Synthesis of the naringinase inhibitors l-swainsonine and related 6-C-methyl-l-swainsonine analogues: (6R)-C-methyl-l-swainsonine is a more potent inhibitor of l-rhamnosidase by an order of magnitude than l-swainsonine

Article abstract of DOI:10.1016/j.tetlet.2007.10.142

Efficient syntheses are reported of the α-l-rhamnosidase inhibitors l-swainsonine [(1R,2S,8S,8aS)-octahydroindolizine-1,2,8-triol], (6R)-C-methyl-l-swainsonine (1R,2S,6R,8S,8aS)-6-methyloctahydro-indolizine-1,2,8-triol, (6S)-C-methyl-l-swainsonine (1R,2S,

Full text of DOI:10.1016/j.tetlet.2007.10.142

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 179–184
Synthesis of the naringinase inhibitors L-swainsonine
and related 6-C-methyl-L-swainsonine analogues:
(6R)-C-methyl-L-swainsonine is a more potent inhibitor of
L-rhamnosidase by an order of magnitude than L-swainsonine
a
a
a
b
˚
Anders E. Hakansson, Jeroen van Ameijde, Graeme Horne, Robert J. Nash,
Mark R. Wormald,e Atsushi Kato,c Gurdyal S. Besra,d Sudagar Gurchad and
George W. J. Fleeta,*
aChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bSummit plc, Institute of Grassland and Environmental Research, Plas Gogerddan, Aberystwyth SY23 3EB, Ceredigion, Wales, UK
cDepartment of Pharmacy, Toyama University Hospital, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
dSchool of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
eGlycobiology Institute, Department of Biochemistry, Oxford University, South Parks Road, Oxford OX1 3QU, UK
Received 9 September 2007; revised 15 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—Efficient syntheses are reported of the a-L-rhamnosidase inhibitors L-swainsonine [(1R,2S,8S,8aS)-octahydroindolizine-
1,2,8-triol], (6R)-C-methyl-L-swainsonine (1R,2S,6R,8S,8aS)-6-methyloctahydro-indolizine-1,2,8-triol, (6S)-C-methyl-L-swainso-
nine (1R,2S,6S,8S,8aS)-6-methyloctahydro-indolizine-1,2,8-triol and related 6-C-methyl hydroxycastanospermines [(1R,2S,
6R,7R,8R,8aR)-6-methyl-octahydroindolizine-1,2,6,7,8-pentaol and (1R,2S,6S,8S,8aS)-6-methyloctahydro-indolizine-1,2,8-triol].
(6R)-C-Methyl-L-swainsonine [Ki = 0.032 lM] is a significantly more potent naringinase inhibitor than L-swainsonine [Ki =
0.45 lM].
Ó 2007 Elsevier Ltd. All rights reserved.
D-Swainsonine, a natural product isolated1 from Swain-
sona canescens, is a powerful inhibitor of a-manno-
sidases—in particular a mannosidase of glycoprotein
processing2—and may be regarded as a mimic of man-
nofuranose. Swainsonine is a potential chemotherapeu-
tic agent for the treatment of cancer3 and accordingly
has attracted much synthetic effort.4 Swainsonine is an
example of a carbohydrate mimic in which the ring oxy-
gen of a sugar is replaced by nitrogen;5,6 such alkaloids
have considerable therapeutic potential.7 Enantiomers
of iminosugars frequently show potent biological activ-
ity;8,9 D-imino sugar mimics usually inhibit D-glycosi-
dases competitively while their L-enantiomers are
generally more potent non-competitive inhibitors.10
non-mammalian sugars may provide new strategies for
the treatment of diseases such as those induced by myco-
bacteria.12 In contrast, there are only a few syntheses13
of L-swainsonine 1. This Letter reports a very efficient
synthesis of L-swainsonine 1. There have been limited
studies on the effect of alkyl branches on iminosugars
which usually cause significant loss of glycosidase inhibi-
tion.14 Introduction of carbon substituents at C-6 and
C-7 of D-swainsonine leads to some reduction in the
efficacy of a-mannosidase inhibition.15 This Letter also
describes the synthesis of epimeric 6-C-methyl
L-swainsonines 2 and 3, in which the 6(R)-epimer 2 is
the best inhibitor of naringinase yet reported and shows
the first example of significant enhancement of glycosi-
dase inhibition by the introduction of a branching alkyl
group. Synthetic dihydroxyswainsonines [hydroxycast-
anospermines] have been known for some time;16,17
two such pentahydroxyindolizidines were isolated from
the leaves of Eugenia uniflora18 but some doubt has
been cast on the proposed structures.19 This Letter
also describes the first syntheses of carbon branched
L-Swainsonine 1 is a potent inhibitor of naringinase (an
L-rhamnosidase);11 inhibition of enzymes that process
*
Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.142

˚
A. E. Hakansson et al. / Tetrahedron Letters 49 (2008) 179–184
180
pentahydroxyindolizidines, 6(R)- 4 and 6(S)-5 L-dihydr-
oxyswainsonines; again the substitution of a methyl
group at C-6 of L-swainsonine significantly enhances
inhibition of naringinase.
protection of lactone 6 using pentan-3-one as described
by Burke21 allowed access to the C-5 hydroxyl function
(55% yield) to give 7, and to lactone 822 [60% yield] in
which the configuration of both C-4 and C-5 had been
inverted. Further functional group manipulation gave
diol 9 on a multigram scale in 47% yield (28% from 7;
15% from 6). Periodate cleavage of 9 gave aldehyde 10
which on in situ treatment with the stabilised Wittig re-
Diol 9, the key intermediate for the synthesis of all the L-
swainsonine derivatives described in this Letter, has
been used for the synthesis of the potent rhamnosidase
inhibitor L-DIM 11 and may be prepared from the read-
ily available glucoheptonolactone 6 (Scheme 1).20 Initial
agent Bu3P@CHCO2Me afforded the E-enoate 12 as an
22
oil, ½aꢀD ꢁ8.5 (c, 1.0, CHCl3), in 81% yield (Scheme 2).
OH
OH
OH
OH
OH
HO
HO
HO
HO
HO
OH
HO
OH
OH
OH
OH
OH
OH
OH
OH
N
N
N
N
N
N
6
HO
HO
Me
Me
Me
Me
D-swainsonine
1 L-swainsonine
2
3
4
5
OH
HO
O
O
O
O
O
O
OH
4
HO
O
O
O
55%
60%
47%
OH
O[Si]
OH
O[Si]
CHO
1
OH
5
OH
O
OH
O
N
N
O
N
O
O
O
H
O
CH2OH
OH
HOH2C
Ph
Ph
OH
O
O
6
7
8
9
10
11
Scheme 1. For details of conversion of 6 to 9, see Ref. 20.
O
O
O
O
O
O
N
O
O
O
O
O
OH
OH
HO
(iv)
(i)
(i)
(iii)
+
O[Si]
O[Si]
O[Si]
O[Si]
O[Si]
(v)
(ii)
N
N
N
N
N
Ph
MeO2C
Ph
Ph
Ph
Me
OH
Me
OH
CO2Me
CO2Me
12
14-Z
(iii)
14-
E
9
13
1
HO
OH
O
O
O
O
O
O
O
O
(vii)
(iv)
(vi)
+
OH
O
OH
O[Si]
O[Si]
O
OH
N
Me
N
N
N
N
Ph
OH
OH
OH
OH
HO
17
O
Me
O
O
Me
19
Me
Me
4
15
16
(iv)
+
HO
OH
OH
Me
OH
HO
HO
O
O
O
O
OH
OH
OH
(vii)
(iv)
O
OH
N
N
N
Me
O
Me
OH
N
N
Ph
OH
OH
OH
OH
HO
O
Me
Me
20
18
5
2
3
Scheme 2. Reagents: (i) NaIO4, MeOH, H2O; (ii) Bu3P@CHCO2Me (81% over two steps); (iii) H2, Pd(OH)2, dioxane/H2O, 6:1 (95%); (iv) BH3,
THF; then CF3CO2H:H2O, 9:1 (82%); (v) Bu3P@C(Me)CO2Me (81% over two steps); (vi) TBAF, pyridinium chloride, THF; K2OsO4, NMO,
(DHQ)2AQN; (vii) H2, Pd(OH)2, dioxane/H2O, 6:1; then K2CO3, MeOH.

˚
A. E. Hakansson et al. / Tetrahedron Letters 49 (2008) 179–184
181
3
Table 2. JHH NMR coupling constants (Hz) of 1, 2 and 3 in 2H2O at
pH 9
Hydrogenation of 12 in aqueous dioxane in the presence
of palladium hydroxide on carbon gave lactam 13 in
95% yield. Reduction of the amide 13 with borane in
THF, followed by deprotection of the product with
aqueous trifluoroacetic acid formed L-swainsonine 1 in
82% yield (9.8% overall from 6, 17.9% from 7).23 This
synthetic route allows the preparation of significant
amounts of crystalline L-swainsonine 1.
1
2
3
C5H–C5H0
C5H–C6H
C5H0–C6H
C6H–C6CH3
C6H–C7H
C6H–C7H0
C7H–C7H0
C7H–C8H
C7H0–C8H
C8H–C8aH
C8aH–C1H
C1H–C2H
C2H–C3H
C2H–C3H0
C3H–C3H0
nd
nd
nd
—
nd
nd
nd
ꢁ10.9
3.0b
10.9
6.5
ꢁ11.2
1.5b
3.7
7.4
4.2
2.0b
5.3
11.4
ꢁ12.3
4.6
ꢁ12.6
For the synthesis of the branched 6(R)- 2 and 6(S)-3 C-
methylswainsonines, diol 9 was cleaved by periodate and
then treated in situ with Bu3P@C(Me)CO2Me to give a
mixture of enoates 14-Z and 14-E in a ratio of 1:4 and
81% combined yield. Hydrogenation of the mixture 14
in aqueous dioxane in the presence of palladium hydrox-
ide on carbon gave lactams 15 and 16 as separable oils in
43% and 28% yields, respectively; the stereochemistry at
C-6 of 15 and 16 was deduced from the products of sub-
sequent reactions. The reduction of 15 by borane in
THF, followed by deprotection of the crude product
with aqueous trifluoroacetic acid, afforded 6R-C-
methyl-L-swainsonine 224 in 77% yield. Similar treat-
ment of 16 gave 6S-C-methyl-L-swainsonine 325 in
81% yield, the structure of which was firmly established
by X-ray crystallographic analysis.26 6R-C-Methyl-L-
swainsonine 2 is the most potent inhibitor of L-rhamnos-
idase yet reported.
4.3
4.5
10.6
9.8a
3.3
11.0
9.7
3.7
11.3
9.6
3.7
5.7
5.9
2.5
7.9
6.0
2.4
8.0
1.6a
8.3
ꢁ10.7
ꢁ11.0
ꢁ11.0
a Couplings determined from HSQC because of overlap in the 1H 1D
spectrum.
b Couplings estimated by simulation of the 1D spectrum.
Table 3. 13C NMR (125.7 MHz) assignments (ppm) of 1, 2 and 3 in
2H2O at pH 9, referenced to acetone at 30.90 ppm
1
2
3
C5
C6
51.93
23.43
—
32.73
66.61
73.07
69.95
69.31
60.85
59.20
29.63
18.63
41.52
66.21
72.72
69.69
69.55
60.62
58.07
28.86
19.11
38.49
63.66
73.88
70.12
69.53
61.65
C6CH3
C7
The solution NMR structures of the methyl substituted
compounds 2 and 3 were compared with that of L-
swainsonine 1. Full 1H and 13C assignments for all three
compounds are given in Tables 1–3.
C8
C8a
C1
C2
C3
3
The JHH coupling constant values are sensitive to both
the relative configurations of the ring protons and to the
ring conformation.27 The values of the C7H/H0–C8H–
C8aH–C1H–C2H–C3H/H0 coupling constants are very
similar for 1, 2 and 3 (Table 2) indicating the same
relative configurations at these carbons and that all three
compounds adopt the same ring conformation, with
the C7H0, C8H and C8aH protons axial and the C7H
and C1H protons equatorial. The large C5H0–C6H–
C7H0 couplings in 2 indicate that these three protons
are all axial, and so the C6 methyl group is equatorial.
The lack of a large coupling between C6H and either
C5H, C5H0, C7H or C7H0 in 3 indicates that C6H is
equatorial, and so the C6 methyl group is axial. These
patterns of coupling constants and the patterns of NOEs
(not shown) for all three compounds are fully consistent
with the ring conformation, or its enantiomer, reported
for the crystal structure of swainsonine diacetate.28
Thus, methylation at the C6 position has no effect on
the overall ring conformation of 1.
Table 1. 1H NMR (500 MHz) assignments (ppm) of 1, 2 and 3 in 2H2O
at pH 9, referenced to acetone at 2.220 ppm
1
2
3
The 6(R)- 4 and 6(S)- 5 C-methyl dihydroxyswainso-
nines were also prepared. Attempts at dihydroxylation
C5H
C5H0
C6H
C6H0
C6CH3
C7H
C7H0
C8H
C8aH
C1H
C2H
C3H
C3H0
2.912a
1.964a
1.716
1.514
—
2.054
1.234
3.798
1.925a
4.254
4.347
2.889a
2.566
2.870
1.640
1.71
2.749
2.135
2.07
—
—
0.899
2.059
0.962
3.826
1.883
4.240
4.349
2.863
2.531
1.048
1.882
1.424
4.018
1.843
4.235
4.331
2.850
2.493
O
O
O
O
H
H
H
H
H
O
O
4
N
O
4
N
O
2
2
Ph
Ph
HO
Me
OH
H
OH
HO
Me
17
18
a Chemical shifts determined from HSQC because of overlap in the 1H
1D spectrum.
Figure 1. NOEs used to determine the relative stereochemistries of 17
and 18.

˚
A. E. Hakansson et al. / Tetrahedron Letters 49 (2008) 179–184
182
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
OH
OH
OH
OH
OH
OH
OH
N
N
N
N
N
HO
HO
Me
Me
Me
Me
1
2
3
4
5
IC50 0.13 μM
KI = 0.45 μM
IC50 0.034 μM
KI = 0.032 μM
IC50 1.17 μM
KI = 1.1 μM
IC50 21.3 μM
IC50 9.2 μM
Inhibition of α-L-rhamnosidase
HO
OH
OH
HO
OH
OH
HO
OH
OH
HO
OH
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
N
N
N
N
N
21
IC50 530 μM
22
IC50 610 μM
23
IC50 = 700 μM
24
IC50 = 50 μM
25
IC50 = 265 μM
Figure 2. IC50 (lM) of naringinase inhibition by L-swainsonine analogues.
of the major enoate 14-E under a number of different
conditions failed; however, initial deprotection of the
silyl ether in 14-E using tetrabutylammonium fluoride
(TBAF) and pyridinium chloride in THF (76% yield),
followed by dihydroxylation with potassium osmate
and N-methylmorpholine-N-oxide (NMO) in the pres-
ence of (DHQ)2AQN, afforded the separable lactones
1729 and 1830 in a combined yield of 72% in a ratio of
3:1 (Fig. 1).
thus, whereas dihydroxyswainsonine 22 showed an IC50
value of 610 lM, the introduction of a 6S-methyl group
in 5 lowered the IC50 value to 9.2 lM.
In summary, this Letter reports an efficient synthesis of
L-swainsonine 1 and several analogues with a branching
C-6 methyl group. The introduction of a methyl group
at C-6 in most L-swainsonine analogues increases the
a-L-rhamnosidase inhibition and, in particular, the 6R-
C-methyl analogue 2 is the most potent naringinase
inhibitor yet described.
The stereochemical outcome was assigned by the NOE
experiments indicated in Figure 2, since the cis-hydr-
oxylation of the E-enoate 14-E guaranteed a trans-
relationship between the hydroxyl substituents in the
lactone ring. Hydrogenation of 17, the major product,
in the presence of Pearlman’s catalyst (20% Pd(OH)2/
C) in dioxane, followed by treatment with potassium
carbonate in methanol promoted rearrangement of lac-
tone 17 to lactam 19; reduction of lactam 19 with borane
in THF, followed by deprotection with aqueous trifluoro-
acetic acid afforded the 6(R)-methyl branched dihydroxy-
swainsonine 4.31 A similar sequence of reactions on 18
gave, via lactam 20, the 6(S)-epimer 532 in 22% yield.
References and notes
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Chem. 1979, 32, 2257–2264.
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20
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21
9. (a) Scofield, A. M.; Fellows, L. E.; Nash, R. J.; Fleet, G.
W. J. Life Sci. 1986, 39, 645–651; (b) Behling, J. R.;
Campbell, A. L.; Babiak, K. A.; Ng, J. S.; Medich, J.;
Farid, P.; Fleet, G. W. J. Tetrahedron 1993, 49, 3359–3368;
(c) Fleet, G. W. J.; Smith, P. W. Tetrahedron 1986, 42,
5685–5691; (d) Fleet, G. W. J.; Nicholas, S. J.; Smith, P.
W.; Evans, S. V.; Fellows, L. E.; Nash, R. J. Tetrahedron
Lett. 1985, 26, 3127–3130.
+79.5 (c 2.65, H2O) {lit.17 mp 143–145 °C; ½aꢀD +84.3 (c,
1.02, H2O)}. For NMR data, see Tables 1–3.
24. Selected data for 6R-C-methyl-L-swainsonine 2: mp 166–
22
167 °C (H2O); ½aꢀD +77.5 (c 2.57, H2O); for NMR data,
see Tables 1–3.
25. Data for 6S-C-methyl-L-swainsonine 3: mp 148–150 °C
22
(decomp., H2O); ½aꢀD þ 43:7 (c 1.72, H2O); For NMR
data, see Tables 1–3.
˚
10. (a) 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, 2036–2044; (b) Asano,
N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi,
I.; Kato, I.; Ouchi, H.; Takahata, H.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2005, 16, 223–229; (c) Yu, C. Y.;
Asano, N.; Ikeda, K.; Wang, M. X.; Butters, T. D.;
Wormald, M. R.; Dwek, R. A.; Winters, A. L.; Nash, R.
J.; Fleet, G. W. J. Chem. Commun. 2004, 1936–1937.
11. Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A. A.;
Griffiths, R. C.; Jones, M. G.; Smith, C.; Fleet, G. W. J.
Tetrahedron Lett. 1996, 37, 8565–8568.
26. Hakansson, A. E.; Horne, G.; Fleet, G. W. J.; Watkin, D.
J. Acta Crystallogr., Sect. E 2007, 63, o210–o212.
27. Wormald, M. R.; Nash, R. J.; Hrnciar, P.; White, J. D.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
1998, 9, 2549–2558.
28. Skelton, B. W.; White, A. H. Aust. J. Chem. 1980, 33, 435–
439.
20
29. Data for 17: Rf = 0.20 (EtOAc/cyclohexane, 1:2); ½aꢀD
+23.2 (c 2.32, CHCl3); IR (film) m = 3440 (OH), 1785
(C@O) cmꢁ1; H NMR (400 MHz, CDCl3) d = 7.33–7.21
1
(m, 5H, ArH), 4.81 (d, J3,4 = 7.7 Hz, 1H, H-3), 4.70–4.64
(m, 2H, H-6, H-7), 4.61 (br s, 1H, OH), 4.47 (dd, J =
12. (a) Lee, R. E.; Smith, M. D.; Pickering, L.; Fleet, G. W. J.
Tetrahedron Lett. 1999, 40, 8689–8692; (b) Lee, R. E.;
Smith, M. D.; Nash, R. J.; Griffiths, R. C.; McNeil, M.;
Grewal, R. K.; Yan, W.; Besra, G. S.; Brennan, P. J.;
Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 6733–
6736.
13. (a) Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609–
1612; (b) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S.
Synlett 1995, 404–406.
14. (a) Blanco, M. J.; Sardina, F. J. J. Org. Chem. 1998, 63,
3411–3416; (b) Burley, I.; Hewson, A. T. Tetrahedron Lett.
1994, 35, 7099–7102; (c) Bols, M. Tetrahedron Lett. 1996,
37, 2097–2100; (d) Hotchkiss, D. J.; Kato, A.; Odell, B.;
Claridge, T. D. W.; Fleet, G. W. J. Tetrahedron: Asym-
metry 2007, 18, 500–512.
1.0 Hz, J3,4 = 7.7 Hz, 1H, H-4), 3.99 (d, JArCHa,ArCHb =
13.4 Hz, 1H, ArCHa), 3.07 (app d, J = 12.5 Hz, 2H, H-8a,
ArCHb), 2.95–2.93 (m, 1H, H-5), 2.75 (br s, 1H, OH), 2.13
(dd, J7,8b = 4.9 Hz, J8a,8b = 11.5 Hz, 1H, H-8b), 1.94–1.74
(m, 2H, C(CH2CH3)2), 1.68–1.53 (m, 2H, C(CH2CH3)2),
1.49 (s, 3H, 2-Me), 1.02 (t, JEt = 7.5 Hz, 3H, C(CH2-
CH3)2), 0.87 ppm (t, JEt = 7.5 Hz, 3H, C(CH2CH3)2); 13C
NMR (100 MHz, CDCl3) d = 177.3 (C@O), 138.0, 128.4,
128.4, 127.2 (ArC), 116.4 (C(CH2CH3)2), 81.4 (C-4), 80.8
(C-7), 77.5 (C-6), 76.3 (C-2), 72.7 (C-3), 67.5 (C-5), 60.1
(C-8), 58.6 (ArCH2), 28.5, 28.3 (C(CH2CH3)2), 19.3 (2-
Me), 8.5, 7.6 ppm (C(CH2CH3)2); HRMS m/z (ESI +ve):
[M+H]+ calcd for C21H30NO6, 392.2068; found, 392.2067.
20
30. Data for 18: Rf = 0.28 (EtOAc/cyclohexane, 1:2); ½aꢀD
+31.8 (c 2.06, CHCl3); IR (film) m = 3418 (OH), 1784
1
15. Pearson, W. H.; Hembre, E. J. Tetrahedron Lett. 2001, 42,
8273–8276.
(C@O) cmꢁ1; H NMR (400 MHz, CDCl3) d = 7.34–7.22
(m, 5H, ArH), 5.03 (dd, J4,5 = 1.5 Hz, J3,4 = 2.8 Hz, 1H,
H-4), 4.80 (dd, J5,6 = 5.0 Hz, J6,7 = 6.4 Hz, 1H, H-6),
16. (a) Chen, Y.; Vogel, P. Tetrahedron Lett. 1992, 33, 4917–
4920; (b) Chen, Y.; Vogel, P. J. Org. Chem. 1994, 59,
2487–2496; (c) Picasso, S.; Chen, Y.; Vogel, P. Carbohydr.
Lett. 1994, 1, 1–8; (d) Overkleeft, H. S.; Pandit, U. K.
Tetrahedron Lett. 1996, 37, 547–550; (e) Izquierdo, I.;
4.63–4.59 (m, 2H, H-3, H-7), 4.47 (d, JArCHa,ArCHb
=
12.8 Hz, 1H, ArCHa), 3.28 (dd, J4,5 = 1.4 Hz,
J5,6 = 5.0 Hz, 1H, H-5),3.07 (d, J8a,8b = 11.9 Hz, 1H,
H-8a), 3.05 (d, JArCHa,ArCHb = 12.8 Hz, 1H, ArCHb),

˚
A. E. Hakansson et al. / Tetrahedron Letters 49 (2008) 179–184
184
2.08 (dd, J7,8b = 5.1 Hz, J8a,8b = 11.9 Hz, 1H, H-8b), 1.83
2.37–2.29 (m, 2H, H-50, H-8a), 1.21 ppm (s, 3H, 6-Me);
13C NMR (100 MHz, D2O) d = 74.5 (C-7), 72.7 (C-6),
70.2 (C-1), 69.7 (C-2), 65.5 (C-8), 64.8 (C-8a), 59.5
(C-3), 56.6 (C-5), 23.1 ppm (6-Me); HRMS m/z (ESI
+ve): [M+H]+ calcd for C9H18NO5, 220.1179; found,
220.1188.
(q, JEt = 7.6 Hz, 2H, C(CH2CH3)2), 1.58 (s, 3H, 2-Me),
1.60–1.52 (m, 2H, C(CH2CH3)2), 0.99 (t, JEt = 7.6 Hz, 3H,
C(CH2CH3)2), 0.86 ppm (t, JEt = 7.6 Hz, 3H, C(CH2-
CH3)2); 13C NMR (100 MHz, CDCl3) d = 176.5 (C@O),
136.7, 128.8, 128.6, 127.5 (ArC), 116.3 (C(CH2CH3)2),
80.8 (C-6), 79.5 (C-3), 78.2 (C-4), 77.6 (C-2), 77.0 (C-7),
68.4 (C-5), 60.3 (ArCH2), 59.4 (C-8), 28.3, 26.6
(C(CH2CH3)2), 17.6 (2-Me), 8.6, 8.4 ppm (C(CH2CH3)2);
HRMS m/z (ESI +ve): [M+H]+ calcd for C21H30NO6,
20
32. 6(S)-Methyl branched dihydroxyswainsonine 5 ½aꢀD +27.7
(c 0.85, H2O); 1H NMR (400 MHz, D2O) d = 4.38–4.31
(m, 1H, H-2), 4.18 (dd, J = 3.5 Hz, J = 5.8 Hz, 1H, H-1),
3.60 (app t, J = 10.0 Hz, 1H, H-8), 3.32 (d, J = 9.3 Hz,
1H, H-7), 2.87–2.81 (m, 2H, H-3, H-5), 2.52 (dd,
392.2068; found, 392.2068.
20
J2;3 ¼ 8:1 Hz, J3;3 ¼ 10:7 Hz, 1H, H-30), 2.10–2.01 (m,
2H, H-50, H-8a), 1.23 ppm (s, 3H, 6-Me); 13C NMR
(100 MHz, D2O) d = 80.9 (C-7), 72.7 (C-6), 71.7 (C-8a),
70.0 (C-2), 69.6 (C-1), 68.2 (C-8), 62.0 (C-5), 60.2 (C-3),
20.3 ppm (6-Me); HRMS m/z (ESI ꢁve): [MꢁH]ꢁ calcd
for C9H16NO5, 218.1023; found, 218.1023.
0
0
31. 6(R)-Methyl branched dihydroxyswainsonine 4: ½aꢀD
1
+36.2 (c 1.05, H2O); H NMR (400 MHz, D2O) d = 4.36
0
(ddd, J2,3 = 2.8 Hz, J1,2 = 5.7 Hz, J2;3 ¼ 8:5 Hz, 1H,
H-2), 4.18 (dd, J1,8a = 3.7 Hz, J1,2 = 5.7 Hz, 1H, H-1),
4.11 (dd, J7,8 = 3.3 Hz, J8,8a = 10.4 Hz, 1H, H-8), 3.61 (d,
J7,8 = 3.3 Hz, 1H, H-7), 2.88 (dd, J2,3 = 2.8 Hz,
J8,8a = 10.9 Hz, 1H, H-3), 2.69–2.62 (m, 2H, H-30, H-5),
33. For details of the enzyme assays see Ref. 20.