A concise and efficient synthesis of (+)-preussin

Article abstract of DOI:10.1515/hc-2013-0236

A novel and efficient synthesis of (+)-preussin (7) starting from N-butoxycarbonyl-L-phenylalaninal (1) is described. This natural product was synthesized under mild conditions and with good overall yield.

Full text of DOI:10.1515/hc-2013-0236

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2014; 20(1): 47–50
DOI 10.1515/hc-2013-0236ꢀ
EAnzco Bo. nArécviasloe-Gaarcnía*d efficient synthesis of (+)-preussin
Abstract: A novel and efficient synthesis of (+)-preussin
Compound 7 is a naturally occurring pyrrolidine
(7) starting from N-butoxycarbonyl-L-phenylalaninal (1) alkaloid isolated from the fermentation of Aspergillus
is described. This natural product was synthesized under ochraceus [14, 15]. It has been shown to possess a potent
mild conditions and with good overall yield.
antifungal activity [16]. Its interesting structural features
and remarkable biological activity have made preussin
Keywords: cyclization; phenylalanine; pyrrolidines; an attractive target for synthetic chemists, and several
vinylation.
approaches to the preparation of 7 have been reported
[17–33]. To demonstrate the synthetic utility of the metho-
dology of Arévalo-García and Colmenares [34], the details
of a novel synthetic process leading to the preparation of
this natural product, (2S,3S,5R)-(+)-preussin (7) are com-
municated here.
*Corresponding author: Enzo B. Arévalo-García, Educational
Research Institute, Górczewska 8, Warsaw, 01–180, Poland; and
EARTH University, P.O. Box 4442-1000, San José, Costa Rica,
e-mail: ebarevalog@gmail.com
Introduction
Results and discussion
The pyrrolidine ring is a significant motif found in many From the retrosynthetic analysis (not shown), it was
natural and unnatural bioactive molecules. It occurs in clear that the target compound 7 could be acquired from
a range of pheromones, alkaloids, drug candidates, and the readily available precursor 1 [35] (Scheme 1). Thus,
other important compounds [1–4] that are antibacterial the synthesis of 7 started with the reaction of aldehyde
and neuroexcitatory agents, venoms, or fungicides [5–9]. 1 (1 eq.) in THF with vinylmagnesium bromide (4 eq.) at
Consequently, molecules which possess the pyrrolidine 0°C affording a syn-amino alcohol [36, 37] as the major
motif are often promising drug candidates for use in the product (syn:antiꢀ= ꢀ94:6) in 76% yield. Protection of the
pharmaceutical industry, and enantomerically pure pyr- hydroxy group of this adduct (1 eq.) with tert-butyldi-
rolidines are excellent chiral building blocks in asymmet- methylsilyl chloride (2.2 eq.) in pyridine afforded pro-
ric synthesis [8, 10–13]. Accordingly, there is continuous tected alcohol 2 [38] in 90% overall yield. Hydroboration
research towards the stereocontrolled access to function- of 2 with 9-borabicyclo[3.3.1]nonane (1.4 eq.) in the pres-
alized pyrrolidines. One of those important compounds is ence of hydrogen peroxide and sodium hydroxide at
preussin (structure 7 in Scheme 1).
room temperature afforded alcohol 3 in 81% yield [38].
Boc
H
Boc
H
O
Boc
H
H2C=CHMgBr, THF
9-BBN
N
MsCl, Et3N
CH2Cl2
N
N
Ph
OH
Ph
H
Ph
TBSCl, imidazole, pyridine
NaOH, 30% H2O2
OTBS
OTBS
1
2
3
n-C8H17P+Ph3I
n-BuLi, THF
OTBS
Ph
OTBS
OTBS
Ph
s-BuLi, TMEDA
Ph
N
N
N
DMF
1 atm H2, 10% Pd/C, EtOH
O
Boc
nC8H17 Boc
Boc
4
5
6
OH
LiAlH4, THF, 50oC
NaOH
Ph
N
nC8H17 Me
7
Scheme 1ꢀSynthesis of (+)-preussin (7).
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48ꢀ ꢀE.B. Arévalo-García: Synthesis of (+)-preussin
Next, the primary hydroxyl group in 3 was activated (2S,3S)-1-(tert-Butoxycarbonyl)-3-tert-butyl-
by the reaction with MeSO2Cl (2.9 eq.) in the presence
dimethylsiloxy-2-(phenylmethyl)pyrrolidine
of Et3N in dichloromethane. This reaction proceeded
(4)
smoothly and was followed by an intramolecular SN2 dis-
A solution of alcohol 3 [38] (900 mg, 2.19 mmol) and Et3N (0.88 mL,
placement affording the cyclized product 4 in 71% yield.
6.35 mmol) in dichloromethane (5 mL) at -5°C was treated with
Following Beak’s methodology [39–42], lithiation of 4
MeSO2Cl (0.49 mL, 6.35 mmol). The mixture was stirred at -5°C to
with s-BuLi (1.3 eq.) in the presence of TMEDA followed
0°C for 20 min and then warmed to ambient temperature. Stirring
by the reaction of the resultant 2-lithiopyrrolidine with
N,N,-dimethylformamide (1.5 eq.) provided a mixture of
aldehydes (cis:transꢀ= ꢀ93:7) from which the major product
5 was obtained in 78% yield by flash chromatography.
Treatment of aldehyde 5 with the Wittig reagent gener-
ated in situ from n-octyltriphenylphosphonium iodide
(1.5 eq.) and n-butyllithium (1.6 eq.) afforded an olefin
was continued for another 1 h and then the mixture was quenched
by addition of saturated NH4Cl (6 mL) and H2O (3 mL). The aque-
ous layer was extracted with dichloromethane (3ꢀ× ꢀ10 mL), and the
extract was washed with brine and dried over anhydrous Na2SO4.
The solvent was then removed under reduced pressure and the
product was purified by flash column chromatography eluting with
10% EtOAc in petroleum ether to afford 4 (610 mg, 71%) as a color-
1
less oil; H NMR: δ 7.08 (m, 5H), 4.10 (dt, J ꢀ= ꢀ 7.0 Hz and 7.0 Hz, 1H),
(83%), which was rapidly hydrogenated (1 atm. H2, 10% 4.0 (dt, J ꢀ= ꢀ 6.1 Hz and 6.0 Hz, 1H), 3.68 (m, 2H), 3.01 (m, 2H), 1.95 (m,
2H), 1.35 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR: δ
Pd/C, rt, EtOH) obtaining 6 [43] in quantitative yield.
154.9, 139.5, 129.6, 128.3, 126.0, 79.5, 71.0, 61.9, 43.4, 34.5, 31.3, 28.4;
The end-game was accomplished through the one-pot
20.1, -5.0, -5.1; IR (film): 1720, 1600, 1405, 1352, 1255, 837 cm-1. Anal.
reported procedure, leading to the deprotection/reduc-
Calcd for C22H37NO3Si: C, 67.47; H, 9.52; N, 3.58. Found: C, 67.39; H,
tion (LiAlH4/NaOH) [44] of 6, completing the synthesis
9.51; N, 3.61.
1
of (+)-preussin (7), in 91% yield (Scheme 1). Its H NMR
and 13C NMR spectra are virtually identical to literature
data [14, 15, 24, 26, 27, 29]. Its specific optical rotation
[α]D25 =+26.8° (c 1.1, CHCl3) that is greater than the lit-
erature value [α]D25 =+22.0° (c 1.0, CHCl3) demonstrates
that product 7 of high optical purity was obtained. The
high chemical purity is strongly supported by the excel-
lent results of elemental analysis.
(2S,4S,5S)-1-(tert-Butoxycarbonyl)-4-tert-
butyldimethylsiloxy-5-(phenylmethyl)pyrro-
lidine-2-carbaldehyde (5)
To a stirred solution of 4 (0.962 g, 2.45 mmol) in ether (10 mL) under
nitrogen atmosphere was added TMEDA (0.482 mL, 3.19 mmol). The
solution was cooled to -65°C and s-BuLi (1.38 M in cyclohexane,
2.46 mL, 3.19 mmol) was added dropwise. The solution was allowed
to warm to -30°C and was stirred for another 30 min. It was then
cooled to -78°C and treated with DMF (0.284 mL, 3.68 mmol). Afer
10 min the mixture was quenched with saturated NH4Cl (3 mL),
Conclusions
A new efficient, stereoselective route to biologically allowed to warm to room temperature, and diluted with ether
(30 mL). The aqueous layer was extracted with ether (3ꢀ× ꢀ6 mL)
important (+)-preussin was developed. The strategy can
and the combined ether solutions were washed with brine, dried
be extended to the synthesis of other members of this
(Na2SO4), filtered, and concentrated under reduced pressure. The
class of biologically active products, and further studies
residue was chromatographed on silica gel (hexane/ethyl acetate,
in this field are currently underway.
90:10) to afford 0.803 g (78%), (diastereoselectivity, 93:7) of 5, as a
colorless oil; 1H NMR: δ 9.25 (br s, 1H), 7.15 (m, 5H), 4.18 (dt, J ꢀ= ꢀ 6.1 Hz
and 7.2 Hz, 1H), 4.09 (m, 1H), 3.85 (dt, J ꢀ= ꢀ 2.0 Hz and 7.4 Hz, 1H),
2.90 (m, 2H), 2.1 (m, 2H), 1.44 (s, 9H), 0.90 (s, 9H), 0.05 (s, 3H), -0.04
(s, 3H); 13C NMR: δ 201.0, 156.6, 139.0, 136.0, 129.0, 128.2, 71.0, 68.0,
61.0, 60.3, 33.3, 27.0, 26.1, 21.3, 18.3, -4.0; IR (film): 2730, 1730, 1705,
1570, 815 cm-1. Anal. Calcd for C23H37NO4Si: C, 65.83; H, 8.89; N, 3.34.
Found: C, 65.79; H, 8.85; N, 3.43.
Experimental
Solvents and all other reagents were obtained from Aldrich, Fluka
or Avocado. Solvents were dried using common laboratory meth-
ods [45], and their evaporation was performed in a rotary evapora-
tor under reduced pressure. Analytical thin-layer chromatography
(TLC) was performed on a pre-coated Merck silica-gel 60 F254 TLC
plate. Purification was performed by flash column chromatog-
raphy [46] on silica gel (Kieselgel-60, Merck, 230–400 mesh).
The NMR spectra were recorded with a Bruker Avance spectrom-
eter in CDCl3 at 300 MHz (1H NMR) and 75 MHz (13C NMR). The IR
spectra were recorded on a Jasco FT/IR-430 spectrophotometer.
Yields refer to chromatographically and spectroscopically pure
compounds.
(2S,3S,5R)-(+)-Preussin (7)
A solution of 6 (500 mg, 0.97 mmol) in THF (5 mL) was stirred at 0°C
under nitrogen atmosphere and treated dropwise using a syringe
with a solution of LiAlH4 (5.85 mL, 5.85 mmol, 1 M in THF). The result-
ing mixture was heated under reflux until the starting material was
consumed as determined by TLC analysis (approx. 10 h). The reac-
tion mixture was then cooled to 0°C, quenched with water (2 mL),
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E.B. Arévalo-García: Synthesis of (+)-preussinꢀ
ꢀ49
and diluted with diethyl ether (10 mL). Aqueous NaOH (5 mL, 10 M) 2935, 2900, 1457, 1400, 1170 cm-l. Anal. Calcd for C21H35NO: C, 79.4; H,
and water (1 mL) were then added and an insoluble white precipitate 11.1; N, 4.41. Found: C, 79.1; H, 10.9; N, 4.39.
was formed. The organic supernatant was decanted to an Erlenmeyer
flask and the precipitate was washed with diethyl ether. The com-
Acknowledgments: The author is grateful to Mrs Agnieszka
bined organic extracts were dried over anhydrous Na2SO4, filtered,
Chilicka for proofreading this paper and to EARTH Univer-
sity and the Educational Research Institute for partial sup-
port of this work.
and concentrated under reduced pressure. The oily residue was sub-
jected to flash chromatography eluting with hexane/ethyl acetate,
5:1, to afford 280.2 mg (91%) of (+)-preussin as a colorless oil; 1H NMR:
δ 7.21 (m, 5 H), 3.5 (m, 1 H), 2.86 (m, 2 H), 2.3 (s, 3H), 2.23 (m, 1H), 1.69
(m, 1 H), 1.46 (m, 1 H), 2.66–2.60 (m, 2 H), 1.30–1.18 (m, 16 H), 0.88
(t, J ꢀ= ꢀ 7.0 Hz, 3H); 13C NMR: δ 138.5, 129.2, 128.4, 126.0, 71.5, 68.7, 53.4,
38.6, 35.0, 33.5, 31.8, 29.9, 29.5, 29.3, 29.0, 26.3, 22.7, 14.1; IR (film): 3400,
Received December 12, 2013; accepted January 9, 2014
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