Practical synthesis of trans-dihydroxybutyrolactols as chiral C4 building blocks and their application to the synthesis of polyhydroxylated alkaloids

Article abstract of DOI:10.1039/c3ra43232g

Practical syntheses of trans-dihydroxybutyrolactols 2a, 2b and 2c from inexpensive chiral pool compounds l-ascorbic, d- and l-tartaric acid have been achieved on a multigram-scale. The synthetic applications of these chiral building blocks have been demonstrated in the efficient total or formal synthesis of polyhydroxylated alkaloids (+)-lentiginosine and (-)-deacetylanisomycin in concise routes. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra43232g

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Practical synthesis of trans-dihydroxybutyrolactols as
chiral C4 building blocks and their application to the
synthesis of polyhydroxylated alkaloids†
Cite this: RSC Adv., 2013, 3, 20298
*
*
Jing Zeng, Qian Zhang, Hong-Kui Zhang and Anqi Chen‡
Received 26th June 2013
Practical syntheses of trans-dihydroxybutyrolactols 2a, 2b and 2c from inexpensive chiral pool compounds
L-ascorbic, D- and L-tartaric acid have been achieved on a multigram-scale. The synthetic applications of
these chiral building blocks have been demonstrated in the efficient total or formal synthesis of
polyhydroxylated alkaloids (+)-lentiginosine and (ꢀ)-deacetylanisomycin in concise routes.
Accepted 16th August 2013
DOI: 10.1039/c3ra43232g
www.rsc.org/advances
mimics to inhibit various glycosidases in a reversible or
competitive manner, as well as tested for anticancer, anti-HIV
Introduction
and immunoregulatory activities.1 The natural abundance of
polyhydroxylated alkaloids and their remarkable, diverse
bioactivities have stimulated much interest in the total
synthesis of these compounds.2 However, one of the major
challenges of their total syntheses lies in the efficient and
stereoselective construction of the contiguous polyhydroxy
groups. Despite the signicant advancement in the enantio-
and diastereoselective construction of polyhydroxy systems,
such as asymmetric dihydroxylation and epoxidation reactions,
the most common and powerful strategy remains to be the
‘chiron’ approach in which chiral building blocks (or synthons)
generated from readily available, optically pure natural mole-
cules are used as the starting materials.
Structural motifs containing vicinal chiral polyhydroxy groups
are ubiquitous and commonly found in natural products with
therapeutic signicance, exemplied by polyhydroxylated alka-
loids. In the past few decades, more than 100 polyhydroxylated
alkaloids have been isolated, which can be categorised into
pyrrolidines, piperidines, pyrrolizidines, indolizines and nor-
tropanes based on their structural skeletons (Fig. 1). Poly-
hydroxylated alkaloids have also been classied as iminosugars
or azasugars due to their structural similarity to carbohydrates.
As a result, these iminosugars have been used as carbohydrate
Among the polyhydroxy chiral synthons, dihydroxybutyr-
olactols (Scheme 1, 1a–d) have long been recognized as valuable,
versatile building blocks and been widely utilized in the total
synthesis of natural products. The general strategy of the
synthetic application of dihydroxybutyrolactols includes nucle-
ophilic addition and Wittig reactions on the lactol moiety, which
is the equivalent of a masked aldehyde, to enable C–C bond
Fig. 1 Representative bioactive naturally occurring polyhydroxylated alkaloids.
Department of Chemistry and the Key Laboratory for Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering, Xiamen University, Fujian
361005, P. R. China. E-mail: hkzhang@xmu.edu.cn
† Electronic supplementary information (ESI) available: NMR spectra of all
compounds. See DOI: 10.1039/c3ra43232g
‡ Current address: Institute of Chemical and Engineering Sciences, 8 Biomedical
Grove, Neuros, #07-01, Singapore 138665. Email: chen_anqi@ices.a-star.edu.sg.
Scheme 1 Dihydroxybutyrolactols as building blocks.
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formation and further chemical transformations and function-
alisations.3 However, the successful application of this strategy
has mainly been limited to cis-dihydroxybutyrolactols whereas
that of trans-dihydroxybutyrolactols is much less explored.4 In
conjunction with our continuing efforts in the exploration of new
synthetic applications of dihydroxybutyrolactols as building
blocks,5 we report herein practical and scalable syntheses
of trans-dihydroxybutyrolactols (1c and 1d) and their application
in the synthesis of polyhydroxylated alkaloids.
Results and discussion
Our study commenced with the development of practical
synthetic routes to trans-dihydroxybutyrolactols. We rst exam-
ined the synthesis of lactone 4, a precursor to lactol 1c, from
L-ascorbic acid (3) in a way similar to that for the preparation
of D-(ꢀ)-erythronolactone from D-ascorbic acid.6 Although D-(ꢀ)-
erythronolactone is commercially available and can be readily
prepared, the synthesis of its diastereomeric analogue 4 is
challenging due to its highly hygroscopic nature. Nevertheless,
by modifying Tenji's two-step procedure,7 notably by addition of
sodium chloride to facilitate water removal and extraction aer
evaporation, we were able to obtain 4 from 3 in near 80% yield in
15 gram scale. Bis-TBS protection followed by DIBAL-H reduc-
tion and quenching the reaction at a low temperature (ꢀ78 ꢁC)
provided the protected trans-dihydroxylactol 2a in nearly 70%
overall yield and >10 gram scale from 3 (Scheme 2).
We next investigated the practical synthesis of 2b which is
the enantiomer of 2a using D-tartaric acid 6a as the starting
material (Scheme 3). Esterication followed by benzyl protec-
tion of 6a afforded 8a in excellent yield. Reduction of 8a with
KBH4/LiCl led to 1,4-diol 9a in 85% yield. Selective oxidation of
9a by 2-iodoxybenzoic acid (IBX) in DMSO produced the desired
lactol 2b in 87% yield. The lactol 2c, which is the benzyl pro-
tected equivalent of 2a, was obtained in 64% overall yield in the
same sequence from L-tartaric acid 6b. These short routes
provide convenient and practical access to both TBS and benzyl
protected trans-dihydroxybutyrolactols (2a–c) in multigram
scales for synthetic applications.
Scheme 3 Synthesis of 2b and 2c from tartaric acid. (a) H2SO4 (cat. amount),
EtOH, reflux, 98%; (b) BnBr, Ag2O, rt, 48 h, 88%; (c) LiCl, KBH4, THF, reflux, 85%;
(d) IBX, DMSO, rt, 5 h, 87%.
protected trans-dihydroxybutyrolactols is much less studied.4a,9
With the protected trans-dihydroxylactols (2a–c) in hand, we set
out to investigate their reaction with various Grignard reagents
(Table 1). The reaction with various organomagnesium reagents
under different conditions (Table 1, entry 1–6) afforded the
addition products in excellent yields and in modest syn selec-
tivity (ca. 3.6 : 1) as determined by 1H NMR analysis of the
product. This level of selectivity is consistent with those reported
in the literature4a,9 and appeared to be not sensitive to temper-
ature as reactions carried out at both ꢀ78 ꢁC and 0 ꢁC gave very
similar selectivities (Table 1, entry 3, 4). The stereochemistry of
1
the products was conrmed by H NMR spectroscopic correla-
tion of lactones II and III to known close analogues IV and V (ref.
10) (Scheme 4). Thus, consecutive oxidation with IBX and Dess–
Martin periodinane (DMP) of diastereomeric mixture 10a
(syn : anti ¼ 3.6 : 1) led to the corresponding lactones (II and III).
1H NMR spectra analyses revealed that the lactone II derived
from the major syn-diastereomer has a smaller H-4, H-5 coupling
constant of 4.8 Hz in agreement with the known IV whereas III
derived from the anti-isomer has a larger coupling constant of
6.6 Hz similar to V. The syn stereochemistry of the major dia-
stereomer was further conrmed in the synthesis of (+)-lentigi-
nosine (Scheme 5, vide infra).
Although the reaction of protected cis-dihydroxybutyrolactol
with Grignard reagents at low temperature is well known to form
anti product with high diastereoselectivity,8 the reaction of
In sharp contrast, the reaction of Grignard reagents with the
corresponding N,O-acetals (VI and VII) formed in situ afforded
predominantly(>99 : 1)thesynaminoalcohols(Table1, entry6, 7).
The high syn selectivity is attributed to the good coordinate prob-
ability of imine to form a strong Cram chelation control model.11
Despite modest syn-selectivity in the Grignard addition
reaction, in view of the convenient and scalable access to the
chiral lactol building blocks and high yielding of the reaction,
we sought to explore their application in the synthesis of natural
products. (+)-Lentiginosine, an indolizidine alkaloid with
potent and selective amyloglucosidase inhibition activity,12,13
was selected as an appropriate target for synthetic studies. As
depicted in Scheme 5, permesylation of the diastereomeric 1,4-
diol mixture 10b (syn : anti ¼ 3.6 : 1) obtained from the addition
of BnO(CH2)4MgBr to 2a (Table 1, entry 2) led to the
Scheme 2 Reagents and conditions: (a) (i) Na2CO3, H2O2, 5–15 ꢁC then charcoal,
75 ꢁC; (ii) 6 M HCl, pH 1.5, evap. to dry, extract with EtOAc at reflux, 79%; (b)
TBSCl, imidazoles, DMF, 0 ꢁC–rt, 93%; (c) DIBAL-H, THF, ꢀ78 ꢁC, 1 h then meth-
anol, 1.0 M HCl pH 3, 94%.
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Table 1 Addition reactions to trans-dihydroxylactols
Entry
1
Substrate
RMgX and conditions
Product
Yielda (%)
Syn : antib
2a
CH2]CHCH2MgBr Et2O/ꢀ78 ꢁ
C
96
93
3.6 : 1
2
3
2a
2b
BnO(CH2)4MgBr THF/0 ꢁ
C
3.6 : 1
3.8 : 1
CH2]CHMgCl THF/ꢀ78 ꢁ
C
96
4
5
6
2b
2c
2b
CH2]CHMgCl THF/0 ꢁ
C
C
91
92
80
3.6 : 1
3.7 : 1
>99 : 1
CH2]CHMgCl THF/0 ꢁ
(i) Benzylamine, 4 A MS; (ii) CH2]CHMgCl THF/0 ꢁC–rt
˚
(i) Benzylamine, 4 A MS; (ii) p-CH3O–C6H4CH2MgCl THF/0 ꢁC–rt
83
>99 : 1
˚
7
2c
a
1
Isolated yields. b Determined by H NMR spectroscopic analysis.
corresponding bismesylate 11. Treatment of 11 with freshly
distilled benzylamine led to the formation of diastereomeric
pyrrolidines 12a and 12b via an efficient one-pot displacement–
cyclization sequence. The diastereomeric mixture was fortu-
nately separable by column chromatography, providing pure
12a and 12b in 18% and 64% yields respectively. However,
removal of the benzyl groups of 12b proved to be quite difficult.
Aer examining various conditions, we nally found that under
hydrogenolysis conditions [Pd(OH)2/C and Pd/C successively,
H2, 1 atm] over four days, alcohol 13 was obtained in 65% yield.
Further intramolecular cyclization of 13 via a one-pot Appel
reaction-cyclization14 led to TBS-protected (+)-lentiginosine 14
in 88% yield. Final TBS deprotection of 14 using TBAF furnished
an efficient total synthesis of (+)-lentiginosine (15) in 5 steps
and 25% overall yield from TBS protected trans-dihydroxylactol
2a. Comparison of the optical rotation of 15 with the reported
value (see Experimental section) conrmed the stereochemistry.
Scheme 4 Stereochemistry confirmation of the Grignard addition products. (a)
IBX, DMSO, rt, 5 h; 80%; (b) DMP, CH2Cl2, rt, 4 h, 62% for II and 17% for III.
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(ꢀ)-anisomycin. Thus Appel reaction and in situ cyclization of
10f led to perbenzylated pyrrolidine 16 in 90% yield. Global
debenzylation by hydrogenolysis provided (ꢀ)-deacetylaniso-
mycin (17) in 76% yield. Since it is well documented that
(ꢀ)-anisomycin can be easily obtained from (ꢀ)-deacetylaniso-
mycin,4a our synthetic route constitutes one of the most concise
total syntheses of (ꢀ)-deacetylanisomycin and formal synthesis
of (ꢀ)-anisomycin.
Conclusion
In conclusion, we have developed two facile synthetic routes to
trans-dihydroxybutyrolactols from inexpensive and abundant
natural chiral starting materials. The overall high yield and
simple chemical transformations enabled their large-scale
syntheses, highlighting the potential industrial applications of
these methodologies. Grignard reactions with these chiral lac-
tols or their aza-analogues provided polyhydroxylated
compounds or amino alcohols. The potential application of the
Grignard addition products were successfully demonstrated in
the concise synthesis of polyhydroxylated alkaloids (+)-lentigi-
nosine and (ꢀ)-deacetylanisomycin.
Scheme 5 Total synthesis of (+)-lentiginosine. (a) MsCl, pyridine, 0 ꢁC, 12 h, 80%;
(b) BnNH2, 80 ꢁC, 48 h, 18% for 12a, 64% for 12b; (c) Pd(OH)2/C, H2, 2 days then
Pd/C, H2, 4 days, 65%; (d) PPh3, CCl4, CH2Cl2, Et3N, 0 ꢁC–rt, 12 h, 88%; (e) TBAF,
THF, overnight, 90%.
Having demonstrated the usefulness of the Grignard addi-
tion product in alkaloid synthesis, we further explored the
synthetic applications of the amino alcohols, such as 10e/10f,
resulting from the reaction of N,O-acetals (VI and VII) with the
Grignard reagents. These would be more advantageous for
alkaloid synthesis as an amine moiety has already been
installed with much higher stereoselectivity, which would avoid
separating the undesired isomer. Envisioning that the amino
alcohols 10e/10f are the acyclic precursors of pyrrolidine alka-
loids, we anticipated that molecules such as anisomycin (Fig. 1)
could be accessed by concise synthetic sequences (Scheme 6).
(ꢀ)-Anisomycin is a pyrrolidine antibiotic isolated from the
fermentation broths of Streptomyces griseolus. It exhibits strong
and selective activity against pathogenic protozoa and fungi,
and has been used clinically for the treatment of Trichomonas
vaginitis and amoebic dysentery.15 In addition, (ꢀ)-anisomycin
has been shown to exhibit antiviral and antitumor activities.16
Furthermore, both anisomycin and deacetylanisomycin have
been employed as fungicides in the eradication of bean mildew
and to inhibit other pathogenic fungi in plants.17 Taking
advantage of the highly stereoselective reaction of the N,O-
acetal (VII) with 4-methoxybenzyl magnesium bromide, we
envisioned that amino alcohol (10f) would provide an efficient
synthesis of (ꢀ)-deacetylanisomycin18 and a formal synthesis of
Experimental section
General experimental procedures
Optical rotations were recorded on a Perkin-Elmer 341 auto-
matic polarimeter. 1H NMR and 13C NMR spectra were recorded
1
on Bruker AV400 spectrometer. Unless otherwise indicated, H
NMR spectra were obtained in CDCl3, and chemical shis are
expressed in parts per million (ppm) relative to internal Me4Si
standard. IR spectra were recorded on a Nicolet Avatar 360 FT-IR
spectrophotometer using lm or KBr pellet techniques. Mass
spectra were recorded on Bruker Dalton Esquire 3000 plus LC-
MS apparatus. HRMS spectra were recorded on a Bruker APEX-
FTMS apparatus. Melting points were determined by a Yanaco
MP-500 melting point apparatus and are uncorrected. Anhy-
drous solvents were obtained according to procedures provided
in the literature.19 Flash column chromatography was per-
formed on silica gel (300–400 mesh, Zhifu Co Ltd, China)
eluꢁting with ethyl acetate (EtOAc) in petroleum ether (PE, 60–
90 C) mixture unless otherwise noted.
L-Threonic acid-4-lactone (4)
To a stirred cooled (ꢂ5 ꢁC) solution of L-ascorbic acid (28.2 g, 0.16
mol) in water (300 mL) was added Na2CO3 (33.9 g, 0.32 mol) in
portions. Aer 30 min, hydrogen peroxide (30% w/w, 35.2 mL)
was added at a rate that maintained the reaction temperature at
<15 ꢁC. The resulting mixture was warmed to 40 ꢁC and stirred for
30 min before portionwise addition of charcoal (Norite SG, 4.0 g).
The temperature of the mixture was gradually raised to 75 ꢁC and
stirred until hydrogen peroxide had completely decomposed
(negative as tested by starch potassium iodide paper). The
mixture was allowed to cool to room temperature and ltered.
The ltrate was acidied to pH 1.5 with 6.0 M HCl aqueous
solution. Sodium chloride (70 g) was then added and the water
was evaporated to dryness under high vacuum. The residue was
Scheme 6 Formal synthesis of (ꢀ)-anisomycin. (a) PPh3, CCl4, CH2Cl2, Et3N, 0 ꢁC–
rt, 12 h, 90%; (b) Pd(OH)2/C, H2, 3 days, 76%.
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extracted with ethyl acetate (500 mL) by heating under reux and
ltered hot through Celite. The lter cake was washed with hot
ethyl acetate (3 ꢃ 100 mL). The combined ltrates were evapo-
rated under reduced pressure to give 4 (15.0 g, 79%) as a white
solid. Mp 62–64 ꢁC (ref. 20), 61–76 ꢁC; [a]D20 +28.3 (c 1.2, H2O),21
[a]2D0 +30.0 (c 1.0, H2O); IR (lm, cmꢀ1): 3353, 2916, 1775; 1H NMR
(500 MHz, CD3COCD3): d 3.93 (dd, J ¼ 6.5, 8.0 Hz, 1H, H-4), 4.23
(dd, J ¼ 5.5, 6.5 Hz, 1H, H-2), 4.34–4.42 (m, 2H, H-3, H-4), 4.97 (d, J
¼ 4.0 Hz, 1H, OH), 5.15 (d, J ¼ 5.5 Hz, 1H, OH); 13C NMR (125
MHz, D2O): d 69.7, 72.4, 73.3, 177.6.
(2S,3S)-Diethyl 2,3-bis(benzyloxy)succinate (8a)
To a suspension of L-tartaric acid diethyl ester (16.4 g, 79.6
mmol) and silver oxide (74.0 g, 319.0 mmol) in anhydrous
acetonitrile (160 mL) was added dropwise benzyl bromide (28.5
mL, 480 mmol) under mechanically stirring. Aer completion
of the addition, the reaction mixture was stirred at room
temperature for 2 days avoiding light. The mixture was ltered
and the ltrate was concentrated under reduced pressure. The
residue was puried by column chromatography on silica gel
with PE : EtOAc (20 : 1) to give 8a (27.2 g, 88%) as a light yellow
oil. [a]2D0 ꢀ101.1 (c 0.8, CHCl3); IR (lm, cmꢀ1): 2988, 1762, 1731,
1443; 1H NMR (400 MHz, CDCl3): d 1.21 (t, J ¼ 7.2 Hz, 6H, CH3),
4.06–4.14 (m, 2H, MeCH2), 4.19–4.27 (m, 2H, MeCH2), 4.42 (s,
2H, CHOBn), 4.48 (d, J ¼ 12.0 Hz, 2H, PhCH2), 4.90 (d, J ¼ 12.0
Hz, 2H, PhCH2), 7.28–7.36 (m, 10H, Ar-H); 13C NMR (100 MHz,
CDCl3): d 4.1, 61.3, 73.2, 78.4, 127.9, 128.3, 128.4, 137.0, 169.2.
(2R,3S)-2,3-Bis(tert-butyldimethylsilyloxy)-g-butyrolactone (5)
To a solution of 4 (5.1 g, 43.6 mmol) in DMF (45 mL) was added
imidazole (13.9 g, 203.0 mmol) and DMAP (265 mg). The
mixture was stirred and cooled to 0 ꢁC followed by dropwise
addition of a solution of TBSCl (18.4 g, 122.0 mmol) in DMF (60
mL) in 60 min. The mixture was allowed to warm to rt and
stirred overnight. The resulting mixture was diluted with
CH2Cl2 (100 mL), washed sequentially with water (5 ꢃ 100 mL),
and brine. The organic phase dried over anhydrous Na2SO4.
Evaporation of the solvents under reduced pressure and puri-
cation of the crude product by ash chromatography on silica
gel (PE : EtOAc ¼ 20 : 1) afforded 5 (14.2 g, 94%) as a white solid.
Mp 52–53 ꢁC; [a]2D0 +46.9 (c 1.1, CHCl3),22 ent-5 [a]2D0 ꢀ51.0 (c 1.0,
CHCl3); IR (lm, cmꢀ1): 1801; 1H NMR (400 MHz, CDCl3): d 0.09
(s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.15 (s, 3H, SiCH3), 0.20 (s,
3H, SiCH3), 0.90 (s, 9H, SiC(CH3)3), 0.93 (s, 9H, SiC(CH3)3), 4.22
(d, J ¼ 6.3 Hz, 1H, H-2), 4.31–4.37 (m, 2H, H-4), 3.87–3.92 (m,
1H, H-3); 13C NMR (100 MHz, CDCl3): d ꢀ5.0, –4.8, –4.7, –4.6,
17.9, 18.2, 25.6, 70.1, 74.5, 75.0, 173.9; ESI-HRMS calcd for
(2R,3R)-Diethyl 2,3-bis(benzyloxy)succinate (8b)
Following the procedures for the preparation of 8a, 8b was
obtained in 87% yield as a white solid. Mp 46–47 ꢁC; [a]D20 +107.9
(c 1.0, CHCl3),23 [a]D20 +105.0 (c 1.0, CHCl3); IR (lm, cmꢀ1): 2988,
1762, 1731, 1443, 1276, 1205, 742, 692; 1H NMR (400 MHz,
CDCl3): d 1.21 (t, J ¼ 7.2 Hz, 6H, CH3), 4.07–4.12 (m, 2H,
MeCH2), 4.21–4.25 (m, 2H, MeCH2), 4.42 (s, 2H, CHOBn), 4.48
(d, J ¼ 12.0 Hz, 2H, PhCH2), 4.90 (d, J ¼ 12.0 Hz, 2H, PhCH2),
7.30–7.34 (m, 10H, Ar-H); 13C NMR (100 MHz, CDCl3): d 14.1,
61.3, 73.2, 78.4, 128.0, 128.3, 128.4, 137.0, 169.2.
(2R,3R)-2,3-Bis(benzyloxy)butane-1,4-diol (9a)
16H38O4NSi2 (M + NH4)+: 364.2334; found: 364.2337.
To a solution of anhydrous lithium chloride (6.4 g, 150 mmol) in
THF (90 mL) was added potassium borohydride (8.2 g, 150
mmol) in one portion and the reaction mixture was stirred at rt
for 4 h under nitrogen. To this solution was added a solution of
8a (23.2 g, 60 mmol) in THF (30 mL) and the resulting mixture
was stirred under reux for 2 h. The reaction was quenched by
the addition of 10% citric acid at 0 ꢁC, followed by addition of 2
M aqueous NaOH until the solution was clear. The mixture was
concentrated under vacuum and the aqueous layer was extrac-
ted with ethyl acetate. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was puried by column chro-
matography on silica gel with PE : EtOAc (3 : 2) to provide 9a
(15.9 g, 87%) as a colorless oil. [a]2D0 ꢀ10.1 (c 0.78, CHCl3); IR
C
(2R,3S)-2,3-Bis(tert-butyldimethylsilyloxy)-g-butyrolactol (2a)
A solution of 5 (11.2 g, 32.4 mmol) in DCM (100 mL) was stirred
rapidly at ꢀ78 ꢁC while a 1.0 M solution of DIBAL-H in toluene
(35.6 mL, 35.6 mmol) was added dropwise under N2 over a
period of 30 min. The resulting reaction mixture was stirred for
ꢁ
1 h at ꢀ78 C before being quenched by dropwise addition of
methanol (10 mL) and further addition of a mixture of ethyl
acetate and water (1 : 1 mixture, 120 mL). To the resulting
mixture was then added 2 M aqueous sulfuric acid until pH 3.
The mixture was transferred into a separatory funnel where
upon the layers were separated and the aqueous phase was
extracted with ethyl acetate. The combined organic phases were
washed with saturated aqueous sodium bicarbonate solution,
then dried and evaporated under reduced pressure. The crude
product was puried by ash chromatography on silica gel with
PE : EtOAc (20 : 1) to afford 2a (11.1 g, 94%) as a colorless oil.
(lm, cmꢀ1): 3435, 2927, 2874, 1450, 1337, 1104; H NMR (400
1
MHz, CDCl3): d 2.34 (br, 2H, OH), 3.68–3.74 (m, 4H, CH2O),
3.82–3.84 (m, 4H, CHO), 4.65 (s, 4H, PhCH2), 7.29–7.38 (m, 10H,
Ar-H); 13C NMR (100 MHz, CDCl3): d 60.8, 72.6, 78.9, 127.9,
128.0, 128.6, 138.0.
1
[a]2D0 +2.0 (c 0.5, CHCl3); IR (lm, cmꢀ1): 3510, 2955; H NMR
(400 MHz, CDCl3) (diastereomixture 1.7 : 1, data of major
isomer): d 0.03–0.15 (m, 12H, SiCH3), 0.89–0.93 (m, 18H,
(2S,3S)-2,3-Bis(benzyloxy)butane-1,4-diol (9b)
SiC(CH3)3), 3.68 (d, J ¼ 12.2 Hz, 1H, OH), 3.99–4.05 (m, 3H, H-3, Following the above procedures for the preparation of 9a, 9b
H-4), 4.08–4.13 (m, 1H, H-2), 5.04 (d, J ¼ 12.2 Hz, 1H, H-1); 13
C
was obtained in 87% yield as a colorless oil. [a]2D0 +10.8 (c 1.0,
NMR (100 MHz, CDCl3): d ꢀ5.0, ꢀ4.7, ꢀ4.6, 17.9, 18.2, 25.7, CHCl3); IR (lm, cmꢀ1): 3435, 2927, 2874, 1450, 1337, 1104; 1H
74.9, 77.2, 80.3, 103.7; ESI-HRMS calcd for C16H36O4Si2Na (M + NMR (400 MHz, CDCl3): d 2.33 (br, 2H, OH), 3.70–3.74 (m, 4H,
Na)+: 371.2044; found: 371.2046.
CH2O), 3.82–3.84 (m, 4H, CHO), 4.65 (s, 4H, PhCH2), 7.26–7.37
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(m, 10H, Ar-H); 13C NMR (100 MHz, CDCl3): d 60.8, 72.6, 78.9, 2.10–2.46 (m, 2H, H-5), 2.8 (s, 2H, OH), 3.63–3.96 (m, 5H, H-1,
127.9, 128.0, 128.6, 138.0.
H-2, H-3, H-4), 4.97–5.07 (m, 2H, H-7), 5.91–5.98 (m, 1H, H-6);
13C NMR (100 MHz, CD3COCD3): d ꢀ5.7, ꢀ5.3, ꢀ5.2, ꢀ5.1, 17.6,
25.1, 25.2, 38.3, 61.8, 72.1, 74.8, 76.4, 115.3, 136.0; ESI-HRMS
calcd for C19H42O4Si2Na (M + Na)+: 413.2514; found: 413.2518.
(3S,4R)-3,4-Bis(benzyloxy)tetrahydrofuran-2-ol (2b)
To a solution of 9a (12.4 g, 41.2 mmol) in acetone (80 mL) was
added a solution of IBX (13.6 g, 16.4 mmol) in DMSO (50 mL).
Aer stirred at rt for 5 h, the reaction mixture was quenched by
(2R,3R)-2,3-Bis(benzyloxy)hex-5-ene-1,4-diol (10c)
the addition of water (40 mL), then ltered and the ltrate was To a solution of 2b (0.9 g, 3.0 mmol) in dry THF (6 mL) was
concentrated under reduced pressure. The residue was parti- added dropwise a solution of vinylmagnesium chloride in THF
tioned between water and CH2Cl2 and the aqueous layer was (15% wt, 4.4 mL, 7.5 mmol) at 0 ꢁC under nitrogen. Aer addi-
extracted with CH2Cl2. The combined organic layers were tion was complete, the reaction mixture was allowed to stir at rt
washed with brine, dried over Na2SO4 and concentrated under for 2 h. The reaction mixture was then quenched with saturated
reduced pressure. The residue was puried by column chro- aqueous NH4Cl and ltered. The ltrate was concentrated under
matography on silica gel with PE : EtOAc (2 : 1) to give 2b (10.8 reduced pressure and extracted with ethyl acetate (30 mL). The
g, 87%) as a colorless oil. [a]2D0 ꢀ12.5 (c 1.2, CHCl3); IR (lm, combined organic solvents were washed with brine, dried over
1
cmꢀ1): 3448, 1610, 1455; H NMR (400 MHz, CD3COCD3) (dia- Na2SO4 and concentrated under reduced pressure. The residue
stereomixture 1.8 : 1, data of major isomer): d 3.93 (dd, J ¼ 8.9, was puried by column chromatography on silica gel with
5.1 Hz, 1H, H-4), 3.98–4.00 (m, 1H, H-2), 4.06–4.14 (m, 2H, H-3, PE : EtOAc (7 : 3) to give 10c (0.92 g, 91%) as a colorless oil.
H-4), 4.52–4.73 (m, 4H, PhCH2), 5.07 (d, J ¼ 6.6 Hz, 1H, OH), [a]2D0 ꢀ18.5 (c 1.3, CHCl3); IR (lm, cmꢀ1): 3402, 3030, 1454; 1H
5.29 (d, J ¼ 6.6 Hz, 1H, H-1), 7.28–7.43 (m, 10H, Ar-H); 13C NMR NMR (400 MHz, CDCl3) (diastereomixture 3.6 : 1): d 2.64 (br, 2H,
(100 MHz, CDCl3): d 69.2, 71.9, 73.0, 81.0, 84.9, 101.0, 127.7, OH), 3.59 (dd, J ¼ 2.5, 5.7 Hz, 1H, H-3), 3.64–3.67 (m, 1H, H-2),
127.9, 128.0, 128.2, 128.5, 128.6, 136.8, 137.4; ESI-HRMS calcd 3.72–3.86 (m, 2H, H-1), 4.35–4.43 (m, 1H, H-4), 4.58–4.75 (m,
for C18H20O4Na (M + Na)+: 323.1254; found: 323.1249.
4H, PhCH2), 5.17–5.26 (m, 1H, H-6), 5.32–5.42 (m, 1H, H-6),
5.87–5.98 (m, 1H, H-5), 7.28–7.36 (m, 10H, Ar-H); 13C NMR (100
MHz, CDCl3): d 60.6, 61.4, 71.1, 72.2, 72.5, 72.6, 73.1, 74.5, 79.0,
79.3, 80.7, 80.8, 115.7, 116.5, 127.9, 128.0, 128.1, 128.2, 128.5,
137.4, 137.6, 137.7, 138.8, 138.1, 138.5; ESI-HRMS calcd for
(3R,4S)-3,4-Bis(benzyloxy)tetrahydrofuran-2-ol (2c)
Following the above procedures for the preparation of 2b, 2c
was obtained in 87% yield as a colorless oil. [a]2D0 +13.5 (c 1.3,
1
C
20H24O4Na (M + Na)+: 351.1567; found: 351.1568.
CHCl3); IR (lm, cmꢀ1): 3443, 1606, 1450; H NMR (400 MHz,
CD3COCD3) (diastereomixture 1.8 : 1, data of major isomer): d
3.93 (dd, J ¼ 8.9, 5.1 Hz, 1H, H-4), 3.97–4.00 (m, 1H, H-2), 4.06–
(2S,3S)-2,3-Bis(benzyloxy)hex-5-ene-1,4-diol (10d)
4.14 (m, 2H, H-3, H-4), 4.54–4.70 (m, 4H, PhCH2), 5.06 (d, J ¼ 5.8 Following the above procedures to prepare of 10c, 10d were
Hz, 1H, OH), 5.29 (dd, J ¼ 5.8, 1.1 Hz, 1H, H-1), 7.28–7.43 (m, obtained in 92% yield as a colorless oil. [a]2D0 +17.8 (c 1.1, CHCl3);
10H, Ar-H); 13C NMR (100 MHz, CDCl3): d 69.2, 71.9, 73.0, 81.0, IR (lm, cmꢀ1): 3406, 3030, 1601, 1453; 1H NMR (400 MHz,
82.2, 101.0, 127.7, 127.9, 128.0, 128.2, 128.5, 128.6, 136.8, 137.4; CDCl3) (diastereomixture 3.7 : 1): d 2.62 (br, 2H, OH), 3.56–3.61
ESI-HRMS calcd for C18H20O4Na (M + Na)+: 323.1254; found: (m, 1H, H-3), 3.62–3.68 (m, 1H, H-2), 3.72–3.86 (m, 2H, H-1),
323.1250.
4.35–4.44 (m, 1H, H-4), 4.58–4.75 (m, 4H, 2 ꢃ PhCH2), 5.16–5.27
(m, 1H, H-6), 5.31–5.42 (m, 1H, H-6), 5.87–5.98 (m, 1H, H-5),
7.25–7.36 (m, 10H, Ar-H); 13C NMR (100 MHz, CDCl3): d 60.6,
61.4, 71.1, 72.2, 72.5, 72.6, 73.1, 74.5, 79.0, 80.7, 80.8, 115.7,
116.5, 127.9, 128.0, 128.2, 128.5, 128.6, 137.4, 137.8, 138.8.
(2S,3S)-2,3-Bis(tert-butyldimethylsilyloxy)hept-6-ene-1,4-diol
(10a)
To a suspension of magnesium turnings (2.2 g, 91.2 mmol) and
several crystals of iodine in dry Et2O (5 mL) wad added a few
drops of allyl bromide under nitrogen. Aer the reaction had
initiated, the mixture was cooled to 0 ꢁC and a solution of allyl
(2S,3S)-8-(Benzyloxy)-2,3-bis(tert-butyldimethylsilyloxy)
octane-1,4-diol (10b)
bromide (1.4 mL, 16.0 mmol) in Et2O (48 mL) was added slowly To a suspension of magnesium turnings (360.0 mg, 15.0 mmol)
during 30 min under vigorously stirring. The resulting mixture and several crystals of iodine in THF (2 mL) wad added dropwise
was allowed to warm to rt and stirred for 1 h followed by cooling a solution of (4-benzyloxy)butyl bromide (2.4 g, 10.0 mmol) in
to ꢀ78 ꢁC. A solution of 2a (1.1 g, 3.2 mmol) in Et2O (4 mL) was THF (10 mL). Aer addition was completed, the resulting
added dropwise and stirred for 1 h followed by being warmed to mixture was heated to reux for 30 min, then cooled to 0 ꢁC and
rt and stirred overnight. The reaction was quenched with sat. a solution of 2a (0.69 g, 2.0 mmol) in THF (5 mL) was added
aq. NH4Cl, extracted with Et2O (3 ꢃ 10 mL). The combined dropwise. Aer addition was completed, the resulting mixture
organic phases were dried and evaporated under reduced was stirred for 2 h at rt, quenched with sat. aq. NH4Cl, extracted
pressure. The residue was puried by ash chromatography on with Et2O (3 ꢃ 10 mL). The combined organic phases were dried
silica gel with PE : EtOAc (10 : 1) to afford 10a (1.2 g, 96%) as a and evaporated under reduced pressure, and the residue was
colorless oil. [a]D20 ꢀ14.6 (c 0.85, CHCl3); IR (lm cmꢀ1): 3434, puried by ash chromatography on silica gel with PE : EtOAc
3000; 1H NMR (400 MHz, CD3COCD3) (diastereomixture): d (10 : 1) to give 10b (0.95 g, 93%) as a colorless oil. [a]D20 ꢀ17.3 (c
1
0.11–0.16 (m, 12H, Si(CH3)2), 0.86–0.95 (m, 18H, SiC(CH3)3), 0.70, CH2Cl2); IR (lm, cmꢀ1): 3443, 1474; H NMR (400 MHz,
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CDCl3): d 0.06–0.15 (m, 12H, Si(CH3)2), 0.88–0.92 (m, 18H, organic layers were washed with brine, dried over Na2SO4. The
SiC(CH3)3), 1.38–1.70 (m, 6H, H-5, H-6, H-7), 2.57 (br, 1H, OH), solvent was removed under reduced pressure and the residue
2.98 (br, 1H, OH), 3.48 (t, J ¼ 6.8 Hz, 2H, H-8), 3.51–3.54 (m, 1H, was puried by ash chromatography on silica gel with
H-3), 3.59–3.77 (m, 4H, H-1, H-2, H-4), 4.50 (s, 2H, PhCH2), 7.27– PE : EtOAc (2 : 1) to give 10f as a colorless oil (1.7 g, 83%).
7.34 (m, 5H, Ar-H); 13C NMR (100 MHz, CDCl3): d ꢀ4.3, ꢀ4.2, [a]D20 ꢀ25.9 (c 0.56, CHCl3); IR (lm, cmꢀ1): 3332, 3060, 1610,
17.6, 17.9, 18.0, 22.1, 22.8, 25.7, 25.8, 29.7, 29.9, 34.0, 35.5, 61.8, 1511, 1454; 1H NMR (400 MHz, CD3COCD3): d 2.70 (d, J ¼ 13.0,
62.7, 67.6, 70.3, 70.5, 72.9, 73.0, 73.8, 75.0, 75.3, 76.0, 77.2, 8.9 Hz, 1H, H-5), 2.82 (br, 2H, OH, NHBn), 3.13–3.24 (m, 2H, H-4,
127.5, 127.6, 128.3, 138.6; ESI-HRMS calcd for C27H2O5Si2Na (M H-5), 3.65–3.71 (m, 3H, H-1, H-2, H-3), 3.74–3.81 (m, 5H, CH3O,
+ Na)+: 535.3245; found: 535.3245.
H-1, PhCH2N), 4.02 (d, J ¼ 12.5 Hz, PhCH2N), 4.38 (d, J ¼ 12.0 Hz,
PhCH2O), 4.51 (d, J ¼ 11.6 Hz, PhCH2O), 4.57 (d, J ¼ 12.0 Hz,
PhCH2O), 4.73 (d, J ¼ 11.6 Hz, PhCH2O), 6.83 (d, J ¼ 8.7 Hz, 2H,
(2R,3R,4S)-4-(Benzylamino)-2,3-bis(benzyloxy)hex-5-en-1-ol (10e)
To a solution of 2b (2.25 g, 7.5 mmol) in dry CH2Cl2 (20 mL) was
Ar-H), 7.02 (d, J ¼ 8.7 Hz, 2H, Ar-H), 7.14–7.38 (m, 15H, Ar-H); 13
C
NMR (100 MHz, CDCl3): d 35.2, 50.9, 55.3, 56.9, 58.9, 71.2, 72.8,
76.7, 77.9, 114.1, 127.5, 127.7, 128.0, 128.2, 128.3, 128.6, 128.7,
128.8, 130.2, 131.2, 138.2, 138.4, 138.7, 159.2; ESI-HRMS calcd
for C20H44NO2Si2 (M + H)+:512.2795; found: 512.2800.
˚
added pulverized 4 A molecular sieves (3 g), followed by ben-
zylamine (0.99 mL, 9.0 mmol). The resulting mixture was stirred
at rt under N2 for 4 h. The molecular sieves was then removed by
ltration and washed with dry CH2Cl2. The combined ltrates
were evaporated under reduced pressure to provide a pale
yellow oil (2.9 g) which was dissolved in dry THF (7.5 mL) and
(3R,4S,5R)-5-Allyl-3,4-bis(tert-butyldimethylsilyloxy)-
dihydrofuran-2(3H)-one (II) and (3R,4S,5S)-5-allyl-3,4-
bis(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (III)
ꢁ
cooled to 0 C. To the solution was added a solution of vinyl-
magnesium chloride in THF (15% wt, 17.8 mL, 30.0 mmol). The
resulting reaction mixture was warmed to rt and stirred for 3 h,
quenched with saturated aqueous NH4Cl. The solid was
removed by ltration and the ltrate was extracted with diethyl
ether (3 ꢃ 10 mL). The combined organic extracts were washed
with brine, dried and evaporated under reduced pressure. The
residue was puried by ash chromatography on silica gel with
PE : EtOA (7 : 3) to afford 10e (2.5 g, 80%) as a colorless oil.
[a]2D0 ꢀ15.9 (c 1.05, CHCl3); IR (lm, cmꢀ1): 3316, 3063, 1496,
1453; 1H NMR (400 MHz, CD3COCD3): d 2.8 (br, 2H, OH, NHBn),
3.41 (dd, J ¼ 3.0, 8.6 Hz, 1H, H-4), 3.55 (d, J ¼ 13.0 Hz, 1H,
PhCH2N), 3.68–3.82 (m, 4H, H-1, H-2, H-3), 3.84 (d, J ¼ 13.0 Hz,
1H, PhCH2N), 4.57 (d, J ¼ 11.7 Hz, 1H, PhCH2O), 4.59 (d, J ¼ 11.7
Hz, 1H, PhCH2O), 4.75 (d, J ¼ 11.3 Hz, 2H, PhCH2O), 5.15–5.26
(m, 2H, CH]CH2), 5.94 (ddd, J ¼ 8.6, 10.3, 17.2 Hz, 1H, CH]
CH2), 7.22–7.36 (m, 15H, Ar-H); 13C NMR (100 MHz, CDCl3): d
50.9, 57.9, 58.8, 71.1, 73.9, 82.5, 117.8, 127.3, 127.7, 127.9, 128.0,
128.4, 128.6, 128.8, 137.9, 138.2, 138.4, 138.8; ESI-HRMS calcd
for C22H29O8S2 (M + H)+: 418.2377; found: 418.2381.
To a solution of 10a (165.0 mg, 0.42 mmol) in acetone (1 mL)
was added a solution of IBX (142.1 mg, 0.51 mmol) in DMSO
(0.4 mL). Aer stirred at rt for 5 h, the reaction mixture was
quenched by the addition of water (10 mL), then ltered and the
ltrate was concentrated under reduced pressure. The residue
was partitioned between water and CH2Cl2 and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated
under reduced pressure to give a crude colorless oil.
To a solution of above oil in CH2Cl2 (0.5 mL) was added a
solution of DMP (216.0 mg, 0.51 mmol) in CH2Cl2 (2 mL) at rt,
the result reaction mixture was stirred for 4 h, then diluted with
water (2 mL), extracted with CH2Cl2 (3 ꢃ 5 mL), The combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure, puried by column
chromatography on silica gel with PE : EtOAc (10 : 1) to give II
(81.2 mg, 62%) and III (22.7 mg, 17%).
II: [a]2D0 +60.5 (c 0.77, CHCl3); IR (lm, cmꢀ1): 2954, 1793; 1H
NMR (400 MHz, CDCl3): d 0.13 (s, 3H, Si(CH3)2), 0.14 (s, 3H,
Si(CH3)2), 0.17 (s, 3H, Si(CH3)2),0.18 (s, 3H, Si(CH3)2), 0.92 (s, 18H,
2 ꢃ SiC(CH3)3), 2.47–2.50 (m, 2H, CH2CH]CH2), 4.14 (d, J ¼ 4.4
(2S,3S,4R)-4-(Benzylamino)-2,3-bis(benzyloxy)-5-(4-methoxy-
phenyl)pentan-1-ol (10f)
To a solution of 2c (1.2 g, 4.0 mmol) in dry CH2Cl2 (20 mL) was Hz, 1H, H-3), 4.21 (pseudo-t, J ¼ 4.8, 4.6 Hz, H-4), 4.56–4.61 (m, 1H,
˚
added pulverized 4 A molecular sieves (1.6 g) followed by ben- H-5), 5.15–5.24 (m, 2H, CH]CH2), 5.82–5.93 (m, 1H, CH]CH2);
zylamine (0.53 mL, 4.8 mmol). The resulting mixture was stirred 13C NMR (100 MHz, CDCl3): d ꢀ5.1, ꢀ4.9, ꢀ4.7, ꢀ4.6, 17.9, 18.1,
for 4 h at rt under nitrogen. The solid was then removed by 25.6, 25.7, 33.4, 74.7, 75.4, 81.3, 118.5, 133.0, 178.8; ESI-HRMS
ltration and washed with dry CH2Cl2. The combined organic calcd for C19H38O4Si2Na (M + Na)+: 409.2206; found: 409.2210.
ltrates were concentrated under reduced pressure to provide
III: [a]2D0 +4.4 (c 0.27, CHCl3); IR (lm, cmꢀ1): 2960, 1795; 1H
the corresponding crude N,O-acetal (VII) a pale yellow oil (1.56 g). NMR (400 MHz, CDCl3): d 0.13 (s, 3H, Si(CH3)2), 0.14 (s, 3H,
To a suspension of magnesium turnings (1.2 g, 48.0 mmol) Si(CH3)2), 0.19 (s, 3H, Si(CH3)2), 0.21 (s, 3H, Si(CH3)2), 0.85 (s,
and iodine (50 mg) in THF (5 mL) wad added dropwise a solution 9H, SiC(CH3)3), 0.92 (s, 9H, SiC(CH3)3), 2.38–2.42 (m, 1H,
of 4-methoxybenzyl chloride (5.4 mL, 40.0 mmol) in THF (40 mL). CH2CH]CH2), 2.55–2.53 (m, 1H, CH2CH]CH2), 3.98 (pseudo-t,
The resulting mixture was heated to reux for 30 min to afford 4- J ¼ 6.5 Hz, H-4), 4.10–4.16 (m, 1H, H-5), 4.26 (d, J ¼ 6.6 Hz, 1H,
methoxybenzyl magnesium chloride which was then cooled with H-3), 5.15–5.22 (m, 2H, CH]CH2), 5.77–5.88 (m, 1H, CH]CH2);
an ice bath and added a solution of the above N,O-acetal in dry 13C NMR (100 MHz, CDCl3): d ꢀ4.8, ꢀ4.5, ꢀ4.4, ꢀ4.0, 17.8, 18.2,
THF (4 mL). The mixture was stirred for 3 h then quenched with 25.6, 25.7, 36.1, 76.0, 77.9, 81.5, 118.9, 132.1, 173.4; ESI-HRMS
sat. aq. NH4Cl, extracted with ether (3 ꢃ 8 mL). The combined calcd for C19H38O4Si2Na (M + Na)+: 409.2206; found: 409.2209.
20304 | RSC Adv., 2013, 3, 20298–20307
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PhCH2N), 3.52 (t, J ¼ 6.6 Hz, 2H, CH2OBn), 3.87 (dd, J ¼ 2.2, 3.6
Hz, 1H, H-3), 3.95–3.96 (m, 1H, H-4), 4.03 (d, J ¼ 13.6 Hz, 1H,
PhCH2N), 4.54 (s, 2H, PhCH2O), 7.28–7.40 (m, 10H, Ar-H); 13C
NMR (100 MHz, CDCl3): d ꢀ4.7, ꢀ4.6, ꢀ4.4, ꢀ4.2, 17.9, 18.0,
22.1, 25.8, 30.2, 31.2, 59.1, 59.7, 70.5, 71.3, 72.9, 78.3, 83.1,
126.6, 127.4, 127.6, 128.1, 128.3, 128.5, 138.7, 140.0; HRMS
calcd for C34H58NO3Si2 (M + H)+: 584.3950; found: 584.3957.
(2S,3S)-8-(Benzyloxy)-2,3-bis(tert-butyldimethylsilyloxy)-1,4-
bis(methansulfonyloxy)octane (11)
To a stirred solution of 4-(dimethylamino)pyridine (DMAP)
(61.0 mg, 0.05 mmol) ꢁand MsCl (0.77 mL, 1.00 mmol) in pyridine
(0.5 mL) cooled to 0 C was added dropwise a solution of 10b
(128.5 mg, 0.25 mmol) in pyridine (0.25 mL). The resulting
ꢁ
reaction mixture was stirred at 0 C for 12 h, then poured into
ice water (5 mL) and extracted with Et2O (3 ꢃ 1 mL). The
combined organic phases were washed with saturated aqueous
CuSO4, dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was puried by ash chro-
matography on silica gel by gradient elution with PE : EtOAc
(20 : 1 to 10 : 1) to give 11 (134 mg, 80%) as a colorless oil.
[a]D20 ꢀ21.4 (c 0.98, CH2Cl2); IR (lm, cmꢀ1): 1598, 1458; 1H NMR
(400 MHz, CDCl3) (diastereomixture 3.7 : 1, data of major
isomer): d 0.09 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.12 (s, 3H,
SiCH3), 0.14 (s, 3H, SiCH3), 0.91 (s, 9H, SiC(CH3)3), 0.92 (s, 9H,
SiC(CH3)3), 1.40–1.43 (m, 2H, H-6), 1.62–1.67 (m, 2H, H-7), 1.82–
1.97 (m, 2H, H-7), 2.99 (s, 3H, CH3SO2), 3.02 (s, 3H, CH3SO2),
3.47 (t, J ¼ 6.3 Hz, 2H, CH2OBn), 3.81 (dd, J ¼ 2.3, 5.4 Hz, 1H, H-
3), 4.02–4.07 (m, 1H, H-2), 4.36 (dd, J ¼ 8.1, 10.2 Hz, 1H, H-1),
4.46–4.52 (m, 3H, PhCH2, H-10), 4.91–4.93 (m, 1H, H-4), 7.27–
7.36 (m, 5H, Ar-H); 13C NMR (100 MHz, CDCl3): d ꢀ4.9, ꢀ4.7,
17.8, 18.0, 22.2, 25.3, 25.6, 25.7, 29.3, 30.7, 36.7, 39.4, 69.6, 70.9,
72.1, 72.8, 79.5, 84.2, 127.4, 127.5, 128.2, 138.4; ESI-HRMS calcd
for C29H60O9NS2Si2 (M + NH4)+: 686.3243; found: 686.3235.
4-[(2S,3S,4S)-3,4-Bis(tert-butyldimethylsilyloxy)pyrrolidin-2-yl]-
butan-1-ol (13)
To a solution of 12b (240.0 mg, 0.41 mmol) in MeOH (5 mL) was
added Pd(OH)2/C (200.0 mg) and the resulting mixture was
stirred under H2 (balloon, 1 atm) for 2 days. The catalyst was
ltered and to the ltrate was added Pd/C (200 mg). The
resulting mixture was stirred for an additional 4 days under H2
(balloon, 1 atm). The solid was ltered and the ltrate was
evaporated under reduced pressure. The residue was puried by
ash chromatography on silica gel with PE : EtOAc (1 : 2) to give
13 (108.0 mg, 65%) as a colorless oil. [a]2D0 +18.5 (c 1.82, CH2Cl2);
IR (lm, cmꢀ1): 3342; 1H NMR (400 MHz, CD3COCD3): d 0.08 (s,
3H, Si(CH3)), 0.09 (s, 3H, Si(CH3)), 0.11 (s, 3H, Si(CH3)), 0.12 (s,
3H, Si(CH3)), 0.90 (s, 9H, SiC(CH3)3), 0.91 (s, 9H, SiC(CH3)3),
1.48–1.58 (m, 6H, H-6, H-7, H-8), 2.06–2.09 (m, 1H, H-2), 2.23
(br, 2H, OH, NH), 2.54 (dd, J ¼ 6.4, 10 Hz, 1H, H-5), 2.87 (dt, J ¼
10, 0.8 Hz, 1H, H-5), 3.54 (t, J ¼ 6.4 Hz, 2H, PhCH2O), 3.83 (dd, J
¼ 2.0, 4.8 Hz, 1H, H-3), 3.97 (dd, J ¼ 2.0, 5.6 Hz, 1H, H-4); 13C
NMR (100 MHz, CDCl3): d ꢀ4.7, ꢀ4.6, ꢀ4.3, ꢀ4.2, 17.8, 18.0,
21.7, 25.8, 25.9, 30.7, 33.0, 62.4, 63.1, 73.7, 78.5, 83.6; ESI-HRMS
calcd for C20H46NO3Si2 (M + H)+: 404.3016; found: 404.3014.
(2R,3S,4S)-Benzyl-2-(4-(benzyloxy)butyl)-3,4-
bis(tert-butyldimethylsilyloxy)pyrrolidine (12a) and
(2S,3S,4S)-1-benzyl-2-(4-(benzyloxy)butyl)-3,4-
bis(tert-butyldimethylsilyloxy)pyrrolidine (12b)
(1S,2S,8aS)-1,2-Bis(tert-butyldimethylsilyloxy)-
octahydroindolizine (14)
Tofreshlydistilledbenzylamine(0.5mL)was added11(146.0mg,
0.22 mmol), the resulting reaction mixture was stirred at 80 ꢁC for
2 days, then cooled and diluted with diethyl ether (3 mL). The
solid was removed by ltration, and the ltrate was concentrated
under reduced pressure. The residue was puried by ash chro-
matography on silica gel with PE : EtOAc (10 : 1) to afford 12a
(21.6 mg, 18%) and 12b (77.7 mg, 64%) as colorless oils.
ꢁ
To cooled (0 C) solution of 13 (80.4 mg, 0.2 mmol) and PPh3
(104.8 mg, 0.4 mmol) in dry CH2Cl2 (1 mL) was added dropwise
fresh distilled CCl4 (38.8 mL, 0.4 mmol). The resulting mixture
was warmed to rt and stirred for 1 h followed by addition Et3N
(56 mL, 0.4 mmol). The resulting reaction mixture was stirred for
12 h followed by evaporation of the solvent. The crude product
was puried by ash chromatography on silica gel with
PE : EtOAc (10 : 1) to give 14 (77.2 mg, 88%) as colorless oil.
12a: [a]2D0 ꢀ14.9 (c 0.94, CH2Cl2); IR (lm, cmꢀ1): 1598, 1466,
1
1361, 1248; H NMR (400 MHz, CDCl3): d 0.08 (s, 3H, SiCH3),
[a]2D0 +8.9 (c 0.80, CHCl3); IR (lm, cmꢀ1): 2933, 2855; H NMR
1
0.09 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.12 (s, 3H, SiCH3), 0.90
(s, 9H, SiC(CH3)3), 0.95 (s, 9H, SiC(CH3)3), 1.44–1.71 (m, 6H, H-
6, H-7, H-8), 2.27–2.31 (m, 1H, H-2), 2.83–2.85 (m, 1H, H-5), 3.19
(dd, J ¼ 10.4, 4.3 Hz, 1H, H-5), 3.51 (t, J ¼ 6.7 Hz, 2H, CH2OBn),
3.57 (d, J ¼ 13.4 Hz, 1H, PhCH2N), 3.95–4.01 (m, 3H, H-3, H-4,
PhCH2N), 4.55 (s, 2H, PhCH2O), 7.27–7.38 (m, 10H, Ar-H); 13C
NMR (100 MHz, CDCl3): d ꢀ4.7, ꢀ4.6, ꢀ4.5, ꢀ4.2, 17.9, 18.1,
23.5, 25.8, 25.9, 28.6, 30.3, 58.9, 60.4, 66.6, 70.5, 72.8, 77.7, 79.3,
126.6, 127.4, 127.6, 128.1, 128.3, 128.7, 138.7, 140.2; HRMS
calcd for C34H58NO3Si2 (M + H)+: 584.3950; found: 584.3945.
12b: [a]2D0 +40.4 (c 0.55, CH2Cl2); IR (lm, cmꢀ1): 1598, 1466,
(400 MHz, CDCl3): d 0.03 (s, 3H, Si(CH3)), 0.05 (s, 3H, Si(CH3)),
0.06 (s, 3H, Si(CH3)), 0.08 (s, 3H, Si(CH3)), 0.87–0.91 (m, 18H,
SiC(CH3)3), 1.16–1.27 (m, 2H, H-6, H-7), 1.53–1.61 (m, 2H, H-6,
H-7), 1.72–1.95 (m, 4H, H-5, H-8, H-8a), 2.52 (dd, J ¼ 7.9, 10.1
Hz, 1H, H-3), 2.84 (dd, J ¼ 2.1, 10.1 Hz, 1H, H-3), 2.91 (dt, J ¼ 3.2,
10.8 Hz, 1H, H-5), 3.72 (dd, J ¼ 4.1, 8.5 Hz, 1H, H-1), 3.98 (ddd, J
¼ 2.1, 4.1, 7.9 Hz, 1H, H-2); 13C NMR (100 MHz, CDCl3): d ꢀ4.7,
ꢀ4.2, ꢀ4.1, 17.9, 18.0, 24.0, 24.9, 25.9, 26.0, 28.7, 53.4, 62.1,
68.4, 78.1, 85.2; ESI-HRMS calcd for C20H44NO2Si2 (M + H)+:
386.2910; found: 386.2905.
1
1361, 1248; H NMR (400 MHz, CDCl3): d 0.08 (s, 3H, SiCH3),
0.09 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.12 (s, 3H, SiCH3), 0.90
(+)-Lentiginosine (15)
(s, 9H, SiC(CH3)3), 0.95 (s, 9H, SiC(CH3)3), 1.50–1.75 (m, 6H, H- To a solution of 14 (38.6 mg, 0.1 mmol) in dry THF (0.5 mL) was
6, H-7, H-8), 2.49–2.52 (m, 1H, H-2), 2.57 (dd, J ¼ 5.2, 10.3 Hz, added TBAF (1 M in THF, 0.4 mL) and the resulting mixture was
1H, H-5), 2.82 (d, J ¼ 10.3 Hz, 1H, H-5), 3.36 (d, J ¼ 13.6 Hz, 1H, stirred overnight at rt. The solvent was evaporated under
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reduced pressure and the crude product was puried by ash
chromatography on silica gel with CH2Cl2 : MeOH : NH3$H2O
(85 : 15 : 1) to give (+)-lentiginosine as a white solid (14.1 mg,
90%). Mp 105–106 ꢁC,24 106–107 ꢁC; [a]D20 +3.1 (c 0.28, MeOH),24
Notes and references
1 I. S. Kim and Y. H. Jung, Heterocycles, 2011, 83, 2489, and
references therein.
1
[a]2D0 +3.1 (c 0.31, MeOH); IR (KBr, cmꢀ1): 3405; H NMR (400
2 For reviews, see: (a) H. Yoda, Curr. Org. Chem., 2002, 6, 223;
(b) M. D. Lopez, J. Cobo and M. Nogueras, Curr. Org. Chem.,
2008, 12, 718; (c) Iminosugars: From Synthesis to Therapeutic
Applications, ed. P. Compain and O. R. Martin, Wiley-VCH,
Weinheim, 2007; (d) B. L. Stocker, E. M. Dangereld,
A. L. Win-Mason, G. W. Haslett and M. S. M. Timmer, Eur.
J. Org. Chem., 2010, 1615; (e) R. Lahiri, A. A. Ansari and
Y. D. Vankar, Chem. Soc. Rev., 2013, 42, 5102; (f)
D. J. Wardrop and S. L. Waidyarachchi, Nat. Prod. Rep.,
2010, 27, 1431; (g) T. Ritthiwigrom, C. W. G. Au and
S. G. Pyne, Curr. Org. Synth., 2012, 9, 583.
MHz, D2O): d 1.24–1.34 (m, 2H, H-6, H-7), 1.42–1.54 (m, 1H, H-
7), 1.62–1.72 (m, 1H, H-6), 1.78–1.88 (m, 1H, H-8), 1.92–2.04 (m,
2H, H-5, H-8a), 2.10 (td, J ¼ 11.9, 3.0 Hz, 1H, H-8), 2.68 (dd, J ¼
11.3, 7.5 Hz, 1H, H-3), 2.87 (dd, J ¼ 11.3, 1.6 Hz, H-3), 2.98 (br d,
J ¼ 11.1 Hz, H-5), 3.68 (dd, J ¼ 3.9, 8.8 Hz, 1H, H-1), 4.09 (ddd, J
¼ 1.8, 3.9, 7.5 Hz, 1H, H-2); 13C NMR (100 MHz, D2O): d 24.8,
25.8, 29.3, 54.5, 62.0, 70.4, 77.4, 84.7.
(2R,3S,4S)-2-(4-Methoxybenzyl)-1-benzyl-3,4-bis(benzyloxy)-
pyrrolidine (16)
3 For selected examples, see: (a) N. G. Argyropoulos, P. Gkizis
and E. Coutouli-Argyropoulou, Tetrahedron, 2008, 64, 8752;
(b) S. Cicchi, M. Marradi, P. Vogel and A. Goti, J. Org. Chem.,
2006, 71, 1614; (c) K. P. Kaliappan, V. Ravikumar and
S. A. Pujari, Tetrahedron Lett., 2006, 47, 981; (d)
A. E. Koumbis and D. D. Chronopoulos, Tetrahedron Lett.,
2005, 46, 4353; (e) X. M. Yu, G. Shen and B. S. J. Blagg, J.
Org. Chem., 2004, 69, 7375; (f) U. M. Krishna, K. D. Deodhar
and G. K. Trivedi, Tetrahedron, 2004, 60, 4829; (g)
A. Trabocchi, G. Menchi, M. Rolla, F. Machetti, I. Bucelli
and A. Guarna, Tetrahedron, 2003, 59, 5251; (h)
A. E. Koumbis, K. M. Dieti, M. G. Vikentiou and J. K. Gallos,
Tetrahedron Lett., 2003, 44, 2513; (i) A. Furstner,
K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann and
R. Mynott, J. Am. Chem. Soc., 2002, 124, 7061; (j) A. G. Myers
and S. D. Goldberg, Angew. Chem., Int. Ed., 2000, 39, 2732;
(k) K. Burgess and I. Henderson, Tetrahedron Lett., 1990, 31,
6949; (l) D. R. Williams and F. D. Klingler, J. Org. Chem.,
1988, 53, 2134.
To a solution of 10f (1.2 g, 2.3 mmol) and PPh3 (1.2 g, 4.7 mmol)
in DMF (12 mL) was added CCl4 (0.46 mL, 4.7 mmol) dropwise
ꢁ
at 0 C. Aer 30 min, the resulting mixture was warmed to rt,
followed by dropwise addition of Et3N (0.66 mL, 4.7 mmol). The
mixture was stirred overnight, ltered, and the ltrate was
concentrated under reduced pressure. The residue was puried
by ash chromatography on silica gel with PE : EtOAc (1 : 2) to
give 16 (1.0 g, 90%) as a colorless oil. [a]2D0 ꢀ66.7 (c 0.39, CHCl3);
1
IR (lm, cmꢀ1): 1511, 1454; H NMR (400 MHz, CDCl3): d 2.29
(dd, J ¼ 5.0, 10.4 Hz, 1H, H-5), 2.83–2.91 (m, 1H, H-5), 2.95–3.05
(m, 1H, (MeO)PhCH2), 3.32–3.38 (m, 2H, H-2, PhCH2N), 3.72 (br
d, J ¼ 13.2 Hz, 1H, H-3), 3.78 (s, 3H, CH3O), 3.92–2.98 (m, 1H, H-
4), 4.04 (d, J ¼ 13.0 Hz, 1H, PhCH2N), 4.32–4.42 (m, 3H,
PhCH2O), 4.50 (d, J ¼ 11.8 Hz, 1H, PhCH2O), 6.78 (d, J ¼ 8.5 Hz,
2H, Ar-H), 7.11 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.21–7.35 (m, 15H, Ar-
H); 13C NMR (100 MHz, CDCl3): d 32.9, 55.3, 58.1, 59.0, 68.4,
71.3, 71.7, 81.2, 83.5, 113.7, 126.9, 127.6, 127.7, 128.0, 128.3,
128.4, 129.1, 130.2, 132.0, 138.1, 138.3, 138.7, 157.8; ESI-HRMS
calcd for C20H42NOSi2 (M + H)+: 494.2690; found: 494.2698.
4 (a) H. Iida, N. Yamazaki and C. Kibayashi, J. Org. Chem.,
1986, 51, 1069. Similar synthesis and applications, see: (b)
D. Vina, T. F. Wu, M. Renders, G. Laamme and
P. Herdewijn, Tetrahedron, 2007, 63, 2634; (c) T. F. Wu,
M. Froeyen, V. Kempeneers, C. Pannecouque, J. Wang,
R. Busson, E. De Clercq and P. Herdewijn, J. Am. Chem.
(2R,3S,4S)-2-(4-Methoxybenzyl)pyrrolidine-3,4-diol
[(ꢀ)-deacetylanisomycin] (17)
To a solution of 16 (493.6 mg, 1.0 mmol) in EtOH (5 mL) was
added Pd(OH)2/C (200.0 mg) and the mixture was stirred under
hydrogen atmosphere (1 atm) at rt for 3 days. The mixture was
ltered and the ltrate concentrated under reduced pressure.
The crude product was puried by ash chromatography on
silica gel with PE : EtOAc (1 : 2) to give (ꢀ)-deacetylanisomycin
(169.0 mg, 76%) as a white solid. Mp 174–175 ꢁC,4a 176–177 ꢁC,25
173–174 ꢁC; [a]2D0 ꢀ21.0 (c 0.39, MeOH),26 [a]2D0ꢀ22.5 (c 0.84,
¨
Soc., 2005, 127, 5056; (d) K.-U. Schoning, P. Scholz,
X. L. Wu, S. Guntha, G. Delgado, R. Krishnamurthy and
A. Eschenmoser, Helv. Chim. Acta, 2002, 85, 4111; (e)
¨
K.-U. Schoning, P. Scholz, S. Guntha, X. Wu,
R. Krishnamuthy and A. Eschnmoser, Science, 2000, 290,
1347; (f) A. B. Smith III, G. A. Sulikowski and K. Fujimoto,
J. Am. Chem. Soc., 1989, 111, 8041.
1
MeOH); H NMR (400 MHz, CDCl3): d 2.76–2.83 (m, 2H, (MeO)
5 (a) J. J. Zhuang, J. L. Ye, H. K. Zhang and P. Q. Huang,
Tetrahedron, 2012, 68, 1750; (b) N. Q. Vu, C. L. L. Chai,
K. P. Lim, S. C. Chia and A. Chen, Tetrahedron, 2007, 63,
7053.
6 (a) A. Gypser, M. Peterek and H. D. Scharf, J. Chem. Soc.,
Perkin Trans. 1, 1997, 1013; (b) N. Cohen, B. Banner,
R. Lopresti, F. Wong, M. Rosenberger, Y. Liu, E. Thom and
A. Liebman, J. Am. Chem. Soc., 1983, 105, 3661.
7 C. C. Wei, S. D. Bernardo and J. P. Tengi, J. Org. Chem., 1985,
50, 3462.
PhCH2), 2.98 (dd, J ¼ 6.5, 12.9 Hz, 1H, H-5), 3.37 (dd, J ¼ 5.4, 12.9
Hz, 1H, H-5), 3.51–3.57 (m, 1H, H-2), 3.82 (s, 3H, CH3O), 3.97–
4.01 (m, 1H, H-3), 4.23–4.28 (m, 1H, H-4), 6.98 (d, J ¼ 8.7 Hz, 2H,
Ar-H), 7.29 (d, J ¼ 8.7 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d
32.2, 51.0, 55.3, 62.5, 76.2, 76.5, 114.2, 130.1, 131.1, 157.4.
Acknowledgements
This work was supported by the NSF of Fujian, China (no.
2010J01049) and the NSF of China (no. 20672089).
20306 | RSC Adv., 2013, 3, 20298–20307
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RSC Advances
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RSC Adv., 2013, 3, 20298–20307 | 20307