Asymmetric synthesis of the four possible fagomine isomers

Article abstract of DOI:10.1021/jo034137u

The asymmetric synthesis of fagomine and its congeners 1-4 has been achieved by catalytic ring-closing metathesis (RCM). The synthesis involved the construction of the piperidene-type chiral building block 5 followed by dihydroxylation, starting from the D-serine-derived Garner aldehyde 6.

Full text of DOI:10.1021/jo034137u

Asym m etr ic Syn th esis of th e F ou r P ossible F a gom in e Isom er s
Hiroki Takahata,*,† Yasunori Banba,‡ Hidekazu Ouchi,† Hideo Nemoto,‡ Atsushi Kato,§ and
Isao Adachi§
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, J apan, and
Faculty of Pharmaceutical Sciences and Department of Hospital Pharmacy, Toyama Medical &
Pharmaceutical University, Sugitani 2630, Toyama 930-0194, J apan
takahata@tohoku-pharm.ac.jp
Received J anuary 31, 2003
The asymmetric synthesis of fagomine and its congeners 1-4 has been achieved by catalytic
ring-closing metathesis (RCM). The synthesis involved the construction of the piperidene-type
chiral building block 5 followed by dihydroxylation, starting from the D-serine-derived Garner
aldehyde 6.
In tr od u ction
it was reported that fagomine isomer 4 (not naturally
occurring) is an inhibitor of lysosomal R-galactosidase A
activity in Fabry lymphoblasts.9 Thus far, the asymmetric
synthesis of 1 has been reported twice,10 whereas no
report of the synthesis of 2 and 3,4-di-epi-fagomine 3 has
been yet appeared. On the other hand, 4-epi-fagomine
(1,2-dideoxygalactstatin) 4 has been obtained once by
transformation from 1.11 In a project focusing on the
chiral synthesis of glycosidase inhibitors, our goal was
the preparation of a new common chiral building block,
hydroxymethylpiperidene 5, which appears to be an ideal
precursor for the synthesis of dihydroxypiperidinols. In
this paper we report on a new synthesis of all fagomine
isomers 1-4 via the preparation of 5 in a straightfor-
ward and stereoselective manner with Garner aldehyde
6 and catalytic ring-closing metathesis (RCM) of the
diene system 9 for the construction of the piperidine
ring.12,13
Polyhydroxylated nitrogen heterocycles (azasugars)
represent sugar analogues in which the ring oxygen has
been substituted for a nitrogen atom. Many of these
compounds, which are frequently inhibitors of carbohy-
drate-processing enzymes, have the potential for use in
a wide range of potential therapeutic strategies including
the treatment of viral infections, cancer, diabetes, tuber-
culosis, and lysosomal storage diseases, and as inhibitors
of the growth of parasitic protozoa.1-5 As a result, the
synthesis of polyhydroxylated piperidines and their
synthetic analogues has attracted a great deal of atten-
tion in recent years.6 Recently the isolation of three
fagomine isomers 1-3 from Xanthocercis zambesiaca
occurring in a southern African dry forest has been
reported.6 Among these, fagomine 1 and 3-epi-fagomine
2 were found to have some activity against mammalian
gut R-glucosidase and â-galactosidase.7 More recently, 1
was reported to have a potent antihyperglycemic effect
in streptozocin-induced diabetic mice and the potentia-
tion for glucose-induced insulin secretion.8 Very recently
† Tohoku Pharmaceutical University.
‡ Faculty of Pharmaceutical Sciences, Toyama Medical & Pharma-
ceutical University.
§ Department of Hospital Pharmacy, Toyama Medical & Pharma-
ceutical University.
Resu lts a n d Discu ssion
(1) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999,
38, 750-770.
(2) Zechel, D. L.; Withers, S. G. Acc. Chem. Res. 2000, 33, 11-18.
(3) Stu¨tz, A. E. Iminosugars as glycosidase inhibitors: nojirimycin
and beond; Wiley-VCH: Weinheim, Germany, 1999.
(4) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100,
4683-4696.
(5) Asano, N.; Nash, R. J .; Molyneux, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 2000, 11, 1645-1680.
(6) (a) Lillelund, V. H.; J ensen, H. H.; Liang, X.; Bols, M. Chem.
Rev. 2002, 102, 515-553. (b) Meyers, A. I.; Andres, C. J .; Resek, J . E.;
Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron
1999, 55, 8931-8952.
(7) Kato, A.; Asano, N.; Kizu, H.; Matsui, K.; Watson, A. A.; Nash,
R. J . J . Nat. Prod. 1997, 60, 312-314.
(8) (a) Nojima, H.; Kimura, I.; Chen F.-J .; Sugiura, Y.; Haruno, M.;
Kato, A.; Asano, N. J . Nat. Prod. 1998, 61, 397-400. (b) Taniguchi,
S.; Asano, N.; Tomino, F.; Miwa, I. Horm. Metab. Res. 1998, 30, 679-
683.
Our synthesis of 5 began with the Wittig reaction of
the D-serine-derived Garner aldehyde 6.14 Treatment of
6 with methyltriphenylphosphonium iodide in the pres-
ence of sodium bis(trimethylsilyl)amide gave olefin 7 in
(9) Fan, J .-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nature Med. 1999, 5,
112-115.
(10) (a) Effenberger, F.; Null, V. Liebigs Ann. Chem. 1992, 1211-
1212. (b) Fleet, G. W. J .; Smith, P. W. Tetrahedron Lett. 1985, 26,
1469-1472.
(11) Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato, A.;
Martin, O. R.; Fan, J .-Q. Eur. J . Biochem. 2000, 267, 4179-4186.
(12) For a preminary communication of this part of this work, see:
Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.; Takahata, H.
Tetrahedron: Asymmetry 2001, 12, 817-819.
(13) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(14) Dondoni, A.; Perrone, D. Org. Synth. 1999, 77, 64-77.
10.1021/jo034137u CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/02/2003
J . Org. Chem. 2003, 68, 3603-3607
3603

Takahata et al.
SCHEME 1 a
SCHEME 2 a
a
Reagents and conditions: (a) Ph3P+CH3I-, NaN(TMS)2, THF.
(b) (i) p-TsOH‚H2O, MeOH; (ii) TBDPSCl, DMAP, imidazole,
CH2Cl2. (c) (i) CF3COOH, CH2Cl2; (ii) 4-bromo-1-butene, K2CO3,
CH3CN; (iii) (Boc)2O, Et3N, THF. (d) Grubbs’ catalyst, CH2Cl2.
63% yield.15 Hydrolysis of 7 with p-toluenesulfonic acid
in MeOH followed by O-silylation afforded 8 in 72% yield.
N-Alkylation of 8 with 4-bromo-1-butene under various
conditions resulted in the recovery of the starting mate-
rial 8.16 However, a three-step sequence [(1) deprotection
of the N-Boc group; (2) alkylation; and (3) N-protection]
provided the butenylated product 9 in 60% overall yield.
RCM of 9 with Grubbs’ catalyst, (benzylidine)bis(tricy-
clohexylphosphine)ruthenium(IV) dichloride, under the
a
Reagents and conditions: (a) Oxone, CF3COCH3, NaHCO3, aq
Na2‚EDTA, CH3CN. (b) Super-Hydride, THF. (c) (i) 35% HCl, 1,4-
dioxane; (ii) Dowex 1× 2 (OH- form). (d) TBAF, THF. (e) (i)
m-CPBA, NaHCO3, CH2Cl2; (ii) TBDPSCl, DMAP, imidazole,
CH2Cl2. (f) H2SO4, 1,4-dioxane, H2O. (g) KOH, 1,4-dioxane, H2O.
with m-CPBA followed by silylation afforded 11 in 64%
overall yield. The acid hydrolysis of the epoxy ring of 10
was accomplished by using a mixture of H2SO4/1,4-
dioxane/H2O in a milliliter ratio of 0.2/3/2,23 and further
treatment with an ion-exchange resin (Amberlite IRA-
410) gave only fagomine 1 in 75% yield. Although a
rationale of this high selectivity remains unclear, we
consider the following explanation: an attack of H2O, as
a nucleophile with backside displacement of the leaving
oxygen in the epoxy-substituted ring, occurs at the more
remote site (4 position) because a nucleophilic attack at
the 3 position has a syn orientation with respect to the
adjacent hydroxymethyl substiuent at the 2 position. In
addition, opening of cyclohexene oxide generally proceeds
in such a fashion that the diaxial reaction product is
obtained. On the other hand, similar treatment of 11
afforded a mixture of 1 and 3,4-di-epi-fagomine 3 in 77%
combined yield and a ratio of 1.3:1, which were separated
by ion-exchange resin (Dowex 1×2 OH- form) chroma-
tography. In this case, due to the anti relation between
the hydroxymethyl substiuent at the 2 position and the
attack orientation, a backside attack of H2O on the epoxy
ring would occur at both the 3 and 4 positions with a
nearly equal probability. In contrast, the basic cleavage
of epoxide 11 with use of a mixture of KOH/1,4-dioxane/
H2O gave 3 preferentially, in a ratio of 5:1 (3 to 1) in
99% combined yield.
The stereoselective dihydroxylation of the double bond
was next examined. Under modified Upjohn conditions,24
the treatment of 5 with a catalytic amount of K2OsO4‚
2H2O (5 mol %) and 4-methylmorpholine N-oxide (1.5
equiv) as a cooxidant gave the diol 17 as a single
diastereoisomer in a high yield of 92%.18 Deprotection of
17 with 10% hydrochloric acid in 1,4-dioxane followed by
treatment with ion-exchange resin (Dowex 1×2 OH-
form) afforded 3-epi-fagomine 2 in 91% yield. Surpris-
ingly, both AD-mix-R- and â-mediated dihydroxylation
provided 17 with no diastereomer detected, in 94% and
96% yields, respectively. Dihydroxylation exclusively
usual conditions gave the desired intermediate 5 {[R]27
D
-150.1° (c 1.04, CHCl3)} in 97% yield.
With the promising educt 5 in hand, our interest was
then directed to the synthesis of all isomers 1-4 of
fagomine. We first introduced the epoxy-functionality into
the double bond to obtain both 1 and 3 containing trans
diols at the 3 and 4 positions. The dioxirane, generated
in situ from Oxone with 1,1,1-trifluoroacetone according
to a recent procedure,17 was reacted with 5 to give a
mixture of stereoisomeric epoxy compounds 10 and 11
which were separated by medium-pressure chromatog-
raphy in a high yield of 90% though the diastereoselec-
tivity was low (ds: 33%).18,19 The stereochemistry of the
epoxy products was determined by the stereoselective
cleavage of the epoxy ring with Super-Hydride. Treat-
ment of 10 with Super-Hydride in THF led to the
hydroxylated product 12 (96%). Complete deprotection
of 12 with hydrochloric acid in 1,4-dioxane followed by
treatment of the resulting salt with an ion-exchange resin
(Dowex 1×2 OH- form) afforded the known (2R,3S)-3-
hydroxy-2-hydroxymethylpiperidine 1320 in quantitative
yield. An analogous procedure, using 11, provided (2R,3R)-
3-hydroxy-2-hydroxymethylpiperidine 1421 and (2S,4R)-
4-hydroxy-2-hydroxymethylpiperidine 1522 as a 1:5 ratio
in 79% combined yield. The syn epoxide 11 was stereo-
selectively obtained by an alternative method. Desilyla-
tion of 5 with TBAF was carried out to afford 16 (97%
yield). Starting with 16, hydroxy-directed epoxidation
(15) This is a two-step yield from the Garner alcohol.14
(16) Several conditions: (1) NaH, N,N-dimethylformamide, 60 °C;
(2) pulverized KOH, cat. n-Bu4NI, THF, reflux; (3) pulverized KOH,
cat. 18-crown-6-ether, THF, reflux.
(17) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J . S.; Wilde,
R. G. J . Org. Chem. 1995, 60, 1391-1407.
(18) In this stage, the stereochemistry remained unknown.
(19) m-CPBA epoxidation resulted in very low yield (6%).
(20) (a) Mocerino, M.; Stick, R. V. Aust. J . Chem. 1990, 43, 1183-
1193. (b) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401-
404.
(21) Enders, D.; J egelka, U. Synlett 1992, 999-1002.
(22) This structure was determined by its HMBC correlation (see
Supporting Information).
(23) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039-
3042.
(24) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973-1976.
3604 J . Org. Chem., Vol. 68, No. 9, 2003

Synthesis of the Four Possible Fagomine Isomers
SCHEME 3 a
(R)-2,2-Dim eth yl-4-vin yloxa zolid in e-3-ca r boxylic Acid
ter t-Bu tyl Ester (7). NaHMDS (1 N, 27.4 mL, 27.4 mmol) in
THF was added dropwise to a suspension of methyltriphenyl-
phosphonium iodide (11.1 g, 27.4 mmol) in THF (32.9 mL) at
-20 °C and the mixture was stirred for 15 min. A solution of
the Garner aldehyde (6, 4.74 g, 20.7 mmol) in THF (20.7 mL)
was added dropwise to the mixture and then the reaction
mixture was stirred at -20 °C overnight. Saturated NH4Cl
was added to the mixture and extracted with ether. The extract
was washed with brine, dried, and evaporated. The residue
was purified by chromatography (5-6% AcOEt in hexane) to
yield 7 (2.61 g, 63%) as an oil; [R]26 -18.9° (c 1.32, CHCl3);
D
[lit.27 [R]20D -17.1° (c 1.20, CHCl3)]; 1H NMR (500 MHz, CDCl3)
δ 1.38 (s, 6H), 1.44 (s, 3H), 1.46 (s, 3H), 1.56 (s, 3H), 3.70 (dd,
J ) 8.7, 2.5 Hz, 1H), 4.00 (dd, J ) 8.9, 6.4 Hz, 1H), 4.22 (br s,
0.5H), 4.35 (br s, 0.5H), 5.09 (m, 1H), 5.19 (br s, J ) 17 Hz,
1H), 5.77 (br d, J ) 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 23.7, 24.9, 26.6, 27.3, 28.5, 59.7, 68.2, 79.6, 94.0, 115.8, 137.5,
152.0; IR (neat) 2979.1, 1697.6, 1382.5 cm-1; HRMS calcd for
a
Reagents and conditions: (a) cat. K2OsO4‚2H2O, NMO, H2O,
acetone. (b) 10% HCl, 1,4-dioxane. (c) (i) OsO4, TMEDA, CH2Cl2;
(ii) 35% HCl, MeOH.
occurred from the less hindered anti side of the siloxy-
methyl substituent, which adopts an axial position due
to 1,3-allylic strain. The dihydroxylation of 16 under the
above modified Upjohn conditions also took place from
the anti side of the hydroxymethyl group followed by
deprotection to give 2 as a single diastereomer in 87%
combined yield. Very recently, Donohoe reported25 that
osminum tetroxide produces a bidendate and reactive
complex with TMEDA, which accomplishes the directed
dihydroxylation of homoallyic alcohols. Therefore, the
oxidation of 16 with use of a combination of OsO4 with
TMEDA followed by deprotection gave 4 and 2 in moder-
ate selectivity (2:1) in 56% and 30% yields, respectively.
In conclusion, a rapid and straightforward route to the
stereoselective asymmetric synthesis of all fagomine
isomers 1-4 (the first total synthesis for 2 and 3) with
use of a common chiral piperidene 5 is described. Pip-
eridene 5 should be useful as a chiral building block for
the synthesis of the piperidine-related alkaloids.26
C
12H21NO3 (M+) 227.1617, found 227.1493.
(S )-[1-(t er t -Bu t yld ip h e n ylsila n yloxym e t h yl)a llyl]-
ca r ba m ic Acid ter t-Bu tyl Ester (8). A mixture of 7 (3.96 g,
17.4 mmol) and p-TsOH‚H2O (910 mg, 4.79 mmol) in MeOH
(163.1 mL) was stirred at room temperature overnight. After
evaporation, saturated NaHCO3 was added to the residue. The
mixture was extracted with AcOEt. The extract was dried and
evaporated to leave a yellow oil. A mixture of the residue (2.96
g), imidazole (1.58 g, 23.2 mmol), DMAP (379 mg, 3.10 mmol),
and TBDPSCl (4.44 mL, 17.1 mmol) in CH2Cl2 (21.7 mL) was
stirred at room temperature overnight. The mixture was
filtered off and the filtrate was washed with brine, dried, and
evaporated. The residue was purified by chromatography
(5-10% AcOEt in hexane) to yield 8 (5.30 g, 72%) as an oil;
[R]25 -27.7° (c 1.02, CHCl3); IR (neat) 2932.5, 1495.6, 1110.5
D
1
cm-1; H NMR (500 MHz, CDCl3) δ 1.08 (s, 9H), 1.47 (s, 9H),
3.64-3.66 (m, 1H), 3.75-3.76 (m, 1H), 4.27 (br s, 1H), 4.87
(br s, 1H), 5.18 (dd, J ) 10.2, 1.2 Hz, 1H), 5.24 (dd, J ) 17.5,
1.2 Hz, 1H), 5.85 (ddd, J ) 12.5, 10.4, 5.3 Hz, 1H), 7.35-7.46
(m, 6H), 7.65-7.75 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.5,
27.0, 28.6, 54.4, 66.1, 79.6, 115.7, 127.7, 129.8, 133.1, 133.2,
135.5, 135.6, 136.4, 155.4; HRMS calcd for C25H35NO3Si (M+)
425.2403, found 425.2373.
Exp er im en ta l Section
(S)-Bu t -3-en yl[1-(ter t-b u t yld ip h en ylsila n yloxym et h -
yl)a llyl]ca r ba m ic Acid ter t-Bu tyl Ester (9). A mixture of
8 (11.6 g, 27.3 mmol) and TFA (131.1 mL) in CH2Cl2 (131.1
mL) was stirred at room temperature for 1 h and evaporated.
To the mixture was added saturated NaHCO3. The mixture
was extracted with CH2Cl2, dried with K2CO3, and evaporated
to leave an yellow oil (8.35 g). K2CO3 (2.206 mg, 15.96 mmol)
was added to a solution of the residue (5.19 g, 15.96 mmol) in
CH3CN (64.4 mL) and the mixture was stirred for 1 h.
4-Bromo-1-butene (1.62 mL, 15.96 mmol) was added to the
mixture and then the reaction mixture was heated at 90 °C
overnight. The insoluble materials were filtered off and the
filtrate was evaporated. To the residue was added CH2Cl2 and
saturated NaHCO3. After being stirred for 30 min, the mixture
was separated in organic and aqueous layers. The aqueous
layer was extracted with CH2Cl2. The combined organic
solvents were dried with K2CO3 and evaporated. Et3N (5.48
mL, 39.3 mmol) was added to a solution of the residue (5.61
g, 14.8 mmol) in THF (56.7 mL) at 0 °C and then a solution of
(Boc)2O (4.2 mL, 18.3 mmol) in THF (28.6 mL) was added to
the mixture over 1 h at the same temperature. After being
stirred at room temperature overnight, the mixture was
evaporated. HCl (1 N) was added to a solution of residue in
ether with ice cooling. The mixture was separated in organic
and aqueous layers. The aqueous layer was extracted with
ether. The combined organic solvents were washed with
saturated NaHCO3, dried, and evaporated. The residue was
Gen er a l P r oced u r es. Melting points were determined
with a Yanaco micro melting point apparatus and are uncor-
rected. Microanalyses were performed by Microanalysis Center
of Toyama Medical & Pharmaceutical University with a
Perkin-Elmer 2400 Series II Analyzer. IR spectra were mea-
sured with a Perkin-Elmer 1600 series FTIR spectrophotom-
1
eter. H NMR spectra were recorded either at 300 MHz on a
Varian Gemini-300, at 400 MHz on a J EOL GSX 400, or at
500 MHz on a Varian Unity-500 with CHCl3 (7.26 ppm) as
internal standard. 13C NMR spectra were recorded at 75 or
100 or 125 MHz with CHCl3 (77.2 ppm) as an internal
standard unless otherwise specified. MS and HRMS were
measured on a J EOL J MS D-200 spectrometer. Optical rota-
tions were measured on
a J ASCO DIP-140 instrument.
Column chromatography was performed on silica gel (Fuji-
Division BW-200 or Merck 60 (No. 9385)) with a medium-
pressure apparatus and a mixture of ethyl acetate/hexane or
acetone/hexane was used as eluent unless otherwise specified.
Purification of products via ion-exchange resin chromatogra-
phy was performed with Dowex 1×2 OH- form, using water
as eluent. The extracts were dried over Na2SO4 unless
otherwise specified. Copies of 1H and 13C NMR spectra are
supplied in the Supporting Information.
(25) (a) Donohoe, T. J .; Mitchell, L.; Waring, M. J .; Helliwell, M.;
Bell, A.; Newcombe, N. J . Tetrahedron Lett. 2001, 42, 8951-8954. (b)
For a review, see: Donohoe, T. J . Synlett, 2002, 1223-1232.
(26) Sabat, M.; J ohnson, C. R. Tetrahedron Lett. 2001, 42, 1209-
1212.
(27) Campbell, A. D.; Raynham, T. M.; Taylor, R. J . K. Synthesis
1998, 1707-1709.
J . Org. Chem, Vol. 68, No. 9, 2003 3605

Takahata et al.
purified by chromatography (3-4% AcOEt in hexane) to yield
9 (4.88 g, 60%) as an oil; [R]25D -0.36° (c 1.02, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.04 (s, 9H), 1.38-1.59 (m, 9H), 2.30 (q,
J ) 7.6 Hz, 1H), 3.14-3.22 (m, 2H), 3.65-3.80 (m, 2H), 4.23
(br s, 0.5H), 4.59 (br s, 0.5H), 4.92-5.21 (m, 4H), 5.68-5.89
(m, 2H), 7.35-7.45 (m, 6H), 7.64-7.67 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 19.5, 27.0, 28.7, 33.6, 45.7, 50.9, 65.2, 79.5,
115.2, 116.1, 127.6, 127.7, 129.6, 129.7, 133.4, 135.6, 135.7,
135.8, 137.1, 155.4; IR (neat) 2933.0, 2859.7, 1693.3; HRMS
calcd for C29H41NO3Si (M+) 479.2863, found 479.2849.
3.96 (br d, J ) 12.2 Hz, 1H), 4.11 (br s, 1H), 4.34 (br s, 1H),
7.37-7.46 (m, 6H), 7.64-7.66 (m, 4H); 13C NMR (100 MHz,
CHCl3) δ 19.1, 19.5, 26.6, 27.1, 28.7, 39.8, 59.0, 61.9, 65.4, 79.9,
127.9, 129.9, 133.1, 133.3, 135.6, 156.0; IR (neat) 3440.4,
2932.3, 2858.6, 1688.4 cm-1; HRMS calcd for C27H39NO4Si
467.2422, found 467.2552.
(2R,3S)-2-Hyd r oxym eth ylp ip er id in -3-ol (13). A solution
of 12 (148.6 mg, 0.31 mmol) and 35% HCl (1.2 mL) in 1,4-
dioxane (1.2 mL) was refluxed for 1 h. The mixture was
evaporated, diluted with H2O, washed with ether, and evapo-
rated. Two drops of 30% NaOH was added to the residue. The
mixture was dissolved with a mixture of CHCl3:IPA (4:1) (15
mL), dried with K2CO3, and evaporated. The residue was
purified by ion-exchange resin chromatography to yield 13 (45
(S)-6-(ter t-Bu tyldiph en ylsilan yloxym eth yl)-3,6-dih ydr o-
2H-p yr id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (5). A
solution of Grubbs’ catalyst (223 mg, 0.271 mmol) in CH2Cl2
(103 mL) was added to a solution of 9 (2.60 g, 5.42 mmol) in
CH2Cl2 (103 mL) under Ar and the reaction mixture was
stirred at room temperature overnight. After evaporation, the
residue was purified by chromatography (4% AcOEt in hexane)
mg, 100%) as a solid; mp 154-155 °C; [R]23 +58.3° (c 1.06,
D
1
MeOH); H NMR (500 MHz, D2O) δ 1.27 (br d, J ) 10.2 Hz,
1H), 1.40 (br d, J ) 10.2 Hz, 1H), 1.65 (br s, 1H), 1.93 (br s,
1H), 2.46 (br s, 2H), 2.91 (br d, J ) 9.4 Hz, 1H), 3.34 (br s,
1H), 3.51 (br s,1H), 3.74 (br s, 1H); 13C NMR (125 MHz, D2O/
free) δ 24.1, 32.9, 45.0, 61.9, 63.1, 68.1; 13C NMR (125 MHz,
D2O/HCl salt) δ 21.0, 31.1, 44.1, 58.6, 62.2, 65.2. Anal. Calcd
for C6H13NO2: C, 54.94; N, 10.68; H, 9.99. Found: C, 54.66;
N, 10.55; H, 9.71.
to yield 5 (2.371 g, 97%) as an oil; [R]27 -150.0° (c 1.04,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.08 (s, 9H), 1.39-1.49
(m, 9H), 1.96 (m, 1H), 2. 22 (m, 1H), 2.93 (m, 1H), 3.71-3.72
(m, 2H), 4.45 (m, 0.5H), 4.64 (m, 0.5H), 5.82 (m, 1H), 5.97 (m,
1H), 7.38-7.45 (m, 6H), 7.68-7.71 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 19.3, 24.9, 26.9, 28.5, 37.4, 39.5, 53.8, 65.3,
79.6, 126.2, 126.8, 127.7, 129.7, 133.4, 135.6, 135.7, 154.7; IR
(2R,3R)-2-Hydr oxym eth ylpiper idin -3-ol (14)an d (2S,4R)-
2-Hyd r oxym eth ylp ip er id in -4-ol (15). Super-Hydride (0.77
mL, 0.77 mmol) was added to a solution of 11 (90.9 mg, 0.19
mmol) in THF (0.8 mL) and the mixture was stirred at 0 °C
for 3 h. Several pieces of ice were added to the mixture. After
the mixture was stirred for 15 min, H2O (1.29 mL) was added
to the mixture. The mixture was extracted with CH2Cl2 (10
mL) three times. The extracts were dried and evaporated. The
residue was purified by chromatography (hexane:AcOEt 3:1)
to yield piperidinols (77.7 mg) as an inseparable mixture. A
solution of the mixture (59.4 mg) and 35% HCl (0.5 mL) in
1,4-dioxane (0.5 mL) was refluxed for 1 h. The mixture was
evaporated, diluted with H2O, washed with ether, and evapo-
rated. Two drops of 30% NaOH was added to the residue. The
mixture was dissolved with a mixture of CHCl3:IPA (4:1) (25
mL), dried with K2CO3, and evaporated. The residue was
purified by ion-exchange resin chromatography to yield 14 and
(neat) 2931.5, 1419.4, 1110.1 cm-1; HRMS calcd for C27H37
NO3Si (M+) 451.2534, found 451.2550.
-
(2R,6S,7R)-2-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-7-
oxa -3-a za bicyclo[4.1.0]h ep ta n e-3-ca r boxylic Acid ter t-
Bu tyl Ester (11) a n d (2R,6R,7S)-2-(ter t-Bu tyld ip h en ylsi-
la n yloxym e t h yl)-7-oxa -3-a za b icyclo[4.1.0]h e p t a n e -3-
ca r boxylic Acid ter t-Bu tyl Ester (10). To a solution of 9
(290 mg, 0.64 mmol) in CH3CN (4.9 mL) was successively
added 4 × 10-4 M Na2‚EDTA (3.2 mL) and CF3COCH3 (0.6
mL) at 0 °C. A mixture of NaHCO3 (419 mg) and Oxone (1.97
g) was added to the reaction mixture over 1 h at 0 °C and the
whole mixture was stirred at the same temperature for 30 min.
H2O (5 mL) was added to the reaction mixture and the mixture
was extracted with CH2Cl2. The extract was dried and
evaporated. The residue was purified by chromatography
(hexane:AcOEt 5:1) to yield 10 and 11 (298 mg) as a diaster-
eomeric mixture. The mixture was repurified by medium-
pressure chromatography (hexane:AcOEt 15:1) to yield 11 (91
15. 14: oil; [R]21 -12.4° (c 2.51, H2O); 1H NMR (400 MHz,
D
D2O) δ 1.32-1.38 (m, 1H), 1.46-1.72 (m, 3H), 2.50 (td, J )
12.3, 3.2 Hz, 1H), 2.68 (ddd, J ) 7.3, 6.0, 1.6 Hz, 1H), 2.90 (d,
J ) 12.7 Hz, 1H), 3.41-3.51 (2H, m), 3.80-3.81 (m, 1H); 13C
NMR (75 MHz, D2O/free) δ 20.6, 31.0, 45.2, 60.0, 62.7, 65.7;
13C NMR (75 MHz, D2O/HCl salt) δ 17.2, 29.2, 44.9, 60.5, 61.1,
63.3; 13C NMR (75 MHz, D2O/p-TsOH salt) δ 18.5, 21.9, 31.0,
46.0, 61.9, 62.7, 64.1, 127.2, 130.2, 142.2, 143.6; HRMS calcd
mg, 30%) and 10 (181 mg, 60%) as oils. 11: [R]24 -71.2° (c
D
1
1.27, CHCl3); H NMR (500 MHz, CDCl3) δ 1.07 (s, 9H), 1.38
(s, 6H), 1.44 (s, 3H), 1.86-2.01 (m, 2H), 2.63-2.67 (m, 1H),
3.34-3.71 (m, 3H), 3.79-3.83 (m, 2H), 4.44-4.45 (m, 0.75H),
4.75 (br s, 0.25H), 7.36-7.41 (m, 6H), 7.69-7.73 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 19.4, 25.3, 26.9, 28.4, 33.6, 51.5,
51.6, 51.9, 61.6, 80.4, 127.8, 129.8, 133.6, 135.6, 135.7, 135.8,
for C6H13NO2 (M+) 131.0879, found 131.0956. 15: oil; [R]21
D
154.3; IR (neat) 2931.7, 1696.0, 1416.1, 1110.8, 1003.5 cm-1
;
+11.2° (c 1.10, H2O); 1H NMR (500 MHz, D2O) δ 0.87 (dd, J )
23.5, 11.8 Hz, 1H), 1.14 (ddd, J ) 24.1, 12.8, 4.5 Hz, 1H), 1.74-
1.79 (m, 2H), 2.42 (td, J ) 12.7, 2.4 Hz, 1H), 2.52-2.57 (m,
1H), 2.90 (ddd, J ) 12.6, 4.3, 2.4 Hz, 1H), 3.30 (dd, J ) 11.2,
7.1 Hz, 1H), 3.38 (dd, J ) 11.3, 4.8 Hz, 1H), 3.53-3.61 (m,
1H); 13C NMR (75 MHz, D2O/free) δ 34.4, 36.9, 43.8, 58.4, 65.7,
68.8; 13C NMR (75 MHz, D2O/HCl salt) δ 31.1, 33.7, 43.1, 57.5,
62.1, 65.8; HRMS calcd for C6H13NO2 (M+) 131.0879, found
131.0881.
HRMS calcd for C27H37NO4Si (M+) 467.2422, found 467.2398.
1
10: [R]26 -50.3° (c 1.42,CHCl3); H NMR (500 MHz, CDCl3)
D
δ 1.06 (s, 9H), 1.40 (s, 9H), 1.88-1.93 (m, 1H), 1.99 (br s, 1H),
3.00 (br s, 1H), 3.28 (br s, 1H), 3.31 (br s, 1H), 3.40-3.88 (m,
3H), 4.50 (br s, 1H), 7.36-7.45 (m, 6H), 7.63-7.67 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 19.3, 22.8, 26.9, 28.5, 50.5, 51.8,
63.8, 80.3, 127.95, 127.96, 129.9, 130.0, 133.109, 135.6, 135.7,
155.3; IR (neat) 2932.3, 1695.4, 1421.5, 1172.1, 1109.9 cm-1
;
HRMS calcd for C27H37NO4Si (M+) 467.2422, found 467.2552.
(S)-6-H yd r oxym et h yl-3,6-d ih yd r o-2H -p yr id in e-1-ca r -
boxylic Acid ter t-Bu tyl Ester (16). TBAF (1.04 mL, 1.04
mmol) was added to a solution of 5 (390 mg, 0.86 mmol) in
THF (10 mL) with ice cooling and the mixture was stirred at
room temperature for 2.5 h. After being diluted with H2O, the
mixture was extracted with AcOEt three times. The extracts
were washed with brine, dried, and evaporated. The residue
was purified by chromatography (hexane:AcOEt 3:1) to yield
(2R,3S)-2-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-3-h y-
d r oxyp ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (12).
Super-Hydride (0.77 mL, 0.77 mmol) was added to a solution
of 10 (181.1 mg, 0.39 mmol) in THF (1.5 mL) and the mixture
was stirred at 0 °C for 3 h. Several pieces of ice were added to
the mixture. After the mixture was stirred for 15 min, H2O
(1.29 mL) was added to the mixture. The mixture was
extracted with CH2Cl2 (10.4 mL) three times. The extracts
were dried and evaporated. The residue was purified by
chromatography (hexane:AcOEt 3:1) to yield 12 (175 mg, 96%)
16 (179.2 mg, 97%) as an oil; [R]24 -227.5° (c 1.02, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 1.91-1.99 (m, 1H),
2.12-2.21 (m, 1H), 2.52 (br s, 0.5H), 2.83-2.90 (m, 1H), 3.17
(br s, 0.5H), 3.57-3.63 (m, 2H), 4.05 (br s, 1H), 4.49 (br s, 1H),
5.57-5.63 (m, 1H), 5.88-5.93 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 25.0, 26.7, 28.6, 39.3, 54.2, 64.8, 80.2, 124.7, 127.5,
as a pale yellow oil; [R]23 -32.9° (c 1.00, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 1.05 (s, 9H), 1.43 (s, 9H), 1.50-1.89 (m,
5H), 2.67 (td, J ) 13.2, 3.1 Hz, 1H), 3.69 (d, J ) 6.6 Hz, 2H),
3606 J . Org. Chem., Vol. 68, No. 9, 2003

Synthesis of the Four Possible Fagomine Isomers
134.7; IR (neat) 3440.0, 2975.8, 2930.1, 1693.0, 1674.3, 1423.6
cm-1; HRMS calcd for C11H19NO3 (M+) 213.1652, found
213.1287.
layer was separated. The aqueous layer was extracted with
CH2Cl2. The combined organic solvents were washed with
brine, dried, and evaporated. The residue was purified by
chromatography (hexane:AcOEt 4:1) to yield 17 (505 mg, 92%)
(2R,6S,7R)-2-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-7-
oxa -3-a za bicyclo[4.1.0]h ep ta n e-3-ca r boxylic Acid ter t-
Bu t yl E st er (11). Alternate method: NaH2PO4 (185.7 mg,
1.55 mmol) and m-CPBA (267 mg, 1.55 mmol) were added to
a solution of 16 (47.9 mg, 0.224 mmol) in CH2Cl2 (4 mL). After
being stirred at room temperature overnight, the mixture was
diluted with AcOEt. The mixture was successively washed
with 10% Na2SO3, H2O, 5% Na2CO3, and brine and dried.
Evaporation yielded (2R,6S,7R)-2-hydroxymethyl-7-oxa-3-
azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (42.3
1
as a white solid; [R]25 -37.4° (c 1.03, CHCl3); H NMR (500
D
MHz, CDCl3) δ 0.89 (s, 9H), 1.27 (s, 9H), 1.42-1.54 (m, 1H),
1.54-1.72 (m, 1H), 2.57-2.73 (m, 3H), 3.51-3.55 (m, 2H),
3.55-3.67 (m, 1H), 3.90 (m, 2H), 4.36 (br s, 1H), 7.21-7.28
(m, 6H), 7.48-7.50 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.3,
27.0, 28.0, 28.5, 39.4, 58.8, 62.0, 67.5, 68.5, 80.1, 127.8, 129.8,
132.8, 132.9, 135.5, 135.6, 155.7; IR (KBr) 3425.8, 2933.0,
1691.3, 1112.0 cm-1; HRMS calcd for C27H39NO5Si (M+)
485.2582, found 485.2611.
mg, 82%) as a yellow oil; [R]21 -106.8° (c 0.59, CHCl3); 1H
D-3-epi-F a gom in e [(2R,3R,4S)-2-Hyd r oxym eth ylp ip er i-
d in e-3,4-d iol] (2). A mixture of 17 (490 mg, 1.01 mmol) in
1,4-dioxane (6.09 mL) and 10% HCl (27.7 mL) was heated at
100 °C for 30 min. After evaporation, the residue was washed
with ether and then purified by ion-exchange resin chroma-
tography to give D-3-epi-fagomine (2) (134.6 mg, 91%) as a
D
NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.88-2.00 (m, 2H), 2.24
(br s, 0.5H), 2.78-2.94 (m, 1.5H), 3.36 (br s, 2H), 3.69-3.81
(m, 3H), 4.37 (br s, 0.5H), 4.53 (br s, 0.5H); 13C NMR (75 MHz,
CDCl3) δ 25.3, 28.6, 33.9, 35.0, 51.2, 51.9, 61.8, 62.4, 80.4; IR
(neat) 3439.0, 2977.3, 2933.4, 1684.8 cm-1; HRMS calcd for
white solid; mp 220-222 °C; [R]26 +74.4° (c 0.95, H2O) [lit.7
C
11H19NO4 (M+) 229.1333, found 229.1309.
D
[R]26 +69° (c 0.5, H2O)]; 1H NMR (500 MHz, D2O) δ 1.56-
D
Imidazole (18.9 mg, 2.78 mmol), DMAP (1 mg), and TBDP-
1.63 (m, 1H), 1.69-1.73 (m, 1H), 2.61-2.68 (m, 2H), 2.70-
2.75 (m, 1H), 3.33 (dd, J ) 10.2, 2.9 Hz, 1H), 3.49 (dd, J )
11.63, 6.5 Hz, 1H), 3.69 (dd, J ) 11.5, 2.9 Hz, 1H), 3.95 (q, J
) 2.9 Hz, 1H); 13C NMR (125 MHz, D2O) δ 31.8, 39.1, 56.5,
62.9, 68.7, 70.3. Anal. Calcd for C6H13NO3: C, 48.97; N, 9.52;
H, 8.90. Found: C, 48.94; N, 9.49; H, 8.98.
Alter n ete Meth od . A solution of NMO (504 mg, 2.15 mmol)
and a solution of K2OsO4‚2H2O (13.2 mg, 35.8 µmol) in water
(0.6 mL) were successively added to a solution of 16 (153 mg,
0.72 mmol) in acetone (6 mL) and the mixture was stirred at
room temperature overnight. Na2SO3 was added to the mixture
and the mixture was stirred. The insoluble materials were
filtered off and the filtrate was evaporated. The residue was
dissolved in 1,4-dioxane (4.3 mL), 10% HCl (12.5 mL) was
added, and the mixture was heated at 60 °C for 1 h, and then
evaporated. The residue was washed with ether and then
purified by ion-exchange resin chromatography to give D-3-
epi-fagomine (2) (91.4 mg, 87%) as a white solid.
D-4-epi-F a gom in e [(2R,3S,4R)-2-Hyd r oxym eth ylp ip er i-
d in e-3,4-d iol] (4). A solution of OsO4 (100 mg, 0.393 mmol)
in CH2Cl2 (1 mL) was added to a solution of 16 (82.1 mg, 0.384
mmol) and TMEDA (48.8 mg, 0.42 mmol) in CH2Cl2 (10 mL)
at -78 °C. The mixture was stirred at the same temperature
for 2 h, warmed to room temperature, and stirred for 1 h. The
reaction mixture was evaporated. The residue was dissolved
in MeOH (10 mL), 35% HCl (3 drops) was added, and the
mixture was stirred at room temperature for 2 h, and then
evaporated. The residue was treated with ion-exchange resin
(Amberlite IRA-410) and then separated by ion-exchange resin
chromatography to give D-4-epi-fagomine (4) (31.4 mg, 56%)
SCl (53 µL, 0.203 mmol) were added to a solution of the
prepared epoxide (42.3 mg, 0.185 mmol) in CH2Cl2 (0.26 mL)
with ice cooling and the mixture was stirred at room temper-
ature overnight. The insoluble materials were filtered off. The
filtrate was washed with brine, dried, and evaporated. The
residue was purified by chromatography (hexane:AcOEt 5:1)
to yield 11 (67.3 mg, 78%) as an oil.
D-F a gom in e [(2R,3R,4R)-2-Hyd r oxym eth ylp ip er id in e-
3,4-d iol] (1). A mixture of 10 (170 mg, 0.356 mmol), 1,4-
dioxane (2.2 mL), H2O (1.46 mL), and H2SO4 (0.15 mL) was
heated at 95 °C for 3 h. After evaporation of the reaction
mixture, the residue was treated with ion-exchange resin
(Amberlite IRA-410) to yield D-fagomine (1) (40 mg, 75%) as a
solid; mp 185 °C; [R]25 +18.0° (c 0.92, H2O) [lit.7 [R]D +19.5°
D
1
(c 1.0, H2O)]; H NMR (500 MHz, D2O) δ 1.31 (ddd, J ) 20.0,
12.8, 4.2 Hz, 1H), 1.83-1.87 (m, 1H), 2.36-2.40 (m, 1H), 2.46
(td, J ) 12.8, 2.56 Hz, 1H), 2.84-2.88 (m, 1H), 3.02 (t, J ) 9.4
Hz, 1H), 3.47-3.43 (m, 1H), 3.50 (dd, J ) 11.5, 6.4 Hz, 1H),
3.72 (dd, J ) 11.5, 2.9 Hz, 1H); 13C NMR (125 MHz, D2O) δ
33.5, 43.4, 61.7, 62.5, 74.0, 74.0.
D-3,4-Di-epi-fa gom in e [(2R,3S,4S)-2-Hyd r oxym eth ylp i-
p er id in e-3,4-d iol] (3). Acid ic Con d ition . A mixture of 11
(90 mg, 0.192 mmol), 1,4-dioxane (1.2 mL), H2O (0.77 mL), and
H2SO4 (0.08 mL) was heated at 95 °C for 3 h. After evaporation
of the reaction mixture, the residue was treated with an ion-
exchange resin (Amberlite IRA-410) to yield a yellow oil, which
was separated by ion-exchange resin chromatography to give
D-fagomine (1) (12.5 mg, 44%) and 3,4-di-epi-fagomine (3) (9.4
mg, 33%) as a yellow oil. 3: [R]25 +13.4° (c 0.32, H2O) [lit.7
D
[R]D -8.7° (c 0.3, H2O)]; 1H NMR (500 MHz, D2O) δ 1.43-1.50
(m, 1H), 1.86 (m, 1H), 2.78 (m, 2H), 3.02-3.06 (m, 1H), 3.56-
3.57 (m, 2H), 3.61 (br s, 1H), 3.80 (br s, 1H); 13C NMR (125
MHz, D2O) δ 28.2, 39.3, 56.0, 61.3, 68.2, 69.1.
and D-3-epi-fagomine (2) (16.8 mg, 30%) as solids. 4: mp 220-
1
222 °C; [R]22 +10.2° (c 1.42, H2O); H NMR (300 MHz, D2O)
D
δ 1.49-1.56 (m, 2H), 2.39-2.49 (m, 1H), 2.57 (td, J ) 6.9, 5.2
Hz, 1H), 2.91 (td, J ) 12.9, 3.3 Hz, 1H), 3.47 (dd, J ) 6.7, 3.4
Hz, 2H), 3.50-3.60 (m, 1H), 3.74 (br s, 1H); 13C NMR (75 MHz,
Ba sic Con d ition . A mixture of 11 (95 mg, 0.20 mmol), 1,4-
dioxane (5.1 mL), and 0.3 M KOH (10.2 mL) was refluxed
overnight. After evaporation, MeOH (1.9 mL) and 6 N HCl
(5.6 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
D-fagomine (1) (4,9 mg, 17%) and D-3,4-di-epi-fagomine (3) (24,6
mg, 82%).
(2R,3R,4S)-2-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-3,4-
d ih yd r oxyp ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester
(17). A solution of 50% NMO (0.79 mL, 3.40 mmol) in water
and a solution of K2OsO4‚2H2O (20.9 mg, 56.7 µmol) in water
(0.9 mL) were successively added to a solution of 5 (512 mg,
1.13 mmol) in acetone (9.1 mL) and the mixture was stirred
at room temperature overnight. Na2SO3 was added to the
mixture and the mixture was stirred. The insoluble materials
were filtered off and the filtrate was evaporated. Cooled 1 N
HCl and CH2Cl2 were added to the residue and the organic
D2O) δ 28.4, 43.6, 59.7, 62.5, 68.5, 70.7. Anal. Calcd for C6H13
-
NO3: C, 48.97; N, 9.52; H, 8.90. Found: C, 48.90; N, 9.53; H,
8.97.
Ack n ow led gm en t. This work was supported in part
by a grant from Uehara Memorial Foundation and by a
Grant-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” from
the ministry of Education, Culture, Sports, Sciences,
and Technology, J apan.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds prepared in this study and
HMBC for product 15. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O034137U
J . Org. Chem, Vol. 68, No. 9, 2003 3607