Access to trans-3,4-Dihydroxy-2-alkylpyrrolidines and piperidines by use of stereodefined cyclic N,O-Acetals as a Diversity-generating element

Article abstract of DOI:10.1002/chem.201404659

A highly efficient and stereoselective synthetic pathway towards trans-3,4-dihydroxy-2-alkylpyrrolidines and piperidines is described. The nature of the protecting groups on the hydroxyl moieties played a crucial role on the trans selectivity. By using this method, a concise total synthesis of (-)-2-epilentiginosine has been achieved.

Full text of DOI:10.1002/chem.201404659

DOI: 10.1002/chem.201404659
Full Paper
&
Heterocycles
Access to trans-3,4-Dihydroxy-2-alkylpyrrolidines and Piperidines
by Use of Stereodefined Cyclic N,O-Acetals as a Diversity-
Generating Element
Soyeong Kang, Dong-gil Kim, and Young Ho Rhee*[a]
Abstract: A highly efficient and stereoselective synthetic
pathway towards trans-3,4-dihydroxy-2-alkylpyrrolidines and
piperidines is described. The nature of the protecting groups
on the hydroxyl moieties played a crucial role on the trans
selectivity. By using this method, a concise total synthesis of
(ꢀ)-2-epilentiginosine has been achieved.
Introduction
With regard to the stereoselectivity of the Lewis acid-medi-
ated carbon–carbon bond formation step, cis stereochemistry
between C2 and C3 substituents was observed when the hy-
droxyl groups were protected with tert-butyldimethylsilyl
(TBDMS) group.[1a] From the viewpoint of controlling stereo-
chemical diversity of the cyclic amine structure, we became in-
terested in developing a synthetic method to generate diaste-
reomeric trans-3,4-dihydroxy-2-alkyl-pyrrolidines and piperi-
dines.[2] This type of structural motif is found in various natural
products, such as (ꢀ)-2-epilentiginosine, and numerous bioac-
tive non-natural analogs, such as aza-sugars, which show inhib-
itory effects against glycosidase.[3] Herein we report that the
protecting group-dependent diversity-generating strategy was
successfully accomplished.
Recently, we reported a new synthetic strategy toward cyclic
amines. A salient feature of this strategy is to use the stereode-
fined cyclic N,O-acetals as the key element, which can be syn-
thesized by the sequential Pd-catalyzed enantioselective hy-
droamination of alkoxyallene and Ru-catalyzed ring-closing-
metathesis (Scheme 1).[1] The cyclic N,O-acetals thus formed
Results and Discussion
At the outset, we envisioned that the nature of the protecting
group would be of crucial importance in achieving high trans
diastereoselectivity. Thus, we first investigated various protect-
ing groups using commercially available trimethylallylsilane as
the source of carbon nucleophile for the synthesis of com-
pound 2 (Table 1). As previously demonstrated, the use of bis-
tert-butylsilyl ether 1a[4] gave 3a in good yield with an excel-
lent level of cis selectivity (Table 1, entry 1). For switching the
diastereoselectivity, we envisaged that the C3-acetoxy group
might induce the trans selectivity via the neighboring group
participation.[2g,5] To our dismay, using bis-acetate 1b based
upon this concept gave the desired product with moderate cis
selectivity in 51% yield (Table 1, entry 2). Thus, the neighboring
group participation in this system seems negligible. We then
decided to tie up two hydroxyl groups to sterically drive the
reaction towards formation of the trans-compound 2. For this
purpose, we first tested 1c, which incorporates a cyclic carbon-
ate group. Indeed, the allylation of this compound, using
BF3·OEt2 as a Lewis acid, afforded the desired product 2c[6] in
81% yield with >25:1 trans selectivity when the reaction was
performed at room temperature (RT) for 24 h in CH2Cl2
(Table 1, entry 3). In this case, a significant amount of starting
Scheme 1. Basic concept.
a stereocontrol element in olefin functionalization reactions,
such as dihydroxylation, and subsequently as a diversity-gener-
ating element for the iminium ion-mediated carbon–carbon
bond formation. This unique strategy allowed or the late-stage
introduction of various alkyl groups in cyclic amines in a highly
stereocontrolled manner.
[a] S. Kang, D.-g. Kim, Prof. Y. H. Rhee
Department of Chemistry
POSTECH (Pohang University of Science and Technology)
Pohang, 790-784 (Korea)
E-mail: yhrhee@postech.ac.kr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404659.
Chem. Eur. J. 2014, 20, 1 – 7
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Table 1. Optimization for the reaction conditions.[a]
Scheme 2. Mechanistic rationale of the stereoselectivity in CꢀC bond forma-
tion.
Entry Substrate Solvent
T
t [h]
Yield [%][b] (ratio 2/3[c])
yields and selectivities in the reaction. In contrast, employing
substrate 1d gave the desired product 7 in even higher yield
(90% ), again with excellent selectivity, when BF3·OEt2 was
used for 4 h (Table 2, entry 2). Thus, the compound 1d was
used for the other transformations. The reaction of ketene silyl
acetal 5c with 1d gave the product 8 in good yield under the
same conditions (Table 2, entry 3). Thus, the steric effect of the
substrates seems to have little effect on the yield of the reac-
tion. The scope of the reaction was also successfully expanded
to the homopropargylic group (Table 2, entry 4). Unlike the
above examples, introduction of the cyanide group in 5e,
alongside BF3·OEt2 as the Lewis acid, only led to the extensive
decomposition of the starting material (Table 2, entry 5).For
5e, the use of TIPSOTf as the Lewis acid was necessary to
obtain the product 10 in 68% yield with high stereoselectivity
(Table 2, entry 6). The scope of the reaction was further ex-
panded to the synthesis of trans-3,4-dihydroxy-2-alkyl-piperi-
dine derivatives (Table 2, entries 7–11). In all cases, excellent
levels of diastereoselectivity were obtained.
1
2
3
4
5
6
1a
1b
1c
1c
1c
1d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
RT
RT
RT
reflux
508C
RT
8
8
24
8
96 (1:23)
51 (1:3.5)
81 (>25:1)[d]
99 (16:1)
2
99 (>25:1)[e]
<2 min 97 (>25:1)
[a] Typical procedure: To a solution of substrate (0.1m) in the solvent was
added the nucleophile (4 equiv) and Lewis acid (3 equiv) at 08C, and the
temperature was slowly raised. [b] Yield of isolated product. [c] Deter-
mined by 1H NMR spectroscopy. [d] Approximately 18% of starting mate-
rial was recovered. [e] TMSOTf was used as Lewis acid.
material was recovered. Increasing the reaction temperature
improved the yield without considerably harming the trans ste-
reoselectivity (Table 1, entry 4). We then varied the Lewis acids.
After extensive studies, we discovered that the use of TMSOTf
in CH3CN at 508C generated the product 2c in near-quantita-
tive yield with excellent trans selectivity (Table 1, entry 5). How-
ever, the reaction at RT again led to poor conversion. We sur-
mised that the electron-withdrawing property of the cyclic car-
bonate group may slow the iminium ion formation. Thus, we
decided to explore the substrate 1d, incorporating a 3-pentyli-
dene protecting group, based upon Matsuda’s work.[7]
From a synthetic viewpoint, the current method proposes
a highly divergent method towards bioactive natural products
and analogs that should be useful both for diversity-oriented
and target-oriented syntheses. To address the utility of the
method in the total synthesis of bioactive natural products,
compound 2a was converted into (ꢀ)-2-epilentiginosine.[9] This
dihydroxylated indolizidine, a metabolite of the fungus Rhizoc-
tonia leguminicol, is known to be a potent inhibitor of glycosi-
dase and is of potential use in anticancer pharmaceuticals. As
depicted in Scheme 3, p-toluenesulfonyl group in 2d was re-
moved in the first step of the synthesis by following the recent
protocol reported by Tomooka.[10] The resulting secondary
amine was subjected to the subsequent allylation without pu-
rification to give 16 in 62% yield (over two steps). Ring-clos-
ing-metathesis of 16 using 2nd generation Grubbs catalyst pro-
ceeded smoothly to provide bicyclic piperidine 17 in 79%
yield. Catalytic hydrogenation of the olefin over platinum
oxide followed by the removal of the acetonide group provid-
ed the desired (ꢀ)-2-epilentiginosine 18 in 67% yield (over
two steps), for which the spectral data were consistent with
the literature values.[9e] Thus, the synthesis of (ꢀ)-2-epilentigi-
nosine was accomplished from 2d in five steps (nine steps
from commercially available p-toluenesulfonyl allylamine). The
chemical efficiency for the synthesis of this natural product
The reaction was completed within 2 min to give the prod-
uct 2d in 97% yield with excellent trans selectivity (Table 1,
entry 6), even when the reaction was carried out at RT. Notably,
the potentially acid-labile 3-pentylidene group proved un-
harmed under these conditions, as indicated by the high yield
and selectivity of the reaction. The trans selectivity of 1c or 1d
can presumably be explained by the attack of the carbon nu-
cleophile onto the iminium ion intermediate from the less-hin-
dered convex face created by the bicyclic structures. In con-
trast, the cis selectivity of bis-silyl ether 1a can be explained by
the stereoelectronic effect[8] in the attack of the carbon nucleo-
phile (Scheme 2).
Having established the optimized conditions, we then tested
an array of carbon nucleophiles to determine the scope of the
reaction (Table 2). First, we investigated the commercially avail-
able enol silyl ether 5b. Using the cyclic carbonate-protected
substrate 1c gave the aminoketone product 6 in 71% yield
within 13 h, with excellent trans selectivity (Table 2, entry 1).
The nature of the Lewis acid was also important, as using
other Lewis acids such as TMSOTf or Sc(OTf)3 led to decreased
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and other derivatives is noteworthy because the CꢀC
bond at the C-2 position is installed at a late stage of
the synthesis.
Table 2. Scope of the Reaction.[a]
Conclusions
In summary, we have developed a new synthetic
strategy for trans-3,4-dihydroxy-2-alkylpyrrolidines
and piperidines using stereodefined cyclic N,O-acetals
as the key element. This method well complements
our previous study on the synthesis of cis diastereo-
mers, and expands the utility of diversity-generating
synthetic strategy derived from N,O-acetals. By using
this approach, a short synthesis of (ꢀ)-2-epilentigino-
sine and other analogues was achieved with high
chemical efficiency. Currently, we are working on the
further expansion of the synthetic utility of stereode-
fined N,O-acetals.
Entry Substrate RꢀM Method[a] Product
R
t
Yield[b] [%]
(cis/trans)[c]
6
71[c]
(1:>25)
90
(1:>25)
80
(1:>25)
86
(1:>25)
1
2
1c
5b
5b
A
A
12 h
3 h
(n=1)
7
1d
(n=1)
8
(n=1)
9
(n=1)
10
(n=1)
10
3
4
1d
1d
5c
A
A
3 h
Experimental Section
5d
5 min
The syntheses of compounds 1c, 1d, 4 are described in
the Supporting Information
[d]
5
6
1d
1d
5e
5e
A
B
20 min
3 h
–
68
(1:>25)
94
(1:>25)
90
(n=1)
11
(n=2)
12
(n=2)
13
(n=2)
14
Representative procedure for the nucleophilic sub-
stitution reaction
7
8
4
4
4
4
4
5a
5b
5c
5d
5e
A
A
A
A
B
10 min
10 min
3 h
(3aS,4S,6aR)-4-Allyl-2,2-diethyl-5-tosyltetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyrrole (2d): To a solution of 1d
(151.4 mg, 0.37 mmol) in CH2Cl2 (4 mL) at 08C was
added allyltrimethylsilane (235 mL, 1.47 mmol) and
BF3·OEt2 (137 mL, 1.11 mmol). The reaction mixture was
stirred at 08C for 5 min, and the temperature was in-
creased to room temperature. The reaction was moni-
tored by TLC and quenched with saturated NaHCO3. The
reaction solution was extracted twice with CH2Cl2
(10 mL) and dried over anhydrous Na2SO4. The organic
layer was concentrated under reduced pressure and pu-
rified by flash column chromatography (hexane/EtOAc=
90:10) to give 2d (130.8 mg, 97%) as a white solid. Rf =
(1:>25)
9
77(1:>25)
89
(1:>25)
61
10
11
15 min
2 h
(n=2)
15
(n=2)
(1:>25)
[a] Method A: BF3·OEt2 was used in CH2Cl2 at RT; Method B: TIPSOTf was used in
CH2Cl2 at RT. [b] trans/cis ratio was determined by 1H NMR spectroscopy. [c] The reac-
tion was conducted at 408C. [d] The starting material decomposed within 20 min.
0.34 (hexane/EtOAc=80:20); m.p. 65–678C; ½aꢁ2D0 = +
1
41.7 (c=0.60 in CHCl3); H NMR (300 MHz, CDCl3): d=7.75 (d, J=
8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.71–5.85 (m, 1H), 5.11–5.16 (m,
2H), 4.62–4.66 (m, 1H), 4.43 (d, J=6.0 Hz, 1H), 3.98 (dd, J=3.9,
8.7 Hz, 1H), 3.48–3.60 (m, 2H), 2.41 (s, 3H), 2.31–2.53 (m, 2H), 1.44
(q, J=7.5 Hz, 2H), 1.10 (q, J=7.5 Hz, 2H), 0.77 (t, J=7.5 Hz, 3H),
0.58 ppm (t, J=7.5 Hz, 3H).; 13C NMR (75 MHz, CDCl3): d=143.5,
136.7, 133.5, 129.8, 127.7, 119.1, 116.5, 84.0, 79.2, 65.7, 54.0, 37.8,
28.9, 28.0, 21.7, 8.7, 8.1 ppm; IR (NaCl): n˜ =2974, 2940, 2882, 1641,
1599, 1462, 1345, 1162, 976 cmꢀ1; HRMS (FAB): m/z calcd for
C19H28NO4S (M+H+) 366.1739, found 366.1743.
(3aS,4S,6aR)-4-Allyl-5-tosyltetrahydro-3aH-[1,3]dioxolo[4,5-
c]pyrrol-2-one (2c): Following the representative procedure, 1c
(31.3 mg, 0.08 mmol) was treated with allyltrimethylsilane (54 mL,
0.34 mmol) and TMSOTf(44 mL, 0.24 mmol) in CH3CN (0.8 mL). The
reaction mixture was stirred at 508C for 2 h. Flash column chroma-
tography (hexane/EtOAc=90:10) afforded 2c (27.2 mg, 99.9%) as
a white solid. Rf =0.28 (hexane/EtOAc=60:40); m.p. 105–1068C;
½aꢁ2D1 = +31.4 (c=0.53 in CHCl3); H NMR (300 MHz, CDCl3): d=7.57
1
(d, J=8.1 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 5.71–5.84 (m, 1H), 5.14–
5.22 (m, 2H), 5.05 (dd, J=4.8, 6.6 Hz, 1H), 4.84 (d, J=6.9 Hz, 1H),
Scheme 3. Synthesis of (ꢀ)-2-epilentiginosine 18.
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4.22 (dd, J=5.1, 8.7 Hz, 1H), 3.89 (d, J=14.1 Hz, 1H), 3.65 (dd, J=
4.8, 14.4 Hz, 1H), 2.29–2.53 (m, 2H), 2.41 ppm (s, 3H).; 13C NMR
(75 MHz, CDCl3): d=152.8, 144.9, 135.6, 132.2, 130.4, 127.2, 120.3,
83.0, 79.7, 65.2, 52.9, 36.9, 21.8 ppm; IR (NaCl): n˜ =2924, 1809,
1344, 1160, 1089, 1057 cmꢀ1; HRMS (FAB): m/z calcd for C15H17NO5S
(M+H+) 323.0827, found 323.0904.
column chromatography (hexane/EtOAc=90:10) afforded
9
(112.0 mg, 85.6%) as a white solid. Rf =0.53 (hexane/EtOAc=
70:30); m.p. 92–938C; ½aꢁ2D0 = +64.6 (c=0.48 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz,
2H), 4.78 (dt, J=1.5, 5.7 Hz, 1H), 4.66 (d, 6.0 Hz, 1H), 4.01 (t, J=
5.1 Hz, 1H), 3.79 (dd, J=5.1, 11.7 Hz, 1H), 3.53 (dd, J=1.8, 12.0 Hz,
1H), 2.61–2.64 (m, 2H), 2.42 (s, 3H), 2.00 (t, J=2.7 Hz, 1H), 1.47 (q,
J=7.5 Hz, 2H), 1.10 (q, J=7.5 Hz, 2H), 0.79 (t, J=7.5 Hz, 3H),
0.56 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=143.7,
136.4, 129.8, 127.6, 116.6, 84.6, 80.5, 79.5, 71.3, 65.0, 54.6, 28.9,
28.0, 24.0, 21.7, 8.7, 8.1 ppm; IR (NaCl): n˜ =3277, 2973, 2941, 2120,
1342, 1162 cmꢀ1; HRMS (FAB): m/z calcd for C19H26NO4S (M+H+)
364.1583, found 364.1585.
(3aS,4S,6aR)-4-(2-Oxo-2-phenylethyl)-5-tosyltetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyrrol-2-one (6): Following the representative
procedure, 1c (29.8 mg, 0.08 mmol) was treated with 1-phenyl-1-
trimethylsiloxyethylene (66 mL, 0.32 mmol) and BF3·OEt2 (30 mL,
0.24 mmol) in CH2Cl2 (0.8 mL). The reaction mixture was stirred at
408C for 12 h. Flash column chromatography (hexane/EtOAc=
60:40) afforded 7 (23.0 mg, 71.0%) as a white solid. Rf =0.41
(hexane/EtOAc=50:50); Mp.<3008C decomp.; ½aꢁ2D1 = +13.8 (c=
0.26, DMSO); 1H NMR (300 MHz, CDCl3): d=7.90–7.93 (m, 2H),
7.72–7.75 (m, 2H), 7.61–7.66 (m, 1H), 7.48–7.53 (m, 2H), 7.33–7.35
(m, 2H), 5.45 (t, J=6.3 Hz, 1H), 5.17 (d, J=6.9 Hz, 1H), 4.36–4.38
(m, 1H), 3.85–4.04 (m, 3H), 3.41–3.49 (m, 1H), 2.42 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=198.4, 145.2, 135.9, 134.7, 134.5,
130.5, 129.2, 128.5, 127.1, 85.0, 81.5, 63.4, 55.4, 53.7, 43.4,
21.8 ppm; IR (NaCl): n˜ =1798, 1689, 1307, 1168, 717 cmꢀ1; HRMS
(FAB): m/z calcd for C20H20NO6S (M+H+) 402.1011, found 402.1013.
(3aS,4S,6aR)-)-2,2-Diethyl-5-tosyltetrahydro-3aH-[1,3]dioxolo[4,5-
c]pyrrole-4-carbonitrile (10): Following the representative proce-
dure, 1d (25.0 mg, 0.06 mmol) was treated with trimethylsilyl cya-
nide (33 mL, 0.24 mmol) and TIPSOTf(49 mL, 0.18 mmol) in CH3CN
(0.6 mL). The reaction mixture was stirred at RT for 3 h. Flash
column chromatography (hexane/EtOAc=80:20) afforded
9
(14.4 mg, 67.6%) as a white solid. Rf =0.44 (hexane/EtOAc=70:30);
m.p. 123–1258C; ½aꢁD20 = +80.6 (c=0.55 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.76 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.1 Hz,
2H), 4.79–4.86 (m, 2H), 4.70 (s, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.18
(dd, J=3.9, 11.4 Hz, 1H), 2.44 (s, 3H), 1.50–1.68 (m, 4H), 0.83–
0.91 ppm (m, 6H).; 13C NMR (75 MHz, CDCl3): d=144.9, 134.2,
130.1, 128.0, 118.2, 114.5, 84.2, 79.3, 55.2, 53.0, 29.6, 29.1, 21.9, 8.6,
7.7 ppm; IR (NaCl): n˜ =2976, 2941, 2883, 2243, 1598, 1463, 1356,
1165, 1115 cmꢀ1; HRMS (FAB): m/z calcd for C17H23N2O4S (M+H+)
351.1379, found 351.1377.
2-(((3aS,4S,6aR)-)-2,2-Diethyl-5-tosyltetrahydro-3aH-[1,3]dioxolo-
[4,5-c]pyrrol-4-yl)-1-phenylethanone (7): Following the represen-
tative procedure, 1d (32.1 mg, 0.08 mmol) was treated with 1-
phenyl-1-trimethylsiloxyethylene (64 mL, 0.31 mmol) and BF3·OEt2
(28 mL, 0.23 mmol) in CH2Cl2 (0.8 mL). The reaction mixture was
stirred at RT for 3 h. Flash column chromatography (hexane/
EtOAc=80:20) afforded 7 (31.0 mg, 89.6%) as a white solid. Rf =
0.43 (hexane/EtOAc=70:30); m.p. 75–778C; ½aꢁ2D0 = +68.6 (c=0.53
in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.94–7.96 (m, 2H), 7.74–
7.76 (m, 2H), 7.57–7.62 (m, 1H), 7.45–7.50 (m, 2H), 7.26–7.29 (m,
2H), 4.91 (t, J=4.8 Hz, 1H), 4.65 (d, J=6.0 Hz, 1H), 4.25 (dd, J=3.0,
7.2 Hz, 1H), 3.81 (dd, J=5.4, 11.7 Hz, 1H), 3.43–3.66 (m, 3H), 2.39
(s, 3H), 1.44 (q, J=7.5 Hz, 2H), 1.04 (q, J=7.5 Hz, 2H), 0.76 (t, J=
7.5 Hz, 3H), 0.53 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=198.2, 143.6, 136.6, 136.0, 133.8, 129.8, 128.9, 128.4, 127.7,
116.5, 85.4, 79.9, 63.3, 55.0, 42.5, 28.8, 27.7, 21.7, 8.7, 8.0 ppm; IR
(NaCl): n˜ =3063, 2972, 2940, 2881, 1685, 1598, 1449, 1342,
(3aS,4S,7aR)-4-Allyl-2,2-diethyl-5-tosylhexahydro-[1,3]dioxolo-
[4,5-c]pyridine (11): Following the representative procedure, 4
(65 mg, 0.153 mmol) was treated with allyltrimethylsilane (97 mL,
0.61 mmol) and BF3·OEt2 (57 mL, 0.46 mmol) in CH2Cl2 (1.5 mL). The
reaction mixture was stirred at 08C for 2 h. Flash column chroma-
tography (hexane/EtOAc=85:15) afforded 11 (54.5 mg, 93.5%) as
a white solid. Rf =0.29 (hexane/EtOAc=80:20); m.p. 92–938C;
1
½aꢁ2D0 = +45.6 (c=1.50 in CHCl3); H NMR (300 MHz, CDCl3): d=7.73
(d, J=8.3 Hz, 2H), 7.27 (d, J=8.2, 2H), 5.96–5.80 (m, 1H), 5.13 (s,
1H), 5.11–5.05 (m, 1H), 4.28–4.09 (m, 3H), 3.39 (dt, J=11.1, 4.5 Hz,
1H), 3.09 (td, J=11.2, 3.4 Hz, 1H), 2.64–2.52 (m, 1H), 2.40 (s, 3H),
2.25 (td, J=14.4, 9.0 Hz, 1H), 1.99–1.85 (m, 1H), 1.74 (ddt, J=14.6,
5.0, 3.4 Hz, 1H), 1.53–1.39 (m, 2H), 1.25 (dq, J=14.0, 7.6 Hz, 1H),
0.99 (dq, J=14.0, 7.6 Hz, 1H), 0.78 (t, J=7.4 Hz, 3H), 0.56 ppm (t,
J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=143.1, 136.0, 134.6,
129.5, 127.9, 118.2, 112.0, 73.5, 68.5, 54.2 40.9, 37.4, 28.8, 27.6, 26.3,
1161 cmꢀ1
;
HRMS (FAB): m/z calcd for C24H30NO5S (M+H+)
444.1845, found 444.1843.
Methyl
2-(((3aS,4S,6aR)-)-2,2-diethyl-5-tosyltetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyrrol-4-yl)-2-methylpropanoate (8): Following
the representative procedure, 1d (30.9 mg, 0.08 mmol) was treated
with methyl trimethylsilyl dimethylketene acetal (61 mL, 0.30 mmol)
and BF3·OEt2 (28 mL, 0.23 mmol) in CH2Cl2 (0.8 mL). The reaction
mixture was stirred at RT for 3 h. Flash column chromatography
(hexane/EtOAc=90:10) afforded 8 (25.6 mg, 80.1%) as a white
solid. Rf =0.47 (hexane/EtOAc=70:30); m.p. 119–1218C; ½aꢁ2D0 = +
21.7, 8.8, 8.7 ppm; IR (NaCl): n˜ =2971, 1219, 1163, 1056, 772 cmꢀ1
HRMS (FAB): m/z calcd for C20H29NO4S (M+H+) 380.1896, found
;
380.1893.
Methyl 2-((3aS,4S,7aR)-2,2-diethyl-5-tosylhexahydro-[1,3]dioxolo-
[4,5-c]pyridin-4-yl)-2-methylpropanoate (12): Following the repre-
sentative procedure, 4 (50 mg, 0.117 mmol) was treated with
methyl trimethylsilyl dimethylketene acetal (95 mL, 0.47 mmol) and
BF3·OEt2 (54 mL, 0.35 mmol) in CH2Cl2 (1.2 mL). The reaction mixture
was stirred at 08C for 10 min. Flash column chromatography
(hexane/EtOAc=80:20) afforded 12 (51.0 mg, 89.7%) as a white
solid. Rf =0.17 (hexane/EtOAc=80: 20); m.p. 104–1058C; ½aꢁ2D0 = +
1
48.3 (c=0.58 in CHCl3); H NMR (300 MHz, CDCl3): d=7.78 (d, J=
8.1 Hz, 2H), 7.30 (d, J=7.8 Hz, 2H), 4.61–4.64 (m, 1H), 4.51 (d, J=
6.0 Hz, 1H), 4.24 (s, 1H), 3.71 (s, 3H), 3.64–3.69 (m, 2H), 2.41 (s,
3H), 1.41 (q, J=7.5 Hz, 2H), 1.35 (s, 3H), 1.23 (s, 3H), 0.70–0.79 (m,
5H), 0.62–0.64 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=176.5,
143.3, 137.0, 129.5, 128.2, 116.1, 83.4, 80.2, 73.0, 56.2, 52.3, 46.9,
27.5, 25.5, 24.5, 22.5, 21.5, 8.6 ppm; IR (NaCl): n˜ =2974, 2944, 2882,
1731, 1598, 1462, 1348, 1161 cmꢀ1; HRMS (FAB): m/z calcd for
C21H32NO6S (M+H+) 426.1950, found 426.1948.
1
104.3 (c=2.40 in CHCl3); H NMR (300 MHz, CDCl3): d=7.80 (d, J=
8.3 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 4.65 (s, 1H), 4.13–4.00 (m, 2H),
3.71 (s, 3H), 3.55 (dt, J=14.9, 4.0 Hz, 1H), 3.16 (ddd, J=14.8, 12.4,
2.4 Hz, 1H), 2.40 (s, 3H), 1.59–1.44 (m, 3H), 1.42 (s, 3H), 1.33 (s,
3H), 1.10 (q, J=7.6 Hz, 2H), 1.02–0.90 (m, 1H), 0.80 (t, J=7.6 Hz,
3H), 0.75 ppm (t, J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
177.3, 143.3, 137.7, 129.5, 128.4, 111.4, 72.3, 70.7, 61.5, 52.5, 47.8,
((3aS,4S,6aR)-)-2,2-Diethyl-4-(prop-2-ynyl)-5-tosyltetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyrrole (9): Following the representative proce-
dure, 1d (148.3 mg, 0.36 mmol) was treated with allenyltri-n-butyl-
tin (360 mL, 1.44 mmol) and BF3·OEt2 (133 mL, 1.08 mmol) in CH2Cl2
(3.6 mL). The reaction mixture was stirred at RT for 5 min. Flash
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40.0, 30.5, 27.8, 26.9, 25.9, 23.4, 21.7, 9.2, 8.6 ppm; IR (NaCl): n˜ =
Synthesis of (ꢀ)-2-epilentiginosine 18
2974, 2942, 1729, 1462, 1258, 1160, 1095, 1020, 922, 773, 554 cmꢀ1
;
((3aS,4S,6aR)-)-4,5-Diallyl-2,2-diethyltetrahydro-3aH-[1,3]dioxolo-
[4,5-c]pyrrole (16): To a solution of 2d (151.3 mg, 0.41 mmol) in
THF (4 mL) was added potassium diphenylphosphide (KPPh2, 0.5m
THF solution, 2.5 mL, 1.23 mmol) at ꢀ788C. The reaction mixture
was stirred for 2 h at the same temperature. Dilute hydrochloric
acid (1 n, 2.0 mL) was added to the reaction mixture and the tem-
perature was raised to room temperature. The resulting mixture
was stirred for 10 min and washed with CH2Cl2 (2 mL). The aqueous
layer was basified with saturated aqueous NaHCO3 and extracted
twice with CH2Cl2 (10 mL), dried over anhydrous Na2SO4. The or-
ganic layer was concentrated under reduced pressure and used
without further purification. To the amine dissolved in THF (4 mL)
was added K2CO3 (227.0 mg, 1.64 mmol) and allylbromide (140 mL,
1.64 mmol). The reaction mixture was stirred at 408C for 4 h. The
resulting mixture was diluted with CH2Cl2 and extracted twice with
CH2Cl2 (10 mL) and water (10 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residual oil was purified by flash column chromatography (hexane/
EtOAc=90:10) to give the product 16 as a colorless oil (64.0 mg,
0.25 mmol, 61.5% over 2 steps). Rf =0.45 (hexane/EtOAc=80:20);
½aꢁ2D4 = +39.7 (c=0.59 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
5.76–5.88 (m, 2H), 5.07–5.22 (m, 4H), 4.57–4.63 (m, 1H), 4.34 (dd,
J=4.5, 7.2 Hz, 1H), 3.37 (dd, J=5.7, 13.8 Hz, 1H), 3.19 (dd, J=6.3,
10.2 Hz, 1H), 2.92 (dd, J=7.5, 13.5 Hz, 1H), 2.63–2.69 (m, 1H), 2.47
(dd, J=4.5, 9.9 Hz, 1H), 2.36–2.44 (m, 1H), 2.08–2.18 (m, 1H), 1.71
(q, J=7.5 Hz, 2H), 1.57 (q, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H),
0.85 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=135.2,
134.9,117.6, 117.43, 117.42, 84.2, 78.0, 67.7, 58.6, 55.4, 34.2, 29.8,
29.4, 8.7, 8.1 ppm; IR (NaCl): n˜ =3078, 2975, 2931, 2882, 2806,
1741, 1698, 1465, 1168, 1084, 924 cmꢀ1; HRMS (FAB): m/z calcd for
C15H26NO2 (MH+) 252.1964, found 252.1966.
HRMS (FAB): m/z calcd for C22H33NO6S (M+H+) 440.2107, found
440.2110.
2-((3aS,4S,7aR)-2,2-Diethyl-5-tosylhexahydro-[1,3]dioxolo[4,5-
c]pyridin-4-yl)-1-phenylethanone (13): Following the representa-
tive procedure, 4 (30 mg, 0.07 mmol) was treated with 1-phenyl-1-
trimethylsiloxyethylene (58 mL, 0.28 mmol) and BF3·OEt2 (26 mL,
0.23 mmol) in CH2Cl2 (0.7 mL). The reaction mixture was stirred at
08C for 2 h. Flash column chromatography (hexane/EtOAc=88:12)
afforded 13 (25.0 mg, 77.5%) as a white solid. Rf =0.18 (hexane/
EtOAc=80:20); m.p. 86–878C; ½aꢁ2D0 = +92.0 (c=1.50 in CHCl3);
1H NMR (300 MHz, CDCl3): d=8.02 (d, J=7.2 Hz, 2H), 7.73 (d, J=
8.1 Hz, 2H), 7.65–7.56 (m, 1H), 7.54–7.45 (m, 2H), 7.26 (d, J=
8.0 Hz, 2H), 4.65 (dd, J=10.9, 3.0 Hz, 1H), 4.29 (s, 2H), 3.66 (dd, J=
16.7, 3.4 Hz, 1H), 3.56 (dt, J=11.0, 4.0 Hz, 1H), 3.18–2.97 (m, 2H),
2.39 (s, 3H), 2.02–1.81 (m, 2H), 1.53–1.38 (m, 2H), 1.38–1.18 (m,
1H), 1.06–0.93 (m, 1H), 0.75 (t, J=7.6 Hz, 3H), 0.52 ppm (t, J=
7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=197.4, 143.4, 136.4, 135.4,
133.8, 129.6, 129.0, 128.6, 127.9, 112.1, 74.0, 68.2, 50.9, 45.4, 37.7,
28.7, 27.9, 26.2, 21.7, 8.7, 8.5 ppm; IR (NaCl): n˜ =2969, 2971, 2938,
1685, 1598, 1449, 1329, 1162, 1098, 966, 772, 670 cmꢀ1; HRMS
(FAB): m/z calcd for C25H31NO5S (M+H+) 458.2001, found 458.1998.
(3aS,4S,7aR)-2,2-Diethyl-4-(prop-2-ynyl)-5-tosylhexahydro-
[1,3]dioxolo[4,5-c]pyridine (14): Following the representative pro-
cedure, 4 (80 mg, 0.19 mmol) was treated with allenyltri-n-butyltin
(280 mL, 0.75 mmol) and BF3·OEt2 (70 mL, 0.56 mmol) in CH2Cl2
(3.6 mL). The reaction mixture was stirred at 08C for 15 min. Flash
column chromatography (hexane/EtOAc=80:20) afforded 14
(63.3 mg, 89.2%) as a white solid. Rf =0.25 (hexane/EtOAc=80:20);
m.p. 71–728C; ½aꢁ2D0 = +67.0 (c=3.20 in CHCl3); H NMR (300 MHz,
1
(3aR,9aS,9bS)-2,2-Diethyl-3a,4,6,9,9a,9b-hexahydro-[1,3]dioxolo-
[4,5-a]indolizine (17): To a solution of 16 (64.0 mg, 0.25 mmol) in
toluene (25 mL) was added 2nd generation Grubbs’ catalyst
(5 mol%). The resulting reaction mixture was stirred at 608C for
1 h. The solvent was removed under reduced pressure and the re-
sulting crude oil was purified by flash column chromatography
(hexane/EtOAc=70:30) to give 17 (43.8 mg, 78.5%) as colorless oil.
Rf =0.14 (hexane/EtOAc=70:30); ½aꢁ2D2 =ꢀ75.2 (c=0.52 CHCl3);
1H NMR (300 MHz, CDCl3): d=5.68–5.74 (m, 2H), 4.71–4.77 (m, 1H),
4.28 (t, J=5.4 Hz, 1H), 3.47–3.52 (m, 1H), 3.32–3.37 (m, 1H), 2.91–
2.96 (m, 1H), 2.37–2.44 (m, 3H), 2.05–2.14 (m, 1H), 1.73 (q, J=
7.2 Hz, 2H), 1.61 (q, J=7.5 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H),
0.88 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=125.1,
124.8, 118.7,85.8,78.0, 64.2, 60.4, 52.1, 30.3, 29.9, 8.8, 8.1 ppm; IR
CDCl3): d=7.71 (d, J=8.1 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 4.49 (dd,
J=7.3, 1.3 Hz, 1H), 4.36–4.25 (m, 1H), 4.21–4.10 (m, 1H), 3.46 (dt,
J=11.1, 4.3 Hz, 1H), 3.02 (td, J=11.4, 3.1 Hz, 1H), 2.80 (ddd, J=
17.0, 4.6, 2.3 Hz, 1H), 2.45–2.35 (m, 1H), 2.41 (s, 3H), 2.09 (t, J=
2.6 Hz, 1H), 2.02–1.89 (m, 1H), 1.84–1.72 (m, 1H), 1.54–1.39 (m,
2H), 1.33–1.22 (m, 1H), 1.01–0.89 (m, 1H), 0.77 (t, J=7.5 Hz, 3H),
0.51 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=143.5,
135.3, 129.6, 127.9, 112.0, 80.5, 73.4, 71.8, 68.3, 53.5, 37.4, 28.7,
27.6, 26.5, 26.3, 21.7, 8.8, 8.5 ppm; IR (NaCl): n˜ =3278(br), 2971,
2939, 2883, 2120, 1598, 1461, 1444, 1164, 1098, 1056, 772, 662 cm-
1; HRMS (FAB): m/z calcd for C20H27NO4S (M+H+) 378.1739, found
378.1741.
(NaCl): n˜ =3034, 2969, 2927, 2808, 1739, 1466, 1084, 928 cmꢀ1
;
(3aS,4S,7aR)-2,2-Diethyl-5-tosylhexahydro-[1,3]dioxolo[4,5-c]pyri-
dine-4-carbonitrile (15): Following the representative procedure, 4
(25 mg, 0.059 mmol) was treated with trimethylsilyl cyanide (29 mL,
0.24 mmol) and TIPSOTf(48 mL, 0.18 mmol) in CH3CN (0.6 mL). The
reaction mixture was stirred at RT for 2 h. Flash column chroma-
tography (hexane/EtOAc=80:20) afforded 15 (13.2 mg, 61.4%) as
a white solid. Rf =0.35 (hexane/EtOAc=70:30); m.p. 124–1258C;
HRMS (FAB): m/z calcd for C13H22NO2 (MH+) 224.1651, found
224.1654.
(3aR,9aS,9bS)-2,2-Diethyloctahydro-[1,3]dioxolo[4,5-a]indolizine:
To a solution of 17 (61.8 mg, 0.28 mmol) in MeOH (3 mL) was
added PtO2 (10 mol%). The resulting reaction mixture was stirred
at RT for 1 h. The solvent was removed under reduced pressure
and the resulting crude oil was purified by flash column chroma-
tography (hexane/EtOAc=70:30) to give the desired hydrogenated
compound (44.6 mg, 70.7%) as colorless oil. Rf =0.14 (hexane/
½aꢁ2D0 = +42.2 (c=0.90 in CHCl3); H NMR (300 MHz, CDCl3): d=7.73
1
(d, J=8.1 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.00 (d, J=1.6 Hz, 1H),
4.51 (dt, J=7.4, 2.7 Hz, 1H), 4.46 (dd, J=7.4, 1.6, 1H), 3.53 (td, J=
10.7, 6.5 Hz, 1H), 3.28–3.13 (m, 1H), 2.51–2.34 (m, 3H), 2.16–2.04
(m, 2H), 1.64–1.47 (m, 4H), 0.86 ppm (t, J=7.4 Hz, 6H),; 13C NMR
(75 MHz, CDCl3): d=144.5, 134.3, 130.0, 127.9, 116.1, 114.3, 74.7,
69.0, 45.6, 36.9, 28.6, 27.6, 24.1, 21.8, 8.8, 8.2 ppm; IR (NaCl): n˜ =
2938, 2236, 1465, 1356, 1219, 1167, 1095, 1076, 772 cmꢀ1; HRMS
(FAB): m/z calcd for C18H24N2O4S (M+H+) 365.1535, found
365.1537.
1
EtOAc=70:30); ½aꢁ2D0 =ꢀ37.1 (c=0.76 in CHCl3); H NMR (300 MHz,
CDCl3): d=4.64–4.71 (m, 1H), 4.19 (t, J=6.3 Hz, 1H), 3.34 (dd, J=
6.6, 9.3 Hz, 1H), 2.95 (br, d, J=10.8 Hz, 1H), 2.30 (dd, J=5.4, 9.3 Hz,
1H), 2.12 (dt, J=3.0, 11.4, 1H), 1.98–2.03 (m, 2H), 1.20–1.80 (m,
5H), 1.72 (1, J=7.5 Hz, 2H), 1.60 (q, J=7.5 Hz, 2H), 0.95 (t, J=
7.5 Hz, 3H), 0.87 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=118.6, 84.9, 77.8, 69.0, 60.5, 52.9, 29.9, 29.4, 29.2, 25.2, 24.3, 8.8,
Chem. Eur. J. 2014, 20, 1 – 7
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Chem. 2002, 67, 7869; f) O. Okitsu, R. Suzuki, S. Kobayashi, J. Org. Chem.
2001, 66, 809; g) C. F. Klitzke, R. A. Pilli, Tetrahedron Lett. 2001, 42, 5605;
h) W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56, 3817.
[3] a) B. G. Winchester, Tetrahedron: Asymmetry 2009, 20, 645; b) M. S. M.
Pearson, M. Mathꢁ-Allainmat, V. Fargeas, J. Lebreton, Eur. J. Org. Chem.
2005, 2159; c) K. Afarinkia, A. Bahar, Tetrahedron: Asymmetry 2005, 16,
1239; d) E.-S. H. El-Ashry, A. El Nemr, Carbohydr. Res. 2003, 338, 2265;
e) N. Asano, R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahedron: Asym-
metry 2000, 11, 1645.
8.1 ppm; IR (NaCl): n˜ =2934, 2858, 2802, 2731, 1466, 1171, 1083,
927 cmꢀ1; HRMS (FAB): m/z calcd for C13H24NO2 (MH+) 226.1807,
found 226.1808.
(1S,2R,8aS)-Octahydroindolizine-1,2-diol (18): Based on a modified
procedure by Harris[11], a solution of bicyclic piperidine (27.0 mg,
0.12 mmol) in a 1:3 mixture of 10% H2SO4 and MeOH (2 mL) was
stirred at 508C for 12 h and cooled to RT. Flash column chromatog-
raphy (MeOH/CH2Cl2 =50:50) afforded 17 (17.5 mg, 92.8%) as a col-
orless oil. Rf =0.44 (MeOH:CH2Cl2 =50:50); ½aꢁ2D8 =ꢀ46.0 (c=0.80 in
[4] Compound 1a was prepared from commercially available (p-toluene-
sulfonyl)allyamine based upon [1].
1
CHCl3); H NMR (300 MHz, CDCl3): d=4.17 (q, J=6.6 Hz, 1H), 3.61
[5] For selected examples on the use of 2-acetoxy moiety as a stereodirect-
ing example, see: a) D. Russowsky, R. Z. Petersen, M. N. Godoi, R. A. Pilli,
Tetrahedron Lett. 2000, 41, 9939; b) A. Bernardi, F. Micheli, D. Potenza, C.
Scolastico, R. Villa, Tetrahedron Lett. 1990, 31, 4949; c) A. P. Kozikowski,
K. L. Sorgi, Tetrahedron Lett. 1982, 23, 2281.
[6] The trans stereochemistry was confirmed by the conversion of 2c and
2d to the corresponding alcohols.
[7] a) S. Ichikawa, N. Tatebayashi, A. Matsuda, J. Org. Chem. 2013, 78,
12065; b) S. Ichikawa, R. Hayashi, S. Hirano, A. Matsuda, Org. Lett. 2008,
10, 5107; c) S. Hirano, S. Ichikawa, A. Matsuda, J. Org. Chem. 2007, 72,
9936.
[8] For discussion of the inside addition effect in the addition of carbon
nucleophiles to oxacarbenium ions, see: a) S. R. Shenoy, D. M. Smith,
K. A. Woerpel, J. Am. Chem. Soc. 2006, 128, 8671; b) C. H. Larsen, B. H.
Ridgway, J. T. Shaw, D. M. Smith, K. A. Woerpel, J. Am. Chem. Soc. 2005,
127, 10879; c) C. H. Larsen, B. H. Ridgway, J. T. Shaw, K. A. Woerpel, J.
Am. Chem. Soc. 1999, 121, 12208.
(t, J=7.8 Hz, 1H), 3.46 (dd, J=6.9, 9.9 Hz, 1H), 3.23 (br, s, 2H), 2.97
(br, d, J=10.8 Hz, 1H), 2.14 (dd, J=5.1, 9.9 Hz, 1H), 1.99–2.12 (m,
2H), 1.80–1.86 (m, 2H), 1.61–1.66 (m, 1H), 1.40–1.54 (m, 1H), 1.21–
1.32 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=75.2, 68.3, 67.4,
62.4, 53.1, 29.2, 25.4, 24.1 ppm; IR (NaCl): n˜ =3373, 2932, 2854,
1653, 1442, 1261, 1144, 1060, 1010 cmꢀ1; HRMS (FAB): m/z calcd for
C8H16NO2 (MH+) 158.1181, found 158.1183.
Acknowledgements
This research was supported by the Nano-Material Technology
Development Program through the National Research Founda-
tion of Korea (NRF).
[9] For other syntheses of epilentiginosine, see: a) A. Rajender, J. P. Rao,
B. V. Rao, Eur. J. Org. Chem. 2013, 1749; b) J.-J. Zhuang, J.-L. Ye, H.-K.
Zhang, P.-Q. Huang, Tetrahedron 2012, 68, 1750; c) T. Muramatsu, S. Ya-
mashita, Y. Nakamura, M. Suzuki, N. Mase, H. Yoda, K. Takabe, Tetrahe-
dron Lett. 2007, 48, 8956; d) D. Sawada, H. Takahashi, S. Ikegami, Tetra-
hedron Lett. 2003, 44, 3085; e) M. O. Rasmussen, P. Delair, A. E. Greene,
J. Org. Chem. 2001, 66, 5438; f) S. H. Lim, S. Ma, P. Beak, J. Org. Chem.
2001, 66, 9056.
Keywords: diastereoselectivity
heterocycles · natural products · synthetic methods
·
enantioselectivity
·
[1] a) H. Kim, W. Lim, D. Im, D.-g. Kim, Y. H. Rhee, Angew. Chem. 2012, 124,
12221; Angew. Chem. Int. Ed. 2012, 51, 12055; b) H. Kim, Y. H. Rhee, J.
Am. Chem. Soc. 2012, 134, 4011; c) H. Kim, Y. H. Rhee, Synlett 2012, 23,
2875.
[2] a) P. Compain, V. Chagnault, O. R. Martin, Tetrahedron: Asymmetry 2009,
20, 672; b) X. Zhou, W.-J. Liu, J.-L. Ye, P.-Q. Huang, Tetrahedron 2007, 63,
6346; c) P. N. M. Botman, F. J. Dommerholt, R. de Gelder, Q. B. Broxter-
man, H. E. Schoemaker, F. P. J. T. Rutjes, R. H. Blaauw, Org. Lett. 2004, 6,
4941; d) P. M. Weintraub, J. S. Sabol, J. M. Kane, D. R. Borcherding, Tetra-
hedron 2003, 59, 2953; e) M. K. S. Vink, C. A. Schortinghuis, J. Luten, J. H.
van Maarseveen, H. E. Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, J. Org.
[10] S. Yoshida, K. Igawa, K. Tomooka, J. Am. Chem. Soc. 2012, 134, 19358.
[11] T. M. Harris, C. M. Harris, J. E. Hill, F. S. Ungemach, H. P. Broquist, B. M.
Wickwire, J. Org. Chem. 1987, 52, 3094.
Received: July 8, 2014
Published online on && &&, 0000
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FULL PAPER
trans-Formers—hydroxyl groups in
disguise: A stereoselective synthetic
pathway towards trans-3,4-dihydroxy-2-
alkylpyrrolidines and piperidines is de-
scribed. The nature of the protecting
groups on the hydroxyl moieties played
a crucial role in the trans selectivity. This
method provided (ꢀ)-2-epilentiginosine
and other nitrogen heterocycles in
a highly efficient manner.
&
Heterocycles
S. Kang, D.-g. Kim, Y. H. Rhee*
&& – &&
Access to trans-3,4-Dihydroxy-2-
alkylpyrrolidines and Piperidines by
Use of Stereodefined Cyclic N,O-
Acetals as a Diversity-Generating
Element
Chem. Eur. J. 2014, 20, 1 – 7
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ