Enantioselective organocatalytic approach to α-methylene-δ- lactones and δ-lactams

Article abstract of DOI:10.1021/jo801582t

(Chemical Equation Presented) We present the first enantioselective organocatalytic approach for the synthesis of α-methylene-δ-lactones and δ-lactams. Our methodology utilizes the Michael addition of unmodified aldehydes to ethyl 2-(diethoxyphosphoryl)ac

Full text of DOI:10.1021/jo801582t

Enantioselective Organocatalytic Approach to
r-Methylene-δ-lactones and δ-Lactams
Łukasz Albrecht,†,‡ Bo Richter,† Henryk Krawczyk,‡ and Karl Anker Jørgensen*,†
Danish National Research Foundation, Center for Catalysis, Department of Chemistry, Aarhus UniVersity,
DK-8000 Aarhus C, Denmark, and Institute of Organic Chemistry, Technical UniVersity (Politechnika),
90-924 Ło´dz´, Zeromskiego 116, Poland
kaj@chem.au.dk
ReceiVed July 17, 2008
We present the first enantioselective organocatalytic approach for the synthesis of R-methylene-δ-lactones
and δ-lactams. Our methodology utilizes the Michael addition of unmodified aldehydes to ethyl
2-(diethoxyphosphoryl)acrylate as the key step affording highly enantiomerically enriched adducts, which
can be transformed into the target compounds maintaining the high stereoselectivity achieved in the first
step. This methodology has been shown to be general and various optically active γ-substituted
R-methylene-δ-lactones and δ-lactams can be easily accessed.
Introduction
In previous years several synthetic routes leading to R-me-
thylene-δ-lactones 1 have been established.4,5 One approach
utilizes Horner-Wadsworth-Emmons olefination of formal-
Stereoselective synthesis of molecules of biological interest
is an important area in organic chemistry. A class of important
molecules is the R-methylene-δ-lactone system 1, which can
be found in several naturally occurring compounds such as
vernolepin 2,1a vernomenin 3,1a pentalenolactone E 4,1b teucri-
umlactone 5,1c artemisitene 6,1d-f and crassin 71g,h (Figure 1),
and which have been shown to possess diverse and potentially
useful biological properties. The R-methylene-δ-lactones are also
very attractive precursors for the preparation of a wide variety
of compounds since they readily undergo conjugate addi-
tions,1d-f,2a reduction of the double bond,2b Diels-Alder
reaction,2c 1,3-Michael-Claisen annulations,2d,e or cross
methathesis.2f On the contrary, the chemistry and biological
properties of their isoelectronic analoguessR-methylene-δ-
lactams 8sare scarcely recognized.3
(2) (a) Le Menn, J. C.; Tallec, A.; Sarrazin, J. Can. J. Chem. 1991, 69, 761.
(b) Demuth, M.; Schaffner, K. Angew. Chem., Int. Ed. Engl. 1982, 21, 820. (c)
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† Aarhus University.
‡ Technical University (Politechnika).
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A. T.; Sim, G. A. J. Am. Chem. Soc. 1968, 90, 3596. (b) Cane, D. E.; Rossi, T.
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10.1021/jo801582t CCC: $40.75
Published on Web 10/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8337–8343 8337

Albrecht et al.
SCHEME 1. Organocatalytic, Enantioselective Approach
for the Synthesis of r-Methylene-δ-lactones 13 and
δ-Lactams 14
FIGURE 1. Natural Products Containing an R-Methylene-δ-lactone
Moiety.
dehyde with diversely functionalized R-diethoxyphosphoryl-δ-
lactones for the introduction of the methylene moiety into the
lactone ring.6,7 However, methods for the enantioselective
synthesis of this class of compounds are quite limited and rely
mainly on chiral auxiliaries7 or the chiral pool approach.5 It
has, e.g., been demonstrated that the Michael reaction of
enamines, derived from enantiomerically pure 1-phenylethy-
lamine and 2-substituted cycloalkanones to dicyclohexylam-
monium 2-(diethoxyphosphoryl)acrylate, can play a crucial role
in the stereoselective synthesis of R-methylene-δ-lactones.7
We believed that the methodologies for the enantioselective
synthesis of R-methylene-δ-lactones and R-methylene-δ-lactams
would significantly benefit from employing catalytic enantiose-
lective reactions for their effective preparation. In this context,
enantioselective organocatalysis is especially attractive since it
has proven useful as a valuable tool for the stereoselective C-C
bond formation.8 In particular, Michael additions of different
carbonyl compounds using simple chiral, secondary amines as
catalysts via either iminium or enamine activation constitute
an effective and atom economical method for the introduction
of stereogenic centers to molecules in an asymmetric fashion.
The immense progress in this field has been recently reviewed
in a large number of papers.8-10
bistrifluoromethylphenyl)trimethylsilylanyloxymethyl]pyrrolidine
1111 as the catalyst, for preparation of highly enantiomerically
enriched γ-substituted R-methylene-δ-lactones 13 and δ-lactams
14 (Scheme 1). We envisioned that reduction of the carbonyl
group in the originally formed adducts followed by lactonization
and finally a Horner-Wadsworth-Emmons reaction of R-di-
ethoxyphosphoryl-δ-lactones with formaldehyde would result
in the formation of γ-substituted R-methylene-δ-lactones 13.
On the other hand, the preparation of R-methylene-δ-lactams
14 would require reductive amination of the Michael adducts
obtained in the first step of synthesis. The following disclosed
results constitute the first example of an organocatalytic
enantioselective synthesis of R-methylene-δ-lactones and δ-lac-
tams (Scheme 1).
Results and Discussion
We began our investigations with the goal of finding appropriate
conditions for the Michael addition of isovaleraldehyde 10a to ethyl
2-(diethoxyphosphoryl)acrylate 9 (Table 1). 2-[Bis(3,5-bistrifluo-
romethylphenyl)trimethylsilanyloxymethyl]pyrrolidine 11 was cho-
sen as the catalyst since it has been recognized as a general
catalyst for various R-,12 ꢀ-,13 and γ-functionalizations14 of
aldehydes. To our delight, the reaction was found to take place
efficiently in CHCl3 at room temperature with 20 mol % of the
catalyst (S)-11 and 10 equiv of the aldehyde 10a (Table 1, entry
1). Under these conditions adduct 12a was formed as a mixture
of two epimers in a ratio of 4:1 with the same absolute
stereochemistry at the C-4 stereogenic center and with different
configuration at the C-2 stereocenter. This was confirmed after
the transformation of the adduct 12a into the corresponding
R-methylene-δ-lactone 13a. Enantiomeric excess determination
Herein, we report our results on the application of the direct,
enantioselective Michael addition of various aldehydes 10 to ethyl
2-(diethoxyphosphoryl)acrylate 9 in the presence of 2-[bis(3,5-
(6) (a) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem. 1993, 58, 5967.
´
(b) Krawczyk, H.; Sliwin´ski, M. Tetrahedron 2003, 59, 9199. (c) Janecki, T.;
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Wojciechowski, J.; Wolf, W. M. Tetrahedron 2007, 63, 12583.
´
(7) (a) Krawczyk, H.; Sliwiñski, J.; Wolf, W. M.; Bodalski, R. Synlett 2004,
´
1995. (b) Krawczyk, H.; Sliwiñski, J.; Wojciechowski, J.; Wolf, W. M.
´
Tetrahedron: Asymmetry 2006, 18, 908. (c) Krawczyk, H.; Sliwiñski, J.;
Wojciechowski, J.; Wolf, W. M. Tetrahedron: Asymmetry 2007, 18, 2712.
(8) For recent reviews on organocatalysis see, e.g.: (a) Dalko, P. L.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; VCH: Weinheim, Germany, 2004. (c) Acc. Chem.
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Int. Ed. 2005, 44, 794. See also: (b) Marigo, M.; Fielenbach, D.; Braunton, A.;
Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (c)
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8338 J. Org. Chem. Vol. 73, No. 21, 2008

R-Methylene-δ-lactones and δ-Lactams
TABLE 1. Screening of Reaction Conditions for the Addition of
Isovaleraldehyde 10a to Ethyl 2-(Diethoxyphosphoryl)acrylate 9a
FIGURE 2. Transition state model for the 2-[bis(3,5-bistrifluorom-
ethylphenyl)trimethylsilylanyloxymethyl]pyrrolidine catalyzed Michael
addition.
aldehyde conv
(equiv)
eec
(%)
entry solvent catalyst (loading)
(%)b
drb
4:1 96
E-enamine, formed in situ from aldehyde and a chiral catalyst,
from the less-hindered Si-face (Figure 2) to avoid unfavorable
steric interactions with the bulky substituent present at C-2 of
the catalyst. The formation of two epimeric products with
different absolute configuration at the C-2 stereocenter and with
the same stereochemistry at the C-4 stereogenic center can be
rationalized by similar accessibility of both enantiofaces of the
acceptor. Moreover, high acidity of the proton at C-2 makes it
very prone to rapid epimerization.
With the optimized reaction conditions in hand (Table 1, entry
4), we turned our attention to effective transformation of the
adduct 12a into R-methylene-δ-lactone 13a (Scheme 2, Table
2, entries 1 and 2). The obtained product 12a was not purified,
but submitted directly to chemoselective reduction with NaBH4
in MeOH at 0 °C affording δ-hydroxyalkanoate 15a, which was
cyclized to the desired R-diethoxyphosphoryl-δ-lactone 16a
under acidic conditions. The corresponding R-diethoxyphos-
phoryl-δ-lactone 16a was formed as a mixture of epimers.
Finally, the Horner-Wadsworth-Emmons olefination of lactone
16a with formaldehyde afforded the target R-methylene-δ-
lactone 13a maintaining the 96% ee achieved in the Michael-
addition step.
In the next stage of the studies, the scope of the elaborated
synthetic protocol was evaluated by reacting ethyl 2-(diethoxy-
phosphoryl)acrylate 9 with various aldehydes 10b-f (Scheme
2, Table 2, entries 3-8). The established reaction sequence
involving Michael addition, chemoselective reduction of the
carbonyl group, cyclization, and finally a Horner-Wadsworth-
Emmons reaction with formaldehyde was proven to be general
and different γ-substituted R-methylene-δ-lactones 13b-f could
be efficiently accessed. In all the cases high enantioselectivities
(g94% ee) of the products were obtained. By analogy, we have
assigned absolute configuration 5S to all R-methylene-δ-lactones
13b-f obtained in the reaction with catalyst (S)-11. It was found
that the Michael addition of 3,3-dimethylbutyraldehyde 10d was
rather slow and after 7 d at rt we still observed the unreacted
phosphonate 9 in the 31P NMR spectrum of the crude reaction
mixture. Increasing the reaction temperature to 40 °C improved
the reaction rate and application of PhCO2H (10 mol %) as the
cocatalyst allowed us to obtain the desired adduct 12d within
24 h (entry 5). Interestingly, the elevated temperature had no
influence on the stereoselectivity of the addition, which was
confirmed after transformation of alkanoate 12d to the corre-
sponding R-methylene-δ-lactone 13d according to our synthetic
protocol. The final product 13d was obtained with 96% ee. It
should also be emphasized that we were able to perform the
Micheal addition of 4-pentenal 10f, which allowed us to
synthesize R-methylene-δ-lactone 13f bearing an allyl substitu-
ent in the γ-position. In this case cyclization of the δ-hydroxy-
alkanoate 15f obtained by chemoselective reduction of the
carbonyl group in the adduct 12f had to be performed by using
catalytic p-TSA in boiling benzene instead of TFA, which was
1
2
3
4
5
6
CHCl3
CHCl3
CHCl3
CHCl3
EtOH
S (20 mol %)
R (20 mol %)
S (10 mol %)
S (10 mol %)
S (10 mol %)
S (10 mol %)
10
10
10
5
100
100
100
100
70
1.7:1 -98
4:1 96
4:1 96
4.7:1 95
4.4:1 Nd
5
MeOH
5
40
a All reactions were performed at 0.25 mmol scale in 2.25 mL of
appropriate solvent for 24 h at rt. b Estimated by 31P NMR of the crude
reaction mixture. c Determined by HPLC on a chiral stationary phase
after transformation into the corresponding R-methylene-δ-lactone 13a.
clearly indicated that both diastereoisomers are formed with 96%
ee at the C-4 stereogenic center. As expected, the application
of the opposite enantiomer of catalyst (R)-11 afforded the
enantiomeric product 12a with 98% ee in 1.7:1 dr (Table 1,
entry 2). Further screening of the reaction conditions showed
that both catalyst loading and excess of the aldehyde can be
reduced to 10 mol % and 5 equiv, respectively, without decrease
of enantioselectivity (entries 3 and 4). It is also noteworthy that
the addition can be performed in EtOH furnishing the desired
product 12a with slightly lower yield, but maintaining high
enantioselectivity (entry 5). Surprisingly, the addition conducted
in MeOH was not chemoselective as formation of unidentified
organophosphorus side products was observed (entry 6).
The absolute configuration of the C-4 stereogenic center in
the product 12a obtained in the reaction with catalyst (S)-11 is
based on the absolute configuration obtained for Michael
addition reactions using the (S)-11 as the catalyst.10a,15 This
assignment allows us to propose the transition state of reaction,
in which ethyl 2-(diethoxyphosphoryl)acrylate 9 approaches the
(13) For recent examples of ꢀ-functionalisations using iminium activation
see e.g. (a) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128,
10354. (b) Rios, R.; Sunde´n, H.; Ibrahem, I.; Zhao, G.; Eriksson, L.; Co´rdova,
A. Tetrahedron Lett. 2006, 47, 8547. (c) Brandau, S.; Maerten, E.; Jørgensen,
K. A. J. Am. Chem. Soc. 2006, 128, 14986. (d) Chen, Y. K.; Yoshida, M.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328. (e) Ibrahem, I.; Rios,
R.; Vesely, J.; Zhao, G.; Co´rdova, A. Chem. Commun. 2007, 8, 849. (f) Vesely,
J.; Ibrahem, I.; Zhao, G.; Rios, R.; Co´rdova, A. Angew. Chem., Int. Ed. 2007,
46, 778. (g) Bertelsen, S.; Dine´r, P.; Johansen, R. L.; Jørgensen, K. A. J. Am.
Chem. Soc. 2007, 129, 1536. (h) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 1983. (i) Carlone, A.; Bartoli, G.; Bosco,
M.; Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46, 4504. (j)
Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Co´rdova,
A. Angew. Chem., Int. Ed. 2007, 46, 4507. (k) Maerten, E.; Cabrera, S.;
Kjærsgaard, A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 8893. (l) Franke,
P. T.; Richter, B.; Jørgensen, K. A. Chem. Eur. J. 2008, 14, 6317. (m) Rueping,
M.; Sugiono, E.; Merino, E. Chem. Eur. J. 2008, 14, 6329. (n) Cabrera, S.;
Reyes, E.; Alemán, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am.
Chem. Soc. 2008, 130, 12031.
(14) (a) For examples of γ-functionalizations see, e.g.: Bertelsen, S.; Marigo,
M.; Brandes, S.; Dine´r, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
(b) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Huang, G.-F.; Su, C.-F.; Liao, J.-H.
J. Org. Chem. 2007, 72, 8459. (c) de Figueiredo, R. M.; Fro¨hlich, R.; Christmann,
M. Angew. Chem., Int. Ed. 2008, 47, 1450.
(15) (a) Franze´n, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (b) Dine´r, P.;
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references cited therein.
J. Org. Chem. Vol. 73, No. 21, 2008 8339

Albrecht et al.
SCHEME 2. Enantioselective Synthesis of r-Methylene-δ-lactones 13a
a Reagents and conditions: (a) aldehyde 10 (5 equiv), catalyst (S)-11 (0.1 equiv), CHCl3, rt, 24 h; (b) NaBH4 (2.5 equiv), MeOH, 0 °C, 1 h; (c) TFA-CH2Cl2
(1:2), rt, overnight; (d) K2CO3 (3 equiv), 36% HCHO (6 equiv), THF/H2O, 0 °C, 1 h.
TABLE 2. Enantioselective Synthesis of γ-Substituted
r-Methylene-δ-lactones 13a
obtain the corresponding R-methylene-δ-lactam with higher
enantiomeric excess.
yield (%)
16b
13
drc
To confirm our assumptions we performed reductive amina-
tion of the aldehyde 12a with aniline under the previously
optimized conditions (Scheme 4, Table 3). Surprisingly, instead
of the expected R-diethoxyphosphoryl-δ-lactam, the isolated
product was the δ-aminoalkanoate 19a. All attempts to cycli-
ze this compound under basic conditions were unsuccessful.
Therefore, we decided to perform the Horner-Wadsworth-
Emmons reaction of formaldehyde with the phosphonate 19a.
We were pleased to find out that the reaction proceeded
efficiently. Under the reaction conditions the originally formed
R-methylene-δ-aminoalkanoate 20 underwent spontaneous cy-
clization to the corresponding R-methylene-δ-lactam 14b.
Synthesis of R-methylene-δ-lactams with aniline instead of
benzylamine as the aminating reagent proved to be more
efficient since the final product was obtained in high 93% ee
(Table 3, entry 1). The opposite enantiomer of 14b also could
be easily accessed in high 94% ee (entry 2) by employing the
Michael adduct ent-12a prepared with the enantiomeric catalyst
(R)-11. The generality of this methodology was additionally
demonstrated by transformation of the Michael adducts 12b,d
to corresponding R-methylene-δ-lactams 14c,d following our
established synthetic protocol. We have found that the corre-
sponding imine-enamine equilibrium as well as the stereo-
chemical outcome of the reaction were strongly dependent on
the bulkiness of the substituent in the γ-position relative to the
ester functionality. More sterically demanding substituents (i-
Pr, t-Bu) suppressed imine-enamine equilibrium favoring the
imine form in the reductive amination step and the correspond-
ing R-methylene-δ-lactams 14b and 14d could be obtained with
good to high enantioselectivity. The formation of the R-meth-
ylene-δ-lactam 14c with the smaller ethyl substituent in the
γ-position proceeded with loss of enantioselectivity indicating
that the formation of the corresponding enamine in the reductive
amination step is more favored than in the other cases.
entry
R
12
16
eed (%)
1
2
3
i-Pr, 10a
i-Pr, 10a
Et, 10b
Bu, 10c
t-Bu, 10d
Bn, 10e
allyl, 10f
allyl, 10f
59
65
58
54
42
40
66
53
62
64
67
77
71
34
87
50
4:1
1.7:1
3.6:1
3:1
6.8:1
4:1
43:57
43:57
55:45
55:45
40:60
55:45
53:47
53:47
13a: 96
13a: -98e
13b: 94
13c: 96
13d: 96
13e: 95
13f: 95
4
5f
6
7g
8g
3.6:1
3.6:1
13f: -98e
a Michael additions performed at 0.5 mmol scale with 10 mol % of
the catalyst (S)-11 in 4.5 mL of CHCl3 for 24 h at rt. b Overall yield for
3 steps. c Estimated by 31P NMR. d Determined by HPLC on a chiral
stationary phase after transformation into the corresponding R-meth-
ylene-δ-lactones 13. e Michael additions performed with the enan-
tiomeric catalyst (R)-11. f Michael addition performed at 40 °C with
PhCO2H (10 mol %) as cocatalyst. g Cyclization performed with p-TSA
(cat.) in boiling benzene for 3 h.
generally used for the cyclizations of the other δ-hydroxyal-
kanoates 15a-e (entry 7). The final R-methylene-δ-lactone 13f
was obtained with high 95% ee. The opposite enantiomer of
the product 13f could also be easily accessed with good en-
antioselectivity (98% ee) by application of the enantiomeric
catalyst (R)-11 in the Michael-addition step (entry 8).
With the general strategy for the synthesis of γ-substituted
R-methylene-δ-lactones 13 being established, we decided to turn
our attention to the preparation of optically active R-methylene-
δ-lactams 14. Employing reductive amination of the enantio-
merically enriched Michael adducts 12 seemed to be attractive
in this respect. In the first attempt, benzylamine was chosen as
the aminating reagent. Reductive amination of the aldehyde 12a
with benzylamine was performed by using sodium triacetoxy-
borohydride as the reducing agent in DCE at room temperature
for 24 h (Scheme 3). The δ-aminoalkanoate 17 underwent
spontaneous lactamization yielding R-diethoxyphosphoryl-δ-
lactam 18 as the only product as a mixture of two epimers in a
ca. 1:1 ratio. Horner-Wadsworth-Emmons olefination of for-
maldehyde with R-diethoxyphosphoryl-δ-lactam 18 furnished
the target R-methylene-δ-lactam 14a. Surprisingly, determina-
tion of the enantiomeric excess indicated that the established
synthetic route proceeded with noticeable decrease of enanti-
oselectivity induced in the Michael addition step. The corre-
sponding R-methylene-δ-lactam 14a was obtained with 84%
ee. This unexpected outcome of the reaction can be rationalized
assuming that the imine originally formed in the reaction of
aldehyde 12a with benzylamine can be in equilibrium with the
corresponding enamine, which would lead to partial racemiza-
tion of the product. To overcome these difficulties we decided
to use aniline instead of benzylamine in the reductive amination
step. We believed that conjugation of the imine CdN double
bond with an aromatic system should significantly suppress the
corresponding imine-enamine equilibrium and allow us to
Conclusion
In conclusion, we have developed a novel, enantioselective,
organocatalytic approach to R-methylene-δ-lactones and δ-lac-
tams which utilize 2-[bis(3,5-bistrifluoromethylphenyl)trimeth-
ylsilylanyloxymethyl]pyrrolidine-catalyzed Michael addition of
various aldehydes to 2-(diethoxyphosphoryl)acrylate as the key
step. Our methodology proved to be general and the corre-
sponding R-methylene-δ-lactones and δ-lactams were obtained
in a highly enantioselective manner.
Experimental Section
General Procedure for Preparation of r-Diethoxyphosphoryl-
δ-lactones 16. In an ordinary vial, the corresponding aldehyde 10
(2.5 mmol) was added to a solution of catalyst 11 (30 mg, 0.05
mmol) in CHCl3 (4.5 mL). After 15 min 2-(diethoxyphosphoryl)-
8340 J. Org. Chem. Vol. 73, No. 21, 2008

R-Methylene-δ-lactones and δ-Lactams
SCHEME 3. Enantioselective Synthesis of N-Benzyl-r-methylene-δ-lactam 14aa
a Reagents and conditions: (a) NaBH(OAc)3 (1.4 equiv), benzylamine (1.05 equiv), DCE, rt, 24 h; (b) t-BuOK (1.2 equiv), Et2O, rt, 0.5 h; then HCHO
(5 equiv), Et2O, rt, 15 min.
SCHEME 4. Enantioselective Synthesis of N-Phenyl-r-methylene-δ-lactams 14b-da
a Reagents and conditions: (a) NaBH(OAc)3 (1.4 equiv), aniline (1.05 equiv), DCE, rt, 24 h; (b) t-BuOK (1.2 equiv), Et2O, rt, 15 min; then HCHO (5
equiv), Et2O, rt, 30 min.
TABLE 3. Enantioselective Synthesis of
(minor), 24.6 (d, J ) 4.7 Hz, minor), 24.9 (d, J ) 4.2 Hz, major),
28.8 (minor), 29.3 (major), 37.0 (d, J ) 5.2 Hz, minor), 38.8 (d, J
) 138.9 Hz, minor), 39.3 (d, J ) 8.3 Hz, major), 39.8 (d, J )
137.8 Hz, major), 62.6 (d, J ) 6.8 Hz), 63.4 (d, J ) 7.0 Hz, minor),
63.4 (d, J ) 6.9 Hz, major), 72.1 (minor), 72.2 (major), 166.6 (d,
J ) 4.1 Hz, major), 166.9 (d, J ) 4.1 Hz, minor); 31P NMR (CDCl3)
δ 23.30 (43%), 23.42 (57%); HRMS calcd for C12H23O5PNa [M
N-Phenyl-r-methylene-δ-lactams 14b-da
yield (%)
entry
R
19
14
drb 19
eec(%)
1
2
3
4
i-Pr, 12a
i-Pr, 12a
Et, 12b
68
66
60
41
55
53
48
59
40:60
40:60
52:48
35:65
14b: 93
14b: -94d
14c: 74
+
+ Na] 301.1181, found 301.1184.
t-Bu, 12d
14d: 94
(5R)-3-Diethoxyphosphoryl-5-ethyltetrahydro-2H-pyran-2-
one (16b): Colorless oil. Yield: 58% with catalyst (S)-11. 1H NMR
(CDCl3) δ 0.89 (t, 3H, J ) 7.5 Hz), 1.26 (t, 3H, J ) 7.0 Hz), 1.27
(t, 3H, J ) 7.0 Hz), 1.60-1.82 (m, 3H), 1.91-2.08 (m, 1H),
2.18-2.36 (m, 1H), 3.01-3.13 (m, 1H), 3.92 (dd, 1H, J ) 8.9,
11.0 Hz, major), 4.00 (t, 1H, J ) 11.0 Hz, minor), 4.08-4.20 (m,
4H), 4.22 (ddd, 1H, J ) 1.7, 3.6, 11.0 Hz, major), 4.36 (ddd, 1H,
J ) 1.7, 4.4, 11.0 Hz, minor); 13C NMR (CDCl3) δ 10.97 (major),
11.03 (minor), 16.1 (d, J ) 6.2 Hz, minor), 16.2 (d, J ) 6.1 Hz,
major), 23.8 (minor), 24.2 (major), 26.6 (d, J ) 4.6 Hz, minor),
27.3 (d, J ) 4.3 Hz, major), 32.1 (d, J ) 4.8 Hz, minor), 34.6 (d,
J ) 8.9 Hz, major), 38.6 (d, J ) 137.1 Hz, minor), 39.7 (d, J )
138.3 Hz, major), 62.4 (d, J ) 6.4 Hz, major), 62.5 (d, J ) 6.1
Hz, minor), 63.2 (d, J ) 6.7 Hz, minor), 63.3 (d, J ) 6.6 Hz, major),
73.17 (minor), 73.25 (major), 166.3 (d, J ) 4.3 Hz, major), 166.5
(d, J ) 4.3 Hz, minor); 31P NMR (CDCl3) δ 23.34 (55%), 23.39
(45%); HRMS calcd for C11H21O5PNa [M + Na]+ 287.1025, found
287.1017.
(5R)-5-Benzyl-3-diethoxyphosphoryltetrahydro-2H-pyran-2-
one (16e): Colorless oil. Yield: 40% with catalyst (S)-11. 1H NMR
(CDCl3) δ 1.15-1.30 (m, 6H), 1.72-2.35 (m, 3H), 2.44-2.60 (m,
2H), 2.99-3.18 (m, 1H), 3.97 (dd, 1H, J ) 2.8, 11.2 Hz, major),
4.00-4.20 (m, 5H), 4.34 (ddd, 1H, J ) 1.2, 4.0, 11.2 Hz),
7.07-7.26 (m, 5H); 13C NMR (CDCl3) δ 16.2 (d, J ) 5.3 Hz,
minor), 16.3 (d, J ) 6.5 Hz, major), 26.8 (d, J ) 4.8 Hz, minor),
27.6 (d, J ) 4.2 Hz, major), 32.3 (d, J ) 4.3 Hz, minor), 35.1 (d,
J ) 8.9 Hz, major), 37.2 (minor), 37.8 (major), 38.9 (d, J ) 135.7
Hz, minor), 39.7 (d, J ) 138.3 Hz, major), 62.6 (d, J ) 6.8 Hz,
major), 62.7 (d, J ) 6.9 Hz, minor), 63.5 (d, J ) 6.4 Hz, minor),
63.6 (d, J ) 6.6 Hz, major), 72.9 (minor), 73.0 (major), 126.6
(minor), 126.7, 128.6 (2×, minor), 128.6 (2×, major), 128.7 (2×,
major), 128.8 (2×, minor), 137.8 (major), 137.9 (minor), 166.3 (d,
J ) 4.4 Hz, major), 166.4 (d, J ) 4.2 Hz, minor); 31P NMR (CDCl3)
δ 23.15 (55%), 23.17 (45%); HRMS calcd for C16H23O5PNa [M
+ Na]+ 349.1181, found 349.1179.
a Michael adducts 12a,b,d were prepared at 0.5 mmol scale with 10 mol
% of the catalyst (S)-11 in 4.5 mL of CHCl3 for 24 h at rt for 12a,b or at
40 °C and with PhCO2H present for 12d. b Estimated by 31P NMR.
c Determined by HPLC on a chiral stationary phase after transformation into
the corresponding R-methylene-δ-lactams 14. d Michael adduct prepared
with the enantiomeric catalyst (R)-11 (10 mol %).
acrylate 9 (118 mg, 0.5 mmol) was added and the resulting mixture
was stirred overnight at room temperature. After complete con-
sumption of acrylate 9 (monitored by 31P NMR spectroscopy) the
solvent was evaporated under reduced pressure. The residue was
dissolved in MeOH (7.5 mL) then cooled to 0 °C and NaBH4 (48
mg, 1.25 mmol) was added in portions. The resulting mixture was
left at 0 °C for 1 h, quenched with 3 N HCl (10 mL), and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (1 mL), TFA (0.5 mL) was added,
and the resulting solution was left without stirring at room
temperature overnight. The solvent was evaporated under reduced
pressure, then the residue was dissolved in CH2Cl2 (20 mL), washed
with saturated NaHCO3 (10 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (EtOAc/pentane 4:1) to afford
R-diethoxyphosphoryl-δ-lactone 16.
Representative Data for r-Diethoxyphosphoryl-δ-lactones 16.
(5S)-3-Diethoxyphosphoryl-5-isopropyltetrahydro-2H-pyran-2-
one (16a): Colorless oil. Yield: 59% using catalyst (S)-11. 1H NMR
(CDCl3) δ 0.94 (d, 3H, J ) 6.3 Hz, major), 0.95 (d, 3H, J ) 6.7
Hz, minor), 0.96 (d, 3H, J ) 6.6 Hz, major), 0.96 (d, 3H, J ) 6.6
Hz, minor), 1.32-1.37 (m, 6H), 1.52-1.72 (m, 2H), 1.85-1.96
(m, 1H), 2.20-2.36 (m, 1H), 3.07-3.19 (m, 1H), 4.07 (dd, 1H, J
) 10.2, 11.1 Hz, major), 4.15-4.26 (m, 5H), 4.34 (ddd, 1H, J )
2.7, 4.1, 11.1 Hz, major), 4.45 (ddd, 1H, J ) 0.7, 4.1, 10.2 Hz,
minor); 13C NMR (CDCl3) δ 16.20 (d, J ) 6.2 Hz, minor), 16.22
(d, J ) 4.7 Hz, minor), 16.26 (d, J ) 6.4 Hz, major), 16.27 (d, J
) 5.8 Hz, major), 19.5 (major), 19.6 (minor), 19.8 (major), 19.8
General Procedure for Preparation of r-Methylene-δ-lactones
13. To a solution of R-diethoxyphosphoryl-δ-lactone 16 (0.2 mmol)
J. Org. Chem. Vol. 73, No. 21, 2008 8341

Albrecht et al.
and aq 37% formaldehyde (90 µL, 1.2 mmol) in THF (0.8 mL) at
0 °C was added a solution of K2CO3 (83 mg, 0.6 mmol) in H2O
(0.8 mL) and the resulting mixture was stirred at 0 °C for 1 h. The
mixture was then quenched with sat. NaCl solution (10 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried over MgSO4 and evaporated. The residue was purified
by flash chromatography on silica gel (eluent: EtOAc/pentane 1:3)
to afford R-methylene-δ-lactone 13.
19.63 (minor), 25.9 (d, J ) 4.9 Hz, major), 26.5 (d, J ) 3.8 Hz,
minor), 29.7 (major), 30.2 (minor), 36.3 (d, J ) 2.7 Hz, minor),
39.8 (d, J ) 12.8 Hz, major), 41.0 (d, J ) 133.4 Hz, major), 41.7
(d, J ) 142.4 Hz, minor), 50.4 (major), 50.5 (minor), 50.5 (minor),
50.6 (major), 61.7 (d, J ) 6.7 Hz, major), 61.9 (d, J ) 6.8 Hz,
minor), 62.7 (d, J ) 6.7 Hz, minor), 62.8 (d, J ) 6.8 Hz, major),
127.0 (2×, minor), 127.1 (2×, major), 127.51 (2×, minor), 127.54
(2×, major), 128.33 (minor), 128.35 (major), 136.5, 136.6, 164.9
(d, J ) 4.8 Hz, major), 165.0 (d, J ) 4.9 Hz, minor); 31P NMR
Representative Data for r-Methylene-δ-lactones 13. (S)-5-
Isopropyl-3-methylenetetrahydropyran-2-one (13a): Colorless
oil. Yield: 62%. The ee was determined by HPLC using a Chiralpak
AD column (hexane/iPrOH 99.5:0.5); flow rate 1.0 mL/min; τminor
) 17.0 min, τmajor ) 19.6 min (96% ee); [R]D -41.4 (c 0.5, CH2Cl2);
1H NMR (CDCl3) δ 0.96 (d, 3H, J ) 6.7 Hz), 0.97 (d, 3H, J ) 6.7
Hz), 1.55-1.60 (m, 1H), 1.72-1.78 (m, 1H), 2.39 (ddt, 1H, J )
2.4, 11.0, 15.8 Hz), 2.74 (ddq, 1H, J ) 2.4, 3.8, 15.8 Hz), 4.11
(dd, 1H, J ) 9.8, 11.0 Hz), 4.40 (ddd, 1H, J ) 2.4, 3.8, 11.0 Hz),
(CDCl3)
δ 26.23 (58%), 26.38 (42%); HRMS calcd for
C19H30NO4PNa [M + Na]+ 390.1810, found 390.1800.
Procedure for the Preparation of N-Benzyl-r-methylene-δ-
lactam 14a. To a stirred solution of a corresponding lactam 18 (115
mg, 0.315 mmol) in Et2O (3.2 mL) was added t-BuOK (42 mg,
0.378 mmol) and the resulting mixture was stirred at room
temperature for 30 min. Then paraformaldehyde (47 mg, 1.575
mmol) was added in one portion. After 15 min the reaction mixture
was quenched with brine (10 mL) and the water layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
over MgSO4 and evaporated. The crude product was purified by
flash chromatography (eluent EtOAc/pentane 1:2).
5.56 (dt, 1H, J ) 1.5, 2.4 Hz), 6.40 (dt, 1H, J ) 1.5, 2.4 Hz); 13
C
NMR (CDCl3) δ 19.7, 20.1, 28.6, 31.9, 39.8, 72.4, 128.4, 133.7,
165.7; HRMS calcd for C9H14O2Na [M + Na]+ 177.0892, found
177.0897.
(R)-5-Butyl-3-methylenetetrahydropyran-2-one (13c): Color-
less oil. Yield: 77%. The ee was determined by HPLC using a
Chiralpak AD column (hexane/iPrOH 99.5:0.5); flow rate 1.0 mL/
min; τminor ) 36.2 min, τmajor ) 39.3 min (96% ee); [R]D -24.57
(S)-1-Benzyl-5-isopropyl-3-methylenepiperidin-2-one (14a):
Colorless oil. Yield: 63%. The ee was determined by HPLC using
a Chiralpak AD column (hexane/iPrOH 96:4); flow rate 1.0 mL/
min; τminor ) 15.0 min, τmajor ) 15.9 min (84% ee); [R]D +16.29
1
1
(c 1.97, CH2Cl2); H NMR (CDCl3) δ 0.83 (t, 3H, J ) 6.7 Hz),
(c 0.62, CH2Cl2); H NMR (CDCl3) δ 0.82 (d, 3H, J ) 6.7 Hz),
1.19-1.27 (m, 6H), 1.90-1.96 (m, 1H, J ) 3.9, 9.3, 10.3 Hz),
2.21 (ddt, 1H, J ) 2.4, 10.3, 15.8 Hz), 2.68 (ddq, 1H, J ) 2.4, 3.9,
15.8 Hz), 3.93 (dd, 1H, J ) 9.2, 10.3 Hz), 4.27 (ddd, 1H, J ) 2.4,
3.9, 10.3 Hz), 5.34 (dt, 1H, J ) 1.6, 2.4 Hz), 6.33 (dt, 1H, J ) 1.6,
2.4 Hz); 13C NMR (CDCl3) δ 13.9, 22.6, 28.8, 30.6, 33.4, 34.4,
73.7, 128.5, 133.4, 165.6; HRMS calcd for C10H16O2Na [M + Na]+
191.1048, found 191.1051.
0.90 (d, 3H, J ) 6.7 Hz), 1.46-1.55 (m, 1H), 1.58-1.66 (m, 1H),
2.28 (ddt, 1H, J ) 2.2, 12.1, 14.6 Hz), 2.65-2.71 (m, 1H), 3.10
(dd, 1H, J ) 9.8, 12.1 Hz), 3.26 (ddd, 1H, J ) 2.2, 4.6, 12.1 Hz),
4.66 (s, 2H), 5.32 (dt, 1H, J ) 1.0, 2.2 Hz), 6.26 (dt, 1H, J ) 1.0,
2.2 Hz), 7.26-7.34 (m, 5H); 13C NMR (CDCl3) δ 19.6, 20.0, 29.7,
33.5, 40.0, 50.8, 51.2, 122.1, 127.3, 128.0 (2×), 128.6 (2×), 137.1,
137.4, 164.3; HRMS calcd for C16H21NONa [M + Na]+ 266.1521,
found 266.1520.
General Procedure for the Preparation of N-Phenyl-r-diethoxy-
phosphoryl-δ-aminoalkanoates 19. In an ordinary vial, the corre-
sponding aldehyde 10 (2.5 mmol) was added to a solution of catalyst
11 (30 mg, 0.05 mmol) in CHCl3 (4.5 mL). After 15 min
2-(diethoxyphosphoryl)acrylate 9 (118 mg, 0.5 mmol) was added
and the resulting mixture was stirred overnight at room temperature.
After complete consumption of acrylate 9 (monitored by 31P NMR
spectroscopy) the solvent was evaporated under reduced pressure.
The residue was dissolved in dry DCE (1.75 mL). Aniline (48 µL,
0.525 mmol) and NaBH(OAc)3 (149 mg, 0.7 mmol) were added,
and the heterogeneous mixture was stirred at rt for 20 h. Saturated
NaHCO3 (10 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo to give the crude N-phenyl-
R-diethoxyphosphoryl-δ-aminoalkanoate 19, which was purified by
flash chromatography, eluting with EtOAc:pentane (1:1).
Representative Data for N-Phenyl-r-diethoxyphosphoryl-δ-
aminoalkanoates 19. Ethyl (5S)-2-diethoxyphosphoryl-5-methyl-
4-((phenylamino)methyl)hexanoate (19a): Pale-yellow oil. Yield:
68% with catalyst (S)-11. 1H NMR (CDCl3) δ 0.83-0.92 (m, 6H),
1.15-1.29 (m, 9H), 1.41-1.64 (m, 2H), 1.69-1.80 (m, 1H),
1.82-2.15 (m, 1H), 2.76-3.17 (m, 3H), 4.02-4.18 (m, 6H),
6.53-6.68 (m, 3H), 7.09-7.13 (m, 2H); 13C NMR (CDCl3) δ 13.9
(major), 14.0 (minor), 16.2 (d, J ) 5.6 Hz, minor), 16.3 (d, J )
4.2 Hz, major), 18.3 (minor), 18.4 (major), 19.6 (major), 19.7
(minor), 26.5 (d, J ) 4.5 Hz, major), 27.2 (d, J ) 4.6 Hz, minor),
29.0, 42.1 (d, J ) 12.7 Hz, minor), 42.6 (d, J ) 12.3 Hz, major),
43.7 (d, J ) 129.9 Hz, major), 44.1 (d, J ) 129.4 Hz, minor),
44.77 (major), 44.83 (minor), 61.3 (minor), 61.4 (major), 62.6 (d,
J ) 5.9 Hz, minor), 62.6 (d, J ) 6.5 Hz, major), 112.4 (2×, minor),
112.5 (2×, major), 116.7 (minor), 116.9 (major), 129.0 (2×, minor),
129.1 (2×, major), 148.1 (minor), 148.4 (major), 169.2 (d, J ) 5.1
Hz, major), 169.4 (d, J ) 5.2 Hz, minor); 31P NMR (CDCl3) δ
23.92 (40%), 24.19 (60%); HRMS calcd for C20H34NO5PNa [M +
Na]+ 422.2072, found 422.2069.
(R)-5-Allyl-3-methylenetetrahydropyran-2-one (13f): Colorless
oil. Yield: 87%. The ee was determined by HPLC using a Chiralpak
OD column (hexane/iPrOH 200:1); flow rate 1.0 mL/min; τminor
)
44.9 min, τmajor ) 46.9 min (95% ee); [R]D -4.24 (c 1.25, CH2Cl2);
1H NMR (CDCl3) δ 1.99-2.08 (m, 3H), 2.24-2.33 (m, 1H), 2.69
(ddd, 1H, J ) 2.0, 4.0, 15.6 Hz), 3.99 (ddd, 1H, J ) 3.2, 8.4, 11.2
Hz), 4.32 (ddd, 1H, J ) 2.0, 3.2, 11.2 Hz), 5.01 (dd, 1H, J ) 0.8,
6.8 Hz), 5.04 (d, 1H, J ) 0.8 Hz), 5.49-5.50 (m, 1H), 5.63-5.73
(m, 1H), 6.34-6.35 (m, 1H); 13C NMR (CDCl3) δ 33.0, 33.8, 35.2,
73.0, 117.6, 128.7, 133.1, 134.4, 165.3; HRMS calcd for C9H12O2Na
[M + Na]+ 175.0735, found 175.0733.
Procedure for the Preparation of N-Benzyl-r-diethoxyphos-
phoryl-δ-lactam 18. In an ordinary vial, the corresponding aldehyde
10a (2.5 mmol) was added to a solution of catalyst 11 (30 mg,
0.05 mmol) in CHCl3 (4.5 mL). After 15 min 2-(diethoxyphos-
phoryl)acrylate 9 (118 mg, 0.5 mmol) was added and the resulting
mixture was stirred overnight at room temperature. After complete
consumption of acrylate 9 (monitored by 31P NMR spectroscopy)
the solvent was evaporated under reduced pressure. The residue
was dissolved in dry DCE (1.75 mL). Benzylamine (59 µL, 0.525
mmol) and NaBH(OAc)3 (149 mg, 0.35 mmol) were added, and
the heterogeneous mixture was stirred at rt for 20 h. Saturated
NaHCO3 (10 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo to give the crude R-diethoxy-
phosphoryl-δ-lactam 18, which was purified by flash chromatog-
raphy on Iatrobeads 6RS-8060, eluting with EtOAc:pentane (1:1).
(5S)-1-Benzyl-3-diethoxyphosphoryl-5-isopropylpiperidin-2-
one (18): Pale-yellow oil. Yield: 67% with catalyst (S)-11. 1H NMR
(CDCl3) δ 0.76 (d, 3H, J ) 6.7 Hz, major), 0.79 (d, 3H, J ) 6.5
Hz, minor), 0.83 (d, 3H, J ) 6.4 Hz, minor), 0.84 (d, 3H, J ) 6.7
Hz, major), 1.25-1.31 (m, 6H), 1.38-1.48 (m, 1H), 1.63-2.01
(m, 2H), 2.11-2.31 (m, 1H), 2.86-3.21 (m, 3H), 4.08-4.25 (m,
4H), 4.37-4.74 (m, 2H), 7.17-7.27 (m, 5H); 13C NMR (CDCl3)
δ 16.17 (d, J ) 6.5 Hz, major), 16.23 (d, J ) 6.6 Hz, minor), 16.3
(d, J ) 6.1 Hz, minor), 19.3 (minor), 19.4 (major), 19.62 (major),
8342 J. Org. Chem. Vol. 73, No. 21, 2008

R-Methylene-δ-lactones and δ-Lactams
Ethyl (5S)-2-diethoxyphosphoryl-5,5-dimethyl-4-((phenylami-
no)methyl)hexanoate (19c): Pale-yellow oil. Adduct 12d was
prepared according to the procedure for 16d at 40 °C. Yield: 41%
with catalyst (S)-11. 1H NMR (CDCl3) δ 0.89 (s, 9H, major), 0.91
(s, 9H, minor), 1.13-1.31 (m, 9H), 1.65-2.26 (m, 3H), 2.65 (dd,
1H, J ) 1.6, 9.6 Hz, minor), 2.83 (dd, 1H, J ) 7.6, 12.0 Hz, major),
3.05-3.25 (m, 2H), 3.98-4.18 (m, 6H), 6.49-6.63 (m, 3H), 7.09
(m, 2H); 13C NMR (CDCl3) δ 14.0 (minor), 14.1 (major), 16.24
(d, J ) 6.2 Hz, major), 16.28 (d, J ) 5.6 Hz, minor), 16.31 (d, J
) 5.8 Hz, major), 16.34 (d, J ) 5.0 Hz, minor), 27.1 (d, J ) 4.6
Hz, minor), 27.4 (d, J ) 4.3 Hz, major), 27.66 (minor), 27.67
(major), 33.3 (major), 33.7 (minor), 44.5 (d, J ) 129.0 Hz, major),
45.4 (major), 45.5 (minor), 45.8 (d, J ) 127.72 Hz, minor), 46.7
(d, J ) 12.1 Hz, major), 47.2 (d, J ) 11.6 Hz, minor), 61.3 (major),
61.6 (minor), 62.8 (d, J ) 6.9 Hz, major), 62.7 (d, J ) 6.7 Hz,
minor), 112.4 (2×, minor), 112.5 (2×, major), 116.6 (minor), 116.9
(major), 129.0 (2×, minor), 129.1 (2×, major), 148.2 (minor), 148.6
(major), 169.2 (d, J ) 5.1 Hz, major), 170.1 (d, J ) 5.0 Hz, minor);
31P NMR (CDCl3) δ 23.65 (35%), 24.52 (65%); HRMS calcd for
C21H36NO5PNa [M + Na]+ 436.2229, found 436.2234.
General Procedure for the Preparation of N-Phenyl-r-methyl-
ene-δ-lactams 14b-d. To a stirred solution of a corresponding
N-phenyl-R-diethoxyphosphoryl-δ-aminoalkanoate 19 (0.2 mmol)
in Et2O (0.4 mL) was added t-BuOK (27 mg, 0.24 mmol) and the
resulting mixture was stirred at room temperature for 30 min. Then
paraformaldehyde (30 mg, 1 mmol) was added in one portion. After
15 min the reaction mixture was quenched with brine (2 mL) and
the water layer was extracted with CH2Cl2 (3 × 4 mL). The
combined organic layers were dried over MgSO4 and evaporated,
yielding N-phenyl-R-methylene-δ-lactams 14b-d, which were
purified by flash chromatography (eluent EtOAc/pentane 1:3).
Representative Data for N-Phenyl-r-methylene-δ-lactams 14.
(R)-5-Ethyl-3-methylene-1-phenylpiperidin-2-one (14c): Color-
less oil. Yield: 48%. The ee was determined by HPLC using a
Chiralpak AD column (hexane/iPrOH 97:3); flow rate 1.0 mL/min;
τmajor ) 26.4 min, τminor ) 28.9 min (74% ee); [R]D +12.79 (c
1.83, CH2Cl2); 1H NMR (CDCl3) δ 0.89 (t, 3H, J ) 7.5 Hz),
1.33-1.41 (m, 2H), 1.89-1.97 (m, 1H), 2.31 (ddt, 1H, J ) 2.1,
12.1, 15.0 Hz), 2.73-2.77 (m, 1H), 3.41 (dd, 1H, J ) 9.3, 12.1
Hz), 3.62 (ddd, 1H, J ) 2.1, 4.4, 12.1 Hz), 5.32 (dt, 1H, J ) 1.5,
2.1 Hz), 6.24 (dt, 1H, J ) 1.5, 2.1 Hz), 7.19-7.22 (m, 3H),
7.31-7.35 (m, 2H); 13C NMR (CDCl3) δ 11.5, 25.8, 35.9, 36.0,
57.1, 123.3, 126.3 (2×), 126.9, 129.3 (2×), 137.4, 143.6, 164.3;
HRMS calcd for C14H17NONa [M + Na]+ 238.1208, found
238.1209.
(S)-5-tert-Butyl-3-methylene-1-phenylpiperidin-2-one (14d):
Colorless oil. Yield: 59%. The ee was determined by HPLC using
a Chiralpak AD column (hexane/iPrOH 90:10); flow rate 1.0 mL/
min; τmajor ) 7.6 min, τminor ) 9.1 min (94% ee); [R]D +11.37 (c
1
1.02, CH2Cl2); H NMR (CDCl3) δ 0.89 (s, 9H), 1.78-1.86 (m,
1H), 2.35 (ddt, 1H, J ) 2.4, 13.2, 15.6 Hz), 2.69-2.75 (m, 1H),
3.50-3.60 (m, 2H), 5.32 (t, 1H, J ) 2.0 Hz), 6.21 (t, 1H, J ) 2.4
Hz), 7.17-7.25 (m, 3H), 7.31-7.37 (m, 2H); 13C NMR (CDCl3) δ
27.5, 31.9, 32.0, 44.4, 53.9, 122.9, 126.4 (2×), 127.0, 129.3 (2×),
138.3, 143.8, 164.4; HRMS calcd for C16H21NONa [M + Na]+
266.1521, found 266.1516.
Acknowledgment. This work was made possible by a grant
from the Danish National Research Foundation and OChem-
School.
Supporting Information Available: General methods, char-
acterization, and NMR data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801582T
J. Org. Chem. Vol. 73, No. 21, 2008 8343