Three-step synthesis of (±)-preussin from decanal

Article abstract of DOI:10.1021/jo5011558

A straightforward and stereoselective synthesis of the alkaloid preussin is described starting from decanal and diethyl 3-diazo-2-oxopropylphosphonate. The key steps are an aza-Michael reaction from an α,β-unsaturated diazoketone followed by a highly stereoselective Cu-catalyzed ylide formation and then a [1,2]-Stevens rearrangement. This strategy is feasible for extension to preussin analogues, demonstrating its utility for the rapid construction of all-cis-substituted pyrrolidines.

Full text of DOI:10.1021/jo5011558

Note
pubs.acs.org/joc
Three-Step Synthesis of ( )-Preussin from Decanal
Isac G. Rosset, Rafael M. P. Dias, Vagner D. Pinho, and Antonio C. B. Burtoloso*
Instituto de Química de Sao Carlos, Universidade de Sao Paulo, CEP 13560-970, Sao Carlos, SP Brazil
̃
̃
̃
S
* Supporting Information
ABSTRACT: A straightforward and stereoselective synthesis
of the alkaloid preussin is described starting from decanal and
diethyl 3-diazo-2-oxopropylphosphonate. The key steps are an
aza-Michael reaction from an α,β-unsaturated diazoketone
followed by a highly stereoselective Cu-catalyzed ylide
formation and then a [1,2]-Stevens rearrangement. This strategy is feasible for extension to preussin analogues, demonstrating
its utility for the rapid construction of all-cis-substituted pyrrolidines.
2,5-Cis-disubstituted pyrrolidine alkaloids1 are vastly found in
nature from animal, vegetable, and fungal sources. Possessing a
diverse array of interesting biological properties, these natural
products and their synthetic analogues are constantly targeted.
Figure 1 illustrate some examples of 2,5-cis-disubstituted
common.1 In view of this and as a part of our studies employing
α,β-unsaturated diazoketones6,7 for constructing piperidine,
indolizidine, and quinolizidine alkaloids, we envisioned that all-
cis-trisubstituted pyrrolidines could also be prepared in a
stereoselective fashion and in two to three steps from these
building blocks. To illustrate, a retrosynthetic analysis is
depicted in Scheme 1 for the synthesis of preussin (1).
Diazoketone (2) could bring the long alkyl chain and could
easily be prepared from decanal and the olefination reagent
diethyl 3-diazo-2-oxopropylphosphonate.6 To incorporate
preussin’s methyl and benzyl groups, an aza-Michael addition8
in the presence of methylbenzylamine could be carried out.
Finally, to construct the pyrrolidine ring and adjust the position
of these groups, ylide formation followed by a [1,2]-Stevens
rearrangement9 could translocate the benzyl group (best
migratory aptitude), leading to the thermodynamically more
stable10 2,5-cis-pyrrolidinone (4). Hydride attack at the less
hindered α face would complete the synthesis.
The synthesis of cyclic amines employing ammonium salts
has been described, and important contributions can be found
in the works of West11 and Clark.12 West described, for the first
time, the synthesis of 2-substituted piperidinones using the
[1,2]-Stevens rearrangement. Clark studied the same cycliza-
tion by means of a [2,3]-sigmatropic rearrangement and
obtained disubstituted pyrrolidines and piperidines, but with no
stereocontrol (or the trans isomer preferentially formed). In
spite of these seminal contributions, to the best of our
knowledge, neither preparation of 2,5-disubstituted pyrrolidines
by the [1,2]-Stevens rearrangement nor study of the stereo-
chemical outcome of these reactions in a nitrogen containing 5-
membered ring was carried out. Herein, we describe how we
accomplished both of these by preparing 2,5-cis-disubstituted
pyrrolidines as single isomers and further synthesizing only cis
alkaloid preussin from decanal in three steps.
Figure 1. Natural and synthetic 2,5-cis-substituted pyrrolidines.
pyrrolidines as well as preussin (1), which was isolated in
1988 from the fungi Aspergillus ochraceus and Preussia sp.2
Preussin exhibits significant antifungal, antiviral, and anti-
bacterial activities and induces apoptosis in several human
cancer cell lines.2,3 Interestingly, all eight stereoisomers of
preussin also display some biological activity,4 and it is possible
that their analogues have the same behavior. Because of this,
several research groups have been involved with the synthesis
of preussin and its analogues, and thus far, more than 20
syntheses have been described.5 The majority have either long
synthetic sequences or low diastereoselectivities. For example,
the shortest synthesis of preussin to date (three steps),
described in the ingenious work of Britton,5e suffers from low
diastereoselectivity in two key steps.
First, unsaturated diazoketone (2) was prepared in 92%
yield13 from decanal, using our recently described method.6
Next, Michael addition of benzylmethylamine furnished the
While there are many methods of preparing 2,5-disubstituted
pyrrolidines in the trans relationship, there are just a few for
synthesizing the cis isomers. The reason is related to their
abundance in nature. That is, the trans isomers are much more
Received: May 23, 2014
© XXXX American Chemical Society
A
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Note
Scheme 1. Synthetic Strategy for the Synthesis of Preussin from Decanal
Table 1. Optimization Study for the Aza-Michael Reaction from Unsaturated Diazoketone (2)
a
b
c
entry
amine (equiv)
base (equiv)
solvent
time (h)
yield (%)
RSM (%)
1
2
3
4
5
6
7
2
2
none
Et2O
THF
THF
THF
THF
THF
THF
48
48
36
12
36
12
10
22
45
60
50
95
95
none
40
22
2
TEA (0.5)
TEA (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
5
2
15
5
10
12
a
b
Unless otherwise noted, all the reactions were carried out using ∼0.1 mmol of diazoketone. Yields after column chromatography purification.
c
RSM = recovered starting material.
Figure 2. Aza-Michael adducts from reactions employing different amines and diazoketones.
aza-Michael adduct (3) in 95% yield13 after a careful
optimization study (Table 1). Using the best conditions
(entry 6 in Table 1), adducts 5−12 were prepared in good
yields from different diazoketones6 and/or secondary amines
(Figure 2) and can also be applied in the synthesis of preussin
analogues.
After synthesis of β-amino diazoketone (3), cyclization to the
ammonium ylide was performed followed by a [1,2] Stevens
rearrangement. We initially used the conditions described by
West in the synthesis of 2-substituted piperidinones11 (entry 1,
Table 2). Though all the starting material was consumed in 5
min, a complex and inseparable mixture of products was formed
(probably by competing reactions such as C−H insertions,
Wolff rearrangement, ylide decomposition, and nonselective
[1,2]-Stevens rearrangements).14 Changing the rhodium
catalysts to copper ones was not sufficiently effective because,
at best, a 35% yield was observed. This occurred when 3 was
heated to 80 °C (entries 3−9 in Table 2). Finally, the use of a
higher reaction temperature (110 °C) and Cu(acac)2 as the
catalyst proved to be the best choice, furnishing (4) in 57%
yield as a single isomer.15
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Note
Table 2. Optimization Studies for the Ammonium Ylide formation and [1,2]-Stevens Rearrangement
entry
catalyst (equiv)
solvent
temp (°C)
time (min)
yield (%)
1
Rh2(OAc)4 (5%)
Rh2(TFA)4 (5%)
Cu(acac)2 (10%)
Cu(tfacac)2 (10%)
Cu(hfacac)2 (10%)
Cu(AcO)2.H2O (10%)
Cu(acac)2 (10%)
Cu(tfacac)2 (10%)
Cu(hfacac)2 (10%)
Cu(acac)2 (10%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene
benzene
benzene
toluene
25
25
5
1
complex mixture
complex mixture
no reaction
complex mixture
32
2
3
25
120
60
1
4
25
5
25
6
25
120
1
no reaction
35
7
reflux
reflux
reflux
reflux
8
1
complex mixture
complex mixture
57
9
1
10
1
Michael adducts 5−11 were also subjected to the conditions
described in entry 10, Table 2. Similar results were observed
with respect to the reaction in the presence of 3, and
pyrrolidinones 13−15 could be obtained in moderate (44−
51%) yields as cis isomers (Figure 3). In the case of the
use of L-Selectride, furnishing preussin in 80% yield as a single
isomer (Scheme 3). All the data for preussin agree with those in
Scheme 3. Hydride Reduction and Synthesis of Preussin
Figure 3. Extension of the method to new 2,5-cis-disubstituted
pyrrolidines.
the literature.2 With the intent to perform the last two steps in a
single reaction vessel, after addition of Cu(acac)2 to the
Michael adduct (3) in toluene under reflux, the solution was
cooled to −10 °C (for NaBH4) or −78 °C (for L-Selectride)
before the hydride was added (neat or as a THF solution,
respectively). Overall yields of 55% and 46% were observed for
each reductant, respectively (Scheme 4). Presumably there was
no change in the diastereoselectivity observed when two
different reductants in the one-pot process were used versus
carrying out the reduction in the purified ketone 4.
In conclusion, we have developed a highly stereoselective
three-step synthesis of ( )-preussin from decanal with an
overall yield of 40%. This work employed α,β-unsaturated
diazoketones as the main building blocks, providing another
example of how these platforms are useful for the short
insertion reactions starting from compounds 8−11, containing
4-methoxy- or 4-nitrobenzyl groups, a complex mixture of
products was observed. Several studies strongly suggest that the
mechanism of the [1,2]-Stevens rearrangement takes place by a
diradical mechanism16 (Scheme 2). Considering this mecha-
nistic proposal, the result described above is probably caused by
similar migratory aptitudes in these groups, as might be
predicted by the relative stabilities of benzyl, 4-methoxybenzyl,
and 4-nitrobenzyl radicals.17
Completion of the synthesis was straightforward after
hydride reduction. Although the reduction with sodium
borohydride led to preussin in 98% yield, a 7:1 diastereoiso-
meric ratio was observed. This was easily circumvented by the
Scheme 2. Proposed Mechanism for the Conversion of 3 to 4: Metal-Catalyzed Ylide Formation Followed by [1,2]-Stevens
Rearrangement
C
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Note
CDCl3) δ 194.6, 139.9, 128.6 (2C), 128.1 (2C), 126.8, 60.6, 58.0, 54.9,
41.5, 36.4, 31.9, 31.0, 29.6 (2C), 29.6, 29.3, 26.8, 22.7, 14.1 ppm;
HRMS (ESI-TOF) calcd for C21H34N3O [M + H+] 344.26964, found
344.26721.
Scheme 4. One-Pot Synthesis of Preussin from Aza-Michael
Adduct 3
4-(Benzylmethylamino)-1-diazoheptan-2-one (5): yellow oil, 26.7
mg (71%); Rf = 0.20 (n-hexanes/AcOEt 7:3); IR νmax = 3083, 3060,
3026, 2955, 2929, 2870, 2789, 2100, 1634, 1454, 1361, 1205, 1151,
1
734, 699, 617 cm−1; H NMR (500 MHz, CDCl3) δ 7.30−7.23 (m,
5H), 5.25 (s, 1H), 3.60 (d, J = 13.5 Hz, 1H), 3.52 (d, J = 13.5 Hz, 1H),
3.13 (quin, J = 6.5, 1H), 2.62−2.58 (m, 1H), 2.26−2.21 (m, 1H), 2.15
(s, 3H), 1.64−1.31 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 194.7, 139.9, 128.6 (2C), 128.2 (2C), 126.9,
60.4, 58.0, 53.4, 36.4, 33.4, 29.7, 20.0, 14.1 ppm; HRMS (ESI-TOF)
calcd for C15H22N3O [M + H+] 260.17574, found 260.17508.
4-(Dibenzylamino)-1-diazoheptan-2-one (6): yellow oil, 33.5 mg
(69%); Rf = 0.43 (n-hexanes/AcOEt 8:2); IR νmax = 3060, 3026, 2953,
2927, 2100, 1650, 1495, 1454, 1362, 1205, 1140, 698, 621, 600 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.35−7.20 (m, 10H), 4.97 (s, 1H),
3.64 (d, J = 13.6 Hz, 2H), 3.47 (d, J = 13.6 Hz, 2H), 3.05−3.01 (m,
1H), 2.67 (dd, J = 13.6, 6.0 Hz, 1H), 2.24−2.22 (m, 1H), 1.68−1.64
(m, 1H), 1.48−1.45 (m, 1H), 1.34−1.24 (m, 2H), 0.82 (t, J = 7.0 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 194.3, 139.8 (2C), 129.0
(4C), 128.2 (4C), 126.9 (2C), 55.5, 53.5 (2C), 41.9, 33.1, 29.7, 20.0,
14.0 ppm; HRMS (ESI-TOF) calcd for C21H26N3O [M + H+]
336.20704, found 336.20584.
synthesis of heterocycles. The strategy can be extended not
only to preussin analogues but also to other all-cis-substituted
pyrrolidines. Moreover, this sequence can be adjusted to be
applied in an asymmetric synthesis of preussin, employing
chiral amines in the aza-Michael reaction.18
EXPERIMENTAL SECTION
4-(Dibenzylamino)-1-diazotridecan-2-one (7): yellow oil, 24.2 mg
(64%); Rf = 0.55 (n-hexanes/AcOEt 8:2); IR νmax = 3084, 3061, 3026,
2926, 2852, 2102, 1647, 1454, 1360, 1246, 1205, 1150, 746, 698, 667,
■
(E)-1-Diazotridec-3-en-2-one (2). In a flame-dried, round-
bottom flask (10 mL) under argon atmosphere were added NaH
(60% in mineral oil) (5.5 mg, 0.227 mmol, 2.0 equiv) and 1.2 mL of
dry THF. The suspension was cooled to 0 °C, and a solution of diethyl
(3-diazo-2-oxopropyl)phosphonate (50.0 mg, 0.227 mmol, 2.0 equiv)
in dry THF (0.2 M) was added. After 10 min, the solution was cooled
to −78 °C, and a solution of decanal (21.5 μL, 0.114 mmol, 1.0 equiv)
in dry THF (0.1 M) was added. After 1 h, the temperature was
immediately allowed to rise to 0 °C and stirred for an additional 1 h,
when a saturated aqueous NH4Cl solution (5 mL) was added to the
reaction vessel. Next, the aqueous layer was extracted with ethyl
acetate (3 × 20 mL), the combined organic layers were washed with
water (15 mL) and brine (15 mL), dried over Na2SO4, and filtered,
and the solvent was removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, diethyl ether/n-
hexanes = 8:2) to give (E)-1-diazotridec-3-en-2-one (23.3 mg; 92%
yield) as a yellow solid (80% in a 2 mmol scale; 70% in a 5 mmol
scale): mp = 65−67 °C; Rf = 0.43 (n-hexanes/acetone 95:05); IR νmax
= 3072, 2955, 2918, 2870, 2847, 2118, 1661, 1603, 1470, 1460, 1389,
1340, 1151, 1109, 976, 943, 681, 584, 525 cm−1; 1H NMR (500 MHz,
CDCl3) δ 6.81 (dt, J = 15.4, 7.0 Hz, 1H), 5.98 (d, J = 15.4 Hz, 1H),
5.32 (s, 1H), 2.19 (2q, J = 7.0 Hz, 2H), 1.53−1.38 (m, 2H), 1.37−1.20
(m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
184.8, 145.4, 127.1, 54.9, 32.2, 31.8, 29.4, 29.3, 29.2, 29.1, 28.1, 22.6,
14.0 ppm/ HRMS (ESI-TOF) calcd for C13H23N2O [M + H+]
223.18049, found 223.17950.
1
613 cm−1; H NMR (400 MHz, CDCl3) δ 7.34−7.21 (m, 10H), 4.97
(s, 1H), 3.63 (d, J = 13.6 Hz, 2H), 3.47 (d, J = 13.6 Hz, 2H), 3.03−
2.98 (m, 1H), 2.66 (dd, J = 13.7, 6.1 Hz, 1H), 2.24−2.21 (m, 1H),
1.71−1.64 (m, 1H), 1.47−1.39 (m, 1H), 1.36−1.22 (m, 14H), 0.89 (t,
J = 7 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 194.3, 139.8
(2C), 129.0 (4C), 128.2 (4C), 126.9 (2C), 55.7, 53.5 (2C), 53.2, 42.0,
31.9, 30.7, 29.6, 29.6, 29.5, 29.3, 26.8, 22.7, 14.1 ppm; HRMS (ESI-
TOF) calcd for C27H38N3O [M + H+] 420.30094, found 420.29984.
4-(Benzyl(4-methoxybenzyl)amino)-1-diazotridecan-2-one (8):
yellow oil, 25.0 mg (62%); Rf = 0.46 (n-hexanes/AcOEt 8:2); IR
νmax = 3065, 2953, 2924, 2853, 2102, 1651, 1510, 1458, 1362, 1300,
1
1248, 1175, 1039, 667, 615 cm−1; H NMR (400 MHz, CDCl3) δ
7.31−7.23 (m, 7H), 6.85 (d, J = 8.5 Hz, 2H), 4.97 (s, 1H), 3.79 (s,
3H), 3.62 (d, J = 13.6 Hz, 1H), 3.56 (d, J = 13.4 Hz, 1H), 3.45 (d, J =
13.6 Hz, 1H), 3.41 (d, J = 13.4 Hz, 1H), 3.05−2.97 (m, 1H), 2.69−
2.62 (m, 1H), 2.26−2.26 (m, 1H), 1.69−1.59 (m, 1H), 1.35−1.28 (m,
1H), 1.27−1.20 (m, 14H), 0.90−0.86 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.4, 158.6, 140.0, 131.8, 130.1 (2C), 129.0 (2C), 128.1
(2C), 126.9, 113.6 (2C), 55.6 (2C), 55.2, 53.3, 52.8, 31.9, 30.7, 29.7,
29.6, 29.6, 29.5, 29.4, 26.8, 22.7, 14.1 ppm; HRMS (ESI-TOF) calcd
for C28H40N3O2 [M + H+] 450.31150, found 450.31039.
4-(Benzyl(4-nitrobenzyl)amino)-1-diazotridecan-2-one (9). yellow
oil, 21.3 mg (51%); Rf = 0,33 (n-hexanes/AcOEt 8:2); IR νmax = 3059,
3026, 2924, 2853, 2102, 1643, 1603, 1520, 1493, 1454, 1344, 1203,
1153, 1109, 851, 745, 700, 617 cm−1; 1H NMR (500 MHz, CDCl3) δ
8.16 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.36−7.29 (m, 5H),
5.03 (s, 1H), 3.92−3.44 (m, 4H), 3.06−2.96 (m, 1H), 2.65−2.61 (m,
1H), 2.31−2.24 (m, 1H), 1.73−1.64 (m, 1H), 1.44−1.36 (m, 1H),
1.35−1.15 (m, 14H), 0.89 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (125
MHz, CDCl3) δ 193.7, 148.0, 147.1, 139.1, 129.5 (2C), 129.0 (2C),
128.3 (2C), 127.3, 123.4 (2C), 56.4, 53.8, 54.4, 53.3, 31.9, 30.9, 29.7,
29.6, 29.6, 29.5, 29.3, 26.9, 22.7, 14.1 ppm/ HRMS (ESI-TOF) calcd
for C27H37N4O3 [M + H+] 465.28602, found 465.28500.
General Procedure for the Michael Addition. 4-(Benzylme-
thylamino)-1-diazotridecan-2-one (3). In a flame-dried, round-
bottom flask (10 mL), under argon atmosphere, were added (E)-1-
diazotridec-3-en-2-one (2) (1 equiv, 0.091 mmol, 20 mg) and dry
THF (1.3 mL, 0.07 M). To this solution were added methylbenzyl-
amine (5 equiv, 0.45 mmol, 60 μL) and a catalytic amount of DBU
(0.5 equiv, 0.045 mmol, 7 μL). The reaction was stirred for 12 h, and
the solvent was then removed. The crude product was purified by flash
column chromatography (silica gel, n-hexanes/ethyl acetate/TEA =
78:20:02) to give 4-(benzylmethylamino)-1-diazotridecan-2-one (3)
(29.7 mg; 95% yield) as a yellow oil. When necessary, a second
purification by column chromatography or preparative TLC was
performed: Rf = 0.25 (n-hexanes/acetone 95:05); IR νmax = 2953,
2926, 2853, 2102, 1651, 1637, 1362 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.30−7.20 (m, 5H), 5.24 (s, 1H), 3.59 (d, J = 13.4 Hz, 1H),
3.51 (d, J = 13.4 Hz, 1H), 3.21−3.02 (m, 1H), 2.59 (m, 1H), 2.23 (m,
1H), 2.14 (s, 3H), 1.64−1.54 (m, 1H), 1.47−1.39 (m, 1H), 1.35−1.22
(m, 14H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz,
4-(Benzyl(4-nitrobenzyl)amino)-1-diazoheptan-2-one (10): yel-
low oil, 29.2 mg (53%); Rf = 0,17 (n-hexanes/AcOEt 8:2); IR νmax
= 3063, 3026, 2955, 2928, 2870, 2854, 2359, 2102, 1636, 1518, 1456,
1
1342, 1136, 1107, 744, 698, 667, 615 cm−1; H NMR (400 MHz,
CDCl3) δ 8.16 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.31−7.20
(m, 5H), 5.04 (s, 1H), 3.81−3.40 (m, 4H), 3.11−2.99 (m, 1H), 2.69−
2.62 (m, 1H), 2.32−2.24 (m, 1H), 1.69−1.61 (m, 1H), 1.47−1.39 (m,
1H), 1.36−1.25 (m, 2H), 0.84 (t, J = 7.1 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ 193.7, 147.9, 147.1, 139.1, 129.5 (2C), 129.0
D
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Note
(2C), 128.3 (2C), 127.3, 123.4 (2C), 56.2, 53.78, 53.3, 41.9, 33.3, 29.7,
20.1, 14.0 ppm; HRMS (ESI-TOF) calcd for C21H25N4O3 [M + H+]
381.19212, found 381.19138.
CDCl3) δ 197.7, 138.5, 129.8 (2C), 128.0 (2C), 126.1, 74.4, 62.4, 42.8,
39.3, 29.7, 21.3, 19.0, 14.3 ppm; HRMS (ESI-TOF) calcd for
C15H22NO [M + H+] 232.16959, found 232.16907.
4-(Benzyl(4-methoxybenzyl)amino)-1-diazoheptan-2-one (11):
yellow oil, 35.4 mg (67%); Rf = 0,3 (n-hexanes/AcOEt 8:2); IR νmax
= 3026, 2955, 2928, 2869, 2853, 2100, 1653, 1612, 1510, 1460, 1454,
1362, 1300, 1247, 1171, 1038, 976, 824, 802, 743, 698, 619, 606 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.36−7.29 (m, 4H), 7.29−7.21 (m,
1,2-Dibenzyl-5-propylpyrrolidin-3-one (15): colorless oil, 8.3 mg
(45%); Rf = 0.38 (n-hexanes/acetone 95:05); IR νmax = 3059, 3028,
2957, 2924, 2870, 2853, 1699, 1651, 1493, 1454, 1207, 698, 667, 621,
1
596 cm−1; H NMR (500 MHz, CDCl3) δ 7.33−7.10 (m, 10H), 3.94
(d, J = 14.5 Hz, 1H), 3.84 (d, J = 14.5 Hz, 1H), 3.17 (t, J = 4.7 Hz,
1H), 2.88−2.81 (m, 3H), 2.36 (dd, J = 17.5, 6.0 Hz, 1H), 1.71 (dd, J =
17.5, 10.5 Hz, 1H), 1.28−1.25 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 215.3, 138.1, 137.4, 130.0 (2C), 129.4
(2C), 128.3 (2C), 127.9 (2C), 127.2, 126.1, 70.9, 59.1, 55.5, 43.0, 36.5,
29.7, 18.8, 14.3 ppm; HRMS (ESI-TOF) calcd for C21H26NO [M +
H+] 308.20089, found 308.19992.
3H), 6.89−6.84 (m, 2H), 5.00 (s, 1H), 3.80 (s, 3H), 3.64 (d, J = 13.6
Hz, 1H), 3.58 (d, J = 13.4 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 3.42 (d,
J = 13.4 Hz, 1H), 3.06−3.04 (m, 1H), 2.69−2.63 (m, 1H), 2.26−2.23
(m, 1H), 1.73−1.63 (m, 1H), 1.52−1.44 (m, 1H), 1.34−1.22 (m, 2H),
0.83 (t, J = 7.1 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 194.4, 158.6,
139.9, 131.7, 130.1 (2C), 128.9 (2C), 128.12 (2C), 126.9, 113.5 (2C),
55.4, 55.2, 53.2, 52.7 (2C), 33.0, 29.7, 20.0, 14.0 ppm; HRMS (ESI-
TOF) calcd for C22H28N3O2 [M + H+] 366.21760, found 366.21667.
4-(Benzyl(methyl)amino)-5-((tert-butyldimethylsilyl)oxy)-1-diazo-
pentan-2-one (12): yellow oil, 23.5 mg (78%); Rf = 0.38 (n-hexanes/
AcOEt 8:2); IR νmax = 3086, 2952, 2930, 2889, 2856, 2104, 1655,
1541, 1466, 1360, 1256, 1132, 1111, 1007, 945, 839, 779, 735, 698,
( )-2-Benzyl-1-methyl-5-nonylpyrrolidin-3-ol, Preussin (1).
Reduction with NaBH4. In a flame-dried, round-bottom flask (10 mL),
under argon atmosphere, was added 2-benzyl-1-methyl-5-nonylpyrro-
lidin-3-one (4) (8.4 mg, 0.026 mmol, 1 equiv) in dry MeOH (530 μL).
This solution was cooled to −10 °C and NaBH4 (2.1 mg, 0.052 mmol,
2 equiv) added. The reaction was stirred at this temperature for 15
min. The solvent was removed under low pressure, and the material
was purified by flash column chromatography (silica gel, n-hexanes/
acetone = 50:50) to give preussin (1) (8.08 mg; 98% yield, dr = 7:1)19
as a colorless oil: Rf = 0.20 (n-hexanes/acetone 95:05); IR νmax = 3369,
1
669, 613, 519 cm−1; H NMR (500 MHz, CDCl3) δ 7.30−7.20 (m,
5H), 5.33 (s, 1H), 4.36 (m, 2H), 3.80−3.68 (m, 3H), 3.35−3.28 (m,
1H), 2.57−2.51 (m, 1H), 2.26 (s, 3H), 1.06−0.83 (m, 9H), 0.09 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 194.2, 139.9, 128.5 (2C), 128.1
(2C), 126.8, 62.9, 62.2, 61.5, 58.9, 37.7, 29.7, 25.8 (3C), 18.2, −5.4
(2C) ppm; HRMS (ESI-TOF) calcd for C19H32N3O2Si [M + H+]
362.22583, found 362.22565.
1
2855, 2924, 2853, 1456, 743, 700, 611 cm−1; H NMR (500 MHz,
CDCl3) δ 7.33−7.25 (m, 4H), 7.22−7.17 (m, 1H), 3.83 (s, 1H),
2.97−2.81 (m, 2H), 2.36 (s, 3H), 2.33−2.29 (m, 1H), 2.20 (m, 3H),
1.72 (t, J = 10.5 Hz, 2H), 1.45 (dd, J = 13.7, 6.2 Hz, 1H), 1.45−1.20
(m, 14H), 0.88 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 139.3, 129.3 (2C), 128.4 (2C), 126.1, 73.7, 70.4, 66.0, 39.3,
38.5, 33.5, 31.9, 29.9, 29.7, 29.6, 29.6, 29.3, 26.3, 22.7, 14.1 ppm;
HRMS (ESI-TOF) calcd for C21H36NO [M + H+] 318.27914, found
318.27744.
General Procedure to the Ylide Formation/Stevens Rear-
rangement. 2-Benzyl-1-methyl-5-nonylpyrrolidin-3-one (4). In a
flame-dried round-bottom flask (10 mL), under argon atmosphere,
was added 4-(benzylmethylamino)-1-diazotridecan-2-one (20 mg,
0.0583 mmol, 1 equiv) dissolved in dry toluene (1.2 mL, 0.05 M).
The system was heated to reflux temperature, and then Cu(acac)2 (1.6
mg, 5.83 μmol, 0.1 equiv) was added at once. The reaction proceeded
instantly with N2 release. Next, the reaction was cooled to room
temperature, and the solvent was removed. The crude material was
purified by flash column chromatography (silica gel, n-hexanes/
acetone/TEA = 94:04:02) to give 2-benzyl-1-methyl-5-nonylpyrroli-
din-3-one (4) (10.5 mg; 57% yield). When necessary, a second
purification by column chromatography or preparative TLC was
performed: colorless oil; Rf = 0.55 (n-hexanes/acetone 95:05); IR νmax
= 2953, 2924, 2853, 1705, 1637, 1628, 1601, 1562, 1522, 1510, 1497,
Reduction with L-Selectride. In a flame-dried, round-bottom flask
(10 mL), under argon atmosphere, was added 2-benzyl-1-methyl-5-
nonylpyrrolidin-3-one 4 (20 mg, 0.063 mmol, 1 equiv) in dry THF
(2.6 mL). This solution was cooled to −78 °C, and a 1 M solution of
L-Selectride in THF (220 μL, 0.222 mmol, 3.5 equiv) was added. The
reaction was stirred at this temperature for 15 min. Next, the reaction
was quenched with 100 μL of MeOH, 100 μL of H2O, 100 μL of a
40% solution of H2O2, and 100 μL of a solution of NaOH 2 M. After
that, 10.0 mL of H2O was added. The mixture was extracted with
AcOEt (3 × 50 mL) and dried with Na2SO4 ,and the solvent was
removed. The material was purified by flash column chromatography
(silica gel, n-hexanes/acetone = 50:50) to give 2-benzyl-1-methyl-5-
nonylpyrrolidin-3-ol (16.0 mg; 80% yield, dr = 100:0) as colorless oil.
One-Pot Ylide Formation/Stevens Rearrangement/Carbonyl
Reduction. In a flame-dried, round-bottom flask (10 mL), under
argon atmosphere, was added 4-(benzylmethylamino)-1-diazotridecan-
2-one (30 mg, 0.0874 mmol, 1 equiv) dissolved in dry toluene (1.2
mL, 0.05 M). The system was heated to reflux, and then Cu(acac)2
(2.4 mg, 8.74 μmol, 0.1 equiv) was added. Next, the reaction was
cooled to −10 °C (NaBH4 reduction) or −78 °C (L-Selectride
reduction). Next, an ethanolic solution of NaBH4 (2 equiv) or a 1 M
THF solution of L-Selectride (3.5 equiv) was added. After 15 min, the
reaction was quenched and the product isolated as described above for
each type of reduction. The crude material was then purified by flash
column chromatography (silica gel, n-hexanes/acetone = 50:50) to
give ( )-2-benzyl-1-methyl-5-nonylpyrrolidin-3-ol, preussin (1) in
55% yield (15.2 mg; dr = 7:1; NaBH4) or 46% yield (12.7 mg; dr =
10:0; L-Selectride).
1
1456, 1439, 1410, 1377, 1286, 1265, 700, 611 cm−1; H NMR (500
MHz, CDCl3) δ 7.30−7.11 (m, 5H), 3.05 (dd, J = 14.3, 4.7 Hz, 1H),
2.85 (dd, J = 14.4, 5.2 Hz, 1H), 2.75 (t, J = 4.9 Hz, 1H), 2.51−2.43 (m,
1H), 2.38 (dd, J = 17.9, 6.1 Hz, 1H), 2.31 (s, 3H), 1.77 (dd, J = 17.8,
10.9 Hz, 1H), 1.25 (m, 16H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 214.8, 138.5, 129.7 (2C), 128.0 (2C), 126.1,
74.4, 62.5 42.8, 39.3, 35.9, 32.9, 31.9, 29.8, 29.6, 29.5, 29.3, 25.6, 22.7,
14.1 ppm/ HRMS (ESI-TOF) calcd for C21H34NO [M + H+]
316.26349, found 316.26187.
1,2-Dibenzyl-5-nonylpyrrolidin-3-one (13): colorless oil, 8.2 mg
(44%); Rf = 0.45 (n-hexanes/acetone 95:05); IR νmax = 3078, 3026,
2955, 2926, 2853, 1717, 1653, 1558, 1456, 1373, 1205, 1153, 1080,
1
1030, 752, 698, 667, 611, 547 cm−1; H NMR (500 MHz, CDCl3) δ
7.42−7.15 (m, 10H), 4.23 (2d, J = 4.5 Hz, 1H), 3.63 (m, 2H), 3.10
(m, 1H), 2.75 (dd, J = 14.4, 8.9 Hz, 1H), 2.68−2.61 (m, 1H), 2.33
(dd, J = 14.0, 4.6, Hz, 1H), 2.06−2.00 (m, 1H), 1.75−1.70 (m, 1H),
1.30−1.21 (m, 15H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (125
MHz, CDCl3) δ 209.7, 142.0, 139.6, 128.7 (2C), 128.5 (2C), 128.4
(2C), 127.6 (2C), 127.5, 127.0, 60.0, 55.4, 50.8, 44.7, 43.9, 31.9, 29.7,
29.7, 29.6, 29.5, 29.4, 29.3, 22.7, 14.1 ppm; HRMS (ESI-TOF) calcd
for C27H38NO [M + H+] 392.29479, found 392.29367.
2-Benzyl-1-methyl-5-propylpyrrolidin-3-one (14): colorless oil, 9.1
mg (51%); Rf = 0.40 (n-hexanes/acetone 95:05); IR νmax = 3085, 3062,
3027, 2955, 2930, 2870, 2789, 2100, 1634, 1454, 1361, 1151, 734, 699,
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.26−7.12 (m, 5H), 3.06 (dd, J
= 14.4, 4.9 Hz, 1H), 2.85 (dd, J = 14.3, 4.9 Hz, 1H), 2.75 (t, J = 4.9
Hz, 1H), 2.31 (s, 3H), 1.82−1.72 (m, 2H), 1.58−1.46 (m, 1H), 1.36−
1.19 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz,
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra of all new compounds and preussin. This material
is available free of charge via the Internet at http://pubs.acs.org.
E
dx.doi.org/10.1021/jo5011558 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(17) The B3LYP calculated bond dissociation enthalpies of toluene,
4-methoxytoluene, and 4-nitrotoluene differ by less than 1 kcal/mol.
See: Pratt, D. A.; Wright, J. S.; Ingold, K. U. J. Am. Chem. Soc. 1999,
121, 4877.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: antonio@iqsc.usp.br.
(18) This could be verified by a recent example and ongoing studies
in our laboratory.
(19) The isomers can be separated by column chromatography.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank FAPESP (Research Supporting Foundation of the
State of Sao Paulo) for financial support (2012/04685-5) and a
fellowship to I.G.R. (2010/18801-1) and V.D.P. (2008/09653-
9). We also thank CNPq (307905/2009-8) for a research
fellowship to A.C.B.B and a fellowship to R.M.P.D. (2011/
160522-0). We also thank IQSC-USP for use of their facilities
and HRMS (FAPESP 2009/54040-8).
REFERENCES
■
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dx.doi.org/10.1021/jo5011558 | J. Org. Chem. XXXX, XXX, XXX−XXX