New building block for polyhydroxylated piperidine: Total synthesis of 1,6-dideoxynojirimycin

Article abstract of DOI:10.1021/jo702480y

(Chemical Equation Presented) (3R,4S)-3-Hydroxy-4-N-allyl-N-Boc-amino-1- pentene 10, an important precursor for the synthesis of polyhydroxylated piperidines, has been achieved as a single diastereomer without racemization via vinyl Grignard addition to N-Boc-N-allyl aminoaldehyde 9, which was derived from an enantiopure natural amino acid. Having forged a tetrahydropyridine ring scaffold 13 from 10 in 85% yield via RCM using Grubbs II catalyst, we were able to effect its stereodivergent dihydroxylation, via a common epoxide intermediate to yield a range of interesting hydroxylated piperidines, including ent-1,6-dideoxynojirimycin (ent-1,6-dDNJ) 1 (28% overall yield) and 5-amino-1,5,6-trideoxyaltrose 2 (29% over all yield) in excellent dr. To the best of our knowledge, our synthesis of ent-1,6-dDNJ 1 is the most expeditious to date.

Full text of DOI:10.1021/jo702480y

the alkaloid natural product 1,6-dideoxynojirimycin (1,6-dDNJ)
and its analogues have proven to be of huge therapeutic
potential.4 Numerous strategies to synthesize 1,6-dDNJ and other
iminosugars, from both carbohydrate and non-carbohydrate
sources, have been developed (Figure 1).5
New Building Block for Polyhydroxylated
Piperidine: Total Synthesis of
1,6-Dideoxynojirimycin
Rajesh Rengasamy, Marcus J. Curtis-Long,† Woo Duck Seo,
Seong Hun Jeong, Ill-Yun Jeong,‡ and Ki Hun Park*,†
DiVision of Applied Life Science (BK21 program), EB-NCRC,
Gyeongsang National UniVersity, Jinju 660-701, South Korea,
and 12 New Road, Nafferton, Driffield, East Yorkshire YO25
4JP, UK, and Radiation Research DiVision, Korea Atomic
Energy Research Institute, Jeongeup, 580-185, South Korea
FIGURE 1. Target structures.
khpark@gsnu.ac.kr
However, these routes generally lack directness and require
an array of protection/deprotection steps, and the overall
stereoselectivity often also can be low.6 One particularly
attractive methodology for the synthesis of iminosugars relies
upon Grubbs metathesis7 of a chiral nonracemic allylic alcohol
to fashion the ring skeleton. To date, this approach has been
significantly underutilized within the literature, however, some
important examples have been communicated.8 This approach
proceeds via tetrahydropyridine 13, a multifaceted and highly
versatile chiral synthon (Figure 2).
ReceiVed October 24, 2007
(3R,4S)-3-Hydroxy-4-N-allyl-N-Boc-amino-1-pentene 10, an
important precursor for the synthesis of polyhydroxylated
piperidines, has been achieved as a single diastereomer
without racemization via vinyl Grignard addition to N-Boc-
N-allyl aminoaldehyde 9, which was derived from an
enantiopure natural amino acid. Having forged a tetrahy-
dropyridine ring scaffold 13 from 10 in 85% yield via RCM
using Grubbs II catalyst, we were able to effect its stereo-
divergent dihydroxylation, via a common epoxide intermedi-
ate to yield a range of interesting hydroxylated piperidines,
including ent-1,6-dideoxynojirimycin (ent-1,6-dDNJ) 1 (28%
overall yield) and 5-amino-1,5,6-trideoxyaltrose 2 (29% over
all yield) in excellent dr. To the best of our knowledge, our
synthesis of ent-1,6-dDNJ 1 is the most expeditious to date.
FIGURE 2. Retrosynthetic plan for the synthesis of ent-1,6-dDNJ 1.
The synthesis of this crucial enantiopure intermediate was
achieved by a Grubbs metathesis reaction of an enantiopure
dienyl alcohol. We chose principally to showcase the versatility
(3) (a) Azenevo, P. B.; Creemer, L. J.; Daniel, J. K.; King, C. H. R.;
Liu, P. S. J. Org. Chem. 1989, 54, 2539. (b) Butters, T. D.; Dwek, R. A.;
Platt, F. M. Glycobiology 2005, 15, 43R. (c) Wu, S.-F.; Lee, C.-J.; Liao,
C.-L.; Dwek, R. A.; Zitzmann, N.; Lin, Y.-L. J. Virol. 2002, 76, 3596. (d)
Gross, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res.
1995, 1, 935. (e) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV.
2000, 100, 4683.
Herein we document our continued efforts to develop efficient
stereoselective routes to polyhydroxylated heterocycles.1 Our
focus in this instance is directed at piperidine derivatives.
Research into these systems has blossomed in recent years
because of their unique chemical architecture which mirrors the
transition states of the enzymatic glycolysis reaction.2 Certain
iminosugars have already been evaluated or accredited as
therapies for a wide range of maladies.3 Among these species,
(4) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575.
(5) Carbohydrates: (a) Taylor, C. M.; Barker, W. D.; Weir, C. A.; Park,
J. H. J. Org. Chem. 2002, 67, 4466. (b) Taylor, C. M.; Weir, C. A. Org.
Lett. 1999, 1, 787. Non-carbohydrates: (c) Delair, P.; Brot, E.; Kanazawa,
A.; Greene, A. E. J. Org. Chem. 1999, 64, 1383. (d) Martin, R.; Alcon,
M.; Pericas, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896.
(6) An, J. N.; Meng, X. B.; Yao, Y.; Li, Z. J. Carbohydr. Res. 2006,
341, 2200.
* Corresponding author. Tel.: +82-55-751-5472. Fax: +82-55-757-0178.
† Gyeongsang National University.
(7) Nicolaou, K. C.; Bulger, P.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490.
‡ Korea Atomic Energy Research Institute.
(1) (a) Kim, J. H.; Long, M. J. C.; Kim, J. Y.; Park, K. H. Org. Lett.
2004, 6, 2273. (b) Kim, J. H.; Curtis-Long, M. J.; Seo, W. D.; Ryu, Y. B.;
Yang, M. S.; Park, K. H. J. Org. Chem. 2005, 70, 4082.
(2) Asano, N.; Kizu, H.; Oseki, K.; Tomioka, E.; Matsui, K.; Okamoto,
M.; Babat, M. J. Med. Chem. 1995, 38, 2349.
(8) (a) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi,
I. J. Org. Chem. 2003, 68, 3603. (b) Ouchi, H.; Mihara.; Takahata, H. J.
Org. Chem. 2005, 70, 5207. (c) Martin, R.; Moyano, A.; Pericas, M. A.;
Riera, A. Org. Lett. 2000, 2, 93-95. (d) Takahata, H.; Banba, Y.; Ouchi,
H.; Nemoto, H. Org. Lett. 2003, 5, 2527-2529.
10.1021/jo702480y CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/12/2008
2898
J. Org. Chem. 2008, 73, 2898-2901

SCHEME 1. Synthesis of Crucial Vinyl Carbinol
Intermediate 10
SCHEME 2. Synthesis of Oxazolidin-2-one 11: Proof of
Stereoselectivity
TABLE 1. Generality of Nucleophilic Addition to Amino Aldehyde
SCHEME 3. Metathesis Reaction
product distributionb
entry
Ra
anti (%)
syn (%)
yieldc (%)
1
2
3
4
methyl
vinyl
ethynyl
phenyl
98
>99
>99
>99
>2
1
92
96
96
93
1
1
of the R-center by conversion of 10 to the corresponding
Moscher’s ester 12 and comparison to a racemic counterpart.
Treatment of 7 under standard RCM conditions using Grubbs
I catalyst afforded the desired chiral nonracemic lynchpin,
tetrahydropyridine 13 (Scheme 3). However, this product was
obtained as a readily chromatographically separable 60:40
mixture with enamide 14. Additives were unable to ameliorate
this ratio.13 Such side reactions have been widely documented
in the Grubbs protocol, leading to significant reductions in
product yield.14 However, when Grubbs II catalyst was em-
ployed, an 85:15 mixture of products was observed. Purification
delivered 13 in 85% yield. In 13, due to Paulsen strain
minimization, the methyl and hydroxyl appendages are both
pseudoaxial.15
Our first effort to derivatize 13 involved Pd catalyzed
hydrogenation of the olefin. This proceeded smoothly to afford
piperidine 3 in 92% yield after N-Boc deprotection (Scheme
4). Proton-directed epoxidation of 13 was next attempted.16
Treatment of 13 with m-CPBA afforded the desired oxirane syn
to the alcohol motif 15 as a single diastereomer. Axial hydroxyl
functions in cyclohex-2-enol systems usually proffer low
diastereoselectivities in m-CPBA epoxidations.17
a All reactions were carried out in THF at 0 °C. b Ratio calculated from
1H NMR spectrum of crude mixture. c Isolated yield.
of 13 via the expeditious total synthesis of ent-1,6-dDNJ 1 and
its diastereomer 2.
Synthesis of the pivotal anti-allylic alcohol intermediate 10
commenced with enantiopure N-Boc-L-alanine methyl ester 4,
which was converted to the corresponding O-TBS-protected
alcohol 6 (Scheme 1). Subsequent treatment with allyl bromide/
NaH afforded N-allyl 7, which was selectively O-deprotected
then oxidized under Swern conditions to generate amino
aldehyde 9. This product was readily transformed to allylic
alcohol 10 via nucleophilic addition of vinyl Grignard in 98%
yield with >99:1 anti/syn dr.9
As addition to aldehyde 9 occurred with unprecedented levels
of stereoselectivity,9 we investigated the reaction scope with
respect to different carbanionic nucleophiles. Excellent anti
selectivity was observed across the range of nucleophiles studied
(Table 1). Importantly, although similar approaches have been
documented, such high selectivity across a range of substrates
has to the best of our knowledge not been observed.10
The diastereoselectivity was demonstrated by conversion of
10 to oxazolidin-2-one 11 by base-catalyzed intramolecular
However, in this case the axial methyl substituent probably
serves to shield the anti face. Treatment of 15 with KOH
proceeded via trans diaxial ring opening (Furst Plattner control)18
to unveil a triol motif with all adjacent groups anti, as a single
regioisomer.
cyclization (Scheme 2).11 Analysis of the C(4)H and C(5)H J
3
coupling constants within 11 as well as NOESY data revealed
that there was a cis relationship between these two groups. The
stereochemical outcome is consistent with the reaction occurring
under polar Felkin-Ahn control.12 The nucleophilic addition
process was shown to occur without epimerization (>95% ee)
(12) Mengle, A.; Reiser, O. Chem. ReV. 1999, 99, 1191.
(13) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(14) Moise, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 1695.
(15) (a) Johnson, F. Chem. ReV. 1968, 68, 375. (b) Paulsen, H.; Todt,
K. Angew. Chem., Int. Ed. 1966, 5, 899.
(16) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. (b) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958.
(17) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem. Soc. B
1970, 1374.
(9) For similar protocols using N,N-dibenzylamino aldehydes and
Garner’s aldehyde, see: Reetz, M. T. Chem. ReV. 1999, 99, 1121.
(10) Gryko, D.; Zofia, U -L.; Jurczak. J. Tetrahedron: Asymmetry 1997,
8, 4059.
(11) (a) Seo, W. D.; Curtis-Long, M. J.; Ryu, Y. B.; Lee, J. H.; Yang,
M. S.; Lee, W. S.; Park, K. H. J. Org. Chem. 2006, 71, 5008. (b) Delair,
P.; Einhorn, C.; Einhorn, J.; Luche, J. L. J. Org. Chem. 1994, 59, 4680.
(18) Furst, A.; Plattner, J. HelV. Chim. Acta 1949, 32, 275.
J. Org. Chem, Vol. 73, No. 7, 2008 2899

SCHEME 4. Manipulation of Tetrahydropyridine
Intermediate
warmed to room temperature, and after 30 min, the reaction mixture
was quenched with H2O and extracted with CH2Cl2. The organic
layer was washed with 0.5 N HCl and brine, dried over Na2SO4,
and filtered, and the solvent was removed by rotary evaporation to
give 9 as yellow oil: 1H NMR (300 MHz; CDCl3) δ 1.35 (3H, d,
J ) 6.8 Hz), 1.45 (9H, s), 3.76 (2H, m), 4.17 (1H, m), 5.22 (2H,
m), 5.83 (1H, t, J ) 6.6 Hz); 13C NMR (300 MHz; CDCl3) δ 1.0,
12.8, 28.2, 50.38, 61.36, 118.2, 134.0, 199.6; FAB-MS obsd
214.1526, calcd 214.1443 [(M + H)+, M ) C11H19NO3]. A
precooled solution of vinylmagnesium bromide (4.3 mL, 32.35
mmol) in dry THF was added dropwise under N2 to a stirred
solution of 9 (2.3 g, 10.78 mmol) in dry THF at 0 °C. After the
solution was stirred at that temperature for 10 min (TLC control),
a saturated aqueous solution of ammonium chloride (10 mL) was
added, and the reaction mixture was allowed to reach room
temperature then extracted with EtOAc. The extracts were washed
with brine, dried over Na2SO4, and evaporated. The product was
purified by flash column chromatography (hexanes/EtOAc ) 80:
The crude product consisted of approximately a 90:10 mixture
of N-Boc 1 and ent-1,6-dDNJ 1. Boc deprotection followed by
Dowex chromatography generated ent-1,6-dDNJ 1 as a single
20) to afford compound 10 (2.55 g, 98%) as a colorless oil: [R]20
D
1
-0.3 (c 1, CHCl3); H NMR (300 MHz; CDCl3) δ 1.22 (3H, d, J
) 7 Hz), 1.43 (9H, s), 3.68 (3H, m), 3.79 (1H, m), 5.10 (3H, m),
5.30 (1H, m), 5.78 (2H, m); 13C NMR (300 MHz; CDCl3) δ 12.1,
15.2, 28.3, 49.8, 57.7, 76.0, 80.1, 115.7, 116.3, 115.7, 135.3, 138.5,
156.4; FAB-MS obsd 242.1764, calcd 242.1756 [(M + H)+, M )
C13H23NO3].
product, [R]20 -13.3 (c 0.67, H2O) in 83% yield.19 As
D
anticipated, the [R]D value was similar in magnitude and
opposite in sign to the literature value quoted for 1,6-dideox-
ynojirymicin [R]20D +12.7 (c 0.8, H2O). The alternative addition
regioisomer 2 was accessed as a single product by reaction of
epoxide 15 with H2SO4 followed by Dowex chromatography.8,20
The regioselectivity in this instance can be ascribed to N-Boc
hydrolysis, and subsequent conformational flip, occurring prior
to epoxide ring opening.21b The stereochemistry of both target
compounds was confirmed by 2D-NOESY and 1H NMR
coupling constant data. It is important to note that in the
synthesis of 1 and 2 four contiguous stereocenters were set up
in four overall steps using three stereoselective transformations,
each of which occurred with absolute control.
(4S,5R)-3-Allyl-4-methyl-5-vinyloxazolidin-2-one (11). To a
solution of 10 (100 mg, 0.414 mmol) in 2 mL of THF was added
a solution of t-BuOK (70 mg, 0.621 mmol) in THF at -78 °C.
After being stirred for 10 h at room temperature, the reaction
mixture was quenched with satd aq NH4Cl (15 mL) and extracted
with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was
evaporated, and the residue was purified by flash column chroma-
tography on silica gel (hexane/EtOAc ) 80:20) to give compound
11 (65 mg, 94%) as a colorless oil: 1H NMR (300 MHz; CDCl3)
δ 1.10 (3H, d, J ) 6.6 Hz), 3.57 (1H, dd, J ) 7.5, 15.6 Hz), 3.92
(1H, m), 4.15 (1H, m), 4.93 (1H, t, J ) 1.0 Hz), 5.24 (2H, m),
5.40 (2H, m), 5.82 (2H, m), 3.84 (2H, m); 13C NMR (300 MHz;
CDCl3) δ 13.8, 44.5, 53.6, 78.0, 118.3, 119.9, 131.1, 132.3, 157.3;
EI-MS (m/z) 167 (M+); HRMS calcd for C9H13NO2 (M+) 167.0946,
found 167.0947.
Representative Example of the Preperation of Mosher’s
Ester. Preparation of (3R,4S)-4-[Allyl(tert-butoxycarbonyl)-
amino]pent-1-en-3-yl 3,3,3-Trifluoro-2-methoxy-2-phenylpro-
panoate (12). DCC (90 mg, 0.43 mmol) was added to a solution
of (R)-(+)-MTPA in acetonitrile (3 mL), which immediately
resulted in the formation of a white precipitate of N,N-dicyclo-
hexylurea. After this had stirred at room temperature for 15 min,
the resulting solution of the MTPA anhydride was filtered through
a pipet capped with cotton wool and added to samples of (R)-10
(100 mg, 0.22 mmol). The resulting clear colorless solutions were
stirred at room temperature for 18 h and then quenched with satd
aqueous NaHCO3 (6 mL). The reaction mixture was extracted with
CHCl3 (3 × 10 mL). The combined organic layers were washed
with brine and dried over Na2SO4. The solvent was evaporated,
and the residue was purified by flash column chromatography on
silica gel (hexane/EtOAc ) 80:20) to give compound 12 (65 mg,
85%) as an oil, with care being taken not to exercise a mechanical
separation of one of the diasteromers over the other: 1H NMR (300
MHz; CDCl3) δ 1.15 (3H, d, J ) 9.5 Hz), 1.47 (9H, s), 3.53 (3H,
s), 3.70 (2H, brs), 4.08 (1H, d, J ) 6.6 Hz), 5.07 (2H, m), 5.35
(2H, m), 5.74 (3H, m), 7.41 (3H, m), 7.50 (2H, m); FAB-MS obsd
458.2156, calcd 458.2154 [(M + H)+, M ) C23H30F3NO5].
In conclusion, we have developed an efficient route to a
highly versatile tetrahydropyridine intermediate 15, and shown
its huge potential by effecting not only the most efficient fully
stereocontrolled synthesis of ent-1,6-dDNJ to date but also
equally expeditious syntheses of analogues. The synthesis of
tetrahydropyridine 15 is expedient, and proceeds via an RCM
reaction of enantiopure allylic alcohol 10, which was accessed
via a substrate directed carbonyl addition reaction. Continued
investigations into the utility of this important synthon are
underway.
Experimental Section
tert-Butyl Allyl((2S,3R)-3-hydroxypent-4-en-2-yl)carbamate
(10). Oxalyl chloride (3.24 mL, 37.15 mmol) was dissolved in 138.6
mL of dry CH2Cl2. The mixture was stirred and cooled to -78 °C,
and DMSO (4.2 mL) was added. The mixture was stirred for 10
min, a solution of 8 (3.2 g, 14.86 mmol) in 10 mL of CH2Cl2 was
added, the resulting mixture was stirred for 15 min, and Et3N was
added (8.28 mL, 59.44 mmol). After 15 min, the mixture was
(19) (a) Bordier, A.; Compain, P.; Martin, O. R.; Ikeda, K.; Naoki, A.
Tetrahedron: Asymmetry 2003, 14, 47-51. (b) Dhavale, D. D.; Saha, N.
N.; Desai, V. N. J. Org. Chem. 1997, 62, 7482. (c) Ning An, J.; Meng, X.
B.; Yao, Y.; Li, Z. j. Carbohydr. Res. 2006, 341, 2200. (d) Defoin, A.;
Sarazin, H.; Streith, J. Tetrahedron 1997, 53, 13783.
(20) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto,
T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005,
48, 2036.
(21) (a) Yeung, Y. Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 9644. (b) In acid, Markovnikov addition dominates over Furst
Plattner: Long, M. J. C.; Smith, A. D.; Davies, S. G. Chem. Commun.
2005, 4536.
(5S,6S)-tert-Butyl 5,6-Dihydro-5-hydroxy-6-methyl-1(2H)-car-
bamate (13). To a solution of 10 (2.1 g, 8.70 mmol) in 218 mL of
dry CH2Cl2 was added Grubbs catalyst (358 mg, 0.43 mmol) under
N2. The reaction mixture was stirred at room temperature overnight.
After all starting material disappeared, 25 mL of water was added
2900 J. Org. Chem., Vol. 73, No. 7, 2008

and stirred vigorously at room temperature for 1 h. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
50 mL). The combined organic layers were washed with brine and
dried (Na2SO4), and solvent was evaporated. The crude mixture
was separated and purified by column chromatography on silica
(2S,3S,4R,5S)-2-Methylpiperidine-3,4,5-triol (2). To a solution
of 15 (200 mg, 0.20 mmol) and 1,4-dioxane (10 mL) was added
0.2 N H2SO4 (10 mL) dropwise and the mixture stirred at room
temperature for 3 h. The residue was separated by ion-exchange
resin chromatography to give 5-amino-1,5,6-trideoxyaltrose 2 (109
mg, 85%): [R]20D -28.2 (c 0.34, H2O); 1H NMR (300 MHz; D2O)
δ 1.05 (3H, d, J ) 6.5 Hz), 2.58 (1H, m), 2.98 (1H, d, J ) 15.0),
3.18 (1H, dd, J ) 4.4, 15.0 Hz), 3.38 (1H, m), 3.49 (1H, t, J )
4.4), 3.64 (1H, dd, J ) 2.0, 9.1 Hz); 13C NMR (300 MHz; D2O) δ
16.7, 41.5, 49.3, 55.1, 56.1, 71.2; EI-MS (m/z) 147 (M+); HRMS
calcd for C6H13NO3 (M+) 147.0895, found 147.0895.
gel (hexane/EtOAc ) 65:35) to afford 13 (1.58 g, 85%): [R]20
D
1
-95.1 (c 1, CHCl3); H NMR (300 MHz; CDCl3) δ 1.07 (3H, d,
J ) 7 Hz), 1.49 (9H, s), 3.57 (1H, d, J ) 19.54), 3.88 (1H, m),
5.97 (2H, m); 13C NMR (300 MHz; CDCl3) δ 14.9, 28.4, 39.8,
60.3, 67.5, 79.9, 124.4, 127.7, 155.6; EI-MS (m/z) 213 (M+); HRMS
calcd for C11H19NO3 (M+) 213.1365, found 213.1364.
(1S,4S,5R,6R)-tert-Butyl5-Hydroxy-4-methyl-7-oxa-3-azabicyclo-
[4.1.0]heptane-3-carbamate (15). To a stirred suspension of 13
(1.1 g, 5.15 mmol) was added m-CPBA (2.67 g, 60%, 15.47 mmol)
at room temperature. The resulting suspension was stirred for 48
h, and satd aq NaHCO3 (10 mL) was added to quench the reaction.
The resulting two-phase mixture was stirred vigorously for 15 min.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(2S,3S)-2-Methylpiperidin-3-ol (3). Compound 13 (100 mg,
0.46 mmol) was dissolved in methanol (5 mL), and 10% palladium
on activated carbon as catalyst was added. Then hydrogen was
bubbled into the mixture and stirring continued at room temperature
for 10 h. The mixture was filtered through a Celite pad. The filtrate
was evaporated, and MeOH (1.9 mL) and 6 N HCl (5.6 mL) were
added to the residue. The mixture was refluxed for 1 h and then
evaporated to give 3 (50 mg, 92%) as an oil. The residue was
separated by ion-exchange resin chromatography to give 3 as off-
1
white solid: mp 126-127 °C; [R]20 -24.4 (c 1, H2O); H NMR
D
(hexane/EtOAc ) 60:40) to give epoxide 15 (790 mg, 67%) as a
(300 MHz; D2O) δ 1.03 (3H, d, J ) 6.3 Hz), 1.22 (1H, m), 1.40
(1H, m), 1.61 (1H, m), 1.87 (1H, m), 2.41 (2H, m), 2.78 (1H, m),
3.10 (1H, m); 13C NMR (300 MHz; D2O) δ 17.0, 23.9, 32.9, 44.4,
56.9, 72.5; EI-MS (m/z) 115 (M+); HRMS calcd for C6H13NO (M+)
115.0997, found 115.0964.
1
pale yellow oil: [R]20 -28.8 (c 1, CHCl3); H NMR (300 MHz;
D
CDCl3) δ 1.09 (3H, d, J ) 7.2 Hz), 1.46 (9H, s), 3.23 (1H, d, J )
15.4), 3.43 (2H, m), 3.71 (1H, brs), 4.32 (2H, m); 13C NMR (300
MHz; CDCl3) δ 15.0, 28.3, 36.8, 50.5, 51.9, 65.5, 80.3, 155.8; EI-
MS (m/z) 229 (M+); HRMS calcd for C11H19NO4 (M+) 229.1314,
found 229.1316.
Acknowledgment. This work was financially supported by
the MOST/KOSEF to the Environmental Biotechnology Na-
tional Core Research Center (Grant No. R15-2003-012-02001-
0), Republic of Korea. R.R. was supported by a grant from the
Brain Korea 21 program (BK21).
(2S,3R,4S,5R)-2-Methylpiperidine-3,4,5-triol (1). A solution of
15 (200 mg, 0.20 mmol), 1,4-dioxane (10 mL), and 0.3 M KOH
(20 mL) was refluxed overnight. After evaporation, MeOH (10 mL)
and 6 N HCl (15 mL) were added to the residue. The mixture was
heated at 60 °C for 1 h and then evaporated to give an oil. The
residue was separated by ion-exchange resin chromatography to
give ent-1,6-dDNJ 1 (106 mg, 83%): [R]20D -13.3 (c 0.67, H2O);
1H NMR (300 MHz; D2O) δ 1.04 (3H, d, J ) 6.3 Hz), 2.32 (1H,
m), 2.41 (1H, m), 2.89 (2H, m), 3.15 (1H, m), 3.37 (1H, m); 13C
NMR (300 MHz; D2O) δ 16.4, 48.5, 54.9, 70.8, 76.2, 77.9; FAB-
MS obsd 148.0970, calcd 148.0974 [(M + H)+, M ) C6H13NO3].
Supporting Information Available: Spectral data and copies
of the 1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO702480Y
J. Org. Chem, Vol. 73, No. 7, 2008 2901