, C(3¢)H3], 1.36–2.04 [10
H, m, C(3)H2, C(4)H2, C(5)H2, C(1¢)H2, C(2¢)H2], 2.75–2.86
[1 H, m, C(6)HA], 2.87–3.00 [1 H, m, C(6)HB], 3.40–3.53 [1
H, br m, C(2)H], 9.19 [1 H, br s, NHA], 9.49 (1 H, br s, NHB].
(16) Munchof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084.
(17) Data for (R)-d-Coniceine Hydrochloride (37·HCl)
(2) Holmes, A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem.
1991, 56, 1393.
(3) (a) Pilli, R. A.; Zanotto, P. R.; Böckelmann, M. A.
Tetrahedron Lett. 2001, 42, 7003. (b) Yamazaki, N.;
Dokoshi, W.; Kibayashi, C. Org. Lett. 2001, 3, 193.
(4) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774.
(5) O’Brien, P.; Porter, D. W.; Smith, N. M. Synlett 2000, 1336.
(6) For a review, see: Davies, S. G.; Smith, A. D.; Price, P. D.
Tetrahedron: Asymmetry 2005, 16, 2833.
Mp 175 °C; [a]D23 –1.5 (c 1.0 in EtOH). IR (KBr): nmax
=
3477 (NH) cm–1. 1H NMR (400 MHz, CD3OD): d = 1.56–
2.35 [10 H, m, C(1)H2, C(2)H2, C(6)H2, C(7)H2, C(8)H2],
2.92–3.22 [3 H, m, C(3)HA, C(5)HA, C(8a)H], 3.55–3.68 [2
H, m, C(3)HB, C(5)HB]. 13C NMR (125 MHz, CD3OD): d =
20.5, 23.5, 24.4, 29.2, 29.5 [C(1), C(2), C(6), C(7), C(8)],
52.8, 53.6 [C(3), C(5)], 68.0 [C(8a)]. HRMS (ESI+): m/z (%)
= 126 (100) [M + H]+. HRMS (ESI+): m/z calcd for C8H16N+
[M + H]+: 126.1283; found: 126.1278.
(7) (a) Davies, S. G.; Kelly, R. J.; Price-Mortimer, A. J. Chem.
Commun. 2003, 2132. (b) Davies, S. G.; Burke, A. J.;
Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A.
D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem.
2004, 2, 1387. (c) Davies, S. G.; Haggitt, J. R.; Ichihara, O.;
Kelly, R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts,
P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630.
(d) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.;
Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A.
J.; Sánchez-Fernández, E. M.; Smith, A. D.; Thomson, J. E.
Tetrahedron: Asymmetry 2007, 18, 2510. (e) Abraham, E.;
Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts,
P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655.
(f) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies,
S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.;
Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.;
Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2008, 6, 1665. (g) Davies, S. G.; Fletcher, A. M.;
Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65, 10192.
(8) (a) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts,
P. M.; Smith, A. D. Synlett 2004, 901. (b) Davies, S. G.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Savory, E. D.;
Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009,
20, 756.
(18) Yamazaki, N.; Dokoshi, W.; Kibayashi, C. Org Lett. 2001,
3, 193.
(19) Within this area, Monterrey et al. have shown that alkylation
of N-Cbz protected piperidin-2-yl-acetates with ethyl bromo-
acetate can lead to successful ring closure by removal of the
N-Cbz protecting group in a tandem hydrogenolysis–
hydrogenation step to give the corresponding hexahydro-
indolizin-3-one; see: Monterrey, I. M. G.; González-Muñiz,
R.; Herranz, R.; Garcia-López, M. T. Tetrahedron 1995, 51,
2729.
(20) The anti-configuration of the alkylation was assigned on
the basis of the established preferential anti-alkylations of
lithium b-amino enolates, see: (a) Davies, S. G.; Walters,
I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1129.
(b) Ledoux, S.; Célérier, J.-P.; Lhommet, G. Tetrahedron
Lett. 1999, 40, 9019.
(21) Data for (1R,8aR)-1-(Hydroxymethyl)octahydro-
indolizine (40)
[a]D23 –35.8 (c 0.50 in EtOH). 1H NMR (400 MHz, CDCl3):
d = 1.13–1.37 (2 H, m), 1.40–1.69 (3 H, m), 1.74–1.87 (4 H,
m), 1.90–2.13 (3 H, m), 3.05–3.40 [2 H, m, C(3)HA, C(5)HA],
3.46 [1 H, dd, J = 10.2, 2.4 Hz, C(1¢)HA], 3.86 [1 H, dd, J =
10.2, 2.8 Hz, C(1¢)HB], 3.95 (1 H, br s, OH). 13C NMR (100
MHz, CDCl3): d = 24.1, 25.3, 25.4, 26.7 [C(2), C(6), C(7),
C(8)], 41.0 [C(1)], 53.6, 53.9 [C(3), C(5)], 64.6 [C(1¢)], 66.2
[C(8a)]. HRMS (ESI+): m/z (%) = 156 [M + H]+.
(22) Both diastereomers of 1-(hydroxymethyl)octahydro-
indolizidine (40) have previously been reported, see:
(a) Nagao, Y.; Dai, W.; Ochiai, M.; Tsukagoshi, S.; Fujitalc,
E. J. Org. Chem. 1990, 55, 1148. (b) Pandey, G.;
Lakshmaiah, G.; Gadre, S. M. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1996, 35, 91. (c) Bertrand, S.;
Hoffmann, N.; Pete, J. Eur. J. Org. Chem. 2000, 2227.
(23) Some discrepancies exist between the reported characteri-
sation data for 40 and its epimer; these will be highlighted in
a forthcoming publication from this laboratory. However,
our synthesis unambiguously confirms the relative and
absolute configuration of 40.
(9) Davies, S. G.; Díez, D.; Dominguez, S. H.; Garrido, N. M.;
Kruchinin, D.; Price, P. D.; Smith, A. D. Org. Biomol. Chem.
2005, 3, 1284.
(10) x-Hydroxy-a,b-unsaturated ester 13 was prepared in
55% yield [96:4 E/Z ratio] via the one-pot treatment of
d-valerolactone with DIBAL-H, tert-butyl 2-(diethoxy-
phosphoryl)acetate and BuLi at –78 °C. See ref. 9 for details.
(11) (a) Enders, D.; Wiedemann, J. Liebigs Ann. 1997, 4, 699.
(b) Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62,
7418. (c) Li, N.; Piccirilli, J. A. J. Org. Chem. 2004, 69,
4751.
(12) Holmes, A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem.
1991, 56, 1393.
(13) For a related example, see ref. 11a.
(14) b-Amino aldehydes are known to be unstable with respect to
retro-Michael reactions; see: Carruthers, W.; Moses, R. C.
J. Chem. Soc., Perkin Trans. 1 1988, 2251.
(15) Data for (S)-Coniine Hydrochloride (34·HCl)
Mp 208 °C (lit.16 mp 214 °C); [a]D23 +9.2 (c 0.33 in EtOH)
Synlett 2010, No. 4, 567–570 © Thieme Stuttgart · New York