Stereocontrolled synthesis of all-syn 3,4-disubstituted l-prolines: Studies of the reductive rearrangement of unactivated tertiary allylic alcohols

Article abstract of DOI:10.1016/j.tet.2013.11.040

We describe a stereocontrolled method that converts tertiary allylic alcohols in pyrrolidine-2-carboxylic acid derivatives prepared from 3-(S)-hydroxy-l-proline to all-syn 3,4-disubstituted l-prolines. A study of various parameters to optimize the reductive rearrangement of tertiary allylic alcohols to tetrasubstituted olefins was conducted.

Full text of DOI:10.1016/j.tet.2013.11.040

Tetrahedron 70 (2014) 439e449
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Stereocontrolled synthesis of all-syn 3,4-disubstituted -prolines:
L
studies of the reductive rearrangement of unactivated tertiary allylic
alcohols
*
ꢀ
Stephen Hanessian , Stephane Dorich, Salma Kassem, Helge Menz,
Amit Kumar Chattopadhyay
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, Station Centre-Ville, C.P. 6128, Montreal, QC H3C 3J7, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a stereocontrolled method that converts tertiary allylic alcohols in pyrrolidine-2-carboxylic
Received 13 September 2013
Received in revised form 7 November 2013
Accepted 13 November 2013
Available online 28 November 2013
acid derivatives prepared from 3-(S)-hydroxy-L-proline to all-syn 3,4-disubstituted L-prolines. A study of
various parameters to optimize the reductive rearrangement of tertiary allylic alcohols to tetrasub-
stituted olefins was conducted.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
In connection with our efforts toward the synthesis of the
tetracyclic core of daphniglaucin C and related azacyclic mole-
Substituted pyrrolidines are prevalent in the structures of many
natural products as single units or as bicyclic to polycyclic variants.1
Although many syntheses have been reported over the years, very
few have addressed methods that lead to an all-syn orientation of
substituents as precursor chirons that can be elaborated into more
complex natural products. Representative structures of complex
alkaloids harboring a substituted pyrrolidine as an embedded core
azacycle are shown in Fig. 1.2 Facile and stereocontrolled access to
such motifs could be useful in the synthesis of alkaloids, and con-
strained peptidomimetics3 with predetermined stereochemistry of
substituents.
cules,4 we considered exploiting the versatile chemistry of
enaminones derived from 3-(S)-hydroxy-L-proline represented by
the generic structure A (Scheme 1). Well-known attack of various
nucleophiles at the 4-position of these enaminones,5 followed by
a second Grignard reagent addition on the resulting
a,b-un-
saturated ketone, could generate a generic tertiary allylic alcohol
(B). Stereoselective reductive removal of the allylic alcohol
would lead to an all-syn orientation of appended substituents
shown as C.
In pursuing this approach, our attention was drawn to a re-
ported allylic alcohol deoxygenation of a substituted L-proline
Fig. 1. Representative examples of complex alkaloids showing embedded 4-(S)-pyrrolidine motifs.
ester (4) in the presence of 5 mol % Pd/C in EtOAc under 1 atm of
hydrogen, by Camplo and co-workers6 (Scheme 2), which led to
the syn-product 5 resulting from hydrogenolysis. This was ratio-
nalized on the basis of steric arguments favoring the
* Corresponding author. E-mail address: stephen.hanessian@umontreal.ca (S.
Hanessian).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.040

440
S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
the tetrasubstituted alkene 13a (63%), accompanied by its exocyclic
regioisomer 14 (10%) and the saturated alcohol 15 (10%). It is note-
worthy that alkene 13a could not be hydrogenated in situ to the
intended 16a, even after hydrogenation with Pd(OH)2/C for 48 h.
However, isolating the tetrasubstituted alkene 13a and subjecting it
to hydrogenation in the presence of 15 mol % Pd/C afforded the all-
Scheme 1. Strategy toward the synthesis of 3,4-disubstituted L-prolines.
syn- -proline derivative 16a in quantitative yield (Scheme 4).
L
Moreover, when the alkene regioisomer 14 was submitted to the
original reaction conditions (Pd(OH)2/C, H2, EtOAc), isomerization
of the double bond to alkene 13a occurred quantitatively.10 How-
ever, the reverse isomerization from 13a to 14 was not possible
under the same conditions. When allowing the hydrogenation with
Pd(OH)2/C to take place for 16 h, it was noted that none of the isomer
14 was observed, while an improved 68% yield of 13a was obtained.
To further understand the requirements of the transformation in
Scheme 4, a catalyst screening was conducted (Table 1). The results
showed that the reaction requires a Pd-based catalyst.11 Wilkin-
son’s, Crabtree’s, Lindlar’s catalysts and, more surprisingly, Raney
nickel, failed to yield any of the desired transposed alkene 13a, and
starting 11a could be recovered (Table 1, entries 1e6). PtO2 gave
exclusively the reduced alcohol 15 (Table 1, entry 7).
The results shown in entries 8e11 seemed to imply that the
transformation involves Pd(0) and not Pd(II)12. However, in the
presence of 5 mol % Pd/C in EtOAc, only the saturated compound 15,
in which deoxygenation had not occurred, was isolated in 95% yield
(Table 1, entry 12). Nevertheless, when lowering the loading of the
catalyst (Table 1, entries 13e17), the deoxygenation product 13a
was observed, albeit in lower yields compared to entries with
Pearlman’s catalyst (Table 1, entries 1 and 2).
Next, we studied the influence of reducing agents on the re-
actions. Firstly, when using ammonium formate,13 no reaction
could be observed, even after heating at reflux in MeOH for three
days and using catalyst loadings as high as 20 mol % (Table 2, entry
1). However, better yields, chemoselectivity and shorter reaction
times were observed in the presence of Et3SiH14 (Table 2, entries
2e5, as compared to Table 1, entry 2). Although similar results were
obtained using the benign and cheaper polymethylhydroxysilane
(PMHS, Table 2, entries 5e7),15 Et3SiH was preferred for practical
reasons.16
Scheme 2. Previous reports on allylic alcohol deoxygenation.
hydrogenolysis of the allylic alcohol rather than the expected re-
duction of the alkylidene appendage. In an independent study on
cholesteroids by Odinokov and co-workers,7 an allylic diol (7) was
subjected to deoxygenation at the tertiary alcohol position with
transposition of the double bond in the presence of Raney nickel in
EtOH under 1 atm of hydrogen to give the tetrasubstituted steroid
8 in an unspecified yield.
2. Results and discussion
Addition of MeMgBr to enaminone 9, readily available from 3-
hydroxy-
-proline4 led to the enone 10a in 84% yield (Scheme 3).
L
A second Grignard addition following the protocol of Knochel and
co-workers8 proceeded in a 1,2-fashion to furnish chemoselectively
the allylic alcohols 11a and 12 as a 5:1 diastereomeric mixture.
Scheme 3. Synthesis of the test alcohols 11a and 12 from 9.
We then undertook a systematic study of different catalysts and
conditions in order to convert 11a into the corresponding all-syn-
Next, a mechanistic study was conducted in order to assess the
potential use of this strategy toward the synthesis of trisubstituted
pyrrolines and pyrrolidines. In the first place, the allylic alcohol 12
(diastereomer of 11a) was subjected to the allylic transposition
conditions (Scheme 5). To our surprise, no transformation could be
observed, even after adding 20 mol % Pd(OH)2/C and carrying out
the reaction over several days.
2,3-substituted-L-proline derivative (Scheme 4). In the presence of
Pd(OH)2/C (Pearlman’s catalyst),9 the major product was found to be
Next, a deuteration experiment in the presence of Pearlman’s
catalyst with D2 instead of H2 afforded monodeuteration products
17 and 18 in a diastereoselective manner. The CD3-analog 19 was
also prepared and subjected to the hydrogenolysis conditions to
give 20 in 68% yield without any loss of deuterium atoms. Fur-
thermore, the acetylated alcohol 21 was subjected to the reductive
transposition conditions and gave the same alkene 13a in 73% yield.
Several proposed mechanisms for Pd-catalyzed hydrogenolysis
of benzylic alcohols have been reported.17 In contrast, examples of
allylic alcohols are scarce. Considering the nature of the products
and the aforementioned experiments (Scheme 5), two plausible
Scheme 4. Allylic hydrogenolysis toward all-syn 3,4-disubstituted L-prolines.

S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
441
Table 1
Metal source screening
pathways can be proposed for the reductive rearrangement. The
first would involve a TsujieTrost type mechanism,18 where water
molecules contained in the wet commercial catalyst could facilitate
the leaving of the hydroxyl group via a reported H-bond activation
of the allylic alcohol.19 After the formation of the
p-allyl in-
termediate 22, a hydride from a neighboring Pd atom would act as
a nucleophile, thus affording products 13a and 14 as shown in
Entry
Catalyst
mol (%) Time
13a (%) 14 (%)
15 (%)
Scheme 6. The formation of the
p-allyl complex would only be
1
2
3
4
5
6
7
8
Pd(OH)2/C
Pd(OH)2/C
RhCl(PPh3)3
[Ir(cod)(PCy3)(py)]PF6
Raney nickel
Lindlar’s catalyst
PtO2
5
5
5
3 h
16 h
3 d
63
68
10
d
10
10
possible if palladium was coordinated anti to the leaving hydroxyl
group, which implies that it would come from the upper face of
n.r.
n.r.
the N-Boc -proline ester derivative 11a. This would explain the
L
5
3 d
5
3 d
n.r.d
diastereoselectivity of the transformation, as only one di-
astereoisomer of 14 is observed (see Schemes 4 and 5).
5
5
5
24 h
16 h
2 d
n.r.
d
d
98
d
d
d
20
95
87
PdCl2
Tracesa
Tracesa
39
60
d
9
Pd(OAc)2
Pd(OAc)2þPPh3
Pd2dba3
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
5
4 d
10
11
12
13
14
15
16
17
5
4 d
18
15
d
d
5
3 d
5
1 h
1
1 h
9
0.25
0.5
0.5b
0.5c
16 h
16 h
16 h
2 d
Tracesa
11
d
d
d
34
39
23
13
25
Solvent concentration used is 0.2 M unless mentioned otherwise.
a
Visible TLC traces.
Solvent concentration: 0.1 M.
Solvent concentration: 0.05 M.
Also tried in MeOH.
b
c
d
Table 2
Reducing agents screening
Scheme 6. TsujieTrost type mechanism for the formation of 13a and 14.
Entry
X
Y
Time
13a (%)
1
2
3
4
5
6
7
8
HCO2NH4, 10 equiv
Et3SiH, 5 equiv
Et3SiH, 10 equiv
Et3SiH, 5 equiv
Et3SiH, 2 equiv
PMHS, 10 equiv
PMHS, 5 equiv
PMHS, 2 equiv
5
5
1
1
1
1
1
1
3 d
n.r.
78a
78a
82
82
80
The second possible pathway would be a McQuillin-type
hydrogenolysis mechanism,20 where a Pd insertion occurs in the
CeO bond (Scheme 7), followed by a nucleophilic substitution with
a hydride coordinated to the Pd surface, as in the TsujieTrost type
mechanism.18,19 For such a reaction, the nucleophilic substitution
can occur in a SN2 or SN20 fashion. The SN2 pathway would thus
result in an inversion of stereochemistry, affording 14 with the
observed stereochemistry. The palladium insertion in the CeO
bond would have to take place on the same face as the alcohol, on
40 min
40 min
40 min
40 min
40 min
40 min
40 min
80
80
Bold highlights the optimal results.
Solvent concentration used is 0.2 M.
a
Some side-products were observed in trace amounts.
Scheme 5. Experiments conducted in order to study the mechanism.
Scheme 7. McQuillin’s hydrogenolysis mechanism.

442
S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
Table 3
the lower face of the molecule. This may be impeded by the ester
group, which adopts a pseudoaxial orientation to avoid A1,2 and A1,3
strains.
Synthesis of allylic alcohols 11aei for substrate scope study
The main difference between the two pathways is the faciality of
the attack of the Pd. In order to differentiate between the two faces,
the -proline analog 28 was synthesized in which the steric hin-
L
drance on the upper face was increased by introducing a tert-butyl
group instead of the methyl group (Scheme 8). No reaction was
observed with 28 in the presence of Pd(OH)2/C (5 mol %) under
1 atm hydrogen, which would suggest increased steric hindrance
on the reactive upper face of the double bond. Moreover, recall that
the allylic alcohol 12, the diastereomer of 11a, was also unreactive.
The lower faces of 11a and 12 are equally hindered by the ester
group, although to a higher extent in 12 because of the methyl
Entry
R
10 (%)
11 (%) (dr)a
1
2
Cyclopentyl (b)
Decyl (c)
59
56
78 (>20:1)
62 (>20:1)
3
70
72 (5:1)
(d)
(e)
4
5
84
65
89 (5:1)
group. According to the
p-allyl formation pathway (Scheme 6,
structure 23), the Pd would have to be coordinated anti to the hy-
droxyl group, which in the case of 12 would imply coordination on
the lower hindered face of the exocyclic double bond. However, if
the McQuillin type hydrogenolysis mechanism were implied, the
insertion of the Pd in the CeO bond of 12 on the upper face will not
be problematic from a steric point of view. The unreactivity of 12
suggests once again that the Pd needs to be coordinated anti to the
hydroxyl group as in the proposed TsujieTrost type mechanism.
63 (>20:1)
(f)
6
7
8
9
Phenethyl (g)
Ph (h)
-OMeePh (i)
-FePh (j)
52
62
59
59
91 (3:1)
89 (15:1)
74 (15:1)
80 (15:1)
r
r
a
Unlike 11a and 12, diastereoisomers were hardly separable for 11e, and in-
separable in all other cases. The dr was calculated upon integration of 1H NMR
signals.
With this selection of allylic alcohols in hand (11aej), the
allylic deoxygenation and double bond transposition was tested
employing the two optimal methods developed (Table 4). It
appeared that a change in the distal substituent of the exocyclic
alkene resulted in a profound effect on the feasibility of the re-
action, as well as the product distribution. Allylic alcohols bearing
alkyl groups (Table 4, entries 1e6) led to allylic deoxygenation in
acceptable yields in the presence of Pearlman’s catalyst. Whereas
a significant improvement was observed when using Et3SiH in
conjunction with Pd/C when R¼Me or cyclopentyl (Tables 2 and 4),
the opposite was observed in the case of compound 11e, for which
a complex mixture was observed (Table 4, entry 5).4
Scheme 8. No reaction with 28 toward reductive transposition conditions.
Another pathway could involve a concerted ‘ene’-type mecha-
nism, where the palladium would first coordinate to the alcohol
followed by a transfer of a hydride to the double bond through
a six-membered ring transition state. This mechanism was dis-
missed after the reaction was carried on the acetate ester 21, and
the olefin 13a was obtained in 73% yield (Scheme 5), since the
PdeO(H)R coordination is theoretically impossible in this case.
However, it is possible that another mechanistic pathway may be
involved for the transformation of 21 to 13a (Scheme 5). Never-
theless, and more importantly, this concerted ‘ene’ pathway would
not account for the formation of the regioisomeric alkene 14.
The possibility of the formation of an allylic carbocations was
also considered. The delocalized carbocations could be subjected to
a ‘hydride’ attack occurring at two positions, giving 13a and 14 as
products. Nonetheless, attempts to trap transient carbocations with
methanol and aniline as nucleophiles were unsuccessful and this
mechanism was not considered any further. Lastly, another path-
way could be derived from the formation of a diene upon elimi-
nation of the tertiary alcohol, either from a carbocation undergoing
an E1 elimination or a direct E2 elimination that could be hydro-
genated to yield products 13a and 14. This pathway to an in-
termediate exocyclic methylene intermediate was ruled out since
the product resulting from the reduction of 19, a deuterated methyl
analog of 11a, retained the CD3 group (Scheme 5). Furthermore,
reduction in the presence of deuterium gas afforded mono-
deuterated products 17 and 18, rather than multiply deuterated
products arising from a presumed diene.21
Table 4
Substrate scope for the reductive allylic transposition
Entry
R
Method A (%)
Method B (%)
1
2
3
Methyl (a)
Cyclopentyl (b)
Decyl (c)
68
73
68
82
79a
62
4
78
76a
(d)
(e)
5
6
70b
70
Complex mixture
54a
(f)
7
8
9
10
Phenethyl (g)
Ph (h)
36c
18d
25d
32e
50
47d
r-OMeePh (i)
-FePh (j)
62d
r
Complex mixture
a
In order to evaluate the applicability of the strategy in the
synthesis of syn-substituted 3,4-L-proline analogs, the scope of the
reaction was next studied for a selection of side-chains. From the
known enaminone 9, different nucleophiles were used to generate
a selection of enones (10bej), then allylic alcohols (11bej, Table 3),
using the same protocol as described previously (Schemes 1 and 3).
Traces of the exocyclic alkene regioisomer were observed.
With concomitant hydrogenolysis of the benzyl ether group.
37% of hydrogenated tertiary alcohol presumably analogous to 15 was isolated.
The all-syn pyrrolidine was partly obtained as an inseparable by-product (>10%
b
c
d
based on 1H NMR).
e
45% of hydrogenated tertiary alcohol presumably analogous to 15 was isolated,
and separated from the all-syn pyrrolidine analogous to 16a.

S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
443
In the case of the phenethyl analog (Table 4, entry 7), modest
yields of the desired tetrasubstituted alkene were obtained. Like-
wise, the phenyl and r-OMeephenyl compounds (Table 4, entries 8
and 9) led to lower yields of the expected tetrasubstituted alkene,
although using Pd/C with Et3SiH afforded slightly better results. It is
of interest that for those analogs, partial over-reduction to the
corresponding pyrrolidine was observed leading to minor in-
air-sensitive compounds. Anhydrous solvents were obtained using
standard drying techniques. Flash chromatography was performed
on 230e400 mesh silica gel with the indicated solvent systems.
Infrared spectra were recorded on a FT-IR spectrometer and are
reported in reciprocal centimeters (cmꢀ1). All nuclear magnetic
resonance spectra were recorded on a 400 MHz spectrometer.
Chemical shifts are recorded in parts per million from tetrame-
thylsilane with the solvent resonance as the internal standard.
Accurate mass measurements were performed on a LC-MSDTOF
instrument using fast atom bombardment (FAB) or electrospray
ionization (ESI) techniques. Protonated molecular ions (MþH)þ
and/or sodium adducts (MþNa)þ were used for empirical formula
confirmation.
separable by-products. Finally, in the case of
r-fluorophenyl-
substituted pyrroline (Table 4, entry 10), a complex mixture was
obtained when using triethylsilane with Pd/C, while hydrogen with
Pd(OH)2/C led directly to a modest yield of the over-reduced all-syn
3,4-disubstituted
In order to assess the ease with which this approach could be
used to generate all-syn 3,4-disubstituted -prolines, selected an-
L-proline.
L
alogs were hydrogenated using Pd/C under 1 atm of hydrogen
(Table 5, see Scheme 4). Hydrogenation was complete, clean and
diastereoselective, affording the intended all-syn 3,4-disubstituted
4.2. Typical procedure for synthesis of enones 10aej
Under argon and in a flame-dried flask, a solution of the
enaminone 9 (1 equiv) in dry THF (0.2 M) was cooled to ꢀ78 ꢁC and
treated with the given Grignard reagent (1.5 equiv) dropwise. After
stirring for 1 h, the dry ice bath was removed and the reaction was
allowed to warm to rt. It was stirred for 30 min at this temperature
before a saturated aqueous solution of NH4Cl was added slowly. The
red biphasic mixture was separated and the aqueous phase was
extracted three times with EtOAc. The combined organic layers
were washed with brine and dried over Na2SO4, and the solvent
was removed under reduced pressure.
L-prolines in moderate to good yields (Table 5, entries 1e8).
Table 5
Hydrogenation to the all-syn 2,3,4-trisubstituted pyrrolidines
Entry
R
Yield (%)
4.2.1. (S,E)-1-tert-Butyl 2-methyl 3-ethylidene-4-oxopyrrolidine-1,2-
dicarboxylate (10a). Obtained from the enaminone 9 (2.00 g,
6.71 mmol) using the general procedures. Purification of the resi-
due by flash chromatography (hexanes/EtOAc¼70/30) gave the title
1
2
3
Methyl (a)
Cyclopentyl (b)
Decyl (c)
quant
80
76
enone (1.51 g, 84%) as a thick colorless oil. ½a D20
þ80.1 (c 1.00,
ꢂ
4
5
70
(d)
(e)
CHCl3); IR (neat): nmax¼2978, 1747, 1705, 1659, 1436, 1394, 1368,
1317, 1259, 1167, 1120, 994, 902, 858, 773, 512 cmꢀ1
;
1H NMR
¼6.91 (1H, q, J¼7.2 Hz),
quant4
(400 MHz, CDCl3), mixture of rotamers:
d
5.28e5.19 (1H, 2s), 4.03e3.91 (2H, m), 3.73 (3H, br s), 2.00 (3H, d,
J¼7.2 Hz), 1.47e1.44 (9H, 2s); 13C NMR (100 MHz, CDCl3), mixture of
6
7
8
Phenethyl (g)
Ph (h)
82
70
67
rotamers:
d
¼196.5, 195.8, 169.9, 153.9, 153.0, 141.1, 137.7, 137.5,
r
-OMeePh (i)
132.4, 132.2, 80.8, 59.8, 59.1, 52.9, 52.5, 52.1, 52.0, 27.8, 27.8, 27.8,
15.0, 14.9; HRMS (ESIMS): calcd for
292.11652, found 292.11554.
C
13H19NO5Na [MþNa]þ
3. Conclusion
We have described a concise and stereocontrolled method to
prepare all-syn 3,4-disubstituted -proline analogs starting with 3-
(S)-hydroxy- -proline. Conversion to the corresponding N,N-
dimethylamino enaminone, followed by conjugate attack with
carbon nucleophiles led to the corresponding 1,4-adducts with
elimination of dimethylamine. LaCl3-mediated addition of MeMgBr
to the ketone gave a mixture of the tertiary alcohols, which were
subjected to a variety of catalytic and chemical reduction condi-
4.2.2. (S,E)-1-tert-Butyl 2-methyl 3-(cyclopentylmethylene)-4-
oxopyrrolidine-1,2-dicarboxylate (10b). Obtained from the enami-
none 9 (2.00 g, 6.71 mmol) using the general procedures. Purifi-
cation of the residue by flash chromatography (hexanes/EtOAc¼80/
L
L
20) gave the title enone (1.30 g, 59%) as a thick colorless oil. ½a D20
ꢂ
þ100.7 (c 1.00, CHCl3); IR (neat): nmax¼2955,1744,1706, 1649,1392,
;
1163, 1119, 1012 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of
rotamers:
d
¼6.73e6.63 (1H, m), 5.29e5.19 (1H, 2s), 4.05e3.89 (2H,
tions. The tetrasubstituted
intermediate, then further reduced to the intended all-syn N-Boc
3,4-disubstituted -proline methyl esters. The process was exem-
plified by the synthesis of the 3-(R)-ethyl-4-(R)-methyl N-Boc
D-3 pyrroline was isolated as a discrete
m), 3.73e3.71 (3H, 2s), 3.00e2.87 (1H, m), 1.93e1.84 (1H, m),
1.81e1.62 (5H, m), 1.46e1.44 (9H, 2s), 1.40e1.28 (2H, m); 13C NMR
L
(100 MHz, CDCl3), mixture of rotamers:
d
¼197.5, 196.8, 170.9, 170.7,
L-
154.3, 153.5, 147.6, 147.4, 129.8, 129.5, 81.2, 81.2, 60.3, 59.5, 53.4,
52.9, 52.7, 52.6, 40.2, 40.2, 33.1, 32.6, 32.5, 28.3, 28.2, 25.8, 25.8,
25.7; HRMS (ESIMS): calcd for C17H25NO5Na [MþNa]þ 346.16249,
found 346.16390.
proline methyl ester and related aliphatic and aromatic analogs.
These compounds can be useful as versatile intermediates toward
the synthesis of alkaloids and as constrained peptidomimetics with
predetermined absolute stereochemistry.
4.2.3. (S,E)-1-tert-Butyl 2-methyl 4-oxo-3-undecylidenepyrrolidine-
1,2-dicarboxylate (10c). Obtained from the enaminone 9 (1.20 g,
4.03 mmol) using the general procedures. Purification of the resi-
due by flash chromatography (hexanes/EtOAc¼90/10) gave the title
4. Experimental section
4.1. General information
enone (880 mg, 56%) as a thick colorless oil. ½a D20
þ78.9 (c 1.00,
ꢂ
All non-aqueous reactions were run in flame-dried glassware
under a positive pressure of argon with exclusion of moisture from
reagents and glassware using standard techniques for manipulating
CHCl3); IR (neat): nmax¼2930, 2861, 1747, 1656, 1460, 1439, 1394,
1371, 1321, 1258, 1203, 1163, 1121, 1019, 907, 862, 775, 739,
632 cmꢀ1; 1H NMR (400 MHz, CDCl3), mixture of rotamers:
d¼6.81

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S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
(1H, br s), 5.25e5.16 (1H, 2s), 4.02e3.92 (2H, m), 3.70 (3H, s),
2.38e2.30 (2H, m), 1.46e1.40 (11H, 2s), 1.24 (14H, br s), 0.87e0.83
the title enone (685 mg, 62%) as a thick colorless oil. ½a D20
þ143.8
ꢂ
(c1.00, CHCl3); IR (neat): nmax¼2985, 1747, 1707, 1629, 1601, 1498,
1480, 1454, 1438, 1396, 1371, 1320, 1259, 1210, 1162, 1124,
1055, 1015, 939, 911, 863, 763, 694, 632 cmꢀ1; 1H NMR (400 MHz,
(3H, m); 13C NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼197.2,
196.5, 170.5, 154.3, 153.4, 143.3, 143.0, 131.6, 131.3, 81.2, 81.2, 60.3,
59.6, 53.3, 52.9, 52.5, 52.4, 31.8, 29.5, 29.5, 29.4, 29.3, 28.2, 28.2,
28.1, 22.6, 14.0; HRMS (ESIMS): calcd for C22H37NO5Na [MþNa]þ
418.25639, found 418.25722.
CDCl3), mixture of rotamers:
7.50e7.42 (3H, m), 5.77e5.61 (1H, 2s), 4.10e3.99 (2H, m),
d
¼7.82e7.78 (2H, m), 7.58 (1H, br s),
3.66 (3H, br s), 1.50 (9H, s); 13C NMR (100 MHz, CDCl3), mixture
of rotamers:
d
¼198.2, 197.5, 169.7, 169.5, 153.9, 153.1, 137.4,
4.2.4. (S,E)-1-tert-Butyl 2-methyl 3-(3-(1,3-dioxolan-2-yl)propyli-
dene)-4-oxopyrrolidine-1,2-dicarboxylate (10d). Obtained from
the enaminone 9 (1.20 g, 4.03 mmol) using the general pro-
cedures with 3 equiv of Grignard reagent.22 Purification of the
residue by flash chromatography (hexanes/EtOAc¼70/30) gave
137.2, 132.0, 131.3, 131.0, 128.6, 128.5, 128.4, 128.1, 127.9, 81.2,
81.1, 60.8, 60.1, 52.2, 52.2, 52.0, 51.6, 36.3, 27.9, 24.3; HRMS
(ESIMS): calcd for
354.13106.
C
18H21NO5Na [MþNa]þ 354.13119, found
the title enone (1.00 g, 75%) as a thick colorless oil. ½a D20
ꢂ
þ52.9 (c
4.2.8. (S,E)-1-tert-Butyl 2-methyl 3-(4-methoxybenzylidene)-4-
oxopyrrolidine-1,2-dicarboxylate (10i). Obtained from the enami-
none 9 (1.90 g, 6.37 mmol) using the general procedures. Purifi-
cation of the residue by flash chromatography (hexanes/EtOAc¼80/
1.00, CHCl3); IR (neat): nmax¼3464, 2977, 1746, 1704, 1394,
1162, 1034, 916, 857, 773, 734, 648, 597 cmꢀ1
;
1H NMR
¼6.85 (1H, td, J¼7.8,
(400 MHz, CDCl3), mixture of rotamers:
d
2.1 Hz), 5.32e5.23 (1H, 2s), 4.94e4.90 (1H, m), 4.07e3.92 (4H,
m), 3.87e3.82 (2H, m), 3.76e3.75 (3H, 2s), 2.56e2.48 (2H,
m), 1.88e1.81 (2H, m), 1.50e1.47 (9H, 2s); 13C NMR (100 MHz,
20) gave the title enone (1.35 g, 59%) as a thick colorless oil. ½a D20
ꢂ
þ130.0 (c1.00, CHCl3); IR (neat): nmax¼2982, 2849, 1748, 1733, 1706,
1628, 1598, 1517, 1396, 1371, 1259, 1162, 1122, 1055, 1029, 769,
CDCl3), mixture of rotamers:
d
¼197.2, 196.5, 170.4, 154.3, 153.5,
632 cmꢀ1; 1H NMR (400 MHz, CDCl3), mixture of rotamers:
d
¼7.77
142.2, 142.0, 131.8, 131.5, 103.3, 81.3, 81.3, 65.1, 65.0, 60.2, 59.5,
53.4, 52.9, 52.6, 52.5, 32.0, 32.0, 28.3, 28.3, 24.1, 24.0; HRMS
(2H, d, J¼7.2 Hz), 7.48 (1H, d, J¼4.4 Hz), 6.98e6.89 (2H, m),
5.69e5.55 (1H, 2s), 4.06e3.92 (2H, m), 3.83 (3H, s), 3.65 (3H, s), 1.47
(ESIMS): calcd for
378.15232.
C
17H25NO7Na [MþNa]þ 378.15109, found
(9H, s); 13C NMR (100 MHz, CDCl3), mixture of rotamers:
d¼198.3,
197.7, 170.2, 170.0, 162.2, 154.2, 153.4, 137.5, 137.2, 133.9, 125.9,
125.6, 125.0, 114.4, 114.3, 81.3, 81.2, 61.3, 60.5, 55.3, 53.3, 52.4, 52.4,
52.3, 51.9, 28.2; HRMS (ESIMS): calcd for C19H23NO6Na [MþNa]þ
384.14176, found 384.14056.
4.2.5. (S,E)-1-tert-Butyl 2-methyl 3-(4-((tert-butyldiphenylsilyl)oxy)
butylidene)-4-oxopyrrolidine-1,2-dicarboxylate (10f). Obtained
from the enaminone 9 (1.2 g, 4.04 mmol) using the general pro-
cedures. Purification of the residue by flash chromatography
(hexanes/EtOAc¼80/20) gave the title enone (1.44 g, 65%) as
4.2.9. (S,E)-1-tert-Butyl 2-methyl 3-(4-fluorobenzylidene)-4-
oxopyrrolidine-1,2-dicarboxylate (10j). Obtained from the enami-
none 9 (1.20 g, 4.04 mmol) using the general procedures. Purifi-
cation of the residue by flash chromatography (hexanes/EtOAc¼80/
a thick colorless oil. ½a D20
þ19.9 (c 1.00, CHCl3); IR (neat):
ꢂ
nmax¼2934, 2859, 1747, 1710, 1428, 1393, 1255, 1160, 1109, 823,
740 cmꢀ1
;
1H NMR (400 MHz, CDCl3), mixture of rotamers:
20) gave the title enone (825 mg, 59%) as a thick colorless oil. ½a D20
ꢂ
d
¼7.68e7.63 (4H, m), 7.44e7.36 (6H, m), 6.87e6.82 (1H, m),
þ238.4 (c 1.00, CHCl3); IR (neat): nmax¼2985, 1742, 1703, 1630, 1602,
1514,1482, 1438,1395,1371,1329,1301,1238,1160,1125,1053,1015,
914, 862, 834, 786, 775, 736, 632 cmꢀ1; 1H NMR (400 MHz, CDCl3),
5.29e5.20 (1H, 2s), 4.08e3.93 (2H, m), 3.73e3.67 (5H, m),
2.63e2.40 (2H, m), 1.77e1.67 (2H, m), 1.50e1.46 (9H, 2s),
1.07e1.06 (9H, 2s); 13C NMR (100 MHz, CDCl3), mixture of
mixture of rotamers:
d
¼7.86 (2H, t, J¼7.2 Hz), 7.54 (1H, d, J¼4.4 Hz),
rotamers:
d
¼197.1, 196.4, 170.4, 154.3, 153.5, 142.8, 142.6, 135.5,
7.21e7.11 (2H, m), 5.73e5.58 (1H, 2s), 4.06e3.99 (2H, m), 3.68 (3H,
133.5, 133.5, 129.6, 127.6, 81.2, 81.2, 63.0, 62.8, 60.2, 59.5, 53.3,
52.9, 52.5, 52.4, 30.9, 30.9, 28.2, 28.2, 26.8, 26.8, 26.5, 26.2, 19.1,
19.1; HRMS (ESIMS): calcd for
574.25954, found 574.25680.
br s), 1.51 (9H, s). 13C NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼198.0, 197.4, 169.6, 169.5, 165.3, 162.7, 153.9, 153.0, 136.1, 135.8,
C
23H41NO4SiNa [MþNa]þ
133.6, 133.5, 127.9, 127.6, 115.9, 115.8, 114.6, 114.4, 81.3, 81.1, 60.8,
60.0, 52.3, 52.3, 52.0, 51.6, 27.9; HRMS (ESIMS): calcd for
C
18H20NFO5Na [MþNa]þ 372.12177, found 372.12254.
4.2.6. (S,E)-1-tert-Butyl 2-methyl 4-oxo-3-(3-phenylpropylidene)
pyrrolidine-1,2-dicarboxylate (10g). Obtained from the enaminone
9 (1.60 g, 5.37 mmol) using the general procedures. Purification of
the residue by flash chromatography (hexanes/EtOAc¼85/15) gave
4.3. Typical procedure for synthesis of allylic alcohols (11aej)
Under argon and in a flame-dried flask, the starting enone
(1 equiv) was dissolved in dry THF (0.2 M) and commercial solution
of LaCl3$2LiCl (0.6 in THF, 1.05 equiv) was added at rt. The mixture
was allowed to stir as such for 1 h, then it was cooled to ꢀ78 ꢁC and
MeMgBr (3.0 M in Et2O, 1.5 equiv) was added dropwise. The
resulting brownish solution was stirred at ꢀ78 ꢁC for 1 h, then
quenched at ꢀ78 ꢁC with aqueous saturated NH4Cl. The biphasic
mixture was separated and the aqueous phase was extracted three
times with Et2O. Special care was taken to avoid acidic wash (no
1 M HCl), as analogous intermediates were shown to decompose
rapidly under such conditions. The combined organic layers were
washed with brine and dried over Na2SO4, and the solvent was
removed under reduced pressure.
the title enone (1.04 g, 52%) as a thick colorless oil. ½a D20
þ70.5 (c
ꢂ
1.00, CHCl3); IR (neat): nmax¼3034, 2982, 2937, 2360, 1745, 1703,
1655, 1607, 1499, 1481, 1457, 1439, 1395, 1370, 1322, 1258, 1204,
1161, 1122, 1025, 997, 917, 860, 773, 749, 701, 632 cmꢀ1 1H NMR
;
(400 MHz, CDCl3), mixture of rotamers:
d
¼7.31e7.24 (2H, m),
7.24e7.16 (3H, m), 6.87e6.80 (1H, m), 5.24e5.08 (1H, 2s),
4.06e3.92 (2H, m), 3.71e3.70 (3H, 2s), 2.78e2.60 (4H, m),
1.49e1.46 (9H, 2s); 13C NMR (100 MHz, CDCl3), mixture of
rotamers:
d
¼197.1, 196.4, 170.3, 154.3, 153.4, 141.6, 141.4, 140.2,
132.2, 131.9, 128.6, 128.6, 128.4, 128.4, 128.4, 128.3, 126.4, 81.3,
60.3, 59.6, 53.3, 52.9, 52.6, 52.5, 34.2, 31.4, 31.3, 28.3, 28.2; HRMS
(ESIMS): calcd for
382.16318.
C
20H25NO5Na [MþNa]þ 382.16249, found
4.3.1. (2S,4S,E)-1-tert-Butyl 2-methyl 3-ethylidene-4-hydroxy-4-
methylpyrrolidine-1,2-dicarboxylate (11a) and (2S,4R,E)-1-tert-butyl
2-methyl 3-ethylidene-4-hydroxy-4-methylpyrrolidine-1,2-
dicarboxylate (12). Obtained from the enone 10a (1.00 g,
3.72 mmol) using the general procedures. Purification of the
4.2.7. (S,E)-1-tert-Butyl 2-methyl 3-benzylidene-4-oxopyrrolidine-
1,2-dicarboxylate (10h). Obtained from the enaminone 9 (1.00 g,
3.35 mmol) using the general procedures. Purification of the
residue by flash chromatography (hexanes/EtOAc¼85/15) gave

S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
445
residue by flash chromatography (hexanes/EtOAc¼70/30) gave the
title allylic alcohol (785 mg, 74%) as a thick yellowish oil. Com-
(1H, d, J¼11.2 Hz), 2.33e2.22 (2H, m), 1.78e1.68 (2H, m), 1.38e1.35
(9H, 2s), 1.38e1.30 (3H, m); 13C NMR (100 MHz, CDCl3), mixture of
pound 11a: ½a 2D0
ꢂ
þ67.8 (c 1.00, CHCl3); IR (neat): nmax¼3464, 2969,
rotamers:
d
¼173.6, 173.3, 154.3, 153.3, 139.3, 138.6, 126.4, 103.6,
2928, 1707, 1398, 1367, 1259, 1170, 1140, 1116, 990, 899, 769 cmꢀ1
;
103.5, 80.4, 80.4, 80.2, 76.3, 75.4, 64.8, 64.7, 60.7, 60.5, 60.4, 59.7,
52.8, 52.5, 32.8, 32.7, 28.1, 28.1, 23.2, 21.2, 21.0; HRMS (ESIMS): calcd
for C18H29NO7Na [MþNa]þ 394.18412, found 394.18362.
1H NMR (400 MHz, CDCl3), mixture of rotamers:
qd, J¼7.0, 1.7 Hz), 4.93e4.86 (1H, 2s), 4.13e3.90 (1H, 2s), 3.84e3.73
(1H, m), 3.82e3.79 (3H, 2s), 3.31e3.26 (1H, m), 1.78e1.76 (3H, 2s),
1.46e1.44 (9H, 2s), 1.41e1.40 (3H, 2s); 13C NMR (100 MHz, CDCl3),
d¼5.82e5.77 (1H,
4.3.5. (2S,4S,E)-1-tert-Butyl 2-methyl 3-(4-((tert-butyldiphenylsilyl)
oxy)butylidene)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate
(11f). Obtained from the enone 10f (500 mg, 0.907 mmol) using the
general procedures. Purification of the residue by flash chroma-
tography (hexanes/EtOAc¼80/20) gave the title allylic alcohol
mixture of rotamers:
d
¼173.5, 173.1, 154.1, 139.6, 138.9, 128.4, 125.9,
121.8, 80.3, 76.3, 76.1, 75.2, 60.5, 60.3, 60.3, 60.0, 59.6, 52.6, 52.3,
29.6, 29.3, 28.0, 27.9, 20.7, 20.5, 14.0, 13.9; HRMS (ESIMS): calcd for
C
14H23NO5Na [MþNa]þ 308.14684, found 308.14627. Compound
12: ½a 2D0
ꢂ
þ78.8 (c 1.00, CHCl3); IR (neat): nmax¼3432, 2976, 1747,
(325 mg, 63%) as a thick yellowish oil. ½a D20
þ63.2 (c 1.00, CHCl3); IR
ꢂ
1683, 398, 1167, 1133, 999, 774 cmꢀ1
;
1H NMR (400 MHz, CDCl3),
(neat): nmax¼3474, 2933, 2861, 1705, 1395, 1162, 1107, 1001, 821,
mixture of rotamers:
d
¼5.90e5.85 (1H, m), 5.09e4.99 (1H, 2s),
739, 704 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotamers:
;
3.77e3.68 (1H, m), 3.75e3.74 (3H, 2s), 3.49e3.46 (1H, 2s), 2.08 (1H,
d
¼7.71e7.66 (4H, m), 7.47e7.36 (6H, m), 5.75e5.68 (1H, m),
br s), 1.82e1.80 (3H, 2s), 1.48e1.44 (12H, 2s); 13C NMR (100 MHz,
4.93e4.89 (1H, 2s), 4.18e3.97 (1H, 2s), 3.87e3.76 (1H, m),
3.77e3.76 (3H, 2s), 3.74e3.65 (2H, m), 3.29e3.26 (1H, 2s),
2.46e2.16 (2H, m), 1.73e1.61 (2H, m), 1.49e1.44 (9H, s), 1.40e1.39
(3H, 2s), 1.09e1.07 (9H, 2s); 13C NMR (100 MHz, CDCl3), mixture of
CDCl3), mixture of rotamers:
d
¼171.0, 154.6, 153.7, 142.6, 142.2,
122.0, 121.9, 80.5, 80.4, 76.1, 61.1, 60.6, 59.9, 59.3, 52.1, 52.0, 28.3,
28.2, 27.3, 27.2, 14.5, 14.4; HRMS (ESIMS): calcd for C14H23NO5Na
[MþNa]þ 308.14684, found 308.14747.
rotamers:
d
¼173.7, 173.4, 154.1, 153.1, 139.0, 138.2, 135.2, 135.1,
133.4, 129.3, 127.3, 126.8, 80.3, 80.3, 76.1, 75.2, 62.8, 62.5, 60.5, 60.3,
59.6, 52.6, 52.3, 31.4, 31.3, 28.0, 27.9, 26.5, 26.5, 25.1, 24.9, 20.7, 18.9;
HRMS (ESIMS): calcd for C32H45NO6SiNa [MþNa]þ 590.29084,
found 590.29197.
4.3.2. (2S,4S,E)-1-tert-Butyl 2-methyl 3-(cyclopentylmethylene)-4-
hydroxy-4-methylpyrrolidine-1,2-dicarboxylate
(11b). Obtained
from the enone 10b (770 mg, 2.38 mmol) using the general pro-
cedures. Purification of the residue by flash chromatography
(hexanes/EtOAc¼70/30) gave the title allylic alcohol (635 mg, 78%)
4.3.6. (2S,4S,E)-1-tert-Butyl 2-methyl 4-hydroxy-4-methyl-3-(3-
as a thick yellowish oil. ½a D20
ꢂ
þ103.5 (c 1.00, CHCl3); IR (neat):
phenylpropylidene)pyrrolidine-1,2-dicarboxylate
(11g). Obtained
nmax¼3473, 2952, 2869, 1703, 1396, 1340, 1253, 1209, 1159, 1113,
from the enone 10g (500 mg, 1.33 mmol) using the general pro-
cedures. Purification of the residue by flash chromatography
(hexanes/EtOAc¼70/30) gave the title allylic alcohol (477 mg, 91%)
;
998, 929, 907, 881 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of
rotamers:
d
¼5.57e5.54 (1H, 2s), 4.90e4.83 (1H, 2s), 3.76e3.74 (3H,
2s), 3.70e3.67 (1H, 2s), 3.25e3.23 (1H, 2s), 2.73e2.66 (1H, m),
1.83e1.73 (1H, m), 1.67e1.53 (4H, m), 1.41e1.38 (9H, 2s), 1.36e1.35
(3H, m) 1.22e1.15 (3H, m); 13C NMR (100 MHz, CDCl3), mixture of
as a thick yellowish oil. ½a D20
þ72.4 (c 1.00, CHCl3); IR (neat):
ꢂ
nmax¼3454, 3034, 2983, 2936, 1735, 1703, 1607, 1500, 1481, 1457,
1395, 1370, 1258, 1205, 1155, 1116, 996, 974, 933, 907, 861, 819, 773,
rotamers:
d
¼174.1, 173.8, 154.5, 153.5,137.3, 136.6,132.5,132.5, 80.6,
750, 701, 627 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotam-
;
80.5, 76.4, 75.5, 65.8, 60.9, 60.7, 60.6, 59.9, 53.1, 52.8, 39.7, 33.3, 32.8,
28.3, 28.2, 25.5, 25.5, 25.4, 21.3, 21.1, 15.2; HRMS (ESIMS): calcd for
ers:
d
¼7.32e7.25 (2H, m), 7.25e7.20 (3H, m), 5.77 (1H, t, J¼7.7 Hz),
4.83e4.69 (1H, 2s), 4.14e3.89 (1H, 2s), 3.79e3.76 (3H, 2s),
3.80e3.72 (1H, m), 3.26e3.23 (1H, 2s), 2.74e2.65 (2H, m),
2.52e2.44 (2H, m), 1.48e1.44 (9H, 2s), 1.45e1.41 (3H, m); 13C NMR
C
18H29NO5Na [MþNa]þ 362.19379, found 362.19431.
4.3.3. (2S,4S,E)-1-tert-Butyl 2-methyl 4-hydroxy-4-methyl-3-
undecylidenepyrrolidine-1,2-dicarboxylate (11c). Obtained from the
enone 10c (415 mg, 1.05 mmol) using the general procedures. Pu-
rification of the residue by flash chromatography (hexanes/
EtOAc¼80/20) gave the title allylic alcohol (265 mg, 62%) as a thick
(100 MHz, CDCl3), mixture of rotamers:
d
¼173.9, 173.4, 171.0, 154.5,
153.5, 141.3, 141.0, 139.8, 139.0, 128.4, 126.5, 126.3, 126.2, 126.1,
126.1, 80.7, 80.7, 76.5, 75.7, 60.9, 60.7, 60.5, 59.8, 53.1, 52.7, 35.2,
35.2, 35.1, 30.7, 30.7, 28.3, 28.3, 21.3, 21.1; HRMS (ESIMS): calcd for
C
21H29NO5Na [MþNa]þ 398.19379, found 398.19474.
yellowish oil. ½a D20
þ99.1 (c 1.00, CHCl3); IR (neat): nmax¼3480,
ꢂ
2932, 2862, 1736, 1711, 1398, 1371, 1259, 1217, 1173, 997, 907,
4.3.7. (2S,4S,E)-1-tert-Butyl 2-methyl 3-benzylidene-4-hydroxy-4-
methylpyrrolidine-1,2-dicarboxylate (11h). Obtained from the
enone 10h (475 mg, 1.44 mmol) using the general procedures.
Purification of the residue by flash chromatography (hexanes/
EtOAc¼80/20) gave the title allylic alcohol (443 mg, 89%) as a thick
768 cmꢀ1; 1H NMR (400 MHz, CDCl3), mixture of rotamers:
d¼5.72
(1H, t, J¼7.7 Hz), 4.91e4.83 (1H, 2s), 3.84e3.74 (1H, m), 3.81e3.78
(3H, 2s), 3.30e3.27 (1H, 2s), 2.19e2.10 (2H, m), 1.47e1.44 (9H, 2s),
1.42e1.41 (3H, 2s), 1.43e1.25 (16H, m), 0.89 (3H, t, J¼6.7 Hz); 13C
NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼174.1, 173.7, 154.5,
yellowish oil. ½a D20
þ234.9 (c 1.00, CHCl3); IR (neat): nmax¼3430,
ꢂ
153.5, 138.8, 138.1, 127.9, 127.8, 80.7, 80.6, 76.5, 75.6, 61.0, 60.8, 60.7,
60.0, 53.0, 52.6, 31.9, 29.6, 29.6, 29.5, 29.3, 29.3, 29.0, 29.0, 28.3,
28.3, 22.7, 21.2, 21.0, 14.1; HRMS (ESIMS): calcd for C23H41NO5Na
[MþNa]þ 434.28769, found 434.28790.
2984, 2253, 1694, 1481, 1451, 1396, 1370, 1257, 1214, 1160, 1116,
1083, 1002, 912, 860, 818, 733, 698, 649, 633 cmꢀ1
;
1H NMR
¼7.50e7.26 (5H, m), 6.75
(400 MHz, CDCl3), mixture of rotamers:
d
(1H, br s), 5.26e5.13 (1H, 2s), 4.57e4.32 (1H, 2s), 3.77e3.73 (1H, m),
3.72e3.70 (3H, 2s), 3.40e3.36 (1H, dd, J¼11.2, 4.4 Hz), 1.56 (3H, s),
1.47e1.44 (9H, 2s); 13C NMR (100 MHz, CDCl3), mixture of rotam-
4.3.4. (2S,4S,E)-1-tert-Butyl 2-methyl 3-(3-(1,3-dioxolan-2-yl)pro-
pylidene)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate
(11d). Obtained from the enone 10d (500 mg, 1.41 mmol) using the
general procedures. Purification of the residue by flash chroma-
tography (hexanes/EtOAc¼70/30) gave the title allylic alcohol
ers:
d
¼173.5, 173.0, 154.0, 153.0, 139.3, 138.4, 134.7, 134.5, 134.4,
128.5, 128.4, 128.1, 127.9, 127.8, 127.8, 127.5, 126.5, 126.4, 80.5, 80.4,
77.2, 76.3, 60.8, 60.7, 59.5, 58.9, 52.7, 52.3, 28.0, 27.9, 26.7, 21.8, 21.5;
HRMS (ESIMS): calcd for C19H25NO5Na [MþNa]þ 370.16249, found
370.16292.
(375 mg, 72%) as a thick yellowish oil. ½a D20
þ75.4 (c 1.00, CHCl3); IR
ꢂ
(neat): nmax¼3464, 2978, 2876, 1747, 1704, 1396, 1161, 1020, 937,
898, 854, 767 cmꢀ1
rotamers:
¼5.68e5.64 (1H, m), 4.93e4.82 (2H, m), 3.97e3.94 (2H,
m), 3.87e3.82 (2H, m), 3.72e3.70 (3H, 2s), 3.72e3.66 (1H, m), 3.20
;
1H NMR (400 MHz, CDCl3), mixture of
4.3.8. (2S,4S,E)-1-tert-Butyl 2-methyl 4-hydroxy-3-(4-methoxy
benzylidene)-4-methylpyrrolidine-1,2-dicarboxylate (11i). Obtained
from the enone 10i (500 mg, 1.39 mmol) using the general
d

446
S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
procedures. Purification of the residue by flash chromatography
(hexanes/EtOAc¼70/30) gave the title allylic alcohol and its minor
diastereomer in an inseparable mixture (385 mg, 74%, dr¼3:1) as
292.15110, found 292.15193. Compound 14: 1H NMR (400 MHz,
CDCl3), mixture of rotamers:
2s), 3.66e3.65 (3H, 2s), 3.64e3.58 (1H, m), 3.24e3.16 (1H, m),
2.79e2.58 (1H, m), 1.69e1.66 (3H, 2s), 1.40e1.36 (9H, 2s), 1.12e1.07
d¼5.47e5.42 (1H, m), 4.87e4.76 (1H,
a thick yellowish oil. ½a D20
þ192.6 (c 1.00, CHCl3); IR (neat):
ꢂ
nmax¼3437, 2983, 2845, 2256, 1694, 1610, 1516, 1459, 1397, 1370,
(3H, m); 13C NMR (100 MHz, CDCl3), mixture of rotamers:
171.4, 154.3, 153.6, 140.8, 140.1, 122.1, 120.6, 120.5, 79.7, 79.6, 60.9,
60.4, 52.7, 52.2, 51.7, 51.5, 37.7, 36.9, 28.0, 27.9, 27.4, 20.2, 14.4, 14.3.
d¼171.6,
1304, 1254, 1217, 1161, 1138, 1114, 1071, 1035, 911, 831, 731, 649,
633 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotamers:
;
d
¼7.48e7.40 (2H, m), 6.94e6.84 (2H, m), 6.65 (1H, br s), 5.25e5.12
Compound 15: ½a 2D0
ꢂ
ꢀ2.4 (c 1.00, CHCl3); IR (neat): nmax¼3455,
1H
¼4.94e4.44 (1H, 2d,
(1H, 2s), 4.54e4.30 (1H, 2s), 3.82e3.81 (3H, 2s), 3.75e3.72 (3H, 2br
2928, 1701, 1393, 1367, 1214, 1156, 1106, 1029, 899, 767 cmꢀ1
;
s), 3.30 (1H, dd, J¼11.3, 3.9 Hz), 1.53 (3H, s), 1.45e1.43 (9H, 2s); 13
C
NMR (400 MHz, CDCl3), mixture of rotamers: d
NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼173.8, 173.4, 159.6,
J¼9.1 Hz), 4.19e3.94 (1H, 2s), 3.80e3.78 (3H, s), 3.76e3.64 (1H, m),
3.37e3.32 (1H, m), 2.10e2.05 (1H, m), 1.44e1.40 (9H, 2s), 1.28e1.27
(3H, 2s), 1.27e1.18 (1H, m), 1.02 (3H, t, J¼7.4 Hz); 13C NMR
159.3, 154.3, 153.4, 137.1, 136.2, 130.5, 127.3, 126.4, 113.9, 80.8, 80.7,
77.8, 61.3, 61.1, 59.9, 59.2, 55.2, 55.2, 53.1, 52.7, 28.3, 22.2, 22.0;
HRMS (ESIMS): calcd for C20H27NO6Na [MþNa]þ 400.17306, found
400.17332.
(100 MHz, CDCl3), mixture of rotamers:
d
¼175.3, 175.0, 154.0, 153.1,
80.0, 80.0, 77.5, 62.4, 62.1, 60.8, 60.2, 60.0, 53.0, 52.2, 52.1, 51.9, 29.3,
27.9, 27.9, 22.2, 17.0, 16.9, 12.4; HRMS (ESIMS): calcd for
4.3.9. (2S,4S,E)-1-tert-Butyl 2-methyl 3-(4-fluorobenzylidene)-4-
C
14H25NO5Na [MþNa]þ 310.16304, found 310.16074.
hydroxy-4-methylpyrrolidine-1,2-dicarboxylate
(11j). Obtained
from the enone 10j (500 mg, 1.43 mmol) using the general pro-
cedures. Purification of the residue by flash chromatography
(hexanes/EtOAc¼70/30) gave the title allylic alcohol (416 mg, 80%)
4.4.2. (S)-1-tert-Butyl 2-methyl 3-(1-d-ethyl)-4-methyl-1H-pyrrole-
1,2(2H,5H)-dicarboxylate (16) and (2S,4S,Z)-1-tert-butyl 2-methyl 3-
ethylidene-4-d-4-methylpyrrolidine-1,2-dicarboxylate
(17). Obtained from the allylic alcohol 11a (100 mg, 0.351 mmol)
using method A with D2 gas. Purification of the residue by flash
chromatography (hexanes/EtOAc¼80/20) gave the pyrroline 16
(60 mg, 63%) and pyrrolidine 17 (9.5 mg, 10%) as a thick yellowish
oil. Compound 16: 1H NMR (400 MHz, CDCl3), mixture of rotamers:
a 20
as a thick yellowish oil. ½ ꢂD þ174.6 (c 1.00, CHCl3); IR (neat):
nmax¼3440, 2983, 2350, 2256, 1697, 1607, 1513, 1491, 1458, 1396,
1370, 1225, 1160, 1116, 1072, 1014, 910, 859, 837, 820, 774, 732,
648 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotamers:
;
d
¼7.49e7.40 (2H, m), 7.09e7.02 (2H, m), 6.68 (1H, br s), 5.21e5.08
(1H, 2s), 4.44e4.21 (1H, 2s), 3.84e3.74 (1H, m), 3.71e3.69 (3H, 2s),
d
¼4.94e4.86 (1H, 2br s), 4.20e4.11 (1H, m), 4.10e4.01 (1H, m),
3.39e3.33 (1H, 2br s), 1.54 (3H, s), 1.46e1.42 (9H, 2s); 13C NMR
3.75e3.73 (3H, 2s), 1.97e1.86 (1H, m), 1.70e1.68 (3H, 2s), 1.47e1.43
(9H, 2s), 1.01 (3H, t, J¼7.6 Hz); HRMS (ESIMS): calcd for
(100 MHz, CDCl3), mixture of rotamers:
d
¼173.5, 173.0, 163.7, 161.2,
154.3,153.3,139.6,138.7,131.0,130.7,130.6,125.7,125.6,115.6,115.4,
115.1, 80.9, 80.8, 61.1, 61.0, 59.8, 59.1, 53.1, 52.7, 28.3, 22.2, 22.0;
HRMS (ESIMS): calcd for C19H24NFO5Na [MþNa]þ 388.15307, found
388.15441.
C
14H22NDO4Na [MþNa]þ 293.15821, found 293.15779. Compound
17: 1H NMR (400 MHz, CDCl3), mixture of rotamers:
d¼5.47e5.42
(1H, m), 4.87e4.76 (1H, 2s), 3.66e3.65 (3H, 2s), 3.64e3.58 (1H, m),
3.24e3.16 (1H, m), 1.69e1.66 (3H, 2s), 1.40e1.36 (9H, 2s), 1.12e1.07
(3H, m); HRMS (ESIMS): calcd for
293.15821, found 293.15779.
C
14H22NDO4Na [MþNa]þ
4.4. Typical procedure for synthesis of trisubstituted 3-
pyrrolines 13aej
4.4.3. (S)-1-tert-Butyl 2-methyl 3-(cyclopentylmethyl)-4-methyl-1H-
pyrrole-1,2(2H,5H)-dicarboxylate (13b). Obtained from the allylic
alcohol 11b (225 mg, 0.663 mmol) using the general procedures.
Purification of the residue by flash chromatography (hexanes/
EtOAc¼80/20) gave the title pyrroline (155 mg, 73%, method A) as
Method A: the starting allylic alcohol (1 equiv) was dissolved in
EtOAc (0.2 M) and Pd(OH)2 (10 mol %) was added. The resulting
mixture was purged with hydrogen and stirred for 16 h under hy-
drogen atmosphere. The mixture was filtered over Celite and the
solvent was removed under reduced pressure. Method B: a solution
of the starting allylic alcohol (1 equiv) in MeOH (0.2 M) was added
Pd/C (1 mol %), then Et3SiH (2 equiv). The reaction mixture was
stirred at rt for variable times, after which it was filtered through
Celite and the solvent was removed under reduced pressure.
a thick yellowish oil. ½a D20
ꢀ158.3 (c 1.00, CHCl3); IR (neat):
ꢂ
nmax¼2949, 2870, 1749, 1703, 1684, 1446, 1397, 1365, 1241, 1169,
1117, 1016 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotamers:
;
d
¼4.95e4.87 (1H, 2s), 4.25e4.123 (1H, m), 4.11e4.01 (1H, m),
3.75e3.73 (3H, 2s), 2.15e1.94 (3H, m), 1.83e1.75 (1H, m), 1.72e1.70
(3H, 2s), 1.68e1.52 (5H, m), 1.49e1.44 (9H, 2s), 1.27e1.13 (1H, m),
1.08e1.03 (1H, m); 13C NMR (100 MHz, CDCl3), mixture of rotamers:
4.4.1. (S)-1-tert-Butyl
1,2(2H,5H)-dicarboxylate (13a), (2S,4S,Z)-1-tert-butyl 2-methyl 3-
ethylidene-4-methylpyrrolidine-1,2-dicarboxylate (14) and
2-methyl
3-ethyl-4-methyl-1H-pyrrole-
d
¼172.2, 172.6, 154.7, 154.1, 131.9, 131.9, 130.5, 130.3, 80.8, 69.6, 69.2,
58.1, 57.8, 52.8, 52.7, 39.4, 33.8, 33.8, 32.8, 32.1, 29.3, 29.1, 25.8, 25.6,
12.6, 12.6; HRMS (ESIMS): calcd for
346.19888, found 346.19805.
(2S,3S,4S)-1-tert-butyl 2-methyl 3-ethyl-4-hydroxy-4-
methylpyrrolidine-1,2-dicarboxylate (15). Obtained from the allylic
alcohol 11a (200 mg, 0.701 mmol) using the general procedures.
Purification of the residue by flash chromatography (hexanes/
EtOAc¼80/20) gave the title pyrroline 13a (120 mg, 63%, method
AdTable 1, entry 3), the regioisomer 14 (19 mg, 10%) and the hy-
drogenated product 15 (20 mg, 10%) as colorless oils. Compound
C
18H29NO4Na [MþNa]þ
4.4.4. (S)-1-tert-Butyl 2-methyl 3-undecyl-4-methyl-1H-pyrrole-
1,2(2H,5H)-dicarboxylate (13c). Obtained from the allylic alcohol
11c (100 mg, 0.243 mmol) using the general procedures. Purifica-
tion of the residue by flash chromatography (hexanes/EtOAc¼90/
10) gave the title pyrroline (65 mg, 68%, method A) as a thick yel-
13a: ½a 2D0
ꢂ
ꢀ141.8 (c 1.00, CHCl3); IR (neat): nmax¼2968, 2922, 1759,
1H NMR
¼4.94e4.86 (1H, 2br s),
1706, 1400, 1244, 1163, 1117, 1003, 906, 772 cmꢀ1
;
lowish oil. ½a 2D0
ꢀ80.7 (c 1.00, CHCl3); IR (neat): nmax¼2924, 2855,
ꢂ
(400 MHz, CDCl3), mixture of rotamers:
d
1748, 1709, 1457, 1397, 1245, 1169, 1119, 1012, 910, 859, 772,
4.20e4.11 (1H, m), 4.10e4.01 (1H, m), 3.75e3.73 (3H, 2s), 2.25e2.17
(1H, m), 1.97e1.86 (1H, m), 1.70e1.68 (3H, 2s), 1.47e1.43 (9H, 2s),
1.01 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3), mixture of
730 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotamers:
;
d
¼4.89e4.81 (1H, 2br s), 4.20e4.12 (1H, dt, J¼13.8, 4.3 Hz),
4.08e3.98 (1H, m), 3.73e3.71 (3H, 2s), 2.21e2.10 (1H, m), 1.96e1.85
(1H, m), 1.69e1.66 (3H, 2s), 1.46e1.42 (9H, 2s), 1.34e1.20 (18H, m),
0.90e0.85 (3H, m); 13C NMR (100 MHz, CDCl3), mixture of rotam-
rotamers:
d¼171.5, 171.4, 153.4, 152.9, 130.8, 130.6, 129.9, 129.8,
79.6, 79.5, 67.9, 67.4, 56.9, 56.6, 51.6, 51.5, 28.0, 27.9, 18.1, 12.2, 12.1,
11.0, 11.0; HRMS (ESIMS): calcd for
C
14H23NO4Na [MþNa]þ
ers:
d
¼171.9, 171.8, 153.8, 153.3, 130.8, 129.7, 129.7, 80.0, 68.6, 68.1,

S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
447
57.3, 57.0, 52.0, 51.8, 31.9, 29.6, 29.6, 29.6, 29.4, 29.3, 28.4, 28.3, 27.8,
25.3, 22.7, 14.1, 11.6, 11.5; HRMS (ESIMS): calcd for C23H41NO4Na
[MþNa]þ 418.29278, found 418.29227.
4.09e4.04 (1H, m), 3.56 (3H, br s), 3.34e3.28 (1H, m), 2.99e2.87
(1H, m), 1.47 (3H, br s), 1.42e1.39 (9H, 2s); 13C NMR (100 MHz,
CDCl3), mixture of rotamers:
d
¼172.3, 171.5, 153.2, 139.7, 139.5,
138.2, 132.6, 132.5, 128.7, 128.5, 128.4, 128.3, 126.4, 126.3, 80.1, 68.4,
68.0, 62.2, 61.9, 57.3, 57.0, 53.8, 53.2, 51.9, 51.7, 46.1, 45.3, 34.5, 33.7,
31.8, 31.5, 28.4, 28.3, 11.9, 11.8; HRMS (ESIMS): calcd for
4.4.5. (S)-1-tert-Butyl 2-methyl 3-(3-(1,3-dioxolan-2-yl)propyl)-4-
methyl-1H-pyrrole-1,2(2H,5H)-dicarboxylate (13d). Obtained from
the allylic alcohol 11d (100 mg, 0.269 mmol) using the general
procedures. Purification of the residue by flash chromatography
(hexanes/EtOAc¼80/20) gave the title pyrroline (74 mg, 78%,
C
19H25NO4Na [MþNa]þ 354.16758, found 354.16756.
4.4.9. (S)-1-tert-Butyl 2-methyl 3-(4-methoxybenzyl)-4-methyl-1H-
pyrrole-1,2(2H,5H)-dicarboxylate (13i). Obtained from the allylic
alcohol 11i (100 mg, 0.265 mmol) using the general procedures.
Purification of the residue by flash chromatography (hexanes/
EtOAc¼80/20) gave the title pyrroline (59 mg, 62%, method B) as
method A) as a thick yellowish oil. ½a D20
þ75.8 (c 1.00, CHCl3); IR
ꢂ
(neat): nmax¼3473, 2952, 1747, 1710, 1402, 1367, 1247, 1172, 1121,
;
1032, 939, 772 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of
rotamers:
d
¼4.87e4.81 (1H, m), 4.19e4.12 (1H, m), 4.11e4.05 (1H,
2s), 3.98e3.91 (2H, m), 3.88e3.81 (2H, m), 3.73e3.70 (3H, 2s),
2.24e2.16 (1H, m), 2.03e1.95 (1H, m), 1.74e1.59 (7H, m), 1.46e1.41
a thick yellowish oil. ½a D20
ꢀ19.4 (c 1.00, CHCl3); IR (neat):
ꢂ
nmax¼2976, 2937, 1747, 1699, 1611, 1512, 1453, 1394, 1296, 1246,
(10H, s); 13C NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼171.8,
1174, 1146, 1114, 1033, 989, 903, 818, 772, 738 cmꢀ1
;
1H NMR
¼7.16e7.10 (2H, m),
171.6, 153.8, 153.2, 131.6, 129.2, 129.1, 104.3, 80.0, 79.9, 76.9, 68.4,
68.0, 64.9, 57.3, 57.0, 52.0, 51.9, 33.4, 33.3, 28.4, 28.3, 25.0, 22.1, 22.0,
11.6, 11.6; HRMS (ESIMS): calcd for
378.18903, found 378.18871.
(400 MHz, CDCl3), mixture of rotamers:
d
6.88e6.82 (2H, m), 4.40e4.32 (1H, 2d, J¼8.7 Hz), 3.80 (3H, s),
3.70e3.68 (3H, 2s), 2.52e2.40 (2H, m), 2.91e2.83 (2H, m), 1.47 (3H,
br s), 1.41e1.39 (9H, 2s); 13C NMR (100 MHz, CDCl3), mixture of
C
18H29NO6Na [MþNa]þ
rotamers:
d
¼172.4, 172.1, 158.0, 154.6, 154.0, 131.6, 129.6, 129.4,
4.4.6. (S)-1-tert-Butyl 2-methyl 3-(4-((tert-butyldiphenylsilyl)oxy)
butyl)-4-methyl-1H-pyrrole-1,2(2H,5H)-dicarboxylate
(13f). Obtained from the allylic alcohol 11f (200 mg, 0.353 mmol)
using the general procedures. Purification of the residue by flash
chromatography (hexanes/EtOAc¼90/10) gave the title pyrroline
128.7, 113.9, 113.8, 79.9, 79.8, 68.4, 68.0, 62.1, 61.8, 57.3, 57.0, 55.2,
53.7, 53.2, 51.9, 51.7, 46.4, 45.5, 34.5, 33.7, 30.9, 28.4, 28.3, 14.5, 14.3;
HRMS (ESIMS): calcd for C20H27NO5Na [MþNa]þ 384.17814, found
384.17890.
(135 mg, 70%, method A) as a thick yellowish oil. ½a D20
ꢀ58.6 (c 1.00,
ꢂ
CHCl3); IR (neat): nmax¼2934, 2859, 1748, 1708, 1397, 1246, 1173,
4.5. Typical procedure for synthesis of 3,4-disubstituted
1111, 1008 cmꢀ1
;
1H NMR (400 MHz, CDCl3), mixture of rotamers:
L-prolines (16aed, gej)
d
¼7.69e7.64 (4H, m), 7.44e7.36 (6H, m), 4.88e4.82 (1H, 2s),
4.23e4.13 (1H, m), 4.10e3.96 (1H, m), 3.71e3.69 (3H, 2s),
3.68e3.62 (2H, m), 2.20e2.13 (1H, m), 1.93e1.87 (1H, m), 1.66e1.64
(3H, 2s), 1.58e1.49 (4H, m), 1.48e1.42 (9H, s), 1.05 (9H, s); 13C NMR
A solution of starting trisubstituted pyrrolines (1 equiv) in EtOAc
(1.0 M) was added Pd/C (15 mol %) and placed under 1 atm of hy-
drogen. The reaction mixture was stirred as such for 24 h (until MS-
analysis indicated full conversion to the desired product). The
mixture was filtered over Celite and the solvent was removed under
reduced pressure.
(100 MHz, CDCl3), mixture of rotamers:
d
¼171.8, 171.7, 153.7, 153.2,
135.5, 134.0, 131.2, 129.5, 129.4, 127.6, 80.0, 79.9, 68.4, 68.0, 63.5,
57.2, 56.9, 52.0, 51.8, 32.2, 32.1, 28.4, 28.3, 26.8, 25.0, 25.0, 24.0, 23.9,
19.2, 11.6, 11.5; HRMS (ESIMS): calcd for C32H45NO5SiNa [MþNa]þ
574.29592, found 574.29731.
4.5.1. Methyl
3(R)-ethyl-4(R)-methyl
N-Boc
L-prolinate
(16a). Obtained from the trisubstituted pyrroline 13a (35 mg,
0.130 mmol) using the general procedures. The title all-syn 3,4-
4.4.7. (S)-1-tert-Butyl 2-methyl 4-methyl-3-(3-phenylpropyl)-1H-
pyrrole-1,2(2H,5H)-dicarboxylate (13g). Obtained from the allylic
alcohol 11g (100 mg, 0.267 mmol) using the general procedures.
Purification of the residue by flash chromatography (hexanes/
EtOAc¼80/20) gave the title pyrroline (48 mg, 50%, method B) as
disubstituted L-proline (35 mg, quant) was obtained without fur-
ther purification as a thick yellowish oil. ½a D20
ꢀ10.1 (c 1.00, CHCl3);
ꢂ
IR (neat): nmax¼2971, 2934, 2876, 1747, 1703, 1396, 1194, 1172, 1154,
1017, 898, 767 cmꢀ1
rotamers:
3.50e3.45 (1H, m), 3.37e3.27 (1H, 2d, J¼10.4 Hz), 2.33e2.30 (2H,
m), 1.49e1.26 (1H, m), 1.40e1.35 (9H, 2s), 1.24e1.16 (1H, m),
1.00e0.84 (6H, m); 13C NMR (100 MHz, CDCl3), mixture of rotam-
;
1H NMR (400 MHz, CDCl3), mixture of
¼4.25e4.15 (1H, 2d, J¼9.3 Hz), 3.66e3.65 (3H, 2s),
a thick yellowish oil. ½a D20
ꢂ
ꢀ93.6 (c 1.00, CHCl3); IR (neat):
d
nmax¼2977, 2934, 2855, 1748, 1707, 1398, 1247, 1172, 1119, 1011, 908,
745, 700 cmꢀ1 1H NMR (400 MHz, CDCl3), mixture of rotamers:
;
d
¼7.32e7.28 (2H, m), 7.24e7.18 (3H, m), 4.95e4.86 (1H, 2s),
4.24e4.16 (1H, m), 4.11e4.01 (1H, q, J¼15.3 Hz), 3.72e3.71 (3H, br
s), 2.68e2.57 (2H, m), 2.28e2.19 (1H, m), 2.03e1.93 (1H, m),
1.92e1.82 (1H, m), 1.75e1.64 (4H, m), 1.50e1.45 (9H, 2s); 13C NMR
ers:
d
¼172.6,172.4,154.6,154.0, 79.7, 62.2, 61.8, 53.9, 53.4, 51.5, 51.4,
47.2, 46.3, 34.5, 33.5, 29.4, 28.2, 19.4, 19.3, 14.1, 13.9, 12.6, 12.6;
HRMS (ESIMS): calcd for C14H25NO4Na [MþNa]þ 294.16649, found
294.16758.
(100 MHz, CDCl3), mixture of rotamers:
d
¼171.8, 171.7, 153.8, 153.2,
141.8, 131.4, 129.4, 129.2, 128.3, 128.3, 125.8, 80.0, 68.5, 68.0, 57.3,
56.9, 52.0, 51.9, 35.5, 35.4, 29.2, 29.1, 28.4, 28.3, 24.9, 24.9, 11.7, 11.6;
HRMS (ESIMS): calcd for C21H29NO4 [MþH]þ 382.19888, found
382.20035.
4.5.2. Methyl 3(R)-methylcyclopentyl-4(R)-methyl N-Boc L-prolinate
(16b). Obtained from the trisubstituted pyrroline 13b (40 mg,
0.124 mmol) using the general procedures. The title all-syn 3,4-
disubstituted L-proline (32 mg, 80%) was obtained without fur-
4.4.8. (S)-1-tert-Butyl 2-methyl 3-benzyl-4-methyl-1H-pyrrole-
1,2(2H,5H)-dicarboxylate (13h). Obtained from the allylic alcohol
11h (100 mg, 0.288 mmol) using the general procedures. Purifica-
tion of the residue by flash chromatography (hexanes/EtOAc¼80/
20) gave the title pyrroline (45 mg, 47%, method B) as a thick yel-
ther purification as a thick yellowish oil. ½a D20
þ4.3 (c 1.00, CHCl3);
ꢂ
IR (neat): nmax¼2944, 1748, 1702, 1394, 1171, 900 cmꢀ1
;
1H NMR
(400 MHz, CDCl3), mixture of rotamers:
d
¼4.26e4.18 (1H, 2d,
J¼9.5 Hz), 3.70e3.69 (3H, 2s), 3.52e3.46 (1H, m), 3.41e3.27 (1H,
m), 2.59e2.45 (1H, m), 2.33e2.25 (1H, m), 1.87e1.73 (3H, m),
1.64e1.47 (4H, m), 1.44e1.38 (9H, 2s), 1.35e1.22 (2H, m), 1.10e0.99
(2H, m), 0.99 (3H, d, J¼7.3 Hz); 13C NMR (100 MHz, CDCl3), mixture
lowish oil. ½a 2D0
ꢀ56.7 (c 1.00, CHCl3); IR (neat): nmax¼2974, 2925,
ꢂ
2856, 1746, 1702, 1448, 1393, 1246, 1170, 1115, 1013, 904, 860, 769,
700, 560 cmꢀ1
;
1H NMR (400 MHz, CDCl3), mixture of rotamers:
of rotamers:
d¼172.7, 172.5, 154.0, 79.7, 62.4, 62.0, 53.9, 53.4, 51.6,
d¼7.30e7.14 (5H, m), 4.80e4.72 (1H, 2br s), 4.27e4.22 (1H, m),
51.4, 44.1, 43.2, 37.9, 34.9, 33.9, 33.1, 32.5, 32.4, 28.4, 28.3, 25.0, 14.5,

448
S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
14.4; HRMS (ESIMS): calcd for C18H31NO4Na [MþNa]þ 348.21453,
m), 4.33e4.23 (1H, 2d, J¼9.0 Hz), 3.61e3.59 (3H, 2s), 3.47e3.39
(1H, m), 3.33e3.18 (1H, m), 2.92e2.76 (2H, m), 2.51e2.44 (1H, m),
2.19e2.12 (1H, m), 1.39e1.33 (9H, 2s), 1.00 (3H, d, J¼7.3 Hz); 13C
found 348.21486.
4.5.3. Methyl
3(R)-undecyl-4(R)-methyl
N-Boc
L
-prolinate
NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼172.3, 154.0, 139.6,
(16c). Obtained from the trisubstituted pyrroline 13c (34 mg,
0.0860 mmol) using the general procedures. Purification of the
residue by flash chromatography (hexanes/EtOAc¼95/5) gave the
139.5, 128.5, 128.4, 126.2, 79.9, 62.2, 61.8, 53.7, 53.2, 51.7, 51.5,
46.1, 45.2, 34.5, 33.7, 31.8, 31.7, 29.7, 28.4, 28.3, 14.5, 14.3;
HRMS (ESIMS): calcd for C19H28NO4 [MþH]þ 334.20128, found
334.20289.
title all-syn 3,4-disubstituted L-proline (26 mg, 76%) as a thick
yellowish oil. ½a D20
ꢂ
ꢀ3.0 (c 1.00, CHCl3); IR (neat): nmax¼2924, 2855,
1H NMR (400 MHz,
¼4.29e4.19 (1H, 2d, J¼9.4 Hz),
1749, 1703, 1458, 1392, 1175, 1141, 897 cmꢀ1
;
4.5.7. Methyl 3(R)-(r-methoxybenzyl)-4(R)-methyl N-Boc L-prolinate
CDCl3), mixture of rotamers:
d
(16i). Obtained from the trisubstituted pyrroline 13i (30 mg,
0.0795 mmol) using the general procedures. Purification of the
residue by flash chromatography (hexanes/EtOAc¼80/20) gave the
3.71e3.69 (3H, 2s), 3.52e3.45 (1H, m), 3.41e3.26 (1H, m),
2.50e2.37 (1H, m), 2.34e2.22 (1H, m), 1.45e1.39 (9H, 2s),
1.32e1.24 (20H, m), 0.99 (3H, d, J¼7.2 Hz), 0.87 (3H, t, J¼6.7 Hz);
title all-syn 3,4-disubstituted L-proline (20 mg, 67%) as a thick
13C NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼172.6, 172.5,
yellowish oil. ½a D20
ꢂ
ꢀ4.8 (c 0.50, CHCl3); IR (neat): nmax¼2927, 1747,
1H
¼7.15e7.10 (2H, m),
154.6, 154.0, 79.7, 79.7, 62.3, 61.9, 53.9, 53.4, 51.6, 51.4, 45.4, 44.5,
31.9, 29.8, 29.6, 29.5, 29.3, 28.4, 28.3, 28.1, 26.3, 26.3, 22.7, 14.3,
14.1; HRMS (ESIMS): calcd for C23H43NO4Na [MþNa]þ 420.30843,
found 420.30919.
1697, 1512, 1392, 1246, 1173, 1145, 1113, 1033, 901, 818 cmꢀ1
;
NMR (400 MHz, CDCl3), mixture of rotamers:
d
6.86e6.81 (2H, m), 4.38e4.28 (1H, 2d, J¼9.0 Hz), 3.78 (3H, s),
3.68e3.66 (3H, 2s), 3.52e3.40 (1H, m), 3.40e3.27 (1H, m),
2.92e2.76 (2H, m), 2.52e2.46 (1H, m), 2.25e2.17 (1H, m),
1.45e1.40 (9H, 2s), 1.05 (3H, d, J¼7.3 Hz); 13C NMR (100 MHz,
4.5.4. Methyl 3(R)-[butyl-4-(1,3-dioxolanyl)]-4(R)-methyl N-Boc
L
-prolinate (16d). Obtained from the trisubstituted pyrroline 13d
CDCl3), mixture of rotamers:
d
¼172.4, 172.1, 158.0, 154.6, 154.0,
(50 mg, 0.141 mmol) using the general procedures. Purification of
the residue by flash chromatography (hexanes/EtOAc¼80/20) gave
131.6, 131.5, 129.4, 113.9, 113.8, 79.9, 62.1, 61.8, 55.2, 53.8, 53.2, 51.7,
51.5, 46.4, 45.5, 34.4, 33.7, 30.9, 30.8, 28.4, 28.3, 14.4, 14.3; HRMS
(ESIMS): calcd for
386.19334.
the title all-syn 3,4-disubstituted
L
-proline (35 mg, 70%) as a thick
C
20H29NO5Na [MþNa]þ 386.19379, found
yellowish oil. ½a D20
ꢂ
ꢀ1.3 (c 1.00, CHCl3); IR (neat): nmax¼2936, 1747,
1H NMR (400 MHz, CDCl3),
¼4.84 (1H, t, J¼4.7 Hz), 4.29e4.20 (1H, 2d,
1698, 1396, 1144, 1026, 757 cmꢀ1
;
mixture of rotamers:
d
4.5.8. Methyl 3(R)-(r-fluorobenzyl)-4(R)-methyl N-Boc L-prolinate
J¼9.4 Hz), 3.98e3.92 (2H, m), 3.88e3.82 (2H, m), 3.71e3.70 (3H,
2s), 3.52e3.45 (1H, m), 3.42e3.27 (1H, m), 2.51e2.39 (1H, m),
2.33e2.25 (1H, m), 1.68e1.63 (3H, m), 1.49e1.44 (2H, m), 1.45e1.39
(9H, s), 1.33e1.25 (1H, m), 0.99 (3H, d, J¼7.3 Hz); 13C NMR
(16j). Directly obtained from the allylic alcohol 11j (39 mg,
0.107 mmol) using method A. Purification of the residue by flash
chromatography (hexanes/EtOAc¼80/20) gave the title all-syn
3,4-disubstituted
a 2D0
1400, 1178, 1148, 908 cmꢀ1
of rotamers:
L-proline (12 mg, 32%) as a thick yellowish oil.
(100 MHz, CDCl3), mixture of rotamers:
d
¼172.5, 172.4, 154.6, 154.0,
½
ꢂ
þ0.8 (c 1.00, CHCl3); IR (neat): nmax¼2932, 1756, 1706, 1514,
104.2, 79.8, 79.7, 64.9, 62.2, 61.8, 53.9, 53.4, 51.6, 51.4, 45.3, 44.4,
34.7, 33.9, 33.8, 29.7, 28.4, 28.3, 26.3, 26.2, 22.5, 14.3, 14.1; HRMS
;
1H NMR (400 MHz, CDCl3), mixture
d
¼7.19e7.14 (2H, m), 7.01e6.95 (2H, m), 4.39e4.28
(ESIMS): calcd for
380.20434.
C
18H31NO6Na [MþNa]þ 380.20436, found
(1H, 2d, J¼9.0 Hz), 3.67e3.65 (3H, 2s), 3.54e3.48 (1H, m),
3.41e3.27 (1H, m), 2.92e2.76 (2H, m), 2.57e2.50 (1H, m),
2.25e2.19 (1H, m), 1.46e1.40 (9H, 2s), 1.05 (3H, d, J¼7.3 Hz); 13C
4.5.5. Methyl 3(R)-phenylpropyl-4(R)-methyl N-Boc
L
-prolinate
NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼172.2, 172.0,
(16g). Obtained from the trisubstituted pyrroline 13g (16 mg,
0.0426 mmol) using the general procedures. Purification of the
residue by flash chromatography (hexanes/EtOAc¼80/20) gave
162.6, 160.1, 154.6, 153.9, 135.2, 135.1, 135.1, 129.9, 129.8, 115.3,
115.3, 115.1, 115.1, 80.0, 79.9, 62.0, 61.7, 53.7, 53.2, 51.7, 51.5, 46.3,
45.4, 34.5, 33.7, 31.0, 30.9, 29.7, 28.4, 28.3, 14.4, 14.3; HRMS
(ESIMS): calcd for C19H26NFO4Na [MþNa]þ 374.17556, found
374.17381.
the title all-syn 3,4-disubstituted L-proline (13 mg, 82%) as a thick
yellowish oil. ½a D20
ꢀ2.6 (c 1.00, CHCl3); IR (neat): nmax¼2939,
ꢂ
1755, 1707, 1459, 1401, 1370, 1201, 1181, 1147, 898, 751, 703,
633 cmꢀ1
;
1H NMR (400 MHz, CDCl3), mixture of rotamers:
4.6. (2S)-1-tert-Butyl-2-methyl-3-ethyl-4-methyl-d3-2,5-
dihydro-1H-pyrrole-1,2-dicarboxylate (19)
d
¼7.34e7.28 (2H, m), 7.24e7.18 (3H, m), 4.34e4.23 (1H, 2d,
J¼9.3 Hz), 3.71e3.70 (3H, 2s), 3.55e3.49 (1H, m), 3.45e3.32 (1H,
m), 2.65 (2H, t, J¼7.6 Hz), 2.55e2.45 (1H, m), 2.36e2.28 (1H, m),
1.75e1.67 (3H, m), 1.49e1.43 (9H, 2s), 1.37e1.30 (1H, m), 1.01 (3H,
d, J¼7.3 Hz); 13C NMR (100 MHz, CDCl3), mixture of rotamers:
Under argon and in a flame-dried flask, the starting enone 10a
(124 mg, 0.461 mmol) was dissolved in dry THF (2.5 mL) and
commercial solution of LaCl3$2LiCl (0.6 in THF, 0.810 mL,
0.484 mmol) was added at rt. The mixture was allowed to stir as
such for 1 h, then it was cooled to ꢀ78 ꢁC and CD3MgI freshly
prepared from CD3I (4.6 mmol) and Mg turnings (6.9 mmol) in Et2O
(3 mL)was added dropwise. The resulting brownish solution was
stirred at ꢀ78 ꢁC for 1 h, then quenched at ꢀ78 ꢁC with aqueous
saturated NH4Cl. The biphasic mixture was separated and the
aqueous phase was extracted three times with Et2O (3ꢃ10 mL). The
combined organic layers were washed with brine and dried over
Na2SO4, and the solvent was removed under reduced pressure.
Purification of the residue by flash chromatography gave the title
compound as yellowish oil (81 mg, 61%). Rf¼0.4 (hexanes/
EtOAc¼60/40), [KMnO4]. 1H NMR (400 MHz, CDCl3), mixture of
d
¼172.5, 172.4, 154.6, 154.0, 142.1, 142.1, 128.3, 125.8, 79.8, 79.7,
62.2, 61.8, 53.8, 53.3, 51.6, 51.4, 45.3, 44.4, 36.1, 36.1, 34.8, 33.9,
30.0, 28.4, 28.4, 28.4, 28.3, 28.3, 26.2, 26.1, 14.3, 14.1; HRMS
(ESIMS): calcd for
384.21572.
C
21H31NNaO4 [MþNa]þ 384.21453, found
4.5.6. Methyl
3(R)-benzyl-4(R)-methyl
N-Boc
L-prolinate
(16h). Obtained from the trisubstituted pyrroline 13h (18.5 mg,
0.0533 mmol) using the general procedures. Purification of the
residue by flash chromatography (hexanes/EtOAc¼80/20) gave the
title all-syn 3,4-disubstituted L-proline (13 mg, 70%) as a thick
yellowish oil. ½a D20
ꢀ2.1 (c 0.80, CHCl3); IR (neat): nmax¼2982, 2941,
ꢂ
1754, 1702, 1459, 1440, 1398, 1370, 1256, 1201, 1178, 1147, 1118,
rotamers:
d
¼5.82e5.77 (1H, q, J¼7.2 Hz), 4.91e4.83 (1H, 2s),
1023, 991, 913, 773, 736, 703, 633 cmꢀ1
;
1H NMR (400 MHz,
4.09e3.86 (1H, 2s), 3.82e3.71 (1H, 2s), 3.79e3.77 (3H, 2s),
3.27e3.25 (1H, 2s), 1.76e1.74 (3H, 2s), 1.44e1.41 (9H, 2s); HRMS
CDCl3), mixture of rotamers:
d
¼7.25e7.18 (2H, m), 7.17e7.10 (3H,

S. Hanessian et al. / Tetrahedron 70 (2014) 439e449
449
(ESIMS): calcd for C14H20NO5Na [MþNa]þ 311.16567, found
J¼11.6 Hz), 3.78e3.76 (3H, 2s), 3.46e3.41 (1H, 2d, J¼11.2 Hz),
1.76e1.75 (3H, d, J¼4.0 Hz), 1.47e1.44 (9H, 2s), 0.99e0.98 (9H, 2s);
311.16594.
13C NMR (100 MHz, CDCl3), mixture of rotamers:
d
¼173.1, 139.8,
4.7. (2S)-1-tert-Butyl-2-methyl-3-ethyl-4-methyl-d3-2,5-
dihydro-1H-pyrrole-1,2-dicarboxylate (20)
139.3, 125.2, 83.4, 82.7, 81.0, 80.9, 65.1, 62.5, 62.0, 57.4, 56.6, 56.0,
52.9, 52.6, 37.5, 28.7, 28.6, 14.9, 14.8; HRMS (ESIMS): calcd for
C
14H29NO6Na [MþNa]þ 350.19275, found 350.19379.
The starting allylic alcohol 19 (50 mg, 0.174 mmol) was dissolved
in 1 mL EtOAc and Pd(OH)2 (10 mol %) was added. The resulting
mixture was purged with hydrogen and stirred for 16 h under hy-
drogen atmosphere. The mixture was filtered over Celite and the
solvent was removed under reduced pressure. Purification of the
residue by flash chromatography gave the title compound as yel-
lowish oil (32 mg, 68%). Rf¼0.5 (hexanes/EtOAc¼80/20), [KMnO4].
Acknowledgements
We thank NSERC and FQRNT for financial assistance. S.D. and
S.K. would like to thank FQRNT and UNIGE for fellowships. H.M.
would like to thank DFG for a postdoctoral fellowship. We ac-
knowledge a departmental grant from the CFI.
1H NMR (400 MHz, CDCl3), mixture of rotamers:
d¼4.95e4.86 (1H,
2s), 4.19e4.17 (1H, m), 4.07e4.04 (1H, m), 3.76e3.73 (3H, 2s),
2.23e2.20 (1H, m), 1.96e1.94 (1H, m), 1.49e1.44 (9H, 2s), 1.04e1.00
(3H, t, J¼7.6 Hz); HRMS (ESIMS): calcd for C14H20NO4Na [MþNa]þ
295.17076, found 295.16976.
Supplementary data
These data include 1H NMR and 13C NMR spectra of compounds
10aej, 11aej, 12, 13aeg, 14, 15, 16aee,gej and 21. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.11.040.
4.8. (2S,4S,E)-1-tert-Butyl 2-methyl 4-acetoxy-3-ethylidene-4-
methylpyrrolidine-1,2-dicarboxylate (21)
References and notes
A solution of the allylic alcohol 11a (148 mg, 0.500 mmol) in
CH2Cl2 (2.5 mL) was cooled to 0 ꢁC and DMAP (cat.), NEt3 (88
m
L,
1. (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603e626; (b) Clayden, J.; Read, B.;
Hebditch, K. R. Tetrahedron 2005, 61, 5713e5724; (c) Cheng, Y.; Huang, Z. T.;
Wang, M. X. Curr. Org. Chem. 2004, 8, 325e351; (d) Nakada, Y.; Sugahara, T.;
Ogasawara, K. Tetrahedron Lett. 1997, 38, 857e860; (e) Jones, R. C. F.; Howard, K.
J.; Snaith, J. S. Tetrahedron Lett. 1997, 38, 1647e1650.
2. Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936e962; (b) Punniyamurthy,
T.; Irie, R.; Katsuki, T. Chirality 2000, 12, 464e468; (c) Kende, A. S.; Luzzio, M. J.;
Mendoza, J. S. J. Org. Chem. 1990, 55, 918e924.
0.600 mmol), and Ac2O (60
mL, 0.600 mmol) were added. The
reaction mixture was allowed to warm up to rt and stirred for
20 min, after which full conversion was observed. The reaction
mixture was thus quenched with a 1 N HCl solution (5 mL), the
aqueous and organic phases were separated and the aqueous
phase was further extracted with EtOAc (3ꢃ5 mL). The residue
was purified by flash chromatography (hexanes/EtOAc¼80/20) to
give the allylic acetate 21 (170 mg, 99%) as a colorless liquid.
3. Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 124e12511 and references
cited therein.
4. Hanessian, S.; Dorich, S.; Menz, H. Org. Lett. 2013, 15, 4134e4137.
5. For a review, see: (a) Govindh, B.; Diwakar, B. S.; Murthy, Y. L. N. Org. Commun.
2012, 5, 105e119 Selection of articles using this strategy; (b) Andrew, R. J.;
Mellor, J. M. Tetrahedron 2000, 56, 7261e7266; (c) Fontenas, C.; Aït-Haddou, H.;
Bejan, E.; Balavoine, G. G. A. Synth. Commun. 1998, 28, 1743e1753; (d) Shawe, T.
T.; Hansen, D. B.; Peet, K. A.; Prokopowicz, A. S.; Robinson, P. M.; Cannon, A.;
Dougherty, K. E.; Ross, A. A.; Landino, L. M. Tetrahedron 1997, 5, 1547e1556.
Rf¼0.5 (hexanes/EtOAc¼70/30), [KMnO4]. ½a D20
þ38.4 (c 1.00,
ꢂ
CHCl3); IR (neat): nmax¼2964, 2936, 1741, 1702, 1400, 1365, 1244,
1202, 1170, 1109, 1014, 900, 769 cmꢀ1; 1H NMR (400 MHz, CDCl3),
mixture of rotamers:
d
¼5.95e5.79 (1H, m), 4.99e4.87 (1H, 2s),
ꢁ
4.02e3.95 (1H, 2d, J¼12 Hz), 3.67 (3H, s), 3.47e3.40 (1H, 2d,
J¼12 Hz), 1.90e1.88 (3H, d, J¼7.2 Hz), 1.83e1.81 (3H, 2d, J¼6.8 Hz),
1.62 (3H, s), 1.42e1.39 (9H, 2s); 13C NMR (100 MHz, CDCl3),
6. Chabaud, P.; Pepe, G.; Courcambeck, J.; Camplo, M. Tetrahedron 2005, 61,
3725e3731.
7. Shafikov, R. V.; Afon’kina, S. R.; Savchenko, R. G.; Galyautdinov, I. V.; Odinokov,
V. N. Russ. J. Org. Chem. 2007, 43, 305e306.
mixture of rotamers:
d
¼170.9, 170.8, 170.7, 170.5, 154.7, 153.9,
8. Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 497e500.
9. Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663e1664 For this study, 20% w/w
Pd(OH)2/C and 10% Pd/C was always used.
10. (a) Sen, A.; Lai, T.-W. Inorg. Chem. 1984, 23, 3257e3258; (b) Sen, A.; Lai, T.-W.
Inorg. Chem. 1981, 20, 4036e4038.
11. The addition of Brønsted acids, such as camphorsulfonic acid (CSA) and p-tol-
uenesulfonic acid (pTSA) alone led to complex mixtures after several hours.
12. Fulmer, G. R.; Muller, R. P.; Kemp, R. A.; Goldberg, K. I. J. Am. Chem. Soc. 2009,
131, 1346e1347.
137.1, 136.9, 126.9, 126.3, 84.5, 83.5, 80.8, 80.7, 60.8, 60.2, 57.7,
57.6, 52.5, 52.3, 28.7, 28.6, 28.6, 22.4, 22.3, 21.8, 21.5, 15.3, 15.2;
HRMS (ESIMS): calcd for C14H25NO6Na [MþNa]þ 350.15621, found
350.15741.
4.9. (2S,4S,E)-1-tert-Butyl 2-methyl 4-(tert-butyl)-3-
13. For a review, see: Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 20, 91e95.
14. (a) Mandal, P. K.; McMurray, J. S. J. Org. Chem. 2007, 72, 6599e6601; (b) Cole-
man, R. S.; Shah, J. A. Synthesis 1999, 1399e1400.
ethylidene-4-hydroxypyrrolidine-1,2-dicarboxylate (28)
Under argon and in a flame-dried flask, the enone 10a (195 mg,
0.700 mmol) was dissolved in dry THF (3.5 mL) and a commercial
solution of LaCl3$2LiCl (0.6 M in THF, 1.17 mL, 0.700 mmol) was
added at rt. The mixture was allowed to stir as such for 1 h, then it
15. For a review, see: Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 3381e3391.
16. The apolarity of both the studied products and PMHS, combined with the high
boiling point of the latter, rendered the purification difficult and could be fully
accomplished only after multiple chromatographies.
was cooled to ꢀ78 ꢁC and added MeMgBr (350
mL, 3.0 M in Et2O,
17. (a) Muzart, J. Tetrahedron 2005, 61, 9423e9463 and references cited therein. Also
see: (b) Sawadjoon, S.; Lundstedt, A.; Samec, J. S. M. ACS Catal. 2013, 3, 635e642.
18. (a) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292e294 For reviews,
see: (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921e2944; (c) Trost,
B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395e422; (d) Godleski, S. A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, UK, 1991; Vol. 4, Chapter 3.3, Also see: (e) Grossman, R. B. The Art of
Writing Reasonable Organic Reactions Mechanism, 2nd ed.;, 2003; pp 309e310;
(f) Augustine, R. L. Heterogeneous Catalysis for the Synthetic Chemist; M. Dekker:
New York, NY, 1995; pp 525e526.
1.05 mmol) dropwise. The resulting brownish solutionwas stirred at
ꢀ78 ꢁC for 1 h, then quenched at ꢀ78 ꢁC with aqueous saturated
NH4Cl (10 mL). The biphasic mixture was separated and the aqueous
phase was extracted with Et2O (3ꢃ10 mL). Special care was taken to
avoid acidic wash (no 1 M HCl), as analogous intermediates were
shown to decompose rapidly under such conditions. The solvent
was removed under reduced pressure without heating. Purification
of the residue by flash chromatography gave the title compound as
yellowish oil (118 mg, 48%). Rf¼0.4 (hexanes/EtOAc¼70/30),
19. Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085e4088.
20. Khan, A. M.; McQuillin, F. J.; Jardine, I. Tetrahedron Lett. 1966, 2649e2655.
21. Following a suggestion from one of the reviewers, doping the reaction mixture
with 0.5 equiv H2O did not affect the yield or the reaction rate. In the presence
[KMnO4]. ½a 2D0
ꢀ4.7 (c 1.00, CHCl3); IR (neat): nmax¼3463, 2963,
ꢂ
ꢂ
1750,1700,1393,1371,1165,1125,1096,1017, 908, 858, 771 cmꢀ1; 1H
of 4 A molecular sieves, a slight increase in the yield of compound 15 was
observed by TLC.
NMR (400 MHz, CDCl3), mixture of rotamers:
4.90e4.81 (1H, 2s), 3.97e3.94 (1H, 2s), 3.88e3.83 (1H, 2d,
d
¼5.91e5.89 (1H, m),
22. Fukumoto, K.; Suzuki, K.; Nemoto, H.; Kametani, T.; Furuyama, H. Tetrahedron
1982, 38, 3701e3704.