N-sulfinyl amines as a nitrogen source in the asymmetric intramolecular aza-michael reaction: Total synthesis of (-)-pinidinol

Article abstract of DOI:10.1002/chem.201000615

N-Sulfinyl amines have been successfully employed as nitrogen nucleophiles for the asymmetric intramolecular aza-Michael reaction. The synthetic strategy involves a cross-metathesis reaction followed by the Michael-type cyclization, either in a base-catalyzed two-step procedure or in a tandem fashion. The developed methodology allows access to chiral substituted pyrrolidines and piperidines bearing one or two stereocenters and it has been applied to the synthesis of the piperidine alkaloid (-)-pinidinol.

Full text of DOI:10.1002/chem.201000615

FULL PAPER
DOI: 10.1002/chem.201000615
N-Sulfinyl Amines as a Nitrogen Source in the Asymmetric Intramolecular
Aza-Michael Reaction: Total Synthesis of (À)-Pinidinol
Santos Fustero,*[a, b] Silvia Monteagudo,[a] Marꢀa Sꢁnchez-Rosellꢂ,[b] Sonia Flores,[a]
Pablo Barrio,[a] and Carlos del Pozo*[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
Abstract: N-Sulfinyl amines have been successfully employed as nitrogen nucleo-
philes for the asymmetric intramolecular aza-Michael reaction. The synthetic strat-
egy involves a cross-metathesis reaction followed by the Michael-type cyclization,
either in a base-catalyzed two-step procedure or in a tandem fashion. The devel-
oped methodology allows access to chiral substituted pyrrolidines and piperidines
bearing one or two stereocenters and it has been applied to the synthesis of the pi-
peridine alkaloid (À)-pinidinol.
Keywords: aza-Michael reaction ·
cross metathesis · sulfinylamines ·
piperidines · pyrrolidines
Introduction
tered nucleophile to an a,b-unsaturated functionality, that is,
the aza-Michael reaction, probably is the most direct way
for selectively creating a carbon–nitrogen bond at the b-po-
sition of activated olefins. A plethora of nitrogen-based nu-
cleophiles (such as amines, oximes, carbamates, amides,
azides, hydrazones, or nitrogen-containing heterocycles) and
an ample range of different acceptors (such as a,b-unsatu-
rated aldehydes, ketones, esters, amides, nitroolefins, and
vinyl sulfones) readily participate in this reaction in many
different ways. Additionally, the possibility of performing
acid or basic catalysis, or even uncatalyzed processes, offers
to synthetic organic chemists a vast array of alternatives to
carry out the aza-Michael reaction.
The impressive achievements made to date in the asym-
metric version of this transformation rely on the use of
chiral auxiliaries as the main stereochemical controllers,[4]
whereas the catalytic enantioselective aza-Michael reaction
remained undeveloped until very recently.[5] Among the two
major ways to induce asymmetry, by using chiral amines or
chiral Michael acceptors, the conjugated addition of lithium
amides as homochiral ammonia equivalents is the most pop-
ular approach, and it has been extensively used and stud-
ied.[6] However, most of the work with these chiral amines is
related to intermolecular aza-Michael reactions. The asym-
metric intramolecular version, which represents a straight-
forward way to access nitrogen heterocycles, relies on the
use of enantiomerically pure starting materials and, until
very recently, only a few reports involving enantioselective
organocatalytic processes have been published.[7]
b-Amino carbonyl derivatives bearing a heterocyclic nitro-
gen atom are especially valuable, since they are versatile
synthetic intermediates for the preparation of a wide variety
of heterocycles.[1] Among them, pyrrolidine and piperidine
substructures are worth mentioning due to their ubiquitous
presence in the skeleton of several naturally occurring alka-
loids[2] and their utility as chiral auxiliaries and chiral ligands
in asymmetric catalysis.[3]
Among the traditional methodologies for generating
chiral b-amino carbonyl compounds, asymmetric Mannich-
and aza-Michael-type reactions are the most powerful strat-
egies for the synthesis of these moieties. However, owing to
simplicity and atom economy, 1,4-addition of a nitrogen-cen-
[a] Prof. Dr. S. Fustero, S. Monteagudo, S. Flores, Dr. P. Barrio,
Dr. C. del Pozo
Departamento de Quꢀmica Orgꢁnica, Universidad de Valencia
46100-Burjassot, Valencia (Spain)
Fax : (+34)963.544.939
E-mail: santos.fustero@uv.es
carlos.pozo@uv.es
[b] Prof. Dr. S. Fustero, Dr. M. Sꢁnchez-Rosellꢂ
Laboratorio de Molꢃculas Orgꢁnicas
Centro de Investigaciꢂn Prꢀncipe Felipe
46012-Valencia (Spain)
E-mail: sfustero@cipf.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000615.
Chem. Eur. J. 2010, 16, 9835 – 9845
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9835

Table 1. Preparation of Michael acceptors 4.
On the other hand, N-sulfinyl imines are among the most
popular and efficient substrates reported to date for the ste-
reoselective addition of organometallic reagents to chiral
imines.[8] This is, in fact, a highly reliable method for the
asymmetric construction of chiral amines since the sulfinyl
group is readily cleaved by acidic treatment. However, the
use of N-sulfinyl amines as nitrogen-centered nucleophiles is
very scarce.[9] Once the sulfinyl group has exerted its direct-
ing effect, it is usually removed and the free amino group
employed for further transformations. We envisioned the
possibility of using N-sulfinyl amines both as a nitrogen
source and chiral inducers in the intramolecular aza-Michael
reaction, which would allow for the preparation of chiral
substituted pyrrolidines and piperidines bearing one or two
stereocenters (Scheme 1). In addition, the utility of this
methodology will be illustrated by the synthesis of the piper-
idine natural product (À)-pinidinol.
1
n
2 (R1)
3 (yield [%])[a]
4 (yield [%])[a,b]
1
2
3
4
1a
1a
1b
1b
1
1
2
2
(SS)-2a (pTol)
(RS)-2b (tBu)
(SS)-2a (pTol)
(RS)-2b (tBu)
(SS)-3a (90)
(RS)-3b (67)
(SS)-3c (69)
(RS)-3d (65)
(SS)-4a (70)[c]
(RS)-4b (>99)
(SS)-4c (72)
(RS)-4d (>99)
[a] Isolated yields after column chromatography. [b] Only the E isomer
was detected in all cases. [c] A mixture of diastereoisomeric pyrrolidines
5a and 6a was also obtained in 12% yield.
closing metathesis (RCM) processes.[10] After several at-
tempts, we were delighted to find out that the reaction of
amines 3 with methyl vinyl ketone in the presence of
second-generation Grubbs catalyst I and TiACTHNURGTNEUNG(OiPr)4 led to
the formation of the desired CM compounds 4 in good to
excellent yields in 2 h (Table 1).[11] It is worth mentioning
that when substrate 3a was subjected to the optimized CM
conditions, the corresponding diastereoisomeric pyrrolidines
arising from an intramolecular cyclization were isolated in
12% yield together with the desired product 4a. This result
prompted us to explore this CM aza-Michael tandem pro-
cess independently (see later).
Scheme 1. Synthetic strategy.
To find the optimum conditions for the IMAMR we de-
cided to examine the process with sulfinyl amine (SS)-4a as
a model substrate. The initial attempt was carried out with a
catalytic amount of tBuOK (0.3 equiv) in THF at room tem-
perature. After 30 min, the formation of diastereoisomeric
pyrrolidines (S,SS)-5a and (R,SS)-6a was detected in 87%
yield and in a 21:79 ratio (Table 2, entry 1). When the same
reaction was performed at À408C, we observed an inverted
selectivity, since compounds 5a/6a were isolated in a 77:23
ratio (Table 2, entry 2). When the base was added at À408C
and the reaction mixture was allowed to reach room temper-
ature in 12 h, the 23:77 (5a/6a) ratio was obtained again
(Table 2, entry 3), which proved the reversibility of the pro-
cess, with pyrrolidine (R, SS)-6a as the thermodynamic prod-
uct and (S, SS)-5a as the kinetic one. The use of other bases,
such as lithium/potassium hexamethyl disilazide (LiHMDS
and KHMDS) led to comparable results, that is, 6a was the
major product at room temperature (Table 2, entries 4 and
6), whereas an inverted selectivity was yet again observed at
À408C and kinetic product 5a was formed in a major extent
(Table 2, entries 5 and 7). A slight influence of the counter-
ion was also detected, the lithium salt gave a 36:64 (5a/6a)
ratio at room temperature, whereas the potassium salt af-
forded a 21:79 proportion (Table 2, entries 4 and 6), thus in-
dicating that an increased basicity improved the selectivi-
ty.[12] The same effect was observed at low temperature. The
influence of the solvent was evaluated in the reaction with
Cs2CO3 as a base. In these experiments, we found quite simi-
Results and Discussion
Intramolecular Aza-Michael reaction with N-sulfinyl amines
4 and 9: Our initial efforts were directed at the study of the
intramolecular aza-Michael reaction (IMAMR) on unsubsti-
tuted sulfinyl amines 4 bearing an a,b-unsaturated ketone
moiety. Following our recent results in this field,[7b,d] Michael
acceptors 4 were assembled by means of a cross-metathesis
(CM) reaction between unsaturated N-sulfinyl amines 3 and
an appropriate a,b-unsaturated compound. The CM coun-
terparts 3 were in turn prepared by reductive amination of
unsaturated aldehydes 1 and sulfinyl amines 2 (Table 1).
Metathesis reactions involving a sulfinyl group are very
scarce in the literature and most of them are related to ring-
Abstract in Spanish: En este trabajo se han utilizado N-sulfi-
nilaminas como nucleꢁfilos nitrogenados para la reacciꢁn
aza-Michael intramolecular asimꢀtrica. La estrategia sintꢀtica
implica una reacciꢁn de metꢂtesis cruzada seguida de la ci-
claciꢁn tipo Michael, bien en un proceso en dos pasos catali-
zado por una base, o bien de manera tꢂndem. La metodolo-
gꢃa desarrollada permite la obtenciꢁn de pirrolidinas y piperi-
dinas sustituꢃdas quirales con uno o dos estereocentros y se
ha aplicado a la sꢃntesis del alcaloide derivado de piperidina
(À)-pinidinol.
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Chem. Eur. J. 2010, 16, 9835 – 9845

Total Synthesis of (À)-Pinidinol
FULL PAPER
Table 2. IMAMR of N-sulfinyl amines 4a,b.
chromatography, whereas (S,SS)-5a and (R,SS)-6a were im-
possible to separate. In addition, better selectivities were
achieved in the reaction on (RS)-4b.
Next, the extension of this protocol to the synthesis of the
corresponding piperidine-derived adducts 7 and 8 was exam-
ined. Thus, compounds (SS)-4c and (RS)-4d were subjected
to the conditions mentioned above. When compound 4c was
treated with tBuOK in THF at room temperature, piperidine
(R, SS)-8a was obtained in 85% yield as a single diastereo-
4
Base
[equiv]
T
[8C]
Solvent
t
5+6
(yield
[%])[a]
d.r.
G
G
5/6[b]
1
2
3
4
5
6
7
8
9
4a tBuOK (0.3) RT
4a tBuOK (0.3) À40
THF
THF
THF
THF
THF
THF
THF
THF
30 min 5a+6a
(87)
60 min 5a+6a
(70)
21:79
77:23
23:77
36:64
63:37
21:79
77:23
69:31
75:25
72:28
73:27
85:15
20:80
81:19
78:22
15:85
Table 3. IMAMR on N-sulfinyl amines 4c,d.
4a tBuOK (0.3) À40 to
12 h
5a+6a
(78)
RT
4a LiHMDS
(0.3)
4a LiHMDS
(0.3)
4a KHMDS
(0.3)
4a KHMDS
(0.3)
RT
À40
RT
À40
RT
RT
RT
RT
10 min 5a+6a
(95)
10 min 5a+6a
(98)
10 min 5a+6a
(85)
10 min 5a+6a
(82)
4
Base
[equiv]
T
[8C]
Solvent
t
7+8
d.r.
G
(yield [%])[a] 7/8[b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
4c tBuOK (0.3)
4c tBuOK (0.3)
4c tBuOK (0.3)
RT THF
À40 THF
À78 THF
30 min 8a (85)
>1:99
4a Cs2CO3 (1)
90 min 5a+6a
(87)
30 min 7a+8a (80) 5:95
50 min 7a+8a (81) 11:89
60 min 7a+8a (82) 12:88
7a+8a (66) 5:95
30 min 7b+8b (78) 88:12
4a Cs2CO3 (1)
MeOH 30 min 5a+6a
4c LiHMDS (0.3) À78 THF
(90)
5a+6a
(86)
4c Cs2CO3 (1)
RT MeOH 12 h
RT THF
À40 THF
10 4a Cs2CO3 (1)
11 4a Cs2CO3 (1)
CH2Cl2 5 h
4d tBuOK (0.3)
4d tBuOK (0.3)
2 h
7b+8b (71) 87:13
DMF
THF
THF
THF
THF
THF
90 min 5a+6a
(68)
30 min 5b+6b
(74)
60 min 5b+6b
(69)
12 h
4d LiHMDS (0.3) À40 THF
60 min 7b+8b (68) 87:13
4d Cs2CO3 (1)
RT MeOH 12 h 7b+8b (60) 87:13
12 4b tBuOK (0.3) RT
13 4b tBuOK (0.3) À40
[a] Isolated yields after column chromatography. [b] Ratio determined by
1H NMR spectroscopic integration in the crude reaction mixture.
14 4b tBuOK (0.3) À40 to
5b+6b
(64)
RT
isomer (Table 3, entry 1). When the reaction was performed
at À408C it led to the formation of the same compound 8a
as the major product (Table 3, entry 2). Therefore, unlike
the pyrrolidine formation, in the case of the six-membered
rings, no inversion of the selectivity took place at low tem-
perature. Even at lower temperatures (À788C), the thermo-
dynamic product was mainly obtained (Table 3, entry 3)
even with other bases, such as LiHMDS or Cs2CO3 (Table 3,
entries 4 and 5). However, when substrate (RS)-4d was sub-
jected to the IMAMR, a mixture of piperidines (S,RS)-7b
and (R,RS)-8b, with predominance of 7b, was obtained in all
conditions tested either at different temperatures or with
different bases or solvents (Table 3, entries 6–9).
With these results in hand, it became apparent that com-
plete stereocontrol can be achieved in the formation of pi-
peridine (R,SS)-8a from substrate (SS)-4c, which contains a
p-tolyl group attached to the sulfoxide unit. However, the
formation of the analogous pyrrolidine (R,SS)-6a from the
N-p-tolyl sulfinyl Michael acceptor (SS)-4a took place with a
low level of diastereodifferentiation (see Table 2, entry 1).
The selectivity achieved in both cases could be attributed to
a stacked geometry of the arene and enone moieties, which
would direct the addition of the amide nitrogen to the a,b-
unsaturated ketone. Thus, the presence of an additional
carbon atom between the nitrogen and the carbon acceptor
in (SS)-4c, relative to (SS)-4a, seems crucial to gain an effec-
15 4b LiHMDS
(0.3)
16 4b KHMDS
(0.3)
À40
À40
40 min 5b+6b
(68)
40 min 5b+6b
(64)
[a] Isolated yields after column chromatography. [b] Ratio determined by
1H NMR spectroscopic integration in the crude reaction mixture.
lar selectivities independent from the solvent employed
(THF, MeOH, CH2Cl2, and DMF; Table 2, entries 8–11).
Next, our study was extended to the tert-butyl sulfinyl
amine (RS)-4b. The reaction with tBuOK at room tempera-
ture gave a 85:15 ratio of pyrrolidines (S,RS)-5b and (R,RS)-
6b and, yet again, an inversion of the selectivity was ob-
served at low temperature (Table 2, entries 12 and 13). The
reversibility of the process was confirmed when the reaction
was allowed to reach room temperature after adding the
base at À408C (Table 2, entry 14). The influence of the
counterion was bigger than in the reaction on (SS)-4a, to
such an extent that an inversion of selectivity took place
when the base changed from LiHMDS to KHMDS (Table 2,
entries 15 and 16). It is worth mentioning that the IMAMR
turned out to be more synthetically useful for substrate
(RS)-4b relative to (SS)-4a, since the products (S,RS)-5b and
(R,RS)-6b could be easily separated by means of column
Chem. Eur. J. 2010, 16, 9835 – 9845
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9837

S. Fustero, C. del Pozo et al.
tive p-stacking, hence giving a better facial selectivity in the
formation of piperidine 8a (Scheme 2).[13] Additionally, this
interaction would also explain the difference in selectivity
Scheme 2. The p-stacking interaction between the p-tolyl group and the
a,b-unsaturated ketone.
found between substrate (SS)-4c (Table 3, entry 1) and (RS)-
4d (Table 3, entry 6), which contains a tBu group attached
to the sulfoxide, since in this case only steric effects are op-
erating.
Scheme 4. CM and IMAMR with tert-butyl acrylate.
The stereochemical outcome of the overall process could
also be rationalized on the basis of this stacked geometry.
The addition of the amide nitrogen may be predicted to pro-
ceed through a chairlike transition state. Therefore, in the
transition state leading to the cyclized product (R,SS)-8a,
the sulfoxide oxygen and the amide nitrogen atom should
be located in an anti relationship thus yielding the final pi-
peridine R. The same disposition with the R enantiomer of
the starting sulfoxide is not favored in terms of electronic
and steric effects (Scheme 3).
equimolecular amounts of the diastereoisomeric pyrrolidines
(S,RS)-10a and (R,RS)-11a were obtained in 90% yield.
However, the same reaction performed at À408C led to the
almost exclusive formation of compound 11a (6:94 diaste-
reomeric ratio (d.r.)) in very good yield. In the case of Mi-
chael acceptor (RS)-9b, the same reaction at À408C afford-
ed the piperidine (S,RS)-10b as a single diastereoisomer in
94% yield.[14] Therefore, this two-step methodology allows
for the preparation of homoproline and homopipecolic acid
derivatives in very good yields and with excellent diastereo-
selectivity.
Tandem CM–IMAMR with N-sulfinyl amines 3: As men-
tioned above, in the CM reaction of substrate (SS)-3a with
methyl vinyl ketone, the formation of the corresponding pyr-
rolidine coming from an intramolecular cyclization was de-
tected to a small extent.[15] We then decided to optimize the
conditions of this CM–IMAMR tandem process to obtain
the final nitrogen heterocycles in a single step.
Since the CM between (SS)-3a and methyl vinyl ketone in
the presence of second-generation Grubbs catalyst I gave
5a+6a in 12% yield after 2 h in refluxing CH2Cl2 (Table 1,
entry 1) our first attempt was to increase the reaction time.
Thus, when a solution of (SS)-3a in CH2Cl2 was heated in
the presence of ruthenium catalyst I for 6 h, the correspond-
ing pyrrolidine was obtained in 28% yield as a mixture of
diastereoisomers 5a/6a (85:15 d.r.) (Table 4, entry 1). After
48 h, the yield of the tandem process increased to 70% and
only 10% of the CM product (SS)-4a remained uncyclized
(Table 4, entry 2). To our delight, when using second-genera-
tion Hoveyda–Grubbs catalyst II the tandem sequence took
place almost quantitatively (Table 4, entry 3). Noteworthy is
that the major product in these tandem reactions was the ki-
netic pyrrolidine (S,SS)-5a, contrasting with the reaction on
(SS)-4a under basic conditions at room temperature, for
which the major product was (R,SS)-6a (see Table 2,
Scheme 3. Rationalization of the stereochemical outcome
The next step of our study was focused on the use of
other Michael acceptors distinct from ketones. With this
purpose, compounds (RS)-9a,b bearing an a,b-unsaturated
ester moiety were synthesized by a CM reaction of sulfinyl
amines (RS)-3b,d with tert-butyl acrylate. It was necessary to
use second-generation Hoveyda–Grubbs catalyst II to
obtain good yields in the CM reaction (Scheme 4). When
compound 9a was treated with tBuOK at room temperature,
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Total Synthesis of (À)-Pinidinol
FULL PAPER
Table 4. Tandem CM–IMAMR on N-sulfinyl amines 3.
cases as the minor reaction
products relative to the CM ad-
ducts. Nevertheless, kinetic
products (S,SS)-7a and (R,RS)-
8b were once again the major
diastereoisomers (Table 4, en-
tries 9–12). These results high-
lighted the difficult formation
of piperidines, similarly to what
occurred under basic condi-
tions. Finally, all attempts per-
formed to carry out the tandem
process with alkyl acrylates 9 as
Michael acceptors were unsuc-
cessful, and products coming
from the CM reaction were ob-
tained instead.
3
Catalyst[a]
Conditions
4 (yield
5+6 or 7+8
(yield [%])[b]
d.r.
[%])[b]
G
5/6 or 7/8[c]
1
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
[Ru]-I
CH2Cl2/reflux/6 h
4a (50)
4a (10)
4a (0)
5a+6a (28)
5a+6a (70)
5a+6a (95)
5a+6a (10)
5a+6a (20)
5a+6a (60)
5b+6b (74)
5b+6b (92)
7a+8a (30)
7a+8a (25)
7b+8b (22)
7b+8b (15)
5a/6a
AHCTUNGTRENNUNG
2
[Ru]-I
CH2Cl2/reflux/48 h
AHCTUNGTRENNUNG
3
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-I
CH2Cl2/reflux/48 h
AHCTUNGTRENNUNG
4
toluene/reflux/12 h
4a (23)
4a (21)
4a (14)
4b (9)
AHCTUNGTRENNUNG
5
CH2Cl2/microwaves/1 h/1008C
CH2Cl2/microwaves/7 h/608C
CH2Cl2/reflux/48 h
AHCTUNGTRENNUNG
6
AHCTUNGTRENNUNG
Determination of the absolute
configuration of compounds 5–
8: The absolute configuration
of the newly created stereocen-
ter in pyrrolidines 5,6 and pi-
peridines 7,8 was determined
by chemical correlation. Thus,
commercially available l-Boc-
b-homoproline (Boc=tert-bu-
toxycarbonyl) was transformed
into the corresponding Weinreb
amide (S)-12, which was in turn
treated with methyl magnesium
bromide to render compound
(S)-13. On the other hand, 6b,
7
AHCTUNGTRENNUNG
8
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
CH2Cl2/reflux/48 h
4b (0)
AHCTUNGTRENNUNG
9
CH2Cl2/reflux/48 h
4c (54)
4c (41)
4d (63)
4d (77)
AHCTUNGTRENNUNG
10
11
12
ClCH2CH2Cl/reflux/48 h
CH2Cl2/reflux/48 h
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ClCH2CH2Cl/reflux/48 h
AHCTUNGTRENNUNG
[a] [Ru]-I: Cl2ACHTUNGTRENNUNG(Imes)ACHTUNGTRENNUNG(PCy3)Ru=CH-Ph. [Ru]-II: Cl2ACHTUNGTREN(UNGN Imes)Ru=CH-Ph(o-iPrOC6H4). [b] Isolated yields after
column chromatography. [c] Ratio determined by 1H NMR spectroscopic integration in the crude reaction mix-
ture.
entry 1).[16] To evaluate the influence of the temperature,
(SS)-3a was heated with catalyst II in refluxing toluene for
12 h. Unfortunately, in this case the yield dropped to 10%,
and only 23% of the CM product (SS)-4a could be isolated
(Table 4, entry 4). From this result, it can be deduced that
increasing the temperature has a negative influence on the
tandem process. Bearing in mind our recent results in the
tandem process CM–IMAMR with carbamates,[15] we decid-
ed to carry out the reaction under microwave irradiation
since it dramatically decreases the reaction time. In this
case, under microwave irradiation of (SS)-3a in the presence
of catalyst II no improvement over the regular heating con-
ditions was observed, which yet showed again the negative
effect of the temperature on the tandem protocol (Table 4,
entries 5 and 6). At this point, the optimum conditions (cat-
alyst II, refluxing CH2Cl2 for 48 h) were applied to sub-
strates 3b–d. Thus, (RS)-3b gave the kinetic pyrrolidine
(R,RS)-6b in 92% yield and in a 8:92 (5b/6b) ratio (Table 4,
entry 8). This result demonstrated again the better dia-
the kinetic product obtained in the tandem cyclization of
(RS)-3b, was treated with HCl to remove the tBu sulfinyl
group and the nitrogen atom was protected as an N-Boc
group to afford once again compound 13 (Scheme 5). Com-
paring the optical rotation of derivatives 13 obtained
ACHTUNGTRENNUNGstereoACHTUNGTRENNUNGdifferentiation induced by the tert-butyl sulfinyl group
relative to the p-tolyl sulfinyl group, likewise in the forma-
tion of these pyrrolidines under basic catalysis. Different re-
sults were obtained with substrates 3c,d since the corre-
sponding piperidines 7a,b and 8a,b were obtained in both
Scheme 5. Determination of the absolute configuration of pyrrolidines 6.
DIC=N,N’-diisopropylcarbodiimide; HOBt=N-hydroxybenzotriazole.
Chem. Eur. J. 2010, 16, 9835 – 9845
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9839

S. Fustero, C. del Pozo et al.
Table 5. Synthesis of Michael acceptors 16.
through both routes, we realized that the value found for
the product derived from 6b had an opposite sign to that
obtained from the commercially available homoproline de-
rivative. Consequently, this result allowed us to assign the
absolute configuration R,Rs to pyrrolidine 6b.
The total synthesis of the natural product Pelletierine[17]
was employed to determine the absolute configuration of
the piperidine family. Thus, removal of the chiral auxiliary
of 7b afforded piperidine 14, which contains the complete
skeleton of the natural product (Scheme 6). The optical de-
1
n
RMgX
15 (yield [%], d.r)[a]
16 (yield [%])[a][b]
1
2
3
4
1a
1a
1b
1b
1
1
2
2
iPrMgCl
PhMgCl
iPrMgCl
PhMgCl
15a (83, >99:1)
15b (70, 30:1)
15c (76, >99:1)
15d (63, >99:1)
16a (>99)
16b (82)
16c (93)
16d (84)
[a] Isolated yields after column chromatography. [b] Only the E isomer
was detected in all cases.
Table 6. IMAMR on N-sulfinyl amines 16a–d.
16
n
R
T [8C] t [min] 17+18 (yield [%])[a] d.r. 17/18[b]
Scheme 6. Determination of the absolute configuration of piperidines 7.
1
2
3
4
5
6
7
8
9
16a
16a
16b
16b
16c
16c
16c
16d
16d
1
1
1
1
2
2
2
2
2
2
iPr
iPr
Ph
Ph
iPr
iPr
RT 30
À40 60
RT 30
À40 60
RT 60
À40 90
17a+18a (93)
17a+18a (87)
17b (96)
17b (88)
17c (40)
17c+18c (70)
17c (68)
17d+18d (48)
17d+18d (76)
17d+18d (80)
86:14
21:79
>99:1
>99:1
>99:1
85:15
>99:1
92:8
viation value showed that 14 displayed the opposite configu-
ration of the natural product. Therefore, the absolute config-
uration S,Rs could be assigned to the IMAMR product 7b.
We assumed the same stereochemical outcome for the cycli-
zation of all products reported herein.
iPr À40 to RT 150
Ph
Ph
RT 60
À40 90
74:26
92:8
Evaluation of double asymmetric induction in the IMAMR:
At this point of our study, we were curious about the influ-
ence of a second stereocenter in the IMAMR substrate in
the selectivity of the process. Accordingly, to investigate a
double asymmetric induction in the cyclization, a set of
enantiomerically pure N-sulfinyl amines 16 bearing two
10 16d
Ph À40 to RT 150
[a] Isolated yields after column chromatography. [b] Ratio determined by
1H NMR spectroscopic integration in the crude reaction mixture.
stereo
centers was synthesized. The most direct way to
tendency shown by other substrates, when the reaction was
performed at À408C, the kinetic product 18a was formed to
a major extent (Table 6, entry 2). On the other hand, 16b
displayed a different behavior since it resulted, either at
room temperature or at À408C, in the pyrrolidine
(2S,5R,RS)-17b as a single diastereoisomer (Table 6, entries
3 and 4). From substrate 16c, the piperidine (2S,6R,RS)-17c
was obtained as a single product although in a moderate
40% yield at room temperature (Table 6, entry 5). At
À408C, the final product was obtained in 70% yield al-
though the selectivity dropped to (17c/18c) 85:15 (Table 6,
entry 6). Combining these last results (good selectivity at
room temperature and good yield at low temperature) and
taking advantage of the reversibility of the process, piperi-
dine 17c was obtained as a single product in 68% yield
when, after the addition of the base at À408C, the reaction
was allowed to reach room temperature (Table 6, entry 7).
Likewise, substrate (R,RS)-16d afforded (2S,6R,RS)-17d with
good selectivity (17d/18d 92:8) and moderate yield (48%)
at room temperature (Table 6, entry 8), and in good yield
access these amines was the addition of organometallic re-
agents to the corresponding sulfinyl imines. Since this reac-
tion was described to be more favorable in terms of selectiv-
ity with tert-butyl sulfinyl imines (when compared with pTol
sulfinyl imines), we decided to employ sulfinyl amine (RS)-
2b as the chiral starting sulfoxide.[18]
After condensation of 2b with aldehydes 1a,b, the addi-
tion of Grignard reagents to the intermediate N-sulfinyl
imines at À608C afforded the desired amines (RS)-15 in
good yields and with excellent selectivities. The best condi-
tions to perform the CM reaction were found to involve the
use of ruthenium catalyst II, thus rendering Michael accept-
ors (R,RS)-16 in excellent yields as single diastereoisomers
(Table 5).
The intramolecular aza-Michael addition on substrates
(R,RS)-16a–d was carried out in THF with tBuOK. At room
temperature, 16a furnished a mixture of diastereoisomeric
pyrrolidines (2S,5R,RS)-17a and (2R,5R,RS)-18a in 93%
yield and with a 86:14 ratio (Table 6, entry 1). Following the
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Total Synthesis of (À)-Pinidinol
FULL PAPER
(76%) and poor selectivity (17d/18d 74:26) at À408C
(Table 6, entry 9). Again, by adding the base at low temper-
ature and removing the cooling bath until the reaction
reached room temperature, it was possible to obtain 17d+
18d in a 92:8 ratio and with 80% combined yield (Table 6,
entry 10).
The relative configuration of the newly created stereocen-
ter in the disubstituted pyrrolidines was determined by
NOESY experiments on substrate 17a. We observed posi-
tive NOE effects between protons Ha,Hb and Hc,Hd, clearly
indicating that both substituents of the pyrrolidine ring (at
the 2- and 5-positions) are oriented towards the same direc-
tion. These results allowed us to assign the configuration
(2S,5R,RS) to pyrrolidine 17a (Scheme 7), which showed
that the stereochemical control in the process was exerted
by the sulfinyl group.
Scheme 8. Retrosynthesis of (À)-pinidinol.
methyl analogue 20b. Amine 20a was assembled by follow-
ing the strategy described before for the preparation of com-
pounds 15, that is, by addition of methyl magnesium bro-
mide to the N-sulfinyl imine generated by condensation of
aldehyde 1b and (SS)-2b. To obtain the stereochemistry of
the natural product, it was necessary to use the sulfoxide
(SS)-2b, which is the enantiomer of the starting tert-butyl
sulfinyl amine employed throughout the study. Thus, the de-
sired compound (R,SS)-20a was obtained in good yield
(74%) and with excellent selectivity (96:4 d.r.) with the ap-
propriate absolute configuration at the methyl-containing
stereocenter (Scheme 9). Substrate 20b bearing the
Scheme 7. Determination of the relative configuration of the disubstitut-
ed pyrrolidines and piperidines.
As mentioned before, the last part of our work was relat-
ed to the total synthesis of the natural product (À)-pinidinol
19a. Accordingly, the preparation of this alkaloid allowed us
to indirectly confirm the absolute configuration of the chiral
center generated in the formation of the 2, 6-disubstituted
piperidines 17c,d bearing both substituents in a cis relative
disposition (Scheme 7).
Total synthesis of (À)-pinidinol 19a and its fluorinated ana-
logue 19b: The last step of our study was focused on the ap-
plication of the developed methodology for the preparation
of cis 2,5-disubstituted pyrrolidines and 2,6-disubstituted pi-
peridines to the total synthesis of the natural product (À)-pi-
nidinol[19] and its trifluoromethyl analogue. Although these
substructures are present in several families of compounds
with interesting biological properties,[20] the choice of (À)-pi-
nidinol was based on the fact that only five asymmetric syn-
theses of this compound have been reported to date.[21] Only
those reported by Davis[21a] and Molander[21d] were consis-
tent in reaching the final product in 16 and 19% yield, re-
spectively. In both cases, their synthetic strategy was based
on an intramolecular hydroamination (IMHA) of a 1,3-
amino alcohol bearing a remote olefin (Scheme 8). Our ap-
proach will allow us to generate the complete skeleton of
the natural product through the IMAMR of the Michael ac-
ceptor depicted in Scheme 8.
Scheme 9. Synthesis of sulfinyl amines 20a and 20b.
trifluoroACTHNUTRGNEUGmN ethyl group was assembled through a slightly dif-
ferent strategy, according to a previously described proce-
dure.[22] Trifluoroacetaldehyde ethyl hemiacetal was con-
densed with (SS)-2b to afford a mixture of diastereoisomeric
sulfinyl amines. Without purification, these amines were
treated with an excess of 4-pentenylmagnesium chloride in
THF at À408C, and (S, SS)-20b was obtained with excellent
selectivity (97:3 d.r.) in 67% yield (Scheme 9).
The first step of our synthetic strategy was the prepara-
tion of the starting N-sulfinyl amines 20a and the trifluoro-
Michael acceptors 21a,b were prepared in excellent yields
by the CM reaction of amines 20a,b with methyl vinyl
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9841

S. Fustero, C. del Pozo et al.
ketone in the presence of ruthenium catalyst II. These CM
products were then subjected to the cyclization conditions
that involved the addition of tBuOK at À408C allowing the
reaction mixture to reach room temperature within 2 h. In
this way, piperidines (2R,6R,SS)-22a and (2R,6S,SS)-22b
were obtained in good yields and with excellent diastereose-
lectivities. Reduction of the carbonyl group followed by re-
moval of the sulfoxide chiral auxiliary would lead to the nat-
ural product. However, the reduction of the ketone in the
presence of the sulfoxide moiety was troublesome. All at-
tempts performed by using different reducing agents, that is,
(À)-pinidinol was 40% (from 1b and (S)-2b), which is the
highest yield reported to date in the literature. The trifluoro-
methyl analogue was obtained in 47% overall yield.
Conclusion
The use of N-sulfinyl amines as the nitrogen source in the
asymmetric intramolecular aza-Michael reaction has been
reported for the first time. Following a CM–IMAMR se-
quence, either in a stepwise or in a tandem process, it was
possible to synthesize 2-substituted pyrrolidines and piperi-
dines with good yields and excellent selectivities. Pyrrolidine
(R,RS)-6b was obtained with 92:8 d.r. and 92% yield by
means of the tandem protocol starting from tert-butyl sulfi-
nyl amine (RS)-3b (see Table 4, entry 8). Regarding the pi-
peridine family, (R,SS)-8a was achieved in 85% yield with
complete diastereoselectivity (>99:1) through the base-
mediated IMAMR (see Table 3, entry 1). An inversion of
the selectivity was observed when the reactions performed
under base catalysis or in a tandem fashion (Lewis acid cat-
alysis) were compared.
In addition, 2,5-and 2,6-disubstituted pyrrolidines and pi-
peridines, respectively, were also synthesized in very good
yields and with excellent diastereoselectivities by taking ad-
vantage of the double asymmetric induction concept. Final-
ly, the utility of the developed methodology was demonstrat-
ed by the highly efficient synthesis of the natural product
(À)-pinidinol and its fluorinated analogue.
LiEt3BH, LiACHTUNGTRENNUNG(tBuO)3AlH/LiCl, NaBH4/ZnI2, diisobutylalumi-
num hydride, Bu4NBH4, and NaBH4, different solvents, such
as CH2Cl2, Et2O, toluene, THF, and MeOH, and different
temperatures led to the formation of the desired alcohol in
poor yield (25–30%) and selectivity.[23] These difficulties
prompted us to modify the strategy, and we decided to
change the nitrogen protecting group. Removal of the sulf-
oxide group with HCl in dioxane and subsequent nitrogen
protection afforded Cbz-piperidines (2R,6R)-23a and
(2R,6S)-23b in almost quantitative yields. At this point,
after various attempts to reduce the ketone functionality, we
found that the reaction with NaBH4 in MeOH at À788C
took place in excellent yield and diastereoselectivity. Finally,
the hydrogenolysis of alcohols (2R,2R’,6R)-24a and
(2R,2Rꢅ,6S)-24b followed by acidic treatment gave rise to
the formation of (À)-pinidinol 19a and its fluorinated ana-
logue 19b again in excellent yields (Scheme 10). It is worth
mentioning that the overall yield of the total synthesis of
Experimental Section
General methods: Reactions were carried out under a nitrogen atmos-
phere unless otherwise indicated. Solvents were purified prior to use:
THF and PhMe were distilled from sodium and CH2Cl2 from calcium hy-
dride. The reactions were monitored with the aid of TLC on 0.25 mm
precoated silica-gel plates. Visualization was carried out with UV light
and aqueous ceric ammonium molybdate solution or potassium perman-
ganate stain. Flash column chromatography was performed with the indi-
cated solvents on silica gel 60 (particle size: 0.040–0.063 mm). 1H, 13C,
and 19F NMR spectra were recorded on a 300 MHz spectrometer. Chemi-
cal shifts are given in ppm (d), referenced to the residual proton resonan-
ces of the solvents or fluorotrichloromethane in 19F NMR spectroscopic
experiments. Coupling constants (J) are given in Hertz (Hz). The letters
m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet,
respectively. The letters br indicate that the signal is broad.
General procedure for the cross-metathesis reaction: synthesis of sulfinyl
amines 4, 9, 16, and 21: Methyl vinyl ketone or tert-butyl acrylate
(5.0 equiv) and second-generation Grubbs catalyst I or second-generation
Hoveyda–Grubbs catalyst II (10 mol%) were successively added to a
stirred solution of the corresponding sulfinyl amine (1.0 equiv) and Ti-
AHCTUNGTERG(NNNU OiPr)4 (10 mol%) in dichloromethane (0.1m). The mixture was heated
under reflux for 2 (for compounds 4, 9, and 21) or 12 h (for compounds
16) and then concentrated to dryness and purified by means of flash
chromatography on silica gel by using mixtures of dichloromethane/ethyl
acetate as the eluents.
(E)-7-N-[(SS)-p-Tolylsulfinyl]-3-hepten-2-one (4a): Compound (SS)-4a
(105 mg) was synthesized by following the general procedure described
above by starting from 150 mg of (SS)-3a (0.67 mmol) as a light-brown
oil (70% yield). [a]2D5 =+86.9 (c=1.0 in CHCl3); 1H NMR (300 MHz,
Scheme 10. Synthesis of pinidinol and its trifluoromethyl analogue.
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Total Synthesis of (À)-Pinidinol
FULL PAPER
CDCl3): d=1.60–1.67 (m, 2H), 2.14 (s, 3H), 2.20 (m, 2H), 2.38 (s, 3H),
2.76–2.81 (m, 1H), 2.99–3.10 (m, 1H), 4.26 (t, J=3.2 Hz, 1H), 5.97 (d,
J=16.0 Hz, 1H), 6.66 (dt, J1 =16.0, J2 =6.9 Hz, 1H), 7.28 (d, J=8.1 Hz,
2H), 7.53 ppm (d, J=8.1 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d=
21.1, 26.6, 29.0, 29.5, 40.3, 125.8, 129.5, 131.7, 141.3, 141.6 146.8,
198.0 ppm; HRMS (EI): m/z: calcd for C14H20NO2S: 266.1214 [M++1];
found: 266.1222.
N-[(SS)-p-Tolylsulfinyl]-2R-(2-oxopropyl)piperidine (8a): Compound
(R,SS)-8a was synthesized by following the general procedure described
above (method A) at room temperature by starting from 50 mg of enone
(SS)-4c (0.18 mmol) to afford 42 mg of a white solid (85% yield). M.p.=
81–838C; [a]2D5 =+76.6 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=1.40–1.81 (m, 6H), 2.16 (s, 3H), 2.38 (s, 3H), 2.72 (dd, J1 =16.5, J2 =
7.2 Hz, 1H), 2.95–3.10 (m, 2H), 3.15 (dd, J1 =16.5, J2 =6.0 Hz, 1H), 3.91–
3.98 (m, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.46 ppm (d, J=8.1 Hz, 2H);
13C NMR (75.5 MHz, CDCl3): d=20.5, 21.3, 26.2, 30.5, 30.8, 43.0, 46.2,
52.9, 126.2, 129.5, 140.5, 140.9, 206.1 ppm; HRMS (EI): m/z: calcd for
C15H21NO2S: 279.1293 [M+]; found: 279.1286.
(E)-tert-Butyl 6-N-[(RS)-tert-butylsulfinyl]-2-hexenoate (9a): Compound
(RS)-9a (129 mg) was synthesized by following the general procedure de-
scribed above by starting from 100 mg of (RS)-3b (0.53 mmol) as a light-
brown oil (84% yield). [a]2D5 =À46.7 (c=1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.17 (s, 9H), 1.44 (s, 9H), 1.65–1.74 (m, 2H),
2.18–2.25 (m, 2H), 3.03–3.22 (m, 3H), 5.72 (dt, J1 =15.6, J2 =1.5 Hz, 1H),
6.79 ppm (dt, J1 =15.6, J2 =6.9 Hz, 1H); 13C NMR (75.5 MHz, CDCl3):
d=22.5, 28.0, 29.1, 29.3, 44.9, 55.5, 80.1, 123.7, 146.4, 165.7 ppm; HRMS
(EI): m/z: calcd for C14H27NO3S: 289.1712 [M+]; found: 289.1187.
N-[(RS)-tert-Butylsulfinyl]-2S-(2-oxopropyl)-5R-isopropylpyrrolidine
(17a): Compound (2S,5R,RS)-17a was synthesized by following the gener-
al procedure described above (method A) at room temperature by start-
ing from 25 mg of enone (R,RS)-16a (0.09 mmol) to afford 20 mg of a
light-yellow oil (80% yield). [a]2D5 =À14.7 (c=1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=0.88 (dd, J1 =8.1, J2 =7.1 Hz, 6H), 1.18 (s, 9H),
1.34–1.46 (m,1H), 1.65–1.72 (m, 2H), 1.78–1.89 (m, 1H), 2.03–2.15 (m,
1H), 2.10 (s, 3H), 2.51 (dd, J1 =16.8, J2 =9.4 Hz, 1H), 2.97 (dd, J1 =16.8,
J2 =4.7 Hz, 1H), 3.58–3.64 (m, 1H), 4.10–4.19 ppm (m, 1H); 13C NMR
(75.5 MHz, CDCl3): d=17.5, 20.2, 23.5, 26.5, 30.3, 31.3, 31.4, 51.4, 57.3,
61.0, 61.2, 206.7 ppm; HRMS (FAB): m/z: calcd for C14H28NO2S:
274.1840 [M++1]; found: 274.1845.
(E)-7-N-[(RS)-tert-Butylsulfinyl][(7R)-isopropyl]-3-hepten-2-one (16a):
Compound (R,RS)-16a (141 mg) was synthesized by following the general
procedure described above by starting from 120 mg of (R,RS)-15a
(0.52 mmol) as a light-brown oil (>99% yield). [a]2D5 =+3.5 (c=1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.91 (dd, J1 =8.1, J2 =7.1 Hz,
6H) 1.19 (s, 9H), 1.40–1.68 (m, 2H), 1.87–2.08 (m, 1H), 2.10–2.21 (m,
1H), 2.13 (s, 3H), 2.29–2.45 (m, 1H), 3.00–3.08 (m, 1H), 3.14 (d, J=
7.5 Hz, 1H), 6.05 (d, J=15.9 Hz, 1H), 6.75 ppm (dt, J1 =15.9, J2 =7.1 Hz,
1H); 13C NMR (75.5 MHz, CDCl3): d=17.6, 18.4, 22.6, 26.8, 29.0, 30.3,
32.3, 56.0, 61.4, 131.4, 147.3, 198.4 ppm; HRMS (FAB): m/z: calcd for
C14H28NO2S: 274.1840 [M++1]; found: 274.1834.
N-[(SS)-tert-Butylsulfinyl]-2R-(2-oxopropyl)-6R-methylpiperidine (22a):
Compound (2R,6R,SS)-22a was synthesized by following the general pro-
cedure described above (method A) from À408C to room temperature
by starting from 150 mg of enone (R,SS)-21a (0.59 mmol) to afford 92 mg
of a light-yellow oil (61% yield). [a]2D5 =+1.2 (c=1.0 in CHCl3); 1H and
(E)-8-N-[(SS)-tert-Butylsulfinyl][(8R)-methyl]-3-octen-2-one (21a): Com-
pound (R,SS)-21a (353 mg) was synthesized by following the general pro-
cedure described above by starting from 300 mg of sulfinyl amine (R,SS)-
20a (1.38 mmol) as a light-brown oil (>99% yield). [a]2D5 =+33.4 (c=1.0
in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.17 (s, 9H), 1.24 (d, J=
6.6 Hz, 3H), 1.39–1.58 (m, 4H), 2.17–2.22 (m, 2H), 2.22 (s, 3H), 2.87 (d,
J=6.9 Hz, 1H), 3.33 (m, 1H), 6.04 (d, J=15.9 Hz, 1H), 6.75 ppm (dt,
J1 =15.9, J2 =7.1 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=22.5, 23.1,
24.2 26.9, 32.1, 37.4, 52.1, 55.5, 131.4, 147.6, 198.5 ppm; HRMS (FAB):
m/z: calcd for C13H26NO2S: 260.1684 [M++1]; found: 260.1686.
13C NMR spectra show the presence of rotamers in
a 1:1.2 ratio;
1H NMR (300 MHz, CDCl3): d=1.14 (s, 9H), 1.24 (d, J=7.5 Hz, 3H),
1.34–1.51 (m, 2H), 1.59–1.69 (m, 4H), 2.15 (s, 3H), 2.56–2.63 (m, 1H),
2.85 (d, J=6.6 Hz, 1H), 3.67–3.70 (m, 1H), 4.06–4.08 ppm (m, 1H);
13C NMR (75.5 MHz, CDCl3): d=13.8, 19.8, 21.1, 23.1, 23.9, 28.7, 30.5,
30.6, 30.7, 49.4, 58.0, 58.1, 205.8, 206.7 ppm; HRMS (FAB): m/z: calcd
for C13H26NO2S: 260.1690 [M++1]; found: 260.1692.
General procedure for the synthesis of enantioenriched amines 15 and
20a: TiACTHUNTGRNE(UGN OEt)4 (5.0 equiv) and 4-pentenal or 5-hexenal (1.1 equiv) were
added dropwise to a solution of tert-butylsulfinamide 2b (1.0 equiv) in di-
chloromethane (0.25m). The solution was stirred at room temperature for
20 h. At this time, saturated aqueous NaHCO3 was added until white tita-
nium salts precipitated. The suspension was filtered through a short pad
of Celite washing with small portions of ethyl acetate. The filtrate was ex-
tracted with ethyl acetate and the combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated under
vacuum. The crude mixture was then dissolved in dichloromethane
(0.25m) and cooled down to À608C. The appropriate Grignard reagent
(2.0 equiv) was slowly added at this temperature. After 1.5 h, the reaction
was quenched with saturated NH4Cl and extracted with dichloromethane.
The combined organic extracts were washed with brine, dried over anhy-
drous Na2SO4, concentrated under vacuum, and purified by means of
flash chromatography on silica gel by using n-hexane/ethyl acetate as the
eluents. The absolute configuration for amines 15 was assigned according
to previous results described by Ellman of Grignard additions to tert-bu-
tylsulfinimines.
Synthesis of cyclic b-amino carbonyl derivatives through the IMAMR
Method A: General procedure for the anionic cyclization: The corre-
sponding base (0.3–1 equiv) was added to a solution of sulfinyl amine
(1.0 equiv) in an appropriate solvent (0.1m), and the resulting mixture
was stirred until TLC revealed the disappearance of the starting material
(see Tables 2, 3, and 6 and Schemes 4 and 10). The reaction mixture was
then quenched with saturated aqueous NH4Cl and extracted with di-
chloromethane. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and the solvents were removed under re-
duced pressure. Finally, the crude mixtures were purified by means of
flash chromatography on silica gel by using mixtures of dichloromethane/
ethyl acetate as the eluents.
Method B: General procedure for tandem protocol: The corresponding
sulfinyl amine 3 (1.0 equiv) was dissolved in dichloromethane (0.1m) and
TiACHTUNGTRENNUNG(OiPr)4 (10 mol%) was added dropwise. Methyl vinyl ketone
(5.0 equiv) and second-generation ruthenium alkylidene catalyst I or II
(10 mol%) were successively added. The resulting solution was heated
under the conditions indicated in Table 4 and then it was concentrated to
dryness and purified by means of flash chromatography on silica gel by
using mixtures of dichloromethane/ethyl acetate as the eluents.
N-[(RS)-tert-Butylsulfinyl][(2R)-isopropyl]-6-hepten-1-amine
(15c):
Compound (R,RS)-15c (746 mg) was synthesized by following the general
procedure described above by starting from 485 mg of (R)-(+)-tert-butyl-
sulfinamide 2b (4.00 mmol) as a colorless oil (76% yield). [a]2D5 =À35.6
(c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.90 (dd, J1 =8.1,
J2 =7.1 Hz, 6H), 1.19 (s, 9H), 1.30–1.40 (m,2H), 1.40–1.56 (m, 2H), 1.89–
1.98 (m, 1H), 1.98–2.10 (m, 2H), 3.04 (m, 1H), 3.06 (m, 1H) 4.93 (ddt,
J1 =9.8, J2 =3.4, J3 =1.3 Hz, 1H), 4.98 (ddt, J1 =16.8, J2 =3.4, J3 =1.6 Hz,
1H), 5.78 ppm (ddt, J1 =16.8, J2 =9.8, J3 =3.2 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=17.7, 18.2, 22.6, 25.3, 31.1, 32.3, 33.5, 55.9, 61.8,
144.6, 138.4 ppm; HRMS (FAB): m/z: calcd for C13H28NOS: 246.1891
[M++1]; found: 246.1893.
N-[(RS)-tert-Butylsulfinyl]-2R-(2-oxopropyl)pyrrolidine (6b): Compound
(R,RS)-6b was synthesized by following the general procedure described
above (method B) by starting from 50 mg of sulfinyl amine (RS)-3b
(0.26 mmol) and methyl vinyl ketone to afford 51 mg of a light-yellow oil
(84% yield). [a]2D5 =À26.5 (c=1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.18 (s, 9H), 1.55 (m,1H), 1.70 (m, 2H), 1.88 (m, 1H), 2.17
(s, 3H), 2.60 (dd, J1 =16.8, J2 =8.8 Hz, 1H), 2.95–2.05 (m, 2H), 3.55 (dt,
J1 =7.9, J2 =5.2 Hz, 1H), 4.06 ppm (m, 1H);. 13C NMR (75.5 MHz,
CDCl3): d=23.6, 23.8, 30.6, 31.6, 44.8, 47.7, 56.7, 57.7, 206.8 ppm; HRMS
(EI): m/z: calcd for C11H22NO2S: 232.1371 [M++1]; found: 232.1381.
N-[(SS)-tert-Butylsulfinyl][(2R)-methyl]-6-hepten-1-amine (20a): Com-
pound (R,SS)-20a (640 mg) was synthesized by following the general pro-
Chem. Eur. J. 2010, 16, 9835 – 9845
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9843

S. Fustero, C. del Pozo et al.
cedure described above by starting from 500 mg of (S)-(À)-tert-butylsulfi-
namide (4.12 mmol) as a colorless oil (71% yield). [a]2D5 =+41.8 (c=1.0
in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.17 (s, 9H), 1.24 (d, J=
6.5 Hz, 3H), 1.39–1.49 (m, 4H), 1.98–2.05 (m, 2H), 2.84 (d, J=7.2 Hz,
1H), 3.32 (m, 1H), 4.93 (ddt, J1 =9.8, J2 =3.4, J3 =1.3 Hz, 1H), 4.98 (ddt,
J1 =16.8, J2 =3.4, J3 =1.6 Hz, 1H), 5.76 ppm (ddt, J1 =16.8, J2 =9.8, J3 =
3.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=22.5, 23.2, 24.9, 33.4, 37.4,
52.4, 55.5, 114.6, 138.4 ppm; HRMS (FAB): m/z: calcd for C11H24NOS:
218.1578 [M++1]; found: 218.1574.
(À)-Pinidinol·HCl (19a): Compound (2R,2R’,6R)-19a was synthesized by
following the general procedure described above by starting from 30 mg
of piperidine (2R,2R’,6R)-24a (0.10 mmol) to afford 17 mg of a white
solid (>99% yield). [a]2D5 =À21.4 (c=0.3 in CHCl3). All spectroscopic
data were corroborated by values found in literature.[21d]
General procedure for the synthesis of N-Cbz-protected amines 23: Hy-
drogen chloride (5.0 equiv, 4m solution in 1,4-dioxane) was added at
room temperature to a solution of the corresponding N-tert-butylsulfinyl
piperidine 22 (1.0 equiv) in MeOH (0.1m). After 30 min, the deprotection
was completed and the solution was concentrated to dryness. The amine
hydrochloride was taken up in 1,4-dioxane (0.1m) and then K2CO3 50%
water solution (2.0 equiv) and benzyl chloroformate (2.5 equiv) were con-
secutively added. The solution was stirred for 30 min at room tempera-
ture and concentrated under vacuum. The mixture was poured into a sep-
arating funnel over water and extracted with dichloromethane. The com-
bined organic extracts were washed with brine, dried over anhydrous
Na2SO4, concentrated under vacuum, and purified by means of flash
chromatography on silica gel by using n-hexane/diethyl ether as the elu-
ents.
Acknowledgements
Financial support of this work by the Ministerio de Educaciꢂn y Ciencia
(grant no. CTQ2007-61462) is gratefully acknowledged. M.S.-R., P.B.,
and C.P. express their thanks to the same Institution for a Juan de la
Cierva and a Ramꢂn y Cajal contract, respectively, and S.M. and S.F. ex-
press their thanks for a predoctoral fellowship.
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N-Benzyloxycarbonyl-2R-(2-oxopropyl)-6R-methylpiperidine
(23a):
Compound (2R,6R)-23a was synthesized by following the general proce-
dure described above by starting from 50 mg of piperidine (2R,6R,SS)-
22a (0.19 mmol) to afford 55 mg of a colorless oil (>99% yield). [a]D25
=
À7.1 (c=1.0 in CHCl3); 1H and 13C NMR spectra show the presence of
1
rotamers about the carbamate bond in an 1:4.5 ratio. H NMR (300 MHz,
CDCl3): d=1.16 (d, J=7.2 Hz, 0.5H), 1.25 (d, J=6.6 Hz, 2.5H), 1.52–
1.81 (m, 6H), 2.08 (s, 3H), 2.56 (dd, J1 =15.9, J2 =8.4 Hz, 1H), 2.75 (dd,
J1 =15.6, J2 =10.5 Hz, 0.2H), 2.95 (dd, J1 =16.4, J2 =4.8 Hz, 0.8H), 4.13–
4.20 (m, 0.8H), 4.21–4.29 (m, 0.8H), 4.31–4.42 (m, 0.2H), 4.62–4.68 (m,
0.2H), 5.04–5.51 (m, 2H), 7.26–7.37 ppm (m, 5H); 13C NMR (75.5 MHz,
CDCl3): d=13.4, 14.3, 19.7, 25.4, 27.0, 27.6, 29.7, 29.8, 29.9, 45.9, 46.2,
47.5, 47.7, 48.2, 48.4, 66.6, 66.8, 127.7, 127.8, 128.3, 136.7. 136.8, 155.3,
206.8 ppm; HRMS (FAB): m/z: calcd for C17H24NO3: 290.1756 [M++1];
found: 290.1767.
General procedure for the synthesis of g-amino alcohols 24: NaBH4
(1.5 equiv) was added at À788C to a solution of the corresponding piperi-
dine 23 (1.0 equiv) in MeOH (0.05m). The mixture was stirred at this
temperature for 10 h and then it was quenched with aqueous saturated
NH4Cl and extracted with dichloromethane. The combined organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4, concentrat-
ed under vacuum, and purified by means of flash chromatography on
silica gel by using n-hexane/ethyl acetate as the eluents.
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N-Benzyloxycarbonyl-2R-(2R-hydroxypropyl)-6R-methylpiperidine
(24a): Compound (2R,2R’,6R)-24a was synthesized by following the gen-
eral procedure described above by starting from 46 mg of piperidine
(2R,6R)-23a (0.16 mmol) to afford 45 mg of a colorless oil (92% yield).
[a]2D5 =À28.8 (c=1.0 in CHCl3); 1H and 13C NMR spectra show the pres-
ence of rotamers about the carbamate bond in an 1:1.1 ratio; 1H NMR
(300 MHz, CDCl3): d=1.16 (d, J=6.2 Hz, 3H), 1.24 (d, J=6.5 Hz, 3H),
1.37–1.97 (m, 8H), 3.66–3.83 (m, 1H), 3.96–4.07 (m, 1.6H), 4.24 (m,
0.2H), 3.35 (m, 0.1H), 5.07–5.19 (m, 2H), 7.28–7.36 ppm (m, 5H);
13C NMR (75.5 MHz, CDCl3): d=12.7, 20.6, 23.7, 24.3, 26.3, 45.8, 47.2,
49.5, 66.1, 66.9, 127.8, 127.9, 128.4, 136.6, 156.1 ppm; HRMS (EI): m/z:
calcd for C17H25NO3: 291.1834 [M+]; found: 291.1822.
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Chem. 2008, 120, 3282; Angew. Chem. Int. Ed. 2008, 47, 3238; b) S.
Fustero, J. Moscardꢂ, D. Jimꢃnez, M. D. Pꢃrez-Carriꢂn, M. Sꢁnchez-
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L. K. Rathbone, H. Yang, N. D. Collett, R. G. Carter, J. Org. Chem.
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General procedure for the synthesis of (À)-pinidinol (19a) and its fluori-
nated analogue 19b: 20% Pd(OH)2 (10 mol%) was added to a solution
of the corresponding N-Cbz-protected piperidine 24 (1.0 equiv) in
MeOH (0.05m) and the suspension was stirred under H2 (1 atm) for 2 h.
The reaction mixture was then filtered through a short pad of Celite
washing with diethyl ether. Hydrogen chloride (5.0 equiv, 4m solution in
1,4-dioxane) was added to the filtrate and, after stirring for 30 min, sol-
vents were removed under reduced pressure. Finally, the crude mixture
was washed with diethyl ether to afford the piperidine hydrochlorides 19.
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9844
www.chemeurj.org
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9835 – 9845

Total Synthesis of (À)-Pinidinol
FULL PAPER
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[11] In the absence of the Lewis acid the reaction did not proceed.
Other Lewis acids, such as BF3·OEt2, gave the CM product 4b in
only 21% yield.
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[12] A recent study of the intramolecular aza-Michael reaction under
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sponding CM reaction to obtain the Michael acceptor took place in
only 5% yield, and we decided to use the tert-butyl sulfinyl amine in
the process.
[15] We have previously described in a preliminary communication the
synergistic effect of second-generation Hoveyda–Grubbs catalyst
with boron trifluoride in an analogous tandem process with carba-
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desired diastereoisomer although in a modest 30% yield.
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under base or Lewis acid catalysis has previously been observed: S.
Received: March 10, 2010
Published online: June 11, 2010
Chem. Eur. J. 2010, 16, 9835 – 9845
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9845