An unexpected high erythro-selection in the Grignard reaction with an N,O-acetal: A concise asymmetric synthesis of indolizidine alkaloid (-)-2-epi-lentiginosine

Article abstract of DOI:10.1016/j.tet.2011.12.063

Starting from commercially available lactone 10, a concise and highly diastereoselective synthesis of (-)-(lS,2R,8aS)-2-epi-lentiginosine (2) is described. The synthesis featured an unexpected highly erythro-selective reaction of Grignard reagent 7 with the protected N,O-acetal 8. The stereochemical outcome of this reaction is contrary to the known results involving the reactions with O-benzyl protected aminofuranosides and aminoglycosides. Thus, this method constitutes an extension of the threo-diastereoselective C-C bond formation methodology.

Full text of DOI:10.1016/j.tet.2011.12.063

Tetrahedron 68 (2012) 1750e1755
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An unexpected high erythro-selection in the Grignard reaction with an N,O-acetal:
a concise asymmetric synthesis of indolizidine alkaloid (ꢀ)-2-epi-lentiginosine
*
Jia-Jia Zhuang, Jian-Liang Ye, Hong-Kui Zhang , Pei-Qiang Huang
Department of Chemistry and the Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, No. 422,
South Siming Road, Xiamen, Fujian 361005, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 October 2011
Received in revised form 10 December 2011
Accepted 20 December 2011
Available online 24 December 2011
Starting from commercially available lactone 10, a concise and highly diastereoselective synthesis of
(ꢀ)-(lS,2R,8aS)-2-epi-lentiginosine (2) is described. The synthesis featured an unexpected highly erythro-
selective reaction of Grignard reagent 7 with the protected N,O-acetal 8. The stereochemical outcome of
this reaction is contrary to the known results involving the reactions with O-benzyl protected amino-
furanosides and aminoglycosides. Thus, this method constitutes an extension of the threo-diaster-
eoselective CeC bond formation methodology.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
the fungus Rhizoctonia leguminicola.5a The former has been shown
to be a late intermediate in the biosynthesis of swainsonine in R.
5-Substituted 3,4-cis-dihydroxypyrrolidine constitutes the key
structural feature of a number of azasugars that exhibit a broad
spectrum of bioactivities such as inhibition of glucosidases,1 and
are promising for the development of therapeutic agents against
cancer, diabetes, or viral infections.2 Among them, (þ)-lentigino-
sine (1, Fig. 1) and its C-2 epimer (ꢀ)-2-epi-lentiginosine (2) were
isolated from the leaves of Astragalus lentiginosus.3 (þ)-Lentigino-
sine 1 was found to be a powerful selective inhibitor of amyloglu-
cosidase.4 The first isolation of (ꢀ)-2-epi-lentiginosine was from
leguminicola.5b (ꢀ)-2-epi-Lentiginosine has shown to be a potent
inhibitor of
a-mannosidase with an IC50 value of 4.6 m
M.6
(ꢀ)-Swainsonine (3) is a well-known alkaloid first isolated from
the fungus R. leguminicola,5a,7 which exhibited
a
-mannosidase in-
hibitory properties and other promising biological acitivities.8
A
number of total syntheses of swainsonine (3) have been reported.9
(ꢀ)-Steviamine (4), recently isolated from Stevia rebaudiana
(Asteraceae) leaves,10 was found to be a weak inhibitor of an
galactosaminidase (GalNAcase).11
a-
Due to their remarkable bioactivities, the synthesis of lentigino-
sine and its stereoisomers has attracted much attention, which has
accumulated in a number of enantioselective synthetic approaches12
and some individual syntheses of (ꢀ)-2-epi-lentiginosine.13 In con-
nection with a program aiming at the asymmetric synthesis of bio-
active alkaloids using malic acid14 and tartaric acid15 as the chiral
sources, we were engaged in the synthesis of 3,4-cis-dihydrox-
ypyrrolidine-containing azasugars starting from D-erythronolactone
(10), and the results of this study are reported herein, which include
an erythro (anti)-selective Grignard addition of reagent 7 to the N,O-
acetal 8 and a concise synthesis of (ꢀ)-2-epi-lentiginosine 2.
2. Results and discussion
Our initial target was 2a, a stereoisomer of (ꢀ)-2-epi-lentigi-
nosine, and the retrosynthetic analysis is depicted in Scheme 1. The
key feature of the plan resided in the use of commercially available
chiron 10 as the starting material and the threo(syn)-diaster-
eoselective addition16 of Grignard reagent 7 to N,O-acetal 8 as the
key step to establish the third chiral center (C8a).
Fig. 1. Structures of some naturally occurring polyhydroxylated indolizidines.
* Corresponding author. Tel./fax: þ86 592 2182444; e-mail address: hkzhang@
xmu.edu.cn (H.-K. Zhang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.063

J.-J. Zhuang et al. / Tetrahedron 68 (2012) 1750e1755
1751
surprise, the expected threo-diastereomer (6a) was not observed.16
In the consideration of this fact, the adduct 6 was then converted
into known natural product (ꢀ)-2-epi-lentiginosine (2) (vide infra).
Thus, the addition of Grignard reagent 7 with N,O-acetal 8 turned
out to be erythro-selective.
OBn
OH
BnO
OBn
OH
1
2
3
8a
4
OBn
OH
MsO
BnN
N
NHBn
5 (2,3-trans)
2
(1,8a-trans)
5a
(2,3-cis)
2a (1,8a-cis)
OTBS
6 (3,4-erythro)
OTBS
BrMg
6a
(3,4-threo)
7
HO
OH
BnO
OBn
OBn
BnO
O
HO
O
9
O
10
BnHN
O
8
Scheme 1. Retrosynthetic analysis of 3,4-cis-dihydroxypyrrolidine-containing in-
dolizidines 2/2a.
As described in Scheme 2, Ag2O-catalyzed dibenzylation (BnBr,
MeCN)18 of
able or easily prepared from
D
-erythronolactone (10), which is commercially avail-
D
-isoascorbic acid,17 gave the protected
Scheme 3. Synthesis of amino alcohol 6.
lactone 11 in 76% yield. Compound 11 was treated with DIBAL-H at
ꢀ78 ꢁC in CH2Cl2 to afford the
b-D-erythrofuranose (2,3-trans hemi-
The observed stereochemical outcome of the Grignard addition
with N,O-acetal 8 is in contrast with the reported cases using benzyl
as the hydroxyls protecting group,16,21 where the reactions of all
acetal) 9a as the only isolable diastereomer in 92% yield. The 2,3-
trans relationship was determined by NOESY experiments (Fig. 2).
The observed high diastereoselectivity is attributable to a chela-
tion-directed cis delivery of a hydride to the carbonyl group of 11
to provide trans-diastereomer 9a.
furanosylamines (derived from protected
D
-arabinose,
D-ribose or L-
-glucopyranosyl-
xylose, and primary or secondary amines) and
D
amines produced uniformly threo-adducts as the major di-
astereomers. For a typical example, aldose 12 was transformed into
the corresponding glycosylamine 13, which is then reacted with
Grignard reagent to give threo-adduct 14 via a a-chelation transi-
tion state16f,16g (Fig. 3a). Moreover, the diastereoselectivity of the
addition reaction depends on the protecting group of 1,2-diol.
Further results from a very recent report by Behr and co-workers22
led them to conclude that, in the ribose series, the Grignard reagent
additions with 2,3-O-isopropylidene protected derivatives mainly
give rise to 3,4-erythro-diastereomers (Fig. 3b). Notably, the re-
action of organometallic reagents with furanoses and pyranoses
derived open-chain nitroneehydroxylamine mixtures gave a mix-
ture of threo/erythro-diastereoisomers, and the good to high 1,2-
erythro-diastereoselectivities were observed depending on the
carbon stereocenter adjacent to the nitrone group.25
Scheme 2. Preparation of the
b
-D-erythrofuranose 9a.
Ph
Ph
4.61
4.55
O
3.81O
H
4.25
H
3
4
6.47
In the case of the N,O-acetal 8, quoting the a-chelation control
2
5
model16f fails to interpret the formation of the erythro-adduct. In-
stead, a postulated seven-membered chelating structure26 (18) was
proposed. Grignard reagent would approach from the Si-face of the
iminium ion 18 to avoid steric hindrance with the O-benzyl groups,
which results in the formation of the erythro-diastereomer 6
(Fig. 4). In addition, the erythro-selectivity in this Grignard reaction
seems to be ascribed to the transition state involving either a Fel-
kineAnh or Cornforth model,27 although we prefer the seven-
membered structure for the case of N,O-acetal 8.
HO
4.0H0
O
H5.23
H
3.75
9a
Fig. 2. Observed correlations (in part) in the NOESY of compound 9a.
The addition of organometallic reagents to N,O-acetals has been
shown to be an efficient and versatile method for the synthesis of
azasugars16a,16d and functionalized pyrrolidines.19 The reactions are
considered to pass through imine or iminium intermediates.20 In
The formation of seven-membered chelating structure afforded
a reaction with an iminium ion species suitable for a nucleophilic
addition. That can explain why an excess of Grignard reagent and
much longer reaction time (warmed up to rt and stirred overnight
for 8; 10 min to 1 h for 1216c,16h in Fig. 3a) are required for the
completion of the reaction. It is worthy of mentioning that the
reaction of the dianion of 4-PSBA (4-(phenylsulfonyl)butanic acid)
with a N,O-acetal derived from malic acid produced exclusively the
threo-diastereomer in only 29% yield.28
With these valuable results in hand, we reoriented our target,
and switched to the synthesis of 2-epi-lentiginosine (2) (Scheme 4).
Intramolecular cyclization of amino alcohol 6 using Appel re-
action29 with PPh3/CBr4/Et3N system in CH2Cl2 for 2 h yielded 2-
substituted pyrrolidine 19 in 95% yield. Desilylation of 19 with
TBAF in THF gave alcohol 20 in 90% yield. Treatment of alcohol 20
with MsCl (DMAP, Et3N, rt) afforded mesylate 5, which, without
this context, nucleophilic addition with a-O-benzyl protected N,O-
acetals has been shown to be threo-selective.16,21 Only 2,3-O-iso-
propylidene protected derivatives gave major 1,2-erythro-di-
astereomers.22 Our interest in the chemistry of N,O- and N,S-
acetals15,23 led us to examine the addition of Grignard reagent to
N,O-acetal derivative 8. Thus, N,O-acetal 8 was prepared from b-D-
erythrofuranose (9a) by reaction with benzylamine in the presence
of 4 A molecular sieve. The resultant diastereomeric mixture 8 was
used in the subsequent step without further separation. After re-
moval of the solvent under reduced pressure, the residual N,O-ac-
etal 8 was dissolved in THF, and treated with an excess of Grignard
reagent BrMg(CH2)4OTBS24 (7) (ꢀ78 ꢁC to rt, overnight) to produce
a single diastereomer 6 (yield: 80% over two steps) as indicated in
the 1H NMR spectrum of the crude product (Scheme 3). To our
ꢀ

1752
J.-J. Zhuang et al. / Tetrahedron 68 (2012) 1750e1755
R
HN
5
BnO
O
5
BnO
O
BnO
R'
5
BnO
OH
NHR
OH
R'MgX
1
BnO
1
RNH2
BnO
(a)
2
2
4
OBn
OBn
OBn
14
4,5-threo (syn)
13
12
O
O
O
O
(b)
3
RMgCl
4
PMBHN
1
4
Me
R
HO
PMBHN
H
Me
O
16
3,4-erythro (anti)
15
Fig. 3. Plausible mechanism for the formation of 4,5-threo- and 3,4-erythro-diastereomers 14/16 via Grignard addition.
BnO
OBn
BnO
OBn
RMgBr
H
1
4
BnN
H
O
N
O−MgBr
Bn
8
17
BnO
H
OBn
O
BnO
OBn
OH
H
3
RMgBr
Si attack
then work up
R= (CH2)4OTBS
4
(s)
+
R
RMgBr
N
Bn
NHBn
6
Mg
Br
18
3,4-erythro
Fig. 5. Observed correlations (in part) in the NOESY of indolizidine 21.
Fig. 4. Proposed mechanism for the formation of the erythro-diastereomer 6.
(2) was achieved by increasing the amount of 10% Pd/C to 100%
(weight based on 20) in the catalytic hydrogenolysis conditions,
which directly produced (ꢀ)-2-epi-lentiginosine (2) in 81%. The
purification, was subjected to catalytic hydrogenolysis conditions
[10% Pd/C (60% wt), H2, 5 atm, 5% CF3CO2H in MeOH, rt] to give the
protected 2-epi-lentiginosine 21 in 81% yield from 20.
ꢀ33.6 (c 0.25, H2O); lit.6
[a
]
ꢀ31.7 (c 0.25, H2O)}
20
20
physical {[
a
]
D
D
and spectral data of the synthetic (ꢀ)-2-epi-lentiginosine (2) are
identical with those reported for the natural product.6
3. Conclusions
In summary, a six-step stereoselective synthesis of (ꢀ)-2-epi-
lentiginosine (2) from commercially available chiron
D-eryth-
ronolactone (10) has been achieved with an overall yield of 39%.
The synthesis features an unexpected erythro-diastereoselective
addition reaction and two highly efficient cyclization reactions to
construct the pyrrolidine and piperidine moieties, respectively. This
unambiguous asymmetric synthesis of (ꢀ)-2-epi-lentiginosine
revealed that the addition of Grignard reagent 7 with the protected
N,O-acetal 8 is erythro-stereoselective. The observed highly dia-
stereoselective addition reaction of a Grignard reagent with the
O,O0-dibenzyl group protected N,O-acetal 8 extended the scope of
the powerful threo-diastereoselective CeC bond formation meth-
odology, which would be useful for the synthesis of azasugars and
others N-containing heterocycles.
Scheme 4. Synthesis of (ꢀ)-2-epi-lentiginosine (2).
At this stage, NOESY experiments were undertaken on indoli-
zidine 21 (Fig. 5). The strong NOE correlation between H-8a (dH
2.18) and H-3
a
(
dH 2.35) indicated that C-1 and C-8a are in a trans
4. Experimental
4.1. General
relationship. Thus, the stereochemistry at C-4 of compound 6 was
deduced to be S.
Finally, protected 2-epi-lentiginosine 21 was converted into
(ꢀ)-2-epi-lentiginosine (2) in 89% yield under transfer hydroge-
nation reaction conditions (10% Pd/C, CH3OH, HCO2H). Alterna-
tively, direct conversion of compound 20 to (ꢀ)-2-epi-lentiginosine
Melting points were determined on a X-4 digital micro melting
point apparatus and were uncorrected. Infrared spectra were
measured with a Nicolet Avatar 330 FT-IR spectrometer using film

J.-J. Zhuang et al. / Tetrahedron 68 (2012) 1750e1755
1753
KBr pellet technique. 1H NMR spectra were recorded in CDCl3 on
a Bruker AV400 with tetramethylsilane as an internal standard.
Chemical shifts are expressed in d (ppm) units downfield from TMS.
Mass spectra were recorded by a Bruker Dalton Esquire 3000 plus
LCeMS apparatus. Optical rotations were measured with a Per-
kineElmer 341 automatic polarimeter. THF was distilled over so-
dium, and dichloromethane was distilled over P2O5 prior to use.
Flash column chromatography was carried out on silica gel
(300e400 mesh) with eluent ethyl acetate/petroleum ether
(60e90 ꢁC) (EtOAc/PE).
mixture was filtered and the solvent was removed under reduced
pressure to afford the crude product 8 as a pale yellow oil. The crude
product 8, without further purification, was dissolved in 35 mL of
THF and a 0.4 M THF solution of BrMg(CH2)4OTBS24 (35 mL,
14 mmol) was added dropwise at ꢀ78 ꢁC. The mixture was allowed
to warm slowly to room temperature and stirred overnight. The
reaction was quenched with a saturated NH4Cl aqueous solution
(25 mL), and the aqueous layer was extracted with CH2Cl2
(5ꢂ20 mL). The combined organic phases were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
(EtOAc/PE¼1:5) to provide compound 6 (1.07 g, yield: 80%) as
4.1.1. (2R,3R)-2,3-Bis(benzyloxy)-4-hydroxybutanoic acid 1,4-lactone
(11). To a solution of
D
-erythronolactone (10)17 (2.51 g, 21.2 mmol)
a colorless oil. [
a
]
20 þ1.4 (c 1.0, CHCl3); IR (film): 3302, 3063, 3029,
D
in anhydrous acetonitrile (125 mL) at room temperature was added
benzyl bromide (15.1 mL, 127 mmol). Anhydrous sodium sulfate
(15.0 g, 106 mmol) was then added and the resulting mixture was
stirred for 5 min. Silver (I) oxide (9.83 g, 42.4 mmol) was added in
three portions over 5 min. The mixture was vigorously stirred at
room temperature for 12 h in the dark, and a second portion of
silver (I) oxide (9.83 g, 42.4 mmol) was added. After stirring for
another 12 h, the reaction mixture was filtered through a plug of
Celite to remove the solids, washed with acetonitrile (3ꢂ60 mL).
The combined organic phases were concentrated, and the residue
was purified by flash column chromatography on silica gel (EtOAc/
PE¼1:4) to yield compound 11 (4.81 g, yield: 76%) as a white solid.
2930, 1253, 1098, 1029 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
0.04 (s,
6H, OSi(CH3)2), 0.89 (s, 9H, OSiC(CH3)3), 1.08e1.56 (m, 6H,
CH(CH2)3CH2OSi), 2.86e2.91 (m,1H, CHNHBn), 3.51 (t, J¼6.4 Hz, 2H,
CH2OH), 3.60e3.68 (m, 2H, CH2OTBS), 3.68 (d, J¼12.9 Hz, 1H,
PhCH2N), 3.77 (dd, J¼2.1, 4.3 Hz, 1H, CHCHOBn), 3.82 (d, J¼12.9 Hz,
1H, PhCH2N), 3.93 (dd, J¼8.0, 11.0 Hz, 1H, CH2CHOBn), 4.51 (d,
J¼12.0 Hz, 1H, PhCH2O), 4.56 (d, J¼11.8 Hz, 1H, PhCH2O), 4.65 (d,
J¼12.0 Hz, 1H, PhCH2O), 4.76 (d, J¼11.8 Hz, 1H, PhCH2O), 7.22e7.32
(m,15H, Ar-H); 13C NMR (100 MHz, CDCl3)
d
ꢀ5.3 (2C),18.3, 22.1, 26.0
(3C), 29.8, 32.9, 51.7, 57.7, 58.7, 62.7, 71.6, 73.3, 79.0, 81.4,127.2,127.6
(2C), 127.7, 127.8, 128.2, 128.3 (2C), 128.5, 138.4, 138.6, 139.3; MS
(ESI): m/z 578 (MþHþ,100). Anal. Calcd for C35H51NO4Si: C, 72.75; H,
8.90. Found: C, 73.01; H, 8.63.
Mp 90e93 ꢁC (hexane) [lit.30 mp 89e90 ꢁC (hexane)]. [
a
]
20 þ6.0 (c
D
0.5, CHCl3) {lit.30
[a
]
þ5.9 (c 0.5, CHCl3)}; IR (film): 3033, 1774,
20
D
1167 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 4.15e4.22 (m, 3H), 4.33
4.1.4. (2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(4-(tert-butyldime-
thylsilyloxy)butyl) pyrrolidine (19). To a solution of the protected
amino alcohol 6 (130 mg, 0.22 mmol) in anhydrous CH2Cl2 (2 mL)
at 0 ꢁC were added Et3N (1.2 mL, 8.8 mmol), PPh3 (474 mg,
1.8 mmol), and CBr4 (596 mg, 1.8 mmol). After stirring at 0 ꢁC for
2 h, the mixture was diluted with water (10 mL). The aqueous
phase was separated and extracted with CH2Cl2 (2ꢂ20 mL). The
combined organic phases were washed with brine, dried over
anhydrous K2CO3, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel (EtOAc/
(dd, J¼1.0, 10.3 Hz, 1H), 4.64 (d, J¼12.0 Hz, 1H, OCH2Ph), 4.71 (d,
J¼12.0 Hz, 1H, OCH2Ph), 4.81 (d, J¼12.1 Hz, 1H, OCH2Ph), 4.93 (d,
J¼12.1 Hz, 1H, OCH2Ph), 7.28e7.38 (m, 10H, Ar-H); 13C NMR
(100 MHz, CDCl3)
d 69.5, 71.9, 72.4, 73.9, 74.2, 128.5, 128.4, 128.1,
128.0, 127.9, 127.8, 136.6, 137.1, 173.2; MS (ESI): m/z 321
(MþNaþ, 100).
4.1.2. (2R,3R,4R)-3,4-Bis(benzyloxy)-tetrahydrofuran-2-ol (9a). To
a stirring solution of compound 11 (1.49 g, 5.0 mmol) in CH2Cl2
(65 mL) was added dropwise a 1.0 M THF solution of DIBAL-H
(6.5 mL, 6.5 mmol) at ꢀ78 ꢁC. The solution was stirred at ꢀ78 ꢁC
for 2 h. Then MeOH (2 mL) was added and the solution was
stirred at room temperature overnight. EtOAc (7 mL) and satu-
rated NaHCO3 (3.5 mL) were added, and the mixture was con-
tinued to be stirred for another 6 h. After addition of anhydrous
Na2SO4 (2.0 g), the mixture was filtered and the filtrate was
concentrated. The residue was purified by chromatography on
PE¼1:5) to give compound 19 (117 mg, yield: 95%) as a pale yellow
20
oil. [
a
]
þ12.8 (c 1.0, CHCl3); IR (film): 3063, 3030, 2926, 2856,
D
1100, 1028 cmꢀ1
; d 0.04 (s, 6H,
1H NMR (400 MHz, CDCl3)
OSi(CH3)2), 0.89 (s, 9H, OSiC(CH3)3), 1.24e1.58 (m, 6H,
CH(CH2)3CH2OSi), 2.56 (dd, J¼7.5, 9.2 Hz, 1H, CHCH2NBn),
2.76e2.81 (m, 1H, CHCHNBn), 3.09 (dd, J¼5.8, 9.2 Hz, 1H,
CHCH2NBn), 3.40 (d, J¼12.9 Hz, 1H, PhCH2N), 3.56 (t, J¼6.4 Hz, 2H,
CH2OH), 3.65 (dd, J¼4.9, 4.9 Hz, 1H, CHCHOBn), 3.91 (ddd, J¼4.9,
5.8, 7.5 Hz, 1H, CH2CHOBn), 3.95 (d, J¼12.9 Hz, 1H, PhCH2N), 4.48
(d, J¼12.0 Hz, 1H, PhCH2O), 4.54 (2d superposed, each J¼12.1 Hz,
2H, PhCH2O), 4.69 (d, J¼12.0 Hz, 1H, PhCH2O), 7.22e7.36 (m, 15H,
silica gel (EtOAc/PE¼1:3) to afford compound 9a (1.44 g, yield:
20
92%) as a colorless oil. [
a]
ꢀ9.6 (c 1.0, CHCl3); IR (film): 3415,
D
3063, 3031, 2883, 1454, 1141, 1080 cmꢀ1
;
1H NMR (400 MHz,
Ar-H); 13C NMR (100 MHz, CDCl3)
d
ꢀ5.3 (2C), 18.3, 21.7, 25.9 (3C),
DMSO-d6)
d
3.73 (dd, J¼4.9, 9.0 Hz, 1H, OCH2CHOBn), 3.79 (dd,
J¼2.5, 4.6 Hz, 1H, CHCHOBn), 3.98 (dd, J¼5.6, 9.0 Hz, 1H, OCH2
-
32.6, 33.1, 56.0, 59.5, 63.0, 68.0, 71.5, 71.7, 76.3, 81.2, 126.8, 127.5
(2C), 127.6, 127.9, 128.1, 128.2 (2C), 128.8, 138.3, 138.5, 139.3; MS
(ESI): m/z 560 (MþHþ, 100). Anal. Calcd for C35H49NO3Si: C, 75.09;
H, 8.82. Found: C, 75.34; H, 8.41.
CHOBn), 4.23 (ddd, J¼4.6, 4.9, 5.6 Hz, 1H, CH2CHOBn), 4.56 (d,
J¼9.8 Hz, 1H, OCH2Ph), 4.57 (d, J¼10.5 Hz, 1H, OCH2Ph), 4.59 (d,
J¼10.5 Hz, 1H, OCH2Ph), 4.62 (d, J¼9.8 Hz, 1H, OCH2Ph), 5.20 (dd,
J¼2.5, 5.2 Hz, 1H, CHOH), 6.45 (d, J¼5.2 Hz, 1H, OH), 7.25e7.36 (m,
10H, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d 68.8, 71.5, 71.7, 77.3,
4.1.5. 4-[(2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrrolidin-2-yl]bu-
tan-1-ol (20). To a solution of compound 19 (260 mg, 0.5 mmol) in
THF (2.0 mL) was added dropwise a 1.0 M THF solution of TBAF
(1.5 mL, 1.5 mmol) under nitrogen. The mixture was stirred at room
temperature overnight. Then H2O (5.0 mL) was added, and the
aqueous layer was extracted with CHCl3 (5ꢂ5 mL). The combined
organic phases were washed with brine and the solvent was re-
moved. The residue was purified by flash column chromatography
82.6, 100.2, 127.9 (2C), 128.1 (2C), 128.6 (2C), 138.8 (2C); MS (ESI):
m/z 323 (MþNaþ, 100). Anal. Calcd for C18H20O4: C, 71.98; H, 6.71.
Found: C, 71.78; H, 6.64.
4.1.3. (2R,3S,4S)-4-(Benzylamino)-2,3-bis(benzyloxy)-8-(tert-bu-
tyldimethylsilyloxy)octan-1-ol (6). A solution of compound 9a
(700 mg, 2.3 mmol) in anhydrous toluene (10 mL) was added suc-
ꢀ
cessively 4 A molecular sieve (70 mg) and BnNH2 (320
m
L, 2.8 mmol)
on silica gel (EtOAc/PE¼1:3) to give compound 20 (200 mg, yield:
20
at room temperature with stirring under nitrogen. The mixture was
90%) as a pale yellow oil. [
a
]
D
þ2.0 (c 1.0, CHCl3); IR (film): 3416,
stirred at 50 ꢁC for 10 h. After cooling to room temperature, the
3061, 3028, 2930, 2861, 1453, 1364, 1208, 1140 cmꢀ1 1H NMR
;

1754
J.-J. Zhuang et al. / Tetrahedron 68 (2012) 1750e1755
(400 MHz, CDCl3)
d
1.26e1.58 (m, 6H, CH(CH2)3CH2OH), 2.57 (dd,
7.0 Hz,1H, H-2); 13C NMR (100 MHz, D2O)
d 25.9, 27.2, 30.7, 55.2, 63.1,
J¼7.2, 9.5 Hz, 1H, CHCH2NBn), 2.78e2.82 (m, 1H, CHCHNBn), 3.11
(dd, J¼5.7, 9.5 Hz, 1H, CHCH2NBn ), 3.42 (d, J¼12.9 Hz, 1H, PhCH2N),
3.56 (t, J¼6.4 Hz, 2H, CH2OH), 3.69 (dd, J¼5.1, 5.1 Hz,1H, CHCHOBn),
3.92 (ddd, J¼5.1, 5.7, 7.2 Hz, 1H, CH2CHOBn), 3.95 (d, J¼12.9 Hz, 1H,
PhCH2N), 4.48 (d, J¼12.0 Hz, 1H, PhCH2O), 4.53 (d, J¼11.8 Hz, 2H,
PhCH2O), 4.56 (d, J¼11.8 Hz, 1H, PhCH2O), 4.71 (d, J¼12.0 Hz, 1H,
PhCH2O), 7.21e7.33 (m, 15H, Ar-H); 13C NMR (100 MHz, CDCl3)
69.2, 69.7, 77.4; MS (ESI): m/z 158 (MþHþ, 100).
Acknowledgements
The authors are grateful to the NSF of China (20672089;
20832005), the NFFTBS (No. J1030415), and the National Basic Re-
search Program (973 Program) of China (Grant No. 2010CB833200).
d
21.5, 32.4, 33.0, 56.1, 59.6, 62.8, 67.9, 71.7, 71.9, 76.3, 81.4, 126.9,
127.6 (2C), 127.7, 128.0, 128.2, 128.3 (2C), 128.8, 138.4, 138.6, 139.3;
MS (ESI): m/z 446 (MþHþ, 100). Anal. Calcd for C29H35NO3: C, 78.17;
H, 7.92. Found: C, 77.79; H, 8.10.
Supplementary data
Supplementary data (1H and 13C NMR spectra of compounds 2,
6, 9a, 11, 19, 20, and 21; NOESY spectra of compounds 9a and 19).
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.063.
4.1.6. (1S,2R,8aS)-1,2-Bis(benzyloxy)-octahydroindolizine
(21). To
a stirring solution of compound 20 (500 mg, 1.12 mmol) in CH2Cl2
(10 mL) at 0 ꢁC were added Et3N (0.20 mL, 1.34 mmol) and meth-
ylsulfonyl chloride (0.10 mL, 1.34 mmol). The mixture was stirred
for 3 h. To the resulting mixture was added 10 mL of saturated
NaHCO3 solution. The aqueous layer was extracted with CH2Cl2
(2ꢂ10 mL). The combined organic phases were washed with brine
(10 mL), dried over MgSO4, filtered, and concentrated in vacuo to
give crude product, which was dissolved in a solution of 5%
CF3CO2H in MeOH (10 mL). To the resulting solution was added
10% Pd/C (300 mg). The reaction mixture was stirred under 5 atm
of H2 at room temperature for 24 h. The catalyst was filtered off
through Celite, and the solvent was removed in vacuo. The residue
was purified by flash column chromatography (EtOAc/PE¼1/6) to
References and notes
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Rep. 2008, 25, 139; (b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191.
2. For a review on the therapeutic applications of polyhydroxylated alkaloids, see:
Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phyto-
chemistry 2001, 56, 265.
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Molyneux, R. J.; Harris, T. M. Tetrahedron Lett. 1988, 29, 4815.
give compound 21 (306 mg, yield: 81%) as a white solid. Mp
20
6. Haraguchi, M.; Gorniak, S. L.; Ikeda, K.; Minami, Y.; Kato, A.; Watson, A. A.;
Nash, R. J.; Molyneux, R. J.; Asano, N. J. Agric. Food Chem. 2003, 51, 4995.
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9. For two recent reviews on the total syntheses of (ꢀ)-swainsonine and its ste-
reoisomers, see: (a) Nie, L.; Ba, H.; Haji, A. Chinese J. Org. Chem. 2009, 29, 1354;
(b) Pyne, S. Curr. Org. Synth. 2005, 2, 39.
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11. For the asymmetric synthesis of the unnatural enantiomer of steviamine and C-5
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Nakagawa, S.; Kato, A.; Jia, Y.-M.; van Well, R.; Yu, C.-Y. Org. Lett. 2010, 12, 2562.
12. For two recent syntheses of lentiginosine, see: (a) Liu, S.-W.; Hsu, H.-C.; Chang,
C.-H.; Tsai, H.-H. G.; Hou, D.-R. Eur. J. Org. Chem. 2010, 4771; (b) Cui, L.; Zhang,
L.-M. Sci. China Chem. 2010, 53, 113.
43e46 ꢁC (EtOAc/PE); [
a
]
ꢀ60.0 (c 0.95, CHCl3); IR (film): 3029,
D
2932, 2853, 1453, 1321, 1147 cmꢀ1
1.15e1.26 (m, 2H, H-7, H-8 ), 1.41e1.48 (m, 1H, H-6), 1.60e1.63
(m, 1H, H-6), 1.75e1.78 (m, 1H, H-7), 1.98e2.18 (m, 1H, H-8 ),
2.04e2.10 (m, 1H, H-5
), 2.15e2.20 (m, 1H, H-8a), 2.35 (dd, J¼5.5,
9.6 Hz, 1H, H-3 ), 2.94e2.98 (m, 1H, H-5
), 3.39 (dd, J¼6.6, 9.6 Hz,
1H, H-3
;
1H NMR (500 MHz, CDCl3)
d
b
a
a
a
b
b
), 3.51 (dd, J¼7.1, 8.4 Hz, 1H, H-1), 4.01 (ddd, J¼5.5, 6.6,
7.1 Hz, 1H, H-2), 4.52 (d, J¼11.8 Hz, 1H, OCH2Ph), 4.55 (d, J¼11.8 Hz,
1H, OCH2Ph), 4.59 (d, J¼11.8 Hz, 1H, OCH2Ph), 4.75 (d, J¼11.8 Hz,
1H, OCH2Ph), 7.25e7.36 (m, 10H, Ar-H); 13C NMR (125 MHz, CDCl3)
d
23.8, 25.4, 29.4, 53.1, 60.3, 66.2, 71.9, 72.5, 73.7, 82.3, 127.5, 127.6,
127.9, 128.2 (2C), 128.3, 138.3, 138.4; MS (ESI): m/z 338 (MþHþ,
100). Anal. Calcd for C22H27NO2: C, 78.30; H, 8.06. Found: C, 77.91;
H, 8.10.
13. (a) Muramatsu, T.; Yamashita, S.; Nakamura, Y.; Suzuki, M.; Mase, N.; Yoda, H.;
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14. For a recent example, see: Chen, J.; Huang, P.-Q.; Queneau, Y. J. Org. Chem. 2009,
74, 7457.
4.1.7. (ꢀ)-2-epi-Lentiginosine (2). To a stirring solution of com-
pound 20 (500 mg,1.12 mmol) in CH2Cl2 (10 mL) at 0 ꢁC were added
successively Et3N (0.20 mL,1.34 mmol) and methylsulfonyl chloride
(0.10 mL, 1.34 mmol). The mixture was stirred for 3 h. To the
resulting mixture was added 10 mL of saturated NaHCO3 solution.
The aqueous layer was extracted with CH2Cl2 (2ꢂ10 mL). The com-
bined organic phases were washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated in vacuo to give the crude product
5, which was dissolved in a solution of 5% CF3CO2H in MeOH (10 mL).
To the resulting solution was added 10% Pd/C (500 mg). The reaction
mixture was stirred under 5 atm of H2 at room temperature for 24 h.
The catalyst was filtered off through Celite and the solvent was re-
moved in vacuo. The residue was dissolved in deionized water
(10 mL) and passed through a column of ion-exchange resin (Dowex
1ꢂ8-100, OH form) eluting with deionized water (15 mL). The eluent
15. For a recent example, see: Liu, X.-K.; Qiu, S.; Xiang, Y.-G.; Ruan, Y.-P.; Zheng, X.;
Huang, P.-Q. J. Org. Chem. 2011, 76, 4952.
16. (a) For a review, see: Behr, J.-B.; Plantier-Royon, R. Recent Res. Dev. Org. Chem. 2006,
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Cipolla, L.; Nicotra, F.; Pangrazio, C. Gazz. Chim. Ital. 1996, 126, 663; (d) Cipolla, L.;
Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L. Tetrahedron 1995, 51, 4679; (e) Yoda, H.;
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otra, F.; Paganini, A.; Pangrazio, C.; Panza, L. Tetrahedron Lett. 1993, 34, 4555; (g)
Carcano, M.; Nicotra, F.; Panza, L.; Russo, G. J. Chem. Soc., Chem. Commun.1989, 297;
(h) Nagai, M.; Gaudino, J.; Wilcox, C. S. Synthesis 1992,163; (i) Guerrier, L.; Royer, J.;
Grierson, D. S.; Husson, H.-P. J. Am. Soc. Chem. 1983, 105, 7754.
17. Cohen, N.; Banner, R. L.; Lopresti, R. J.; Wong, F.; Rosenberger, M.; Liu, Y. T.;
Thom, E.; Liebman, A. A. J. Am. Chem. Soc. 1983, 105, 3661.
18. Smith, A. B., III; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099.
19. For a review on the synthesis of chiral piperidines and pyrrolidines via ox-
azolidines, see: Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383.
20. For recent reviews on chiral amine synthesis, see: (a) Nugent, T. C.; El-Shazly,
M. Adv. Synth. Catal. 2010, 352, 753; (b) Friestad, G. K.; Mathies, A. K. Tetrahe-
dron 2007, 63, 2541.
21. For selected examples, see: (a) Takahashi, M.; Maehara, T.; Sengoku, T.; Fujita, N.;
Takabe, K.; Yoda, H. Tetrahedron 2008, 64, 5254; (b) Gautier-Lefebvre, I.; Behr, J.-B.;
Guillerm, G.; Muzard, M. Eur. J. Med. Chem. 2005, 40, 1255; (c) Behr, J.-B.; Erard, A.;
Guillerm, G. Eur. J. Org. Chem. 2002, 1256; (d) Behr, J.-B.; Guillerm, G. Tetrahedron:
Asymmetry 2002,13,111; (e) Eniade, A.; Martin, O. R. Carbohydr. Res. 2002, 337, 273;
(f) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123,
was concentrated in vacuo to give (ꢀ)-2-epi-lentiginosine (2) as
20
a colorless oil (141 mg, yield: 81%). [
a
]
ꢀ33.6 (c 0.25, H2O) {lit.6
D
20
[
a]
ꢀ31.7 (c 0.25, H2O)}; IR (film): 3361, 2933, 1144, 1061 cmꢀ1
;
D
1H NMR (400 MHz, D2O)
d 1.14e1.50 (m, 3H, H-8, H-7, H-6),
1.64e1.70 (m, 1H, H-6), 1.82e1.85 (m, 1H, H-7), 1.97e2.01 (m, 1H, H-
8), 2.02e2.07 (m,1H, H-5
), 2.08e2.15 (m,1H, H-8a), 2.16 (dd, J¼5.2,
10.1 Hz,1H, H-3 ), 2.96e3.00 (m, 1H, H-5
), 3.42 (dd, J¼6.8, 10.1 Hz,
1H, H-3
), 3.60 (dd, J¼7.0, 8.9 Hz, 1H, H-1), 4.18 (ddd, J¼5.2, 6.8,
a
a
b
b

J.-J. Zhuang et al. / Tetrahedron 68 (2012) 1750e1755
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