Highly enantioselective formal aza-Diels-Alder reactions with acylhydrazones and Danishefsky's diene promoted by a silicon Lewis acid

Article abstract of DOI:10.1016/j.tet.2010.03.036

Silicon Lewis acid 3 is effective for the promotion of highly enantioselective cycloaddition reactions of acylhydrazones with Danishefsky's diene (formal aza-Diels-Alder reactions). The reactions are conducted at ambient temperature for 15 min, and produc

Full text of DOI:10.1016/j.tet.2010.03.036

Tetrahedron 66 (2010) 4769–4774
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Tetrahedron
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Highly enantioselective formal aza-Diels–Alder reactions with acylhydrazones
and Danishefsky’s diene promoted by a silicon Lewis acid
*
Sharon K. Lee, Uttam K. Tambar, Nicholas R. Perl, James L. Leighton
Department of Chemistry, Columbia University, 3000 Broadway, MC 3117, New York, NY 10027, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Silicon Lewis acid 3 is effective for the promotion of highly enantioselective cycloaddition reactions of
acylhydrazones with Danishefsky’s diene (formal aza-Diels–Alder reactions). The reactions are con-
ducted at ambient temperature for 15 min, and produce the products in good yield and with high levels
of enantioselectivity. A remarkable solvent-dependent reversal in the sense of absolute stereochemical
induction has been observed. The method has been applied to an efficient and stereoselective synthesis
of the neurokinin 1 receptor antagonist casopitant.
Received 2 February 2010
Received in revised form 8 March 2010
Accepted 9 March 2010
Available online 15 March 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Silicon Lewis Acid
Aza-Diels–Alder
Acylhydrazones
Danishefsky’s Diene
Casopitant
1. Introduction
F
Cl
CO2Me
N
O
Piperidines (and derivatives thereof) represent one of the more
important heterocyclic motifs in all of medicinal chemistry and
they appear with some frequency in both approved drugs and in
ongoing drug development programs (Fig. 1). Although it is difficult
to quantify, it seems likely that synthetic accessibility and in-
accessibility play at least some role in influencing the direction that
such programs take with respect to the piperidine substructures.
Ideally, the synthetic chemistry should reach a point where any
desired piperidine structure with any substitution pattern could be
accessed rapidly and efficiently. While this is certainly a lofty goal, it
is also a worthwhile one, as the drug discovery process might be
made more efficient if questions of ready synthetic accessibility
were removed from the equation.
The diene–imine [4þ2] cycloaddition (aza-Diels–Alder) reaction
provides a direct and potentially powerful entry into substituted
piperidine derivatives, and its full development as a practical
synthetic method with wide scope is a highly desirable goal. Many
research groups have recognized this need, and there have as a re-
sult been several reports of effective enantioselective variants
involving the use of Danishefsky’s diene and various aldimine
derivatives.1 Given the effectiveness of our family of chiral silicon
Lewis acids in the promotion of a variety of transformations of
acylhydrazones,2 we decided to investigate what would be a formal
aza-Diels–Alder reaction in this context with Danishefsky’s diene.3
Me
Ph
Ph
N
N
O
O
S
Clopidogrel
O
Paroxetine
N
H
Fentanyl
Me
F3C
Me
N
N
Casopitant
O
HN
O
MeO
CF3
F
Ph
Dexmethylphenidate
N
N
Me
Ac
Figure 1. Piperidine containing bioactive compounds.
We did so both to add to the list of reactions that are effectively
promoted by these extraordinarily simple and practical Lewis acids
toward the goal of a ‘universal’ Lewis acid, and as the first step in
a program devoted to the development of a more general solution
to the asymmetric aza-Diels–Alder reaction.
2. Results and discussion
The investigation began with the reaction of benzaldehyde-
* Corresponding author.
derived benzoylhydrazone 1 and Danishefsky’s diene in the
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.036

4770
S.K. Lee et al. / Tetrahedron 66 (2010) 4769–4774
Table 1
presence of silicon Lewis acids (Scheme 1). We had at our disposal
phenylsilane 2 and neo-pentoxysilane 3. While 2 has proven
effective for a variety of transformations of acylhydrazones, it
proved ineffective for the addition of silyl ketene acetals in Man-
nich reactions.2e Indeed this ineffectiveness was the necessity that
mothered the invention of silane 3, which performed very well in
the enantioselective Mannich reactions.2e Because of the fact that
the formal aza-Diels–Alder reactions that are the subject of this
investigation are, mechanistically, Mannich reactions followed by
cyclization, it was therefore not entirely surprising when initial
experiments revealed that 2 was ineffective for the reaction of
hydrazone 1 with Danishefsky’s diene. The product dihydropyr-
idinone derivative 4 was formed, but in low yields and with poor
(<40% ee) enantioselectivity. Happily, the Mannich analogy held as
silane 3 proved very much more effective, and when the reaction
was conducted in toluene at ambient temperature for 15 min, 4 was
isolated in 82% yield and 89% ee.
Enantioselective aza-Diels–Alder reactions with acylhydrazones and Danishefsky’s
diene
O
Ar
Ar
O
OMe
NH
H
HN
R
1.5 equiv (S,S)-3
N
N
+
PhCH3, 23 °C, 15 min
OTMS
R
O
Entry
1
R
Ar
Ph
Product
Yield (%) ee (%)
BzHN
N
Ph
82
89
4
Ph
O
BzHN
N
2
3
p-Br–C6H4
Ph
Ph
72
89
O
5
Br
BzHN
N
t-Bu
Ph
Ph
O
N
O
N
Ph
Cl
O
p-CF3–C6H4
77
90
O
6
Si
Si
F3C
Cl
Me
Me
(S,S)-2 Me (~2:1 dr)
(S,S)-3 Me (~2:1 dr)
ArCONH
N
4
5
6
7
p-MeO–C6H4 p-CF3–C6H4
73
85
58
90
90
87
O
7
O
Ph
Ph
OMe
MeO
ArCONH
NH
H
BzHN
Ph
N
1
N
1.5 equiv (S,S)-3
N
+
2-Naphthyl
1-Naphthyl
p-CF3–C6H4
PhCH3, 23 °C, 15 min
O
OTMS
OTMS
Ph
Ph
O
O
8
4
82%, 89% ee
BzHN
O
OMe
N
Ph
NH
H
BzHN
Ph
O
N
N
1.5 equiv (S,S)-3
9
+
CH2Cl2, 23 °C, 15 min
1
ent-4
ArCONH
Me
53%, 33% ee
N
i-PrCH2
i-PrCH2
p-MeO–C6H4
p-MeO–C6H4
33
81
45
92
Scheme 1. Initial discovery of competent silane Lewis acid catalysts.
Me
O
O
10
ArCONH
Me
Along the way, a curious solvent effect was observed: when the
same reaction (with (S,S)-3) was conducted in CH2Cl2, ent-4 was
obtained in 53% yield and 33% ee (Scheme 1). While we have pre-
viously observed significant differences in the magnitude of the
enantioselectivity in various reactions based only on a solvent
switch, this is the first time we have observed a turnover in the
sense of absolute stereochemical induction. The mechanistic origin
of this effect is not at all clear as it appears to be nucleophile-
dependent, and we note that the phenomenon did not occur in
the aforementioned Mannich reactions with silyl ketene acetals,
rendering the effect even more mysterious.
A brief survey of the reaction scope was carried out with respect
to the hydrazone structure (Table 1). As shown, the reaction is
generally successful with a range of aromatic R groups (products
4–9, entries 1–6) providing good yields and enantioselectivities.
Occasionally the parent benzoylhydrazone required electronic
tuning for optimal results as in entries 4 and 5. In order to establish
the scope with respect to aliphatic R groups, isovaleraldehyde-
derived hydrazones were investigated as well, and initial results
were discouraging as the reactions produced 10 with poor effi-
ciency and enantioselectivity (e.g., entry 7). In the course of our
attempts to optimize this transformation CH2Cl2 was evaluated as
solvent, and this consistently led to the production of ent-10 as the
major product establishing that the solvent-dependent reversal in
absolute stereochemical induction described in Scheme 1 is not an
anomalous result limited to hydrazone 1. Additionally, the levels of
enantioselectivity obtained in reactions run in CH2Cl2 were pro-
mising, and upon optimization ent-10 was obtained in 81% yield
and 92% ee (entry 8), albeit using 2.0 equiv of the silane (S,S)-3.
N
8a
Me
ent-10
a
This reaction was performed in CH2Cl2 with 2.0 equiv of (S,S)-3 and 3.0 equiv of
Danishefsky’s diene.
As a demonstration of the power of this method rapidly to
deliver complex piperidine structures, we undertook the de-
velopment of
a brief and efficient synthesis of casopitant,
a neurokinin 1 receptor antagonist (Fig. 1).4 Hydrazone 11 was
prepared and because the synthesis required the opposite sense
of absolute stereochemical induction from that seen in Table 1, it
was treated with the enantiomeric silane (R,R)-3 and Dani-
shefsky’s diene under the standard conditions (Scheme 2). While
we were delighted to find that the desired product 12 was
produced in 90% ee, the efficiency of the reaction was poor as 12
was isolated in only 29% yield. During the course of our attempts
to optimize the efficiency of this transformation, the reaction
was conducted in CH2Cl2. As described above, we expected
a solvent-dependent reversal in the absolute sense of stereo-
chemical induction, and thus (S,S)-3 was employed in this
experiment. Gratifyingly, the steric hinderance of the ortho
methyl group (which is presumably responsible for the poor
efficiency of the reaction in toluene (cf. Table 1, entry 6)) seems
to have a beneficial effect in this case, as 12 was obtained in 82%
yield and 84% ee, a dramatic improvement over the enantiose-
lectivity observed in the reaction of hydrazone 1 in CH2Cl2 (see
Scheme 1, above).

S.K. Lee et al. / Tetrahedron 66 (2010) 4769–4774
4771
O
N
Ar
+
selectivity, the significantly reduced overall yield of this reaction
raises the possibility that the minor (trans) diastereomer is se-
lectively destroyed under these conditions. Either way, we had in
hand a synthetically viable one-pot tandem reduction/reductive
amination that produced 13 in 54% isolated yield.
OMe
OMe
ArHN
N
NH
H
1.5 equiv (R,R)-3
Toluene, 23 °C, 15 min
O
O
OTMS
12
11
29%, 90% ee
F
Me
Completion of the synthesis was straightforward (Scheme 4):
F
F
Me
7
reductive cleavage of the hydrazide N–N bond with SmI2 pro-
Ar = p-MeO-C6H4
O
N
Ar
+
ceeded smoothly and the unpurified product 15 was subjected to
urea formation with known amine 168 and triphosgene to give
casopitant in 58% overall yield (consistent with the fact that 15
went into the urea formation with 84% ee, a minor amount
(w11.5:1) of a diastereomer was formed in this reaction as well).
Formation of the HCl salt was carried out for the purposes of
identification, and the 1H NMR spectrum of the HCl salt in DMSO-d6
matched the reported signals.4 Overall, the synthesis proceeds in
four steps from hydrazone 11 in 26% overall yield.
ArHN
N
NH
H
1.5 equiv (S,S)-3
CH2Cl2, 23 °C, 30 min
OTMS
12
11
82%, 84% ee
F
Me
Me
Scheme 2. Optimization of the aza-Diels–Alder reaction with hydrazone 11.
With efficient access to 12 in enantiomerically enriched form
secured, we turned to the next stereochemical challenge, a dia-
stereoselective reductive amination to install the piperazine ring.
ArHN
N
HN
SmI2
Reduction of the alkene was also required and
a tandem
THF, MeOH
-78 °C
N
N
reduction/reductive amination employing metal-catalyzed
hydrogenation seemed an attractive possibility. Subjection of 12
to Pd(OH)2-catalyzed hydrogenation in the presence of 1-ace-
tylpiperazine did indeed lead to the production of the desired
product 13 as the major product of a 2.3:1 mixture of di-
astereomers isolated in 87% yield (Scheme 3). Hopeful that we
might optimize this reaction for improved diastereoselectivity,
we viewed this as a positive result until we discovered that 13
had been produced in nearly racemic form (<10% ee).5 In
considering the mechanism of this racemization, ketone 14, the
product of the initial alkene reduction, seemed the likely culprit,
and we hypothesized that a retro-Mannich/Mannich reaction
sequence was responsible for the racemization, presumably cat-
alyzed by traces of acid. If this was correct, it seemed that
a simple solution might be to simply add base to the reaction.
Indeed, when the tandem reduction/reductive amination
reaction was repeated in the presence of Hunig’s base under
otherwise identical conditions, 13 was isolated in 54% yield with
complete retention of optical activity.6 Surprisingly, we also
observed a significant boost in the diastereoselectivity of the
reductive amination to 7:1. While one explanation for this is that
the Hunig’s base is somehow directly impacting the kinetic
13
N
N
F
Me
Ac
F
Me 15
Ac
Me
F3C
Me
Triphosgene,
i-Pr2NEt,
N
H
CH2Cl2, reflux
16
CF3
58%
(2 steps)
Me
Me
O
F3C
Me
N
F3C
HCl
Et2O
Me
N
N
Casopitant
O
N
H
N
CF3
F
CF3
F
N
N
N
Cl
Me
Ac
Me
Ac
Scheme 4. Completion of the synthesis of casopitant.
3. Conclusion
Silane Lewis acid
3
is effective for the enantioselective
promotion of (formal) aza-Diels–Alder (ADA) reactions of acyl-
hydrazones with Danishefsky’s diene, adding to the versatility of
this practical family of silicon Lewis acids. The reactions are
extraordinarily simple to perform, and generally provide for good
yields and enantioselectivities. An unusual solvent-dependent
reversal in the sense of absolute stereochemical induction
was observed, but the mechanistic basis for this effect remains
mysterious as the phenomenon seems to be limited to this
particular reaction. A brief and stereoselective synthesis of the
neurokinin 1 receptor antagonist casopitant has been developed
based on the use of the ADA reaction reported herein. The
synthesis establishes the utility of the method in allowing rapid
access to stereochemically and functionally complex bioactive
piperidine derivatives.
HN
N
ArHN
ArHN
Ac
N
N
10 wt. % Pd(OH)2
O
N
160 psi H2
MeOH, 60 °C
13
N
12
(84% ee)
F
Me
F
Me
87%, 2.3:1 dr
Ac
Ar = p-MeO-C6H4
(<10% ee!)
+
ArHN
ArHN
Ar'
ArHN
N
N
N
Ar'
O
OH
Ar'
O
14
ent-14
HN
4. Experimental
4.1. General
N
ArHN
ArHN
Ac
N
N
7:1 dr
10 wt. % Pd(OH)2
O
N
160 psi H2
i-Pr2NEt
13
Me
N
All reactions were carried out under an atmosphere of nitrogen
in flame- or oven-dried glassware with magnetic stirring unless
otherwise indicated. Degassed solvents were purified by passage
through an activated alumina column. Silane Lewis acids (S,S)-3
and (R,R)-3 were prepared from (S,S)- and (R,R)-pseudoephedrine,
12
F
Me
F
Ac
MeOH, 60 °C
54% (84% ee)
(isolated pure major diastereomer)
(84% ee)
Scheme 3. Development of a tandem reduction/diastereoselective reductive amina-
tion reaction.

4772
S.K. Lee et al. / Tetrahedron 66 (2010) 4769–4774
respectively, using the previously reported procedure.2e 4-Fluoro-2-
methylbenzaldehyde, 1-acetylpiperazine, trans-1-methoxy-3-trime-
thylsilyloxy-1,3-butadiene (Danishefsky’s diene), benzhydrazide,
4-methoxybenzhydrazide, and 4-trifluoromethylbenzhydrazide
were purchased from Aldrich. Amine 16 was prepared according to
a literature procedure.9 1H NMR spectra were recorded on a Bruker
DPX-400 (400 MHz) spectrometer and are reported in part per
million from CDCl3 internal standard (7.26 ppm), CD3OD internal
standard (4.78 ppm and 3.31 ppm), or (CD3)2SO internal standard
(2.50 ppm). Data are reported as follows: (s¼singlet, br s¼broad
singlet, br d¼broad doublet, br t¼broad triplet, d¼doublet, t¼triplet,
q¼quartet, quin¼quintet, m¼multiplet, dd¼doublet of doublets,
ddd¼doublet of doublet of doublets, sept¼septet; coupling
constant(s) in hertz; integration). Proton decoupled 13C NMR spectra
were recorded on a Bruker DPX-300 (75 MHz) spectrometer and are
reported in parts per million from CDCl3 internal standard
(77.23 ppm), CD3OD internal standard (49.15 ppm), or (CD3)2SO
internal standard (39.51 ppm). Infrared spectra were recorded on
a Perkin Elmer Paragon 1000 FT-IR spectrometer. Optical rotations
were recorded on a Jasco DIP-1000 digital polarimeter. Low-
resolution mass spectra were obtained on a JEOL HX110 mass spec-
trometer in the Columbia University Mass Spectrometry Laboratory.
157.2, 141.6, 131.1 (q, J¼17.7 Hz), 131.1, 128.8, 128.0, 127.0, 126.2 (q,
J¼4.3 Hz),123.7 (q, J¼270.6 Hz), 65.1, 44.7; IR (thin film) 3244, 3041,
3007, 1662, 1582 cmꢁ1; LRMS (FABþ) calcd for C19H15F3N2O2
([MþH]þ): 361.3, found: 361.2 ([MþH]þ).
4.2.4. Product 7 (Table 1, entry 4). After reaction and workup as in
the representative procedure above, the title compound was
isolated as an oil (73% yield). Analysis by chiral HPLC (Daicel
Chiralpak AD-H, 80:20 hexane/ethanol, 1.0 mL/min, 254 nm) gave
22
90% ee for the product. [
(400 MHz, CDCl3)
a]
¼ꢁ150.6 (c 1.2, CHCl3); 1H NMR
D
d
7.93 (br s, 1H), 7.58 (d, J¼8.5 Hz, 2H), 7.44 (d,
J¼7.5 Hz, 2H), 7.28–7.20 (overlap, 2H), 6.88–6.83 (m, 2H), 5.20 (d,
J¼8.1 Hz, 1H), 5.15 (dd, J¼15.2, 4.7 Hz, 1H), 2.92 (dd, J¼17.1, 15.0 Hz,
1H), 2.61 (ddd, J¼16.6, 4.6, 1.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
192.4, 166.0, 160.0, 156.5, 134.8, 134.1 (q, J¼34.6 Hz), 129.0, 128.8,
127.5, 125.8 (q, J¼3.7 Hz), 123.3 (q, J¼272.9 Hz), 64.9, 55.3, 44.9; IR
(thin film) 3227, 2992, 1646, 1579 cmꢁ1; LRMS (FABþ) calcd for
C20H17F3N2O3 ([MþH]þ): 391.4, found 391.2 ([MþH]þ).
4.2.5. Product 8 (Table 1, entry 5). After reaction and workup as in
the representative procedure above, the title compound was
isolated as an oil (85% yield). Analysis by chiral HPLC (Daicel
Chiralpak OD, 80:20 hexane/isopropanol,1.0 mL/min, 254 nm) gave
22
4.2. Representative procedure for the aza-Diels–Alder
reaction
90% ee for the product. [
(400 MHz, CDCl3)
a
]
ꢁ151.2 (c 1.1, CHCl3); 1H NMR
D
d
7.91 (br d, J¼8.9 Hz, 1H), 7.87–7.78 (m, 4H),
7.55–7.50 (m, 5H), 7.39 (br d, J¼8.3 Hz, 2H), 7.31 (d, J¼8.0 Hz, 1H),
5.44 (dd, J¼16.8, 3.8 Hz, 1H), 5.31 (d, J¼8.4 Hz, 1H), 3.08 (dd, J¼17.8,
15.9 Hz, 1H), 2.75 (dd, J¼16.8, 3.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
4.2.1. Product 4 (Table 1, entry 1). To a solution of silane (S,S)-3
(151 mg, 0.48 mmol) in toluene (3 mL) was added hydrazone 1
(71 mg, 0.32 mmol). After 3 min Danishefsky’s diene (110 mg,
0.64 mmol) was added. After 15 min, the reaction was quenched by
the addition of 1 N HCl (5 mL) and the resulting mixture was stirred
for 5 min. The mixture was extracted with ethyl acetate (3ꢀ5 mL),
and the combined organic phases were dried over Na2SO4, filtered,
and concentrated. Purification of the residue by flash chromatog-
raphy (2:3 hexanes/EtOAc) provided the product (4) as a yellow oil
(76 mg, 82%). Analysis by chiral HPLC (Daicel Chiralpak AD-H, 80:20
d
192.0, 166.1, 156.6, 134.6, 134.5, 134.1 (q, J¼33.3 Hz), 133.4, 133.2,
129.4, 127.9, 127.8, 127.5, 127.4, 126.9, 126.8, 125.8 (q, J¼3.3 Hz),
124.1, 123.2 (q, J¼273.1 Hz), 102.9, 65.7, 44.9; IR (thin film) 3233,
3057, 3010, 1660, 1657, 1586 cmꢁ1
;
LRMS (FABþ) calcd for
C23H17F3N2O2 ([MþH]þ): 411.4, found 411.3 ([MþH]þ).
4.2.6. Product 9 (Table 1, entry 6). After reaction and workup as in
the representative procedure above, the title compound was
isolated as an oil (58% yield). Analysis by chiral HPLC (Daicel
hexane/isopropanol, 1.0 mL/min, 254 nm) gave 89% ee for the
22
product. [
a
]
D
ꢁ151.2 (c 2.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.26
Chiralpak OD, 80:20 hexane/isopropanol,1.0 mL/min, 254 nm) gave
22
(s, 1H), 7.39–7.35 (m, 1H), 7.27–7.20 (m, 9H), 7.16 (d, J¼7.6 Hz, 1H),
87% ee for the product. [
(400 MHz, CDCl3)
a
]
ꢁ132.0 (c 2.1, CHCl3); 1H NMR
D
5.14–5.09 (overlap, 2H), 2.83 (dd, J¼16.4, 15.1 Hz, 1H), 2.53 (ddd,
d
8.29 (s, 1H), 7.91 (d, J¼7.6 Hz, 1H), 7.86 (d,
J¼16.7, 4.5,1.0 Hz,1H); 13C NMR (75 MHz, CDCl3)
d
192.2,167.3,157.1,
J¼8.6 Hz, 1H), 7.73–7.37 (m, 7H), 7.24–7.20 (m, 2H), 7.14–7.12
137.4,132.5,131.4,129.2,129.0,128.7,127.6,127.0,102.2, 65.5, 44.8; IR
(thin film) 3240, 3064, 3006, 1663, 1636, 1519 cmꢁ1; LRMS (FABþ)
calcd for C18H16N2O2 ([MþH]þ): 293.3, found: 293.3 ([MþH]þ).
(overlap, 2H), 6.05–5.99 (m, 1H), 5.35 (m, 1H), 3.28 (m, 1H), 2.82 (br
d, J¼17.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 192.0, 167.5, 157.1,
134.1, 132.8, 132.3, 131.3, 130.7, 129.3, 128.5, 126.9, 126.0, 125.4,
122.6, 102.1, 43.8; IR (thin film) 3236, 3067, 3007, 1641, 1575 cmꢁ1
;
4.2.2. Product 5 (Table 1, entry 2). After reaction and workup as in
the representative procedure above, the title compound was
isolated as an oil (72% yield). Analysis by chiral HPLC (Daicel
LRMS (FABþ) calcd for C22H18N2O2 ([MþH]þ): 343.4, found 343.9
([MþH]þ).
Chiralpak OD, 90:10 hexane/isopropanol, 1.0 mL/min, 254 nm) gave
4.2.7. Product ent-10 (Table 1, entry 8). To a solution of silane (S,S)-
3 (1.34 g, 4.26 mmol) in dichloromethane (28 mL) was added the
hydrazone (R¼i-PrCH2, Ar¼p-MeO–C6H4) (500 mg, 2.13 mmol).
After 3 min Danishefsky’s diene (1.10 g, 6.39 mmol) was added.
After 15 min, the reaction was quenched by the addition of 1 N HCl
(10 mL) and the resulting mixture was stirred for 5 min. The mix-
ture was extracted with dichloromethane (3ꢀ20 mL) and the
combined organic phases were dried over Na2SO4, filtered, and
concentrated. Purification of the residue by flash chromatography
(2:3 hexanes/EtOAc) provided the product as a yellow oil (522 mg,
81% yield). Analysis by chiral HPLC (Daicel Chiralpak AD-H, 90:10
22
89% ee for the product. [
a
]
ꢁ189.62 (c 0.8, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
8.25 (s, 1H), 7.52–7.34 (m, 6H), 7.26–7.24
(overlap, 3H), 5.23–5.18 (overlap, 2H), 2.91–2.81 (m, 1H), 2.65–2.57
(m, 1H); 13C NMR (75 MHz, CDCl3)
d
191.7, 167.1, 157.0, 136.5, 132.6,
132.4, 131.2, 129.2, 128.8, 127.0, 122.9, 102.7, 64.9, 44.7; IR (thin film)
3240, 3005, 1655, 1584 cmꢁ1; LRMS (FABþ) calcd for C18H15BrN2O2
([MþH]þ): 371.2, found: 371.2 ([MþH]þ).
4.2.3. Product 6 (Table 1, entry 3). After reaction and workup as in
the representative procedure above, the title compound was
isolated as an oil (77% yield). Analysis by chiral HPLC (Daicel
hexane/isopropanol, 1.0 mL/min, 254 nm) gave 92% ee for the
22
Chiralpak AD-H, 90:10 hexane/isopropanol, 0.8 mL/min, 254 nm)
product. [
a
]
D
þ52.4 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.89
22
gave 90% ee for the product. [
(400 MHz, CDCl3)
a]
ꢁ205.6 (c 1.6, CHCl3); 1H NMR
(s, 1H), 7.82 (d, J¼9.1 Hz, 2H), 7.12 (d, J¼8.6 Hz, 2H), 6.96 (d,
J¼8.6 Hz, 2H), 5.07 (d, J¼7.6 Hz, 1H), 4.10–4.06 (m, 1H), 3.87 (s, 3H),
2.75 (dd, J¼16.9, 5.0 Hz, 1H), 2.41 (dd, J¼15.8, 11.5 Hz, 1H), 1.65–1.50
D
d
8.50 (s, 1H), 7.62 (d, J¼7.8 Hz, 2H), 7.51–7.47 (m,
3H), 7.41–7.39 (m, 2H), 7.35–7.24 (m, 3H), 5.31 (dd, J¼15.2, 5.1 Hz,
1H), 5.22 (dd, J¼8.5, 1.1 Hz, 1H), 2.85 (dd, J¼16.9, 14.5 Hz, 1H), 2.62
(overlap, 3H); 13C NMR (75 MHz, CDCl3)
d 192.7, 166.2, 163.2, 156.6,
(dd, J¼16.6, 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
191.4, 167.1,
129.3, 123.5, 114.2, 100.7, 59.2, 55.5, 41.9, 39.5, 24.3, 23.7, 21.4; IR

S.K. Lee et al. / Tetrahedron 66 (2010) 4769–4774
4773
(thin film) 3234, 1657, 1606, 1579 cmꢁ1; LRMS (FABþ) calcd for
Ar–H), 6.76–6.67 (overlap, 4H, Ar–H), 4.45 (br d, J¼11.7 Hz, 1H,
Ar–CHN), 3.68 (s, 3H, Ar–OCH3), 3.55–3.50 (m, 4H, CH2NCOCH2),
3.13–3.07 (m, 1H, NNCHH), 2.95–2.93 (m, 1H, NNCHH), 2.54–2.44
(m, 4H, CH2NCH2), 2.32 (s, 3H, Ar–CH3), 2.25 (m, 1H, NCHCH2CH–
Ar), 2.03–2.0 (overlap, 6H, NCOCH3, NNCH2CHH, NNCH2CHH, Ar–
CHCHH), 1.64 (br t, J¼11.8 Hz, 1H, Ar–CHCHH); 13C NMR (75 MHz,
C17H22N2O3 ([MþH]þ): 303.4, found: 303.3 ([MþH]þ).
4.3. Synthesis of hydrazone 11
To
a
solution of 4-fluoro-2-methylbenzaldehyde (5.0 g,
36 mmol) in ethanol (160 mL) was added 4-methoxybenzhy-
drazide (5.5 g, 33 mmol). The reaction mixture was stirred for 5 h
and filtered. The collected solids were washed with hexanes and
dried to provide a white solid (8.3 g, 82% yield). 1H NMR (400 MHz,
CD3OD)
d
170.5, 167.5, 162.8, 161.7 (d, J¼245.4 Hz), 137.6, 137.0,
129.0, 126.0, 116.2 (d, J¼21.5 Hz), 113.6, 112.6 (d, J¼20.4 Hz), 58.8,
56.6, 54.8, 51.4, 50.5, 50.0, 47.7, 42.0, 37.0, 27.5, 20.1, 18.5; IR (thin
film) 3228, 2958, 2923, 2860, 2361, 1629, 1500, 1450, 1248 cmꢁ1
;
CD3OD)
7.85–7.81 (m, 2H, Ar–H), 6.96–6.94 (m, 2H, Ar–H), 6.91–6.87
(overlap, 2H, Ar–H), 3.78 (s, 3H, Ar–OCH3), 2.40 (s, 3H, Ar–CH3); 13
NMR (75 MHz, CD3OD)
d
8.54 (s, 1H, CH]N), 8.01 (dd, J¼10.9, 5.7 Hz, 1H, Ar–H),
LRMS (FABþ) calcd for C26H33FN4O3 ([MþH]þ): 469.6, found: 469.3
([MþH]þ).
C
d
166.8, 165.0 (d, J¼226.1 Hz), 164.5, 147.4,
4.6. Synthesis of casopitant
141.7, 130.7, 130.0, 129.9, 126.0, 118.1 (d, J¼21.7 Hz), 115.0, 114.7 (d,
J¼22.3 Hz), 56.0, 19.3; IR (thin film) 3221, 3042, 1643, 1606,
1257 cmꢁ1; LRMS (FABþ) calcd for C16H15FN2O2 ([MþH]þ): 287.3,
found: 287.2 ([MþH]þ).
To a cooled (ꢁ78 ꢂC) solution of 13 (30 mg, 0.064 mmol) in
degassed methanol(1 mL) wasadded SmI2 (3.2 mL ofa 0.1 M solution
in THF, 0.32 mmol). The cooling bath was removed and the mixture
was allowed to warm to room temperature (w20 min) and the
reaction was then quenched by exposure to air for w2 min. The
resulting mixture was concentrated and diluted with EtOAc (5 mL)
and 1 N NaOH (3 mL). The mixture was extracted with EtOAc
(3ꢀ10 mL). The combined organic phases were washed with brine
(2ꢀ2 mL), dried over Na2SO4, filtered, and concentrated. The
resultingviscousyellowoil wasco-evaporatedwithdichloromethane
(2ꢀ1 mL). To a solution of the residue in dichloromethane (0.5 mL)
was added diisopropylethylamine (0.1 mL) and the resulting mixture
was cooled to 0 ꢂC. A solution of triphosgene (39 mg, 0.13 mmol) in
dichloromethane (0.5 mL) was then added, and the resulting reaction
mixture was allowed to warm to ambient temperature over the
course of w15 min. A solution of amine 16 (54 mg, 0.20 mmol) in
dichloromethane (0.5 mL) was then added. The reaction flask was
fitted with a reflux condenser and the mixture was heated at reflux
for 48 h (oil bath, external temperature 50 ꢂC). After being allowed to
cool to room temperature, the reactionwas quenched by the addition
of aq satd NaHCO3 (2 mL) and the mixture was then extracted with
dichloromethane(3ꢀ5 mL). The combined organicphaseswere dried
over Na2SO4, filtered, and concentrated. Purification of the residue by
flash chromatography (1:5:100 NEt3/EtOH/EtOAc) afforded casopi-
4.4. Synthesis of dihydropyridinone 12
To
a solution of silane (S,S)-3 (141 mg, 0.449 mmol) in
dichloromethane (2.5 mL) was added hydrazone 11 (86 mg,
0.30 mmol). After 3 min, Danishefsky’s diene (155 mg, 0.900 mmol)
was added. After 30 min, the reaction mixture was quenched by the
addition of 1 N HCl (2 mL) and the resulting mixture was stirred for
5 min. The mixture was extracted with dichloromethane
(3ꢀ10 mL), and the combined organic phases were dried over
Na2SO4, filtered, and concentrated. Purification of the residue by
flash chromatography (2:3 hexanes/EtOAc) provided the product as
a yellow oil (87 mg, 82% yield). Analysis by chiral HPLC (Daicel
Chiralpak OD, 87:13 hexane/ethanol, 1.0 mL/min, 254 nm) gave 84%
22
ee for the product. [
CD3OD)
a]
þ184.9 (c 1.4, CHCl3); 1H NMR (400 MHz,
D
d
7.55 (br s, 1H, N–H), 7.51 (dd, J¼8.8, 5.7 Hz, 1H, Ar–H),
7.36–7.33 (m, 2H, Ar–H), 7.31 (d, J¼8.1 Hz, 1H, OCC]CH), 7.00 (dt,
J¼8.0, 2.5 Hz, 1H, Ar–H), 6.86–6.82 (overlap, 3H, Ar–H), 5.59 (dd,
J¼14.7, 4.7 Hz, 1H, NCH–Ar), 5.28 (dd, J¼8.2, 1.4 Hz, 1H, C]CHN).
3.81 (s, 3H), 2.88 (dd, J¼17.6, 15.2 Hz, 1H, Ar–CCHHCO), 2.63 (ddd,
J¼17.2, 4.5, 1.2 Hz, 1H, Ar–CCHHCO), 2.26 (s, 3H, Ar–CH3); 13C NMR
(75 MHz, CDCl3)
d
192.4, 167.2, 163.4, 162.4 (d, J¼248.0 Hz), 158.4,
tant as an oil (23 mg, 58%) as well as a small amount of a diasteromer.
22
139.5 (d, J¼8.5 Hz), 132.2, 129.4, 128.8 (d, J¼8.7 Hz), 123.9, 118.2 (d,
Data for casopitant: [
a
]
ꢁ4.1ꢂ (c 0.3, CHCl3). 1H NMR (400 MHz,
D
J¼22.3 Hz),114.4,114.3 (d, J¼22.3 Hz),102.5, 61.4, 55.8, 45.0,19.5; IR
CDCl3)
d
7.78 (s, 1H, Ar–H), 7.58 (s, 2H, Ar–H), 7.15 (dd, J¼8.7, 6.2 Hz,
(thin film) 3247, 2969, 1652, 1607, 1579, 1500, 1256 cmꢁ1
.
1H, Ar–H), 6.84 (dd, J¼10.0, 2.8 Hz, 1H, Ar–H), 6.78 (dt, J¼9.5, 2.8 Hz,
1H, Ar–H), 5.56 (q, J¼7.1 Hz,1H, NCHCH3), 4.29 (dd, J¼11.8, 2.5 Hz, 1H,
Ar–CHN), 3.64–3.53 (m, 2H, CH2OCNCH2), 3.44 (br t, J¼4.7 Hz, 2H,
CHHOCNCHH), 3.38–3.35 (m, 1H, OCNCHHCH2), 2.86 (t, J¼12.8 Hz,
1H, OCNCHHCH2), 2.73 (s, 1H, NCH3), 2.58–2.50 (overlap, 5H,
CH2NCH2, HCNCH2), 2.44 (s, 3H, NOCH3), 2.07 (s, 1H, Ar–CH3), 2.00–
1.93 (overlap, 2H, CHHCH–Ar, OCNCH2CHH), 1.69–1.57 (m, 1H,
OCNCH2CHH), 1.53–1.46 (m, 1H, CHHCH–Ar), 1.43 (d, J¼7.4 Hz, 3H);
4.5. Synthesis of 13
To a glass liner equipped with a stir bar was added a solution of
12 (422 mg, 1.19 mmol) in methanol (12 mL). Diisopropylethyl-
amine (0.4 mL), 1-acetylpiperazine (305 mg, 2.38 mmol), and 20%
Pd(OH)2/C (42 mg) were added. The glass liner was then placed into
a Parr bomb, and the gas inlet/pressure gage assembly was screwed
onto the bomb apparatus. The bomb was charged to 200 psi with
H2 and slowly vented to 160 psi. The bomb was then immersed in
an oil bath heated to 60 ꢂC. After 48 h, the oil bath was removed and
after the apparatus had cooled to room temperature it was vented.
The residue was diluted with methanol (15 mL) and filtered
through a pad of Celite. After concentration, the resulting viscous
yellow oil was purified via flash chromatography (1:9 MeOH/EtOAc
to 3:7 MeOH/EtOAc) to afford 13 contaminated with silica gel. The
mixture was treated with EtOAc, filtered, and concentrated to af-
ford 13 (300 mg, 54% yield) as a yellow oil. (The minor diastereomer
was isolated as well in this fashion and that isolation allowed us to
determine a dr for the reaction of w7:1.) The relative stereo-
13C NMR (75 MHz, CDCl3)
d
168.8, 165.4, 161.1 (d, J¼243.2 Hz), 143.8,
138.2, 137.0 (d, J¼7.7 Hz), 131.9 (q, J¼35.1 Hz), 127.1, 125.9 (d,
J¼7.7 Hz), 123.2 (q, J¼272.0 Hz), 121.3 (q, J¼4.1 Hz), 117.1 (d,
J¼22.9 Hz),112.7 (d, J¼20.7 Hz), 61.5, 56.4, 52.0, 49.4, 49.0, 48.6, 46.5,
41.6, 36.8, 29.7, 27.7, 21.2, 19.4, 15.5; IR (thin film) 2943, 2829, 2342,
1649, 1434, 1370, 1279, 1169, 1126 cmꢁ1; LRMS (FABþ) calcd for
C30H35F7N4O ([MþH]þ): 616.6, found: 617.4 ([MþH]þ).
4.7. Identity of casopitant
A list of signals in the 1H NMR spectrum of the HCl salt of
casopitant in DMSO-d6 has been published.4 In order to confirm our
synthesis of casopitant, we prepared the HCl salt of our synthetic
material, and took its 1H NMR spectrum in DMSO-d6, and found
complete agreement with the published data. Our spectrum is
reproduced here:
chemistry of 13 was proven to be cis based on 1H NMR COSY and
22
NOESY analysis. Data for 13: [
(400 MHz, CD3OD)
a]
ꢁ1.88 (c 0.4, CHCl3); 1H NMR
D
d
7.60–7.56 (m, 1H, Ar–H), 7.27–7.23 (m, 2H,

4774
S.K. Lee et al. / Tetrahedron 66 (2010) 4769–4774
Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2006, 45, 4796; (m)
Acknowledgements
Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am.
Chem. Soc. 2007, 129, 7216; (n) Shang, D.; Xin, J.; Liu, Y.; Zhou, X.; Liu, X.; Feng, X.
J. Org. Chem. 2008, 73, 630.
2. (a) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596; (b)
Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686; (c) Shirakawa,
S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858; (d) Shirakawa, S.;
Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 9974; (e) Notte, G. T.;
Leighton, J. L. J. Am. Chem. Soc. 2008, 130, 6676; (f) Valdez, S. C.; Leighton, J. L.
J. Am. Chem. Soc. 2009, 131, 14638.
This work was supported by a grant from the National Science
Foundation (CHE-08-09659). S.K.L. is a National Science Foundation
Graduate Research Fellow and U.K.T. is a National Institutes of
Health Postdoctoral Fellow (F32 GM077937). We thank Boehringer-
Ingelheim for a Graduate Fellowship to N.R.P.
3. (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400; (b) Danishefsky, S. J.; DeNinno,
M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15.
References and notes
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1. (a) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749; (b) Bromidge, S.;
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Kobayashi, S.; Kusakabe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225; (f) Yamashita, Y.;
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Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456;
(k) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K. Synlett 2006, 141; (l)
5. This was revealed by completion of the synthesis as described in Scheme 4,
which involves urea formation with enantiomerically pure amine 16. An ap-
proximately 1:1 mixture of diastereomers was obtained from this reaction.
6. This was confirmed by the completion of the synthesis as described in Scheme 4.
7. (a) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994, 50, 4399;
(b) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
8. Kanai, M.; Yasumoto, M.; Kuriyama, Y.; Inomiya, K.; Katsuhara, Y.; Higashiyama,
K.; Ishii, A. Org. Lett. 2003, 5, 1007.
9. Hodges, R.; Martin, J.; Hammil, N. A.; Houson, I. N. PCT Int. Appl. WO
2006067395.