Hydroxylated C-branched pyrrolidines, C-branched prolines and C-branched piperidines from a 2-C-methyl sugar lactone; efficient azide displacement of a tertiary triflate with inversion of configuration

Article abstract of DOI:10.1016/j.tetlet.2008.09.069

The versatility of 3,4-O-isopropylidene-2-C-methyl-d-arabinonolactone [from d-erythronolactone] as a chiron for complex piperidines and pyrrolidines is illustrated by the synthesis of (2R,3S,4S)- and (2R,3S,4R)-dihydroxy-2-C-methyl prolines, 1,4-dideoxy-1,4-imino-4-C-methyl-l-ribitol and 1,4-dideoxy-1,4-imino-4-C-methyl-l-arabinitol, and isofagomine derivatives; the enantiomeric series is equally accessible from l-erythronolactone.

Full text of DOI:10.1016/j.tetlet.2008.09.069

Tetrahedron Letters 49 (2008) 6812–6815
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydroxylated C-branched pyrrolidines, C-branched prolines and C-branched
piperidines from a 2-C-methyl sugar lactone; efficient azide displacement
of a tertiary triflate with inversion of configuration
*
Filipa P. da Cruz, Graeme Horne, George W. J. Fleet
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The versatility of 3,4-O-isopropylidene-2-C-methyl-D-arabinonolactone [from D-erythronolactone] as a
Received 6 August 2008
Revised 3 September 2008
Accepted 12 September 2008
Available online 17 September 2008
chiron for complex piperidines and pyrrolidines is illustrated by the synthesis of (2R,3S,4S)- and
(2R,3S,4R)-dihydroxy-2-C-methyl prolines, 1,4-dideoxy-1,4-imino-4-C-methyl- -ribitol and 1,4-dideoxy-
1,4-imino-4-C-methyl- -arabinitol, and isofagomine derivatives; the enantiomeric series is equally acces-
sible from -erythronolactone.
L
L
L
Ó 2008 Elsevier Ltd. All rights reserved.
Although carbohydrates comprise the most extensive family of
chirons,1 there are only a few examples of the use of C-branched
sugars as chirons in synthesis.2 2-C-Branched carbohydrate lac-
tones are readily available by the Kiliani reaction on ketoses3 or
starting material by short syntheses of hydroxylated pyrrolidines
and piperidines containing a C-methyl substituent.
The protected 2-C-methyl-D-arabinonolactone 3 was prepared
in an overall yield of around 60% from
D
-erythronolactone 1 by
by an Amadori-calcium oxide sequence.4 2-C-Methyl-
D-ribonolac-
acetonation followed by addition of methylmagnesium bromide
to afford the lactols 2, and then a Kiliani reaction with sodium
cyanide (Scheme 1).10 The key transformation of the protected
lactone 3 to the azides 4 and/or 9 proceeded efficiently. The
tertiary ribo-azide 4 may be directly transformed into the C-methyl
pyrrolidines 5 and 6. An inversion of configuration at C-4 in 3
allowed conversion to the bicyclic lactones 7 and 8 which can be
tone has been used in the synthesis of branched 20-5 and 40-6 C-
nucleosides, 4-C-methylpentuloses,7 and of branched imino sug-
ars.8 The protected 2-C-methyl arabinono-lactone 3 can be pre-
pared from D-erythronolactone 1 and has been used in syntheses
of 20-C-methyl nucleosides9 and carbon-branched ketoses.7 This
Letter illustrates the potential of carbon-branched lactone 3 as a
RO
HO
OH
HO
O
OH
CH2OH
Me
HO
OH
CO2H
O
Me
N3
O
HN
O
O
O
Me
N
H
Me
N
H
O
O
7: R = PhCH2
8: R = Ph2CH
1
O
4
5
6
HO
Me
O
O
O
OH
NH2
OH
OH
N3
O
O
3
O
O
HO
OH
OH
OH
HO
OH
CO2H
Me
O
Me
HO
CH2OH
Me
N
H
N
H
N
H
O
N
H
O
2
9
10
11
12
13
Scheme 1. C-Methyl branched prolines and imino sugars from 2-C-methylarabinono-lactone.
* Corresponding author.
E-mail address: george.fleet@chem.ox.ac.uk (G. W. J. Fleet).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.069

F. P. da Cruz et al. / Tetrahedron Letters 49 (2008) 6812–6815
6813
H
N3
O
Me
O
Me
O
O
CF3SO2O
O
+
HO
Me
O
Me
N3
Me
(i)
O
O
O
O
O
O
NOT
O
O
O
O
O
O
O
O
(ii)
3
14
15
4
16
CH2N3
O
O
O
O
O
CF3SO2O
Me
O
O
O
O
O
O
O
O
O
O
O
17
9
Scheme 2. Preparation of the azides 4 and 9. Reagents and conditions: (i) (CF3SO2)2O, pyridine, CH2Cl2; (ii) NaN3, DMF.
converted to the epimeric pyrrolidines 12 and 13. The branched
azidomethyl lactone 9 provides a short synthesis of the isofago-
mine analogues 10 and 11.
azide afforded 9 in which the stereochemistry is determined by
protonation to give the less hindered product. The exact ratio of
4–9 depended on how long the reaction mixture was allowed to
stand in DMF before the addition of azide. If the triflate 14 was left
in DMF at room temperature overnight and then azide was added,
the azide 9 (with none of 4) was formed in 47% overall yield from
the alcohol 3; if azide was not added, the intermediate alkene 1714
could be isolated in 70% yield from 3. Addition of sodium azide to a
solution of pure 17 in DMF did not give any 9, so it seems that the
triflic acid from decomposition of 14 is necessary for catalysis of
the Michael addition.
Esterification of the tertiary alcohol 3 with triflic anhydride in
dichloromethane in the presence of pyridine gave the triflate 14
(Scheme 2). Reaction of 14 in situ with sodium azide in DMF affor-
ded a separable mixture of the azides 4 [mp 88–90 °C; ½a D22
ꢀ
ꢁ129.7
(c, 1.05 in CHCl3), 52% yield] and 9 (mp 90–92 °C; ½a D23
ꢀ
ꢁ168.2 (c,
0.99 in CH3CN) 28% yield) in a combined yield of 80%.
From X-ray crystallographic analysis, the alcohol 311 and the
azides 412 and 913 all exist in a boat conformation in the solid state;
the nucleophilic displacement at the tertiary center in 14 presum-
ably proceeded via an SN1 pathway to give the carbocation 15.
Attack on 15 by the azide from the less hindered side afforded
the major product 4, avoiding an approach of the nucleophile on
a pathway past the flagpole hydrogen; none of the ribo epimer
16 was isolated. The branched azide 9 plausibly arose by loss of
a proton from 15 to the enoate 17 which on Michael addition by
The use of ribo-azide 4 for the synthesis of pyrrolidines contain-
ing a carbon branch is shown in Scheme 3. Reduction of the lactone
4 with lithium borohydride in THF gave the open chain diol 18 (oil,
½
a 2D3
+22.7 (c, 1.02 in MeOH), 90%). Reaction of 18 with tosyl chlo-
ride was unselective; however, reaction of 18 with mesitylsulfonyl
ꢀ
chloride in pyridine resulted in selective esterification of the less
hindered primary alcohol to form the mesitylate 19 (oil; ½a D19
ꢀ
HO
Me
HOH2C
OH
O
O
O
O
O
Me
N3
HO
Me
N3
HO
O
O
Me
N3
O
(i)
(ii)
(iii)
(iv)
Me
HOH2C
N
H
N
H
OMst
OH
O
O
4
18
19
20
6
(v)
Ts = 4-Me-C6H4SO2
(vii)
Mst = 2,4,6-Me3C6H2SO2
HO
Me
HO2C
OH
HO
Me
OH
HO OH
(viii)
N3 OH
N3 OH
(vi)
(ix)
Me
O
Me
O
Me
OTs
BnNH
BnNH
N
N
N3
H
H
CH2OH
O
CH2OTs
O
O
O
21
22
23
5
24
(x)
HO
OH
PhCH2O
HN
N3 OCH2Ph
N3 OCH2Ph
Me
(xi)
(xii)
O
(xiii)
Me
Me
O
HOH2C
N
H
O
CH2OH
CH2OTs
O
O
Me
O
(xv)
(xiv)
25
26
7
12
HO
OH
Ph2CHO
HN
N3 OCHPh2
N3 OCHPh2
(xviii)
Me
(xvii)
(xvi)
O
Me
O
Me
O
HO2C
N
H
CH2OTs
CH2OH
O
Me
O
O
27
28
8
13
Scheme 3. Reagents and conditions: (i) LiBH4, THF, 90%; (ii) MstCl, pyridine, 72%; (iii) H2, Pd, dioxane; (iv) CF3COOH, H2O, dioxane, 83% over 2 steps; (v) CF3COOH, H2O,
dioxane, 89%; (vi) TsCl, pyridine, 68%; (vii) PhCH2NH2, THF, 82%; (viii) H2, Pd, dioxane; (ix) concd HCl 83% over two steps; (x) PhCH2Br, NaH, DMF, 65%; (xi) KOH, dioxane; then
Dowex, 86%; (xii) (CF3SO2)2O, pyridine, CH2Cl2; then H2, Pd/C, dioxane, 72%; (xiii) NaBH4, MeOH; then H2, Pd/C, H2O, 89%; (xiv) NaOH, dioxane-H2O; then H2, Pd/C, H2O, 87%;
(xv) Ph2CHN2, dioxane, heat, 60%; (xvi) KOH, dioxane; then Dowex, 72%; (xvii) (CF3SO2)2O, pyridine, CH2Cl2; then H2, Pd/C, dioxane, 42%; (xviii) NaOH, dioxane-H2O; then H2,
Pd/C, H2O, 90%.

6814
F. P. da Cruz et al. / Tetrahedron Letters 49 (2008) 6812–6815
OH
OH
OH
OH
N3
O
OH
CH2OTs
N3
O
OH
CH2OH
OH
(ii)
(iii)
(iv)
OH
OTs
N3
N
H
O
O
(i)
29
30
31
10
N3
O
O
O
O
N3
NH2
O
OH
(v)
9
N3
N3
O
O
O
(vi)
(vii)
(viii)
OH
O
O
N
N
H
OMs
HO
MsO
OH
Bn
32
33
34
11
Scheme 4. Reagents and conditions: (i) Dowex 50 H+, dioxane, H2O, 85%; (ii) TsCl, DABCO, MeCN, 65%; (iii) LiBH4, THF, 55%; (iv) H2, Pd/C, dioxane, 85%; (v) DIBALH, CH2Cl2;
then LiBH4, THF, 75%; (vi) MsCl, pyridine, 81%; (vii) PhCH2NH2, heat, 72%; (viii) CF3CO2H, dioxane; then H2, Pd/C, dioxane, 72%.
+17.8 (c, 0.90 in CHCl3), 72%). Hydrogenation of the protected azide
19 in the presence of palladium on carbon in dioxane gave the cor-
responding amine which spontaneously cyclized to form the pro-
tected imino sugar 20, which with trifluoroacetic acid in aqueous
sodium hydroxide in aqueous dioxane followed by removal of the
protecting group by hydrogenation gave the proline 13 (90% yield),
identical in all respects to the sample prepared from the benzyl
protected lactone 7.
dioxane (4:1:1) afforded 1,4-dideoxy-4-C-methyl-1,4-imino-
L
-ribi-
Isofagomines, with a carbon branch in a piperidine ring, are a
class of imino sugar glycosidase inhibitors.22 The 2-C-azidomethyl
lactone 9 can be used to synthesize isofagomine analogues con-
taining either epimeric carbon branch (Scheme 4). Hydrolysis of
the azidomethyl lactone 9 with Dowex 50 H+ in aqueous dioxane
tol 615 (83% over two steps; 54% from 4).
An alternative strategy was investigated where the isopropyl-
idene protecting group was removed at an early stage. Hydrolysis
of the protected d-azido 4 with trifluoroacetic acid in aqueous
dioxane (4:1:1) gave the
c
-lactone 2116 (mp 74–76 °C; ½a 2D3
ꢀ
gave the unprotected lactone 29 (mp 98–100 °C; ½a D18
ꢁ1.6 (c,
ꢀ
ꢁ105.5 (c, 1.00 in MeOH), 89% yield), the primary alcohol of which
0.80 in MeCN)) in 85% yield. Selective esterification of primary
alcohol 29 by reaction with tosyl chloride in acetonitrile in the
presence of DABCO afforded the primary tosylate 30 (colorless
was selectively esterified by reaction with tosyl chloride in pyr-
idine to afford the tosylate 22 (mp 108–109 °C; ½a D22
ꢀ
+104.2 (c,
0.98 in MeCN, 68%). Treatment of 22 with benzylamine in THF gave
oil; ½a 1D8
ꢀ
+24 (c, 1.00 in MeCN), 65%). Reduction of the lactone 30
the open chain azidoamide 23 (oil; ½a D21
ꢀ
ꢁ6.2 (c, 1.00 in CHCl3),
with lithium borohydride in THF gave the triol 31 (oil; ½a D22
ꢀ
+4.1
82%). Hydrogenation of the azide 23 in the presence of palladium
on carbon in dioxane gave the corresponding amine which sponta-
neously cyclized to form the pyrrolidine amide 24. The amide 24
was hydrolyzed by concentrated aqueous hydrochloric acid to give
(2R,3S,4R)-dihydroxy-2-C-methyl proline 517 (83% over two steps;
41% from 4). Only one isopropylidene group is used throughout
this sequence.
The epimeric iminosugar 12 and proline 13 required an addi-
tional inversion of configuration at C4 of the D-arabinono-lactone
21. The remaining free alcohol in the tosylate 22 was protected
by treatment with benzyl bromide and sodium hydride in DMF
to give 25; subsequent treatment with potassium hydroxide in
(c, 0.85 in MeCN), 55%); hydrogenation of the azido-tosylate 31
yielded
(3R,4S,5S)
5-hydroxymethyl-3,4-dihydroxypiperidine
(4,5-diepi-isofagomine) 1023 (85% yield; 26% overall yield from
9). The aminomethyl substituent in 11 is epimeric with the
hydroxymethyl group in 10. Reduction of the lactone 9 by initial
reaction with DIBALH in dichloromethane followed by treatment
with lithium borohydride in THF afforded the diol 32 (75%). Ester-
ification of both primary hydroxyl groups in 32 with mesyl chlo-
ride gave dimesylate 35 (81%) which on heating in benzylamine
at 100 °C formed the protected azido-piperidine 34 (oil, ½a D22
ꢀ
ꢁ18.4 (c, 0.95 in CHCl3)) in 72% yield. Removal of the acetonide
in 34 by trifluoroacetic acid in dioxane, followed by hydrogenation,
gave (3R,4S,5R) 5-aminomethyl-3,4-dihydroxypiperidine 1124 in
72% yield.
dioxane afforded the
L
-lyxonate 26 (mp 104–106 °C; ½a D22
ꢀ
+40.6
(c, 1.00 in CHCl3)) in 54% yield over the two steps. Esterification
of 26 with triflic anhydride in the presence of pyridine followed
The enantiomers of all the target compounds may be made from
by catalytic hydrogenation gave the bicyclic lactone 7 [oil; ½a D21
ꢀ
L
-erythronolactone. Both
tone are available from the Humphlett oxygenation of an alkaline
solution of - or -erythronolactone
-arabinose, respectively;25
D-erythronolactone and L-erythronolac-
ꢁ71.0 (c, 1.00 in MeCN)] in 72% yield. Reduction of lactone 7 with
sodium borohydride and removal of the benzyl protecting group by
D
L
D
hydrogenolysis gave 1,4-dideoxy-4-C-methyl-1,4-imino-
L
-arabini-
acetonide can also be prepared by hydrogen peroxide oxidation
of erythrobic acid, followed by acetonation.26 In summary, the va-
lue of an easily available 2-C-methyl lactone 3 (or its enantiomer)
as a divergent intermediate for access to highly functionalized
tol 1218 in 89% yield.
Treatment of the bicyclic lactone 7 with sodium hydroxide in
aqueous dioxane followed by hydrogenation yielded (2R,3S,4S)-
dihydroxy-2-C-methyl proline 13,19 epimeric with 5, in 87% yield.
Benzhydryl may be used as an alternative protecting group:20
treatment of the tosylate 22 with diphenyldiazomethane in
dioxane afforded the benzhydryl ether 27 (60%) which with
potassium hydroxide in aqueous dioxane gave the epimeric alcohol
pyrrolidines and piperidines containing
a carbon branch is
demonstrated; for the majority of the syntheses, only a single iso-
propylidene group is used.
Acknowledgments
28 (mp 121–123 °C; ½a D21
ꢀ
+46.3 (c, 0.80 in CHCl3)) in 72% yield.
Triflation of 28, followed by catalytic hydrogenation, gave the
Financial support (to FPC) provided by the Fundação para a
Ciência e Tecnologia, Portugal is gratefully acknowledged. We
thank Dextra Laboratories Limited, Reading, UK for generous gifts
benzhydryl protected lactone 8 (mp 116–118 °C; ½a D21
ꢁ26.0 (c,
ꢀ
1.00 in MeCN)) in 42% yield; the structure of 8 was firmly
established by X-ray crystallographic analysis.21 Reaction of 8 with
of D-erythronolactone.

F. P. da Cruz et al. / Tetrahedron Letters 49 (2008) 6812–6815
6815
3.35 (1H, dd, J1 ,2 4.8 Hz, J1 ,1 12.7 Hz, H-10), 3.56 (2H, s, H-5, H-50), 4.40 (1H, d,
J3,2 4.7 Hz, H-3), 4.37–4.40 (1H, m, H-2); dC (100.6 MHz, D2O) 16.2 (CH3), 48.7
(C-1), 64.2 (C-5), 68.5 (C-4), 70.3 (C-2), 72.7 (C-3).
0
0
References and notes
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17. Selected data for (2R,3S,4R)-dihydroxy-2-C-methyl proline 5: Glass, ½a D18
ꢀ
+11.2 (c,
0
0.50 in H2O); dH (400 MHz, D2O) 1.40 (3H, s, CH3), 3.03 (1H, dd, J5,5 12.0 Hz, J5,4
7.1 Hz, H-5), 3.41 (1H, dd, J5 ,5 12.0 Hz, J5 ,4 7.1 Hz, H-50), 4.14 (1H, d, J3,4 4.1 Hz,
H-3), 4.20–4.25 (1H, m, H-4); dC (100.6 MHz, D2O) 17.2 (CH3), 47.4 (C-5), 70.0
(C-4), 72.7 (C-2), 74.6 (C-3), 175.8 (C@O).
0
0
18. Selected data for 4-C-methyl imino-
L
-arabinitol 12: Oil, ½a D21
þ 4:1 (c, 1.00 in
ꢀ
0
H2O); dH (400 MHz, D2O) 1.20 (3H, s, CH3), 3.07 (1H, dd, J1,1 12.7 Hz, J1,2 5.0 Hz,
H-1), 3.51–3.57 (2H, m, H-10, H-5), 3.67 (1H, part of an AB system, JAB 12.3 Hz,
H-50), 3.88 (1H, d, J3,2 5.1 Hz, H-3), 4.25–4.29 (1H, m, H-2); dC (100.6 MHz, D2O)
15.2 (CH3), 47.8 (C-1), 63.8 (C-5), 69.5 (C-4), 74.2 (C-2), 77.3 (C-3).
19. Selected data for (2R,3S,4S)-dihydroxy-2-C-methyl proline 13: Mp 200 °C (dec);
0
½ ꢀ þ 6:6 (c, 1.00 in H2O); dH (400 MHz, D2O) 1.50 (3H, s, CH3), 3.33 (1H, d, J5,5
a 2D5
0 0
12.8 Hz, H-5), 3.54 (1H, dd, J5 ,5 12.8 Hz, J5 ,4 4.5 Hz, H-50), 4.28–4.29 (1H, m, H-
4), 4.38 (1H, br s, H-3); dC (100.6 MHz, D2O) 17.5 (CH3), 50.8 (C-5), 73.8 (C-2),
75.2 (C-4), 79.4 (C-3), 176.4 (C-1).
20. Best, D.; Jenkinson, S. F.; Rule, S. D.; Higham, R.; Mercer, T. B.; Newell, R. J.;
Weymouth-Wilson, A. C.; Fleet, G. W. J.; Petursson, S. Tetrahedron Lett. 2008, 49,
2196–2199.
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22. (a) Bols, M. Acc. Chem. Res. 1998, 31, 1–8; (b) Liu, H.; Liang, X.; Sohoel, H.;
Bulow, A.; Bols, M. J. Am. Chem. Soc. 2001, 123, 5116–5117; (c) Kim, Y. J.;
Ichikawa, M.; Ichikawa, Y. J. Org. Chem. 2000, 65, 2599–2602; (d) Xie, J.; Guveli,
T.; Hebbe, S.; Dechoux, L. Tetrahedron Lett. 2004, 45, 4903–4906; (e) Mihara, Y.;
Ojima, H.; Imahori, T.; Yoshimura, Y.; Ouchi, H.; Takahata, H. Heterocycles 2007,
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23. Selected data for (3R,4S,5S) 5-hydroxymethyl-3,4-dihydroxypiperidine 10: Oil,
½ ꢀ ꢁ64.5 (c, 1.0 in H2O); dH (400 MHz, D2O) 2.11 (1H, m, H-5), 2.81 (1H, at, J
a 2D2
12.7 Hz, H-6), 3.06 (1H, br d, J 12.7 Hz, H-2), 3.30–3.38 (2H, m, H-60, H-20),
3.58–3.70 (3H, m, H-4, H-50a, H-50b), 4.07 (1H, br s, H-3); dC (100.6 MHz, D2O)
36.9 (C-5), 45.1 (C-6), 48.5 (C-2), 59.9 (C-50), 65.7 (C-3), 68.0 (C-4).
13. Punzo, F.; Watkin, D. J.; Jenkinson, S. F.; da Cruz, F. P.; Fleet, G. W. J. Acta
Crystallogr. 2006, E62, o321–o323.
24. Selected data for (3R,4S,5R) 5-aminomethyl-3,4-dihydroxypiperidine 11: Oil, ½a D22
ꢀ
14. Selected data for enoate 17: Mp 96–98 °C; ½a D21
ꢁ212 (c, 0.70 in CHCl3); mmax
ꢀ
-4.5 (c, 1.1 in H2O); dH (400 MHz, D2O) 1.97–2.05 (1H, m, H-5), 2.65 (1H, t, J
12.3 Hz, H-60), 2.74 (1H, t, J 11.6 Hz, H-20), 2.85–2.95 (3H, m, H-2, H-6, H-50a),
(KBr disc) 1734 (C@O) cmꢁ1
;
dH (400 MHz, CDCl3) 1.36, 1.48 (6H, 2 ꢂ s,
0
0
2 ꢂ CH3), 4.05 (1H, dd, J5,5 12.8 Hz, J5,4 2.2 Hz, H-5), 4.38 (1H, dd, J5 ,5 12.8 Hz,
3.00 (1H, dd, J5 b,5 a 13.3 Hz, J5 b,5 6.7 Hz, H-50b), 3.68 (1H, ddd, J 11.0 Hz, J
4.7 Hz, J 2.7 Hz, H-3), 3.95 (1H, br s, H-4); dC (100.6 MHz, D2O) 37.1 (C-5), 39.4
(C-50), 40.7 (C-6), 43.3 (C-2), 67.3, 67.6 (C-3, C-4).
0
0
0
J5 ,4 1.9 Hz, H-50), 4.57 (1H, d t, J 2.0 Hz, J4,3 7.5 Hz, H-4), 4.97 (1H, d, J3,4 7.5 Hz,
0
H-3), 5.85, 6.28 (2H, 2 ꢂ s, H-20a, H-20b); dC (100.6 MHz, CHCl3) 24.5, 26.3
(2 ꢂ CH3), 67.7 (C-5), 72.6 (C-4), 74.9 (C-3), 110.6 (CMe2), 130.1 (C-20), 135.1
(C-2), 166.7 (C-1).
25. Humphlett, W. J. Carbohydr. Res. 1967, 4, 157–164.
26. Cohen, N.; Banner, B. L.; Laurenzano, A. J.; Carozza, L. Org. Synth. 1984, 63, 127–
135.
15. Selected data for 4-C-methyl imino-
L
-ribitol 6: Oil, ½a D21
ꢀ
ꢁ12.5 (c, 1.00 in H2O); dH
0
(400 MHz, D2O) 1.29 (3H, s, CH3), 3.21 (1H, dd, J1,2 3.0 Hz, J1,1 12.7 Hz, H-1),