α,β-unsaturated diazoketones as platforms in the asymmetric synthesis of hydroxylated alkaloids. Total synthesis of 1-deoxy-8,8a- diepicastanospermine and 1,6-dideoxyepicastanospermine and formal synthesis of pumiliotoxin 251D

Article abstract of DOI:10.1021/jo301967w

A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,β-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.

Full text of DOI:10.1021/jo301967w

Note
pubs.acs.org/joc
α,β-Unsaturated Diazoketones as Platforms in the Asymmetric
Synthesis of Hydroxylated Alkaloids. Total Synthesis of 1‑Deoxy-
8,8a-diepicastanospermine and 1,6-Dideoxyepicastanospermine and
Formal Synthesis of Pumiliotoxin 251D
Barbara Bernardim, 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 versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines
is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement,
followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,β-unsaturated diazoketone. The strategy also
permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of
pumiliotoxin 251D.
ydroxylated nitrogen heterocycles are well-known for
five castanospermine stereocenters has been proven to cause
significant changes in these biological activities.8 For example,
1-deoxycastanospermine inhibits N-acetyl-β-D-glucosaminidase,
whereas castanospermine itself does not. In the same way, 1-
deoxy-6,8a-diepicastanospermine and 1-deoxy-6-epicastano-
spermine exhibit much stronger α-mannosidades and α-
fucosidade inhibition than castanospermine.8 As a result, plenty
of castanospermine analogues, as well as other hydroxylated
cyclic systems, have been developed in the last few decades to
be employed in glycoscience.9 Considering that, concise and
versatile approaches to these compounds, especially diversity-
oriented ones, are of tremendous potential value.
H
their ability to act as potent α and β-glycosidase
inhibitors.1 Many of these heterocycles are widespread in
nature, some examples being nojirimycin,2 lentiginosine,3
swainsonine,4 and castanospermine5 (Chart 1). Castanosper-
Chart 1. Examples of Some Hydroxylated Alkaloids
As a part of our ongoing studies to use α,β-unsaturated
diazoketones as multifunctional platforms/building blocks,10,11
we envisioned that hydroxylated indolizidines could be easily
prepared in just four to five steps in a diversity-oriented fashion,
starting from proline-derived diazoketone 1 (Scheme 1).
Compound 1 possesses all of the carbons necessary to
construct an indolizidine system as well as all the desired
functionalities to provide mono-, di-, and trihydroxylated
indolizidines. For example, Wolff rearrangement12 from 1,
followed by dihydroxylation or epoxidation reactions, could
provide oxygen-functionalized esters 2 or 3, respectively. Ester
2 could lead to dihydroxylated indolizidines13 in two steps after
mine,5 for example, is isolated from the trees Castanospermum
australe and Alexa leiopetale and possesses a plethora of
interesting biological activities such as the inhibition of HIV
infectivity, angiogenesis, and thyroglobulin secretion.6 Casta-
nospermine has also been demonstrated to act as an antitumor
agent.7 These wide ranges of biological effects in vivo and in
vitro are produced mainly due to the strong inhibition of some
types of α and β-glycosidases. Interestingly, modification of the
Received: September 13, 2012
Published: October 15, 2012
© 2012 American Chemical Society
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Scheme 1. Strategy for the Syntheses of Hydroxylated Indolizidines from α,β-Unsaturated Diazoketone 1
Scheme 2. Synthesis of 1,6-Dideoxycastanospermine (4), a Dihydroxylated Indolizidine
Cbz removal/cyclization and lactam reduction. On the other
hand, the β-elimination of compound 3 could provide γ-
hydroxylated α,β-unsaturated ester 5 to furnish, after two or
three steps, mono- and trihydroxylated indolizidines,13
respectively. Herein, to evaluate the usefulness of α,β-
unsaturated diazoketones as common platforms to the synthesis
of tri-, di- and monohydroxylated indolizidines, we focused on
the total synthesis of 1-deoxy-8,8a-diepicastanospermine 6, 1,6-
dideoxyepicastanospermine 4, and the formal synthesis of
octahydroindolizidin-8-ol 7 (as well as pumiliotoxin 251D),
respectively.
ment from diazoketone 1 can also be carried out, although in a
lower 76% yield and with a cost of 50 mol % of the expensive
silver triflate catalyst.16 As an extension of the photochemical
Wolff rearrangement from unsaturated diazoketones, we also
synthesized new β,γ-unsaturated esters 11−13 (Figure 1) in
To evaluate our proposal, we first prepared 1,6-dideox-
yepicastanospermine, a dihydroxylated indolizidine previously
synthesized by Koskinen.14 We started our work from proline-
derived α,β-unsaturated diazoketone 1 (Scheme 2). Compound
1 (70% yield; >99% ee; single E isomer) can be prepared from
L-prolinal and 3-diazo-2-oxopropylphosphonate, employing our
recently described methodology.10 Next, prior to the
conversion of 1 into key dihydroxylated ester 2, Wolff
rearrangement in the presence of MeOH was carried out as
described by us during the total synthesis of the alkaloid
indolizidine 167B.11 For this transformation, photochemical
conditions were applied, furnishing the desired β,γ-unsaturated
ester 8 (Scheme 2) in an almost quantitative yield after 4 h at
25 °C using a Xenon arc lamp with IR filter and with no need
for purification.15 As an alternative, thermal Wolff rearrange-
Figure 1. Synthesized β,γ-unsaturated esters to be applied in other
types of hydroxylated alkaloids.
quantitative yields. Ester 11, for example, may be applied in the
synthesis of polyhydroxylated piperidines applying a similar
strategy to the one depicted in scheme 1. On the other hand, Z-
β,γ-unsaturated ester 1317 can be applied to the same sequence
described for compound 4 (scheme 2), leading to all cis 1,6-
dideoxycastanospermine. Finally, ester 12 could lead to
pyrrolidines after a few transformations.18
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Scheme 3. Total Synthesis of 1-Deoxy-8,8a-diepicastanospermine (6) and Formal Synthesis of Pumiliotoxin 251D
To accomplish the synthesis of 1,6-dideoxycastanospermine,
compound 8 was then submitted to a highly selective
dihydroxylation reaction in the presence of OsO4/NMO19
(dr = 20:1)20 to provide lactone 9 in 66% yield after column
chromatography and diastereomer separation. Diol 2 could not
be detected after the dihydroxylation reaction and suffered
lactonization upon its formation. Completion of the synthesis
was then straightforward. The exposure of lactone 9 in the
presence of H2/Pd removed the Cbz protecting group, with
subsequent lactone ring-opening by the free amino group, to
afford lactam 10 in a 94% yield. The reduction of 10 using the
classical LiAlH4 reductive protocols21 was somewhat tedious
initially, furnishing many byproducts. In this case, amide
reduction in the presence of BH3·SMe2 seemed to be the best
choice,22 furnishing 1,6-dideoxyepicastanospermine 4 in a 71%
yield. All of the spectroscopic data for 4 are in complete
accordance with those published by Koskinen.14
Having succeeded in preparing 1,6-dideoxycastanospermine
4, we then turned our attention to preparing the more complex
1-deoxy-8,8a-diepicastanospermine 6 (Scheme 3) via epoxy
ester 3. 1-Deoxy-8,8a-diepicastanospermine has already been
synthesized, and important contributions were provided by
Chan,23 Martin,24 Koskinen,25 and Fisera.26 Epoxy ester 3, also
prepared from α,β-unsaturated diazoketone 1, could be applied
not only in the synthesis of 6 but also in the formal synthesis of
pumiliotoxin 251D.27,28 Pumiliotoxins are well-known for their
cardiotonic activities since they are positive modulators of
sodium chanels.29 To accomplish that, epoxidation of β,γ-
unsaturated ester 8 with m-chloroperbenzoic acid furnished
epoxide 3. The addition of base (DBU) to the same reaction
flask provided γ-hydroxylated α,β-unsaturated esters 5a and 5b
in a 67% yield (4:1 inseparable mixture)20,30 after a β-
elimination/epoxide-opening reaction. Interestingly, osmium
tetraoxide-catalyzed dihydroxylation of this diastereomeric
mixture proved to be completely face-selective in each isomer,
furnishing 14a and 14b in a 71% yield20,30 (Scheme 3).
Submission of 14a and 14b to a one-pot Cbz deprotection/
cyclization in the presence of H2/Pd furnished pure lactam 15
in 73% yield after column chromatography and isomer
separation. Borane reduction of 15 led to 1-deoxy-8,8a-
diepicastanospermine 6 in a 70% yield. Once again, all of the
spectroscopic data for 6 are in accordance with those published
in the literature.24,25
The formal syntheses of monohydroxylated indolizidines
were also achieved in a single step from advanced intermediates
5a and 5b as illustrated in Scheme 3 (formal synthesis of
pumiliotoxin 251D and octahydroindolizidin-8-ols). One-pot
reduction, Cbz-deprotection, and lactamization of this mixture
afforded known hydroxy lactams 16a and 16b in 76% yield.
This mixture can be converted to pumiliotoxin 251D after a
Swern oxidation reaction, followed by a sequence of six steps as
described by Sudau.27,28 Octahydroindolizidin-8-ols can also be
easily achieved from 16a and 16b as described by Huang,31
Lee,32 and Wee.22 In this later case, benzoate derivatization is
necessary for complete diastereomeric mixture separation.
In conclusion, we have demonstrated that α,β-unsaturated
diazoketones are powerful platforms to be applied in a number
of diverse approaches to mono-, di-, and trihydroxylated
indolizidines. The straightforward syntheses of 1,6-dideoxycas-
tanospermine and 1-deoxy-8,8a-diepicastanospermine from
diazoketone 1 in just four to five steps, employing simple and
mild transformations, exemplifies that. To the best of our
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Note
solvent was evaporated in rotary evaporator to furnish ester 8 (265.0
knowledge, the strategy presented here also constitutes the
shortest approach for the preparation of these types of
hydroxylated indolizidines, taking into consideration equivalent
starting materials with respect to price and accessibility.
Moreover, the possibility of using different α,β-unsaturated
diazoketones along with this strategy, as well as diazoketones
like 1 with a Z geometry, also offers flexibility for the
preparation of other alkaloids such as quinolizidines, piper-
idines, pyrrolidines, and even new indolizidines.
mg, 0,87 mmol, 97%) with no need for purification: [α]20 −30.0 (c
D
1
4.0 CH2Cl2); H NMR (200 MHz, CDCl3, mixture of rotamers) δ
7.30 (bs, 5H), 5.79−5.44 (m, 1H,), 5.18 (d, J = 12.0 Hz, 1H), 5.08 (d,
J = 12.0 Hz, 1H), 4.50−4.31 (m, 1H), 3.66 (s, 3H), 3.53−3.41 (m,
2H), 3.16−2.96 (m, 2H), 2.08−1.68 (m, 4H); 13CNMR (50 MHz,
CDCl3, mixture of rotames) δ 172.0, 155.0, 137.0, 134.3, 134.0, 128.4,
127.8, 122.0, 66.6, 58.4, 51.8, 46.6, 46.4, 37.3, 32.2, 31.3, 29.7, 23.5,
22.8; FT-IR (neat, cm−1) 2954, 2927, 1737, 1701, 1452, 1411, 1353,
1270, 1189, 1170; HRMS (ESI) calcd for C17H21NNaO4 [M + Na]+
326.1363, found 326.1364; Rf: 0.40 (40% EtOAc/hexanes).
(E)-Methyl 5-(benzyloxycarbonylamino)pent-3-enoate (11):
EXPERIMENTAL SECTION
■
1
88.0 mg, 0.33 mmol, 90%; H NMR (600 MHz, CDCl3) δ 7.38−7.30
General Procedures. All solvents were dried and distilled prior to
use by standard procedures. Reagents were purchased at the highest
commercial quality and used without further purification, unless
otherwise stated. Reactions were monitored by thin-layer chromatog-
raphy (TLC), carried out on 0.25 mm silica gel plates using UV light
as visualizing agent and potassium permanganate in aqueous KOH for
staining. Column chromatography was performed using silica gel 60
(particle size 0.063−0.210 mm). Unless stated otherwise, all of the
yields refer to isolated products after flash column chromatography.
The solvent mixtures employed in TLC analysis and in flash column
chromatography purifications are reported as volume by volume and in
percentages. Proton nuclear magnetic resonance (1H NMR) spectra
(m, 5H), 5.76−5.70 (m, 1H), 5.65−5.58 (m, 1H), 5.11 (s, 2H), 4.81
(s, 1H), 3.82 (m, 2H), 3.69 (s, 3H), 3.08 (d, J = 6.6 Hz, 2H);
13CNMR (150 MHz, CDCl3) δ 171.9, 156.2, 136.5, 130.3, 128.5,
128.1, 124.2, 66.8, 51.9, 42.6, 37.4; HRMS (ESI) calcd for
C14H17NNaO4 [M + Na]+ 286.1049, found 286.1084.
(E)-Methyl 4-Phenylbut-3-enoate (12). All of the data are in
accordance with those described in the literature33 (17.5 mg, 0.10
mmol, 98%): 1H NMR (200 MHz, CDCl3) δ 7.36 (m, 5H), 6.50 (d, J
= 15.6 Hz, 1H), 6.29 (dt, J = 15.6, 7.0 Hz, 1H), 3.72 (s, 3H), 3.26 (m,
2H).
(S,Z)-Benzyl 2-(4-methoxy-4-oxobut-1-enyl)pyrrolidine-1-
carboxylate (13): 76.0 mg, 0.25 mmol, 92%; 1HNMR (200
MHz,CDCl3, mixture of rotamers) δ 7.32 (bs, 5H), 5.82−5.32 (m,
2H), 5.24−4.94 (m, 2H), 4.51 (bs, 1H), 3.89−2.64 (m, 7H), 2.26−
1
were recorded using 200, 400, or 600 MHz equipment. For H NMR
spectra, chemical shifts (δ) are referenced from TMS (0.00 ppm).
Coupling constants (J) are reported in Hz. For multiplicities the
following abbreviations were used: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; dd, double doublet; bs; broad singlet; dt, double
triplet. Carbon nuclear magnetic resonance (13C NMR) spectra were
recorded using an NMR spectrometer at 50, 100, or 150 MHz. For 13C
NMR spectra, chemical shifts (δ) are given from CDCl3 (77.0 ppm) or
MeOH (49.0 ppm). Photochemical reactions were carried out using
UV light generated by an Osram 150 Xenon lamp accommodated in
an Oriel Model 8500 Universal arc lamp source with focusing quartz
lens, a water-filled infrared filter, and a thermostated cell holder.
Infrared spectra were obtained using FTIR at 4.0 cm-1 resolution and
are reported in wavenumbers. High resolution mass spectra (HRMS)
were recorded using electron spray ionization (ESI) (hybrid linear ion
trap−orbitrap FT-MS and QqTOF/MS−Microtof−QII model).
(S)-Benzyl 2-(4-Diazo-3-oxobut-1-enyl)pyrrolidine-1-carbox-
ylate (1).10,11 To a suspension of NaH (60% in mineral oil) (272.0
mg, 6.80 mmol, 2.2 equiv) in dry THF (10 mL), under argon
atmosphere and at 0 °C, was added a 0.15 M solution of diethyl 3-
diazo-2- oxopropylphosphonate (1.36 g, 6.20 mmol, 2.0 equiv) in dry
THF. After the mixture was stirred for 15 min at this temperature, the
system was cooled to −78 °C and then a 0.1 M solution of (S)-prolinal
(719.0 mg, 3.10 mmol, 1.0 equiv) in dry THF was added dropwise.
After 1 h, the temperature was allowed to rise naturally to −30 °C,
when a saturated aqueous NH4Cl solution (25 mL) was added to the
reaction vessel. Next, the aqueous layer was extracted with
dichloromethane (3 × 20 mL), and the combined organic layers
were dried over Na2SO4, filtered, and evaporated in rotary evaporator.
Purification by flash column chromatography (30% AcOEt/hexanes)
afforded diazoketone 1 (646.0 mg, 2.20 mmol, 70%) as a stable yellow
13
1.54 (m, 4H); CNMR (50 MHz, CDCl3, mixture of rotamers) δ
171.9, 154.8, 133.4, 128.4, 127.8, 122.1, 121.1, 66.9, 66.5, 54.5, 54.0,
51.8, 46.7, 46.3, 32.9, 32.7, 32.4, 32.1, 29.6, 24.2, 23.5; HRMS (ESI)
calcd for C17H21NNaO4 [M + Na]+ 326.1368, found 326.1402.
(S)-Benzyl 2-((2S,3S)-3-Hydroxy-5-oxotetrahydrofuran-2-yl)-
pyrrolidine-1-carboxylate (9). To a solution of olefin 8 (157.0 mg,
0.52 mmol) in 20 mL of 4:1 acetone/H2O were added, in succession,
N-methylmorpholine N-oxide (243.0 mg, 4.0 equiv, 2.10 mmol) and a
0.15 M aqueous solution of OsO4 (0.26 mL, 0.075 equiv, 0.039
mmol). The solution was stirred for 48 h at room temperature. Next,
after addition of Na2SO3 (1.40 g), the mixture was poured into a
saturated aqueous solution of NaCl and extracted with AcOEt (4 × 15
mL). The organic phase was dried over Na2SO4, filtered, and
concentrated. The diastereoisomers (dr = 20:1) were separated by
column chromatography (70% AcOEt/hexanes) to furnish pure
lactone 9 (104.0 mg, 0.34 mmol, 66%) as a white solid: mp 150−
153 °C; [α]20 −90.4 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3)
D
δ 7.42−7.31 (m, 5H), 5.76 (t, J = 2.1 Hz, 1H), 5.18 (d, J = 12.3 Hz,
1H), 5.14 (d, J = 12.3 Hz, 1H), 4.38−4.34 (m, 2H), 3.95 (dd, J = 10.3,
2.6 Hz, 1H), 3.53−3.42 (m, 2H), 2.67 (dd, J = 4.7, 2.2 Hz, 1H), 2.63
(s, 1H), 2.29−2.22 (m, 1H), 2.11−1.91 (m, 3H); 13CNMR (100
MHz, CDCl3) δ 175.3, 157.1, 135.9, 128.6, 128.3, 128.0, 83.2, 67.8,
67.4, 54.9, 47.2, 38.6, 28.2, 23.0; FT-IR (neat, cm−1) 3301, 2962, 2887,
1774, 1676, 1419, 1359, 1178, 1122, 1027, 767, 734; HRMS (ESI)
calcd for C16H19NNaO5 [M + Na]+ 328.1155, found 328.1167; Rf 0.50
(AcOEt/hexanes 70%).
(7S,8S,8aS)-7,8-Dihydroxyhexahydroindolizin-5(1H)-one
(10). To a solution of lactone 9 (42.0 mg, 0.14 mmol) in dry MeOH
(1.75 mL) was added 10% Pd on charcoal (8.4 mg, 7.9 μmol, 0.06
equiv). The reaction was stirred under hydrogen atmosphere for 12 h,
and then the solution was filtered over filter paper. Solvent evaporation
in rotatory evaporator furnished lactam 10 (22.2 mg, 0.13 mmol) as a
1
oil: H NMR (200 MHz, CDCl3, mixture of rotamers) δ 7.36−7.32
(m, 5H), 6.69 (dd, J = 15.3, 5.7 Hz, 1 H), 6.0−5.8 (2d (rotamers), J =
15.3 Hz, 1H), 5.32−5.01 (m, 3H), 4.54−4.51 (m, 1H), 3.50−3.47(m,
2H), 2.09−1.76 (m, 4H); 13CNMR (50 MHz, CDCl3, mixture of
rotamers) δ 184.2, 154.7, 143.7, 143.1, 136.5, 128.4, 127.9, 126.2, 66.8,
58.1, 57.7, 55.8, 46.8, 46.4, 31.6, 30.9, 23.6, 22.7; FT-IR (neat, cm−1)
3085, 2973, 2879, 2102, 1701, 1656, 1606, 1448, 1413, 1357, 1186,
1107; HRMS (ESI) calcd for C16H17N3NaO3 [M + Na]+ 322.1162,
found 322.1159; [α]20D −93.3 (c 2.25, CH2Cl2); Rf 0.15 (40% EtOAc/
hexanes).
white solid in 94% yield: mp 142−145 °C; [α]20 −29.3 (c 1.27,
D
MeOH); 1H NMR (400 MHz, CD3OD) δ 3.85−3.76 (m, 1H), 3.52−
3.36 (m, 2H), 3.34−3.24 (m, 2H), 2.80 (dd, J = 17.7, 7.0 Hz, 1H),
2.34−2.26 (m, 1H), 2.27 (dd, J = 17.6, 9.4 Hz, 1H), 2.06−1.96 (m,
1H), 1.90−1.76 (m, 1H), 1.68−1.55 (m, 1H); 13C NMR (100 MHz,
CD3OD) δ 169.7, 77.0, 70.8, 62.4, 46.7, 40.1, 32.4, 23.5; FT-IR (neat,
cm−1) 3394, 1608, 1485, 1415, 1288, 1058; HRMS (ESI) calcd for
C8H14NO3 [M + H]+ 172.09682, found 172.09724; Rf 0.23 (MeOH/
CH2Cl2 20%).
(S,E)-Benzyl 2-(4-Methoxy-4-oxobut-1-enyl)pyrrolidine-1-
carboxylate (8).11 A solution of diazoketone 1 (269.0 mg, 0.90
mmol) in dry methanol (3.0 mL), in a 1 cm optical path quartz cell
was irradiated with a Osram 150 Xenon arc lamp (IR filter) for 4 h
under magnetic stirring (nitrogen gas evolution observed). Next, the
(7S,8S,8aS)-Octahydroindolizine-7,8-diol (4). Lactam 10 (20.0
mg, 0,12 mmol) was dissolved in dry THF (2.20 mL) and cooled to 0
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Note
°C. A 2 M solution of BH3·SMe2 in toluene (0.95 mL) was added
dropwise to the solution, and the mixture was stirred at 0 °C for 30
min and then at rt for 12 h. The reaction mixture was then cooled to 0
°C, and EtOH (4 mL) was carefully added. The reaction mixture was
concentrated and the resulting white solid redissolved in EtOH (8
mL). After the mixture was refluxed for 24 h, the solvent was
evaporated and the residue purified in an ion-exchange resin (Dowex
50WX8-100, eluent water and then 5% NH4OH solution) to furnish
1,6-dideoxycastanospermine 4 as a clear oil (13 mg, 0.08 mmol, 71%):
[α]20D −21.5 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.54 (s,
2H), 3.44 (ddd, J = 11.3, 8.6, 5.1 Hz, 1H), 3.30 (t, J = 8.8 Hz, 1H),
3.09 (dt, J = 8.7, 2.3 Hz, 1H), 3.04 (ddd, J = 11.4, 4.6, 2.3 Hz, 1H),
2.30−1.53 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 77.8, 74.5, 67.7,
53.6, 49.5, 32.2, 28.1, 21.9; FT-IR (neat, cm−1) 3371, 2933, 2802,
1458, 1446, 1369, 1325, 1259, 1162, 1114, 1089, 1051, 987; HRMS
(ESI) calcd for C8H16NO2 [M + H]+ 158.11756, found 158.11747; Rf
0.45 (MeOH/CHCl3 50%).
(2S)-Benzyl 2-((E)-1-Hydroxy-4-methoxy-4-oxobut-2-enyl)-
pyrrolidine-1-carboxylate (5a) and (5b). To a solution of olefin
8 (310.0, 1.0 mmol) in 17 mL of dry dichloromethane under magnetic
stirring was added 453 mg (1.8 mmol, 1.8 equiv) of m-
chloroperoxybenzoic acid. The mixture was stirred for 10 h. After
that time, the solution was cooled to 0 °C, and 760 mg (5.0 mmol, 5
equiv) of DBU was carefully added. After addition, the mixture was
allowed to reach to room temperature and stirred for 4 h. After this
period, the volatiles were evaporated in rotary evaporator. Purification
by flash column chromatography (40% AcOEt/hexanes) afforded
allylic alcohols 5a and 5b (dr = 4:1) (214 mg, 0.67 mmol, 67%) as a
stable colorless oil: 1H NMR (400 MHz, CDCl3, mixture of
diastereomers) δ ppm 7.38−7.31 (m, 5H), 6.91 (dd, J = 15.47, 5.20
Hz, 1H), 6.20 (d, J = 15.47 Hz, 1H), 5.16 (s, 2H), 5.02 (bs, 1H), 4.30
(m, 1H), 3.94 (m, 1H), 3.76 (s, 3H), 3.65−3.56 (m, 1H), 3.44−3.38
(m, 1H), 2.02−1.72 (m, 4H); 13C NMR (150 MHz, CDCl3, mixture
of diastereomers) δ 166.8, 157.1, 146.0, 136.3, 128.5, 128.1, 127.8,
122.2, 73.6, 67.4, 63.0, 51.6, 47.9, 27.9, 24.1; FT-IR (neat, cm−1) 3425,
2952, 2883, 1722, 1701, 1419, 1089, 611; HRMS (ESI) calcd for
C17H22NO5 [M + H]+ 320.14925, found 320.14914; Rf 0.35 (50%
EtOAc/hexanes).
1.66−1.54 (m, 1H); 13C NMR (100 MHz, MeOD) δ 170.4, 74.4, 73.8,
71.3, 59.4, 46.7, 32.3, 23.3; FT-IR (neat, cm−1) 3390, 2925, 1625,
1471, 1083; HRMS (ESI) calcd for C8H14NO4 [M + H]+ 188.09173,
found 188.09208; Rf 0.30 (15% MeOH/CH2Cl2).
(6S,7R,8S,8aS)-Octahydroindolizine-6,7,8-triol (6). A solution
of lactam 15 (15.0 mg 0.08 mmol) in THF (1.5 mL) at 0 °C was
added dropwise to BH3·SMe2 in toluene (0.70 mL, 2 M, 16 equiv).
The mixture was stirred at 0 °C for 30 min and then at rt temperature
overnight. The reaction mixture was cooled to 0 °C and then slowly
quenched with ethanol (4 mL). The solvent was removed under
reduced pressure, to the residue was added 95% ethanol (8 mL), and
the mixture was refluxed for 24 h, after which time the less polar
borane complex was completely converted to a polar compound. The
reaction mixture was cooled to room temperature and then treated
with concentrated HCl (12 drops). Ethanol was evaporated off, and
the white solid was dissolved in distilled water (15 mL). The solution
was concentrated under reduced pressure, and the residue was
subjected to ion-exchange chromatography (Dowex 50 × 2−400 ion-
exchange resin, 200−400 mesh) eluting with water and then 5%
NH4OH solution as eluent. The fractions were combined and
concentrated under reduced pressure. The residue was redissolved in
CH2Cl2 (10 mL), dried, filtered, and evaporated to afford 6 (9.0 mg,
0.05 mmol, 70% yield): [α]20D −15.2 (c 1.45, CHCl3); [α]20D −14.5 (c
1
7.0, MeOH); H NMR (400 MHz, MeOD) δ 4.00−3.96 (m, 1H),
3.89 (t, J = 3.2 Hz, 1H), 3.85 (dd, J = 10.2, 2.8 Hz, 1H), 3.49−3.39 (m,
1H), 3.28−3.00 (m, 3H), 2.99−2.88 (m, 1H), 2.34−2.21 (m, 1H),
2.09−1.95 (m, 2H), 1.88−1.69 (m, 1H); 13C NMR (100 MHz,
MeOD) δ 71.4, 70.5, 69.9, 64.7, 54.5, 53.4, 27.6, 20.8.; FT-IR (neat,
cm−1) 3377, 2941, 2923, 1571, 1436, 1108; HRMS (ESI) calcd for
C8H16NO3 [M + H]+ 174.11247, found 174.11251; Rf 0.38 (50%
MeOH/CHCl3).
(8aS)-8-Hydroxyhexahydroindolizin-5(1H)-one (16). To a
solution of esters 5a and 5b (374.0 mg, 1.2 mmol) in MeOH (150
mL) was added 249 mg of 10% Pd on charcoal (0.23 mmol, 0.2
equiv). Next, the reaction was stirred under hydrogen atmosphere for
16 h and the solution filtered over Celite. The solvent was then
evaporated in a rotary evaporator and the residue purified by flash
column chromatography (10% MeOH/EtOAc) to afford lactams 16a
and 16b (dr = 4:1) (138.0 mg, 0.89 mmol) in 76% yield as a colorless
oil. All of the spectroscopic data are in accordance with the ones
described in the literature.22,31,32 16a: 1H NMR (400 MHz, CDCl3) δ
3.63−3.38 (m, 3H), 3.32−3.23 (m, 1H), 2.90 (bs, 1H), 2.59−2.50 (m,
1H), 2.49−2.28 (m, 2H), 2.12−2.04 (m, 1H), 2.02−1.86 (m, 1H),
1.84−1.69 (m, 2H), 1.60−1.47 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 168.4, 71.8, 64.0, 45.6, 31.7, 30.3, 30.1, 22.4; FT-IR (neat,
cm−1): 3360, 2945, 2877, 1614, 1467, 1415, 1321, 1415, 1338, 1321,
1267, 1224, 1142, 1089, 993, 964, 842, 771; HRMS (ESI) calcd for
C8H14NO2 [M + H]+ 156.10191, found 156.10194; Rf 0.20 (10%
MeOH/EtOAc).
(R)-Benzyl 2-((2S,3R,4S)-3,4-Dihydroxy-5-oxotetrahydrofur-
an-2-yl)pyrrolidine-1-carboxylate (14). To a solution of allylic
alcohols (140.0 mg, 0.45 mmol) in 15 mL of 4:1 acetone/H2O were
added, in succession, N-methyl-morpholine-N-oxide (205.0 mg, 1.75
mmol, 4.0 equiv), and OsO4 (0.15 M in H2O, 0.22 mL, 0.033 mmol).
The solution was stirred for 6 h at room temperature. After addition of
Na2SO3 (800 mg), the mixture was poured into a saturated aqueous
solution of NaCl and extracted with AcOEt (4 × 15 mL). The organic
phase was dried over Na2SO4, filtered, and concentrated. Column
chromatography (5% MeOH/CH2Cl2) gave the lactones 14a and 14b
(102.7 mg, 0.32 mmol, 71%) as a mixture of diastereomers (dr =4:1).
1H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 7.43−7.29
ASSOCIATED CONTENT
* Supporting Information
(m, 5H), 5.22−5.04 (m, 2H), 5.02−4.61 (2bs, 1H), 4.58−4.43 (m,
■
1H), 4.41−4.27 (m, 2H), 4.27−4.13 (m, 1H), 3.58−3.38 (m, 2H),
S
13
2.39 (s, 1H), 2.22−1.76 (m, 4H);
C NMR (100 MHz, CDCl3,
NMR spectra of all new and final known compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
mixture of diastereomers) δ 173.7, 156.1, 136.2, 128.5, 128.1, 127.8,
79.9, 74.1, 67.7, 67.4, 58.7, 47.1, 26.3, 23.8; FT-IR (neat, cm−1) 3407,
2952, 2885, 1793, 1672, 1423, 1118; HRMS (ESI) calcd for
C16H19NNaO6 [M + Na]+ 344.1105, found 344.1099; Rf 0.50 (10%
MeOH/CH2Cl2).
AUTHOR INFORMATION
Corresponding Author
*E-mail: antonio@iqsc.usp.br.
■
(6S,7R,8S,8aS)-6,7,8-Trihydroxyhexahydroindolizin-5(1H)-
one (15). To a solution of lactones 14 (40.0 mg, 0.12 mmol) in
MeOH (13 mL) was added 10% Pd on charcoal (25.0 mg, 0.024
mmol, 0.2 equiv). Next, the reaction was stirred under hydrogen
atmosphere for 16 h and the solution filtered over filter paper. The
solvent was then evaporated in a rotary evaporator, and the
diastereoisomers were separated by flash column chromatography
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15% MeOH/DCM) to afford pure lactam 15 (15.0 mg, 0.087 mmol)
1
in 73% yield: [α]20 −16.4 (c 9.0, MeOH); H NMR (400 MHz,
We thank FAPESP (Research Supporting Foundation of the
State of Sao Paulo) for financial support (2012/04685-5) and a
fellowship to V.D.P. (2008/09653-9). We also thank CNPq for
a research fellowship to A.C.B.B. (307905/2009-8) and a
D
MeOD) δ 3.95 (d, J = 3.1 Hz, 1H), 3.90 (t, J = 2.8 Hz, 1H), 3.68 (dd, J
= 8.99, 2.73 Hz,1H), 3.63 (td, J = 10.00, 4.70 Hz, 1H), 3.57−3.37 (m,
2H), 2.34−2.26 (m, 1H), 2.08−1.98 (m, 1H), 1.92−1.78 (m, 1H),
9930
dx.doi.org/10.1021/jo301967w | J. Org. Chem. 2012, 77, 9926−9931

The Journal of Organic Chemistry
Note
(24) Martin, S. F.; Chen, H.-J.; Lynch, V. M. J. Org. Chem. 1995, 60,
276.
student fellowship to B.B. (160428/2011-4). We also thank
IQSC-USP for facilities, Professor Timothy Brocksom
(UFSCar) and Carlos R. D. Correia (UNICAMP) for optical
rotation analysis, Professor Daniel Cardoso for help with the
photochemical system, Eduardo Sanches Pereira do nascimento
for NMR and HRMS (FAPESP 2009/54040-8) acquisitions,
Guilherme Miola Titato for HRMS acquisitions, and DQO-
UFSCar for some NMR analyses.
(25) Koskinen, A. M. .; Kallatsa, O. A. Tetrahedron 2003, 59, 6947.
We thank Professor Ari Koskinen for clarifying the correct optical
rotation for 1-deoxy-8,8a-diepicastanospermine cited in his manuscript
(it should be −15.6 instead of +15.6).
(26) Rehak
2011, 67, 5762.
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, J.; Fisera, L.; Kozisek, J.; Bellovicova, L Tetrahedron
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dx.doi.org/10.1021/jo301967w | J. Org. Chem. 2012, 77, 9926−9931