Total synthesis of the proposed structures of hyacinthacines C2, C3, and their C5-epimers

Article abstract of DOI:10.1016/j.tetlet.2009.06.072

Synthesis and structural confirmation of highly oxygenated pyrrolizidine alkaloids, hyacinthacines C₂ [(1S,2R,3R,5R,7S,7aR)-3,5-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], C₃[(1S,2R,3R,5S,7R,7aR)-3,5-hydroxymethyl-1,2,7-trihydroxyp

Full text of DOI:10.1016/j.tetlet.2009.06.072

Tetrahedron Letters 50 (2009) 4937–4940
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Tetrahedron Letters
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Total synthesis of the proposed structures of hyacinthacines C2, C3, and their
C5-epimers
*
Tetsuya Sengoku, Yasutaka Satoh, Masaki Takahashi, Hidemi Yoda
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and structural confirmation of highly oxygenated pyrrolizidine alkaloids, hyacinthacines
C2 [(1S,2R,3R,5R,7S,7aR)-3,5-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], C3[(1S,2R,3R,5S,7R,7aR)-3,5-
hydroxymethyl-1,2,7-trihydroxypyrrolizidine], and their C5-epimers were achieved on the basis of the
highly divergent method employing (S)-(ꢀ)-2-pyrrolidone-5-carboxylic acid as the starting material.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 May 2009
Revised 12 June 2009
Accepted 15 June 2009
Available online 17 June 2009
Hyacinthacines are a new series of polyhydroxylated pyrrolizi-
dine alkaloids, which were originally isolated from Hyacinthoides
non-scripta and Scilla campanulata as inhibitors of several glycosi-
dases (Fig. 1).1 Their structure and potent bioactivities have at-
tracted a great deal of interest to synthetic chemists, and the
total syntheses of hyacinthacines A and B have been achieved for
this reason.2 Recently, Asano and co-workers have isolated new
hyacinthacines C2 (1a) and C3 (2a) from Scilla socialis, which inhibit
bacterial b-glucosidase as well as bovine liver b-galactosidase.3
Both compounds consist of the highly oxygenated pyrrolizidine
ring, whose oxygenated patterns have never been found in the
other series of hyacinthacines. Specifically, no reports have ap-
peared previously describing synthesis of these compounds. In
the present publication, we report the first total synthesis and
structural confirmation of hyacinthacines C2, C3, and their C5-epi-
mers, respectively, as an initial attempt to reveal the relationship
between their structures and biological activities.
Our synthetic strategy is outlined in Figure 2. We envisaged that
the pyrrolizidine ring system of hyacinthacines C2 (1a), C3 (2a), and
their C5-epimers (1b, 2b) could be constructed from the acyclic
polyols 3 and 4 through intramolecular cyclization. On the other
hand, those would be derived from aldehyde 5 via allylation fol-
lowed by dihydroxylation of the terminal olefin moiety. The key
intermediate 5 could be synthesized from N-protected amide 6,
which can be prepared from commercially available (S)-(ꢀ)-2-pyr-
rolidone-5-carboxylic acid according to the procedure reported in
the previous publications.2m,4
under our developed conditions2m gave the corresponding desired
allyl alcohol with the predominant diastereomeric ratio (83:17) in
totally 81% yield,5 which could be separated by silica gel column
chromatography. In fact, spontaneous cyclization occurred effi-
ciently by the mesylation, leading to the formation of the pyrroli-
dine ring due to the electrophilic nature of the allylic position.
After the replacement of N-Boc to N-Cbz groups through three
steps involving one-pot procedure for deprotection of TBDPS and
Boc groups, oxidative cleavage of the olefin moiety of 8 with
OsO4 and NaIO4 gave the aldehyde 5 without epimerization. Unfor-
tunately, the allylation of 5 with allyl magnesium bromide resulted
in inseparable mixture of allylated products 9 together with unde-
sired bicyclic products 10 (Fig. 3). Alternatively, Reformatsky-type
reaction in saturated NH4Cl aqueous solution2n,6 improved the
yield of
9
(92%) with
a
moderate diastereoselectivity
(9a:9b = 79:21).
As shown in Figure 3, the stereochemistry of the newly formed
chiral center was determined on the basis of NOE experiments on
the bicyclic derivatives 10a and 10b which were independently
prepared from 9a and 9b, respectively, through treatment with
NaH (NaH, THF, 92%: 10a from 9a, 93%: 10b from 9b). Thus, it
has been apparent that we obtained the key intermediates 9 for
the synthesis of hyacinthacines C2 and C3.
With two homoallyl alcohols 9a and 9b in hand, we next turned
to the construction of pyrrolizidine ring systems (Scheme 2). After
protection of the hydroxyl group on 9a with TBSCl, dihydroxylation
Synthesis of homoallyl alcohols 9, precursors of 3 and 4, are
shown in Scheme 1. A new chiral center in 7 could be diastereose-
lectively generated through three steps which include Grignard
reaction of lactam 6, 1,2-reduction of unsaturated ketone, and
cyclization of pyrrolidine ring. In these processes, the 1,2-reduction
HO
7
OH
1
HO
OH
H
N
H
N
N
OH
OH
2
5
3
OH
hyacinthacine backbone
HO
OH
HO
OH
hyacinthacine C2 (1a)
hyacinthacine C3 (2a)
* Corresponding author. Tel./fax: +81 53 478 1150.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
Figure 1. The structures of hyacinthacines.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.072

4938
T. Sengoku et al. / Tetrahedron Letters 50 (2009) 4937–4940
OTBS
HO
X
OH
X
Y
H
N
O
H
O
OH
OTBS
CbzN
Y
OH
OTBDPS
X=H, Y=CH2OH: hyacinthacine C2 (1a)
O
O
O
X=CH OH, Y=H: 5-
-hyacinthacine C2 (1b)
epi
X=H, Y=OH (3a)
X=OH, Y=H (3b)
2
O
H
O
O
BocN
CbzN
OTBDPS
OTBDPS
5
6
OTBS
Y
HO
X
OH
OH
X
H
N
O
H
O
OTBS
CbzN
Y
OH
OTBDPS
X=H, Y=CH2OH: hyacinthacine C3 (2a)
X=H, Y=OH (4a)
X=OH, Y=H (4b)
X=CH OH, Y=H: 5-
-hyacinthacine C3 (2b)
epi
2
Figure 2. Retrosynthesis of hyacinthacines C2 (1a) and C3 (2a)
O
X
Y
H
O
O
O
O
O
O
H
O
a
O
c
d
O
Ref. 2m, 4
O
HN
CbzN
BocN
RN
CbzN
COOH
OTBDPS
OTBDPS
OTBDPS
OTBDPS
6
R = Boc (7)
b
5
X=H, Y=OH (9a)
X=OH, Y=H (9b)
R = Cbz (8)
Scheme 1. Reagents and conditions: (a) (i) vinylmagnesium bromide, THF, ꢀ78 °C, 83%; (ii) NaBH4, CeCl3, MeOH, ꢀ20 °C, 67%; (iii) MsCl, Et3N, 0 °C, 90%; (b) (i) TBAF, THF,
0 °C, then NaH, rt, 98%; (ii) CbzCl, NaHCO3, MeOH, 97%; (iii) TBDPSCl, imidazole, DMF, 97%; (c) (i) OsO4, aq NMO, acetone/t-BuOH, 97%; (ii) NaIO4, THF/H2O = 2/1, 99%; (d) Zn,
3-bromopropene, THF/satd NH4Cl aq = 1/5, rt, 73% (9a), 19% (9b).
2.6%
19.5, 29.9
24.9, 25.2
6.0% 11%
H
9.6% 9.7%
H
H
O
O
H
N
H
O
O
O
O
O
O
H
N
H
N
O
O
O
O
O
O
N
OTBDPS
O
OTBDPS
O
O
O
H
H
OTBDPS
OTBDPS
O
O
10a
10b
11a
11b
Figure 3. Observed NOE (arrow) of 10a and 10b.
Figure 4. 13C NMR chemical shifts of 11 (75 MHz, d in ppm).
of the terminal olefin moiety and subsequent TBS protection of
newly introduced primary hydroxyl group afforded separable dia-
stereomers 3a and 3b in a ratio of approximately 1:1 in 92% three-
step yield.
To consider the C5 stereochemistry of the products, we
decided to convert these compounds into the corresponding
acetonides 11 (Fig. 4) through deprotection of the silyl groups
in 3a and 3b accompanied with simultaneous formation of 5-
membered ring, selective protection of the generated primary
alcohols with TBDPSCl, and protection of the remaining 1,3-
diols as acetonides (TBAF, THF; TBDPSCl, DMAP, Et3N, CH2Cl2;
24.5, 24.6
19.4, 29.9
O
O
O
O
O
O
H
N
H
N
O
O
OTBDPS
O
OTBDPS
O
H
H
O
O
13a
13b
Figure 5. 13C NMR chemical shifts of 13 (75 MHz, d in ppm).
OTBS
H
OH
HO
X
OH
X
Y
TBSO
X
O
H
N
O
H
N
O
H
5
c
a
b
O
O
O
OH
OH
5
OTBS
CbzN
CbzN
Y
Y
OTBDPS
OTBDPS
OTBDPS
9a
X=H, Y=OH (3a)
X=OH, Y=H (3b)
X=H, Y=CH2OTBS (12a)
X=CH2OTBS, Y=H (12b)
X=H, Y=CH2OH:
hyacinthacine C2 (1a)
X=CH2OH, Y=H:
5-
epi
-hyacinthacine C (1b)
2
Scheme 2. Reagents and conditions: (a) (i) TBSCl, imidazole, DMF, 99%; (ii) OsO4, aq NMO, acetone/t-BuOH, 98%; (iii) TBSCl, Et3N, CH2Cl2, 46% (3a), 49% (3b); (b) (i) MsCl, Et3N,
CH2Cl2, 74% (from 3a), 71% (from 3b); (ii) H2, 5% Pd/C, EtOH, 89% (12a), 70% (12b); (c) (i) TBAF, THF; (ii) TFA/H2O = 1/2, 73% (1a), 84% (1b) (two steps).

T. Sengoku et al. / Tetrahedron Letters 50 (2009) 4937–4940
4939
OTBS
OH
HO
X
OH
X
Y
TBSO
O
H
N
O
H
N
O
H
H
c
a
b
O
O
O
OH
OH
OTBS
CbzN
CbzN
X
Y
Y
OTBDPS
OTBDPS
OTBDPS
9b
X=H, Y=OH (4a)
X=OH, Y=H (4b)
X=H, Y=CH2OTBS (14a)
X=CH2OTBS, Y=H (14b)
X=H, Y=CH2OH:
hyacinthacine C3 (2a)
X=CH2OH, Y=H:
5-
epi
-hyacinthacine C (2b)
3
Scheme 3. Reagents and conditions: (a) (i) TBSCl, imidazole, DMF, 97%; (ii) OsO4, aq NMO, acetone/t-BuOH, 98%; (iii) TBSCl, Et3N, CH2Cl2, 48% (4a), 46% (4b); (b) (i) MsCl, Et3N,
CH2Cl2, 82% (from 4a), 75% (from 4b); (ii) H2, 5% Pd/C, EtOH, 91% (14a), 90% (14b); (c) (i) TBAF, THF; (ii) TFA/H2O = 1/2, 72% (2a), 71% (2b) (two steps).
PPTS, 2,2-dimethoxypropane, acetone, 15%: 11a from 3a, 36%:
11b from 3b). As reported previously,7 the two signals of
11a at dc 19.5 and 29.9 ppm in the 13C NMR spectrum are
readily recognized as gem-dimethyl groups in a chair form of
6-membered ring, while those of 11b at dc 24.9 and
25.4 ppm are recognized as gem-dimethyl groups in a twist
boat conformation. Thus, the stereochemistry of 1,3-diols at
the two chiral centers is assigned as syn-11a and anti-11b,
respectively.
Acknowledgments
The authors thank Professor Asano for his helpful advice and
discussion about the structure of hyacinthacines. This work was
supported in part by a Grant-in-Aid for Scientific Research from Ja-
pan Society for the Promotion of Science.
References and notes
In the next step, the hydroxyl groups of 3a and 3b at C5 were
converted to the corresponding mesylate and used for cyclization
process which proceeded via deprotection of the Cbz groups, giving
rise to 12a and 12b, respectively. Finally, desilylation of 12 with
TBAF and acidic hydrolysis of the acetonide protecting group with
TFA yielded hyacinthacine C2 (1a)8 and its C5-epimer (1b),9 respec-
tively, which were purified by ion-exchange column chromatogra-
phy. It should be noted that the spectroscopic data of the synthetic
1a were fully consistent with those of the natural sample.3,8 More-
1. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson,
A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1.
2. (a) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry 2001, 12,
1807; (b) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry 2002, 13,
1581; (c) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron
Lett 2003, 44, 2315; (d) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron:
Asymmetry 2003, 14, 3933; (e) Desvergnes, S.; Py, S.; Vallée, Y. J. Org. Chem.
2005, 70, 1459; (f) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett 2005, 7, 2587;
(g) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70, 7297; (h)
DewiꢀWülfing, P.; Blechert, S. Eur. J. Org. Chem. 2006, 8, 1852; (i) Izquierdo, I.;
Plaza, M. T.; Tamayo, J. A.; SanchezꢀCantalejo, F. Eur. J. Org. Chem 2007, 36,
6078; (j) Kaliappan, K. P.; Das, P. Synlett 2008, 841; (k) Reddy, P. V.; Veyron, A.;
Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem. 2008, 6, 1170; (l)
over, optical rotation of the synthetic 1a (½a D25
ꢁ
+12.8, H2O, c 0.2)
also completely agreed with that of the natural sample ([a]
D
ˇ
Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Yánez, V.; Re, D. L.; SanchezꢀCantalejo,
+12.9, H2O, c 0.2), confirming the absolute configuration as drawn
in Figure 1.
F. Tetrahedron 2008, 64, 4613; (m) Sengoku, T.; Satoh, Y.; Takahashi, M.; Yoda,
H. Tetrahedron 2008, 64, 8052; (n) Donohoe, T. J.; Thomas, R. E.; Cheeseman, M.
D.; Rigby, C. L.; Bhalay, G.; Linney, I. D. Org. Lett. 2008, 10, 3615; (o) Zhang, T.-X.;
Zhou, L.; Cao, X.-P. Chemical Research in Chinese Universities 2008, 24, 469; (p)
Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826.
3. Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda,
K.; Asano, N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993.
Having elucidated the synthetic pathway to hyacinthacine C2,
our next objective was to synthesize hyacinthacine C3 (2a) with
a similar synthetic methodology described above (Scheme 3).
Starting from 9b, pyrrolizidine precursors 4 which serve as
complementary stereoisomers of 3, were produced in three
steps with excellent yields. The stereochemical assignments of
4a and 4b were secured by comparable analysis of the 13C
NMR chemical shifts for gem-dimethyl carbons of their aceto-
nide derivatives 13a and 13b (Fig. 5), respectively, as discussed
above (39%: 13a from 4a, 17%: 13b from 4b). Each of the iso-
mers of 4 underwent efficient cyclization to two pyrrolizidine
stereoisomers 14a and 14b via mesylation/hydrogenolysis se-
quences. Complete removal of the all protecting groups in 14a
and 14b afforded hyacinthacine C3 (2a)10 and its C5-epimer
(2b),11 respectively. Unfortunately, the NMR spectra of these
synthetic samples do not match with those of the reported3,10
and hence the revision in the stereochemical assignment of
the natural isolate is required, which will be the subject of fur-
ther work.
In summary, the total synthesis of the hyacinthacines C2 and
C3 has been achieved along with the derivation of the two C5-
epimers, employing the divergent methods for generating the
well-defined stereocenters of the synthetic intermediates from
(S)-(ꢀ)-2-pyrrolidone-5-carboxylic acid. Comparison of the char-
acterization data for the synthetic sample of hyacinthacine C3
with the corresponding natural product has given some indica-
tion of the inconsistency in the product stereochemistry. As
far as we are aware of, this is the first report on synthetic elab-
oration of the hyacinthacines C2 and C3 as well as their C5-
epimers.
4. (a) Ikota, N. Chem. Pharm. Bull 1993, 41, 1717; (b) Ikota, N. Chem. Pharm. Bull
1992, 40, 1925; (c) Smith, A. B., III; Salvatore, B. A.; Hull, K. G.; Duan, J. J.-W.
Tetrahedron Lett 1991, 32, 4859; (d) Hamada, Y.; Tanada, Y.; Yokokawa, F.;
Shioiri, T. Tetrahedron Lett 1991, 32, 5983.
5. Ikota, N. Tetrahedron Lett. 1992, 33, 2553.
6. Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910.
7. Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945.
8. Synthetic hyacinthacine C2 1a: ½a D25
ꢁ
+12.8 (c 0.2, H2O) {lit. [a] +12.9 (c 0.22,
D
H2O)}; IR (NaCl) 3312 (O–H), 2926 (C–H), 1043 (C–O) cmꢀ1 1H NMR (D2O) d
;
4.40 (m, 1H, CH), 4.17 (t, J = 4.3 Hz, 1H, CH), 3.85 (dd, J = 7.8, 4.3 Hz, 1H, CH),
3.85 (dd, J = 11.7, 6.9 Hz, 1H, CH2), 3.66 (dd, J = 11.7, 4.8 Hz, 1H, CH2), 3.58 (dd,
J = 12.0, 5.1, Hz, 1H, CH2), 3.54 (dd, J = 12.0, 5.7 Hz, 1H, CH2), 3.42 (J = 6.9,
4.5 Hz, 1H, CH), 3.35 (m, 1H, CH), 3.25 (m, 1H, CH), 2.04 (m, 1H, CH2), 1.78 (m,
1H, CH2); 13C NMR (D2O) d 78.2 (CH), 75.4 (CH), 75.1 (CH), 70.7 (CH), 66.3 (CH2),
66.2 (CH), 64.3 (CH2), 64.2 (CH), 40.8 (CH2). Anal. Calcd for C9H17NO5: C, 49.31;
H, 7.82; N, 6.39. Found: C, 49.12; H, 7.88; N, 6.64.
9. Synthetic 5-epi-hyacinthacine C2 1b: ½a D25
ꢁ
+13.7 (c 0.2, H2O); IR (NaCl) 3312 (O–
H), 2924 (C–H), 1030 (C–O) cmꢀ1 1H NMR (D2O) d 4.53 (m, 1H, CH), 4.36 (t,
;
J = 5.1 Hz, 1H, CH), 3.91 (dd, J = 7.4, 5.1 Hz, 1H, CH), 3.72 (dd, J = 11.4, 4.4 Hz,
1H, CH2), 3.59 (dd, J = 12.2, 6.4 Hz, 1H, CH2), 3.56–3.53 (m, 2H, CH2 and CH),
3.52 (dd, J = 11.4, 5.3 Hz, 1H, CH2), 3.39 (m, 1H, CH), 3.10 (m, 1H, CH), 2.15 (m,
1H, CH2), 1.76 (m, 1H, CH2); 13C NMR (D2O) d 74.9 (CH), 73.2 (CH), 72.9 (CH),
72.7 (CH), 69.8 (CH), 68.2 (CH), 66.0 (CH2), 63.7 (CH2), 39.1 (CH2). Anal. Calcd for
C9H17NO5: C, 49.31; H, 7.82; N, 6.39. Found: C, 49.18; H, 7.83; N, 6.68.
10. Synthetic hyacinthacine C3 2a: ½a D22
ꢁ
+8.8 (c 0.3, H2O); IR (NaCl) 3312 (O–H), 2928
(C–H), 1038 (C–O) cmꢀ1 1H NMR (D2O) d 4.58 (m, 1H, CH), 4.16 (t, J = 4.2 Hz,
;
1H, CH), 3.98 (dd, J = 7.8, 4.2 Hz, 1H, CH), 3.83–3.71 (m, 3H, 3CH2), 3.62 (dd,
J = 11.2, 5.8 Hz, 1H, CH2), 3.49 (m, 1H, CH), 3.38 (t, J = 4.2 Hz, 1H, CH), 3.20 (dt,
J = 7.8, 5.1 Hz, 1H, CH), 2.13 (m, 1H, CH2), 1.92 (m, 1H, CH2); 13C NMR (D2O) d
75.5 (CH), 75.0 (CH), 70.9 (CH), 69.2 (CH), 63.0 (CH2), 62.5 (CH), 62.5 (CH), 61.4
(CH2), 38.3 (CH2). Anal. Calcd for C9H17NO5: C, 49.31; H, 7.82; N, 6.39. Found: C,
49.15; H, 7.87; N, 6.35.Natural hyacinthacine C3 (Ref. 3): 1H NMR (D2O) d 4.56
(ddd, J = 4.4, 2.5, 2.5 Hz, 1H, CH), 4.32 (t, J = 4.4 Hz, 1H, CH), 4.04 (dd, J = 9.5,
4.4 Hz, 1H, CH), 3.85 (dd, J = 12.6, 3.2 Hz, 1H, CH2), 3.85 (overlapped, 1H, CH),
3.84 (overlapped, 2H, CH2, CH), 3.79 (dd, J = 12.0, 6.2 Hz, 1H, CH2), 3.69 (dd,

4940
T. Sengoku et al. / Tetrahedron Letters 50 (2009) 4937–4940
J = 12.6, 3.2 Hz, 1H, CH2), 3.50 (m, 1H, CH), 2.07 (m, 1H, CH2), 1.93 (m, 1H, CH2);
1H, CH2), 3.52 (dd, J = 11.2, 6.4 Hz, 1H, CH2), 3.49 (dd, J = 11.6, 6.2 Hz, 1H, CH2),
3.40 (dd, J = 11.2, 5.3 Hz, 1H, CH2), 3.23 (t, J = 4.2 Hz, CH), 2.99 (m, 1H, CH), 2.76
(ddd, J = 9.0, 6.2, 3.9 Hz, 1H, CH), 2.25 (m, 1H, CH2), 1.50 (m, 1H, CH2); 13C NMR
(D2O) d 75.8 (CH), 74.4 (CH), 71.7 (CH), 70.4 (CH), 70.2 (CH), 69.0 (CH), 65.9
(CH2), 63.9 (CH2), 39.0 (CH2). Anal. Calcd for C9H17NO5: C, 49.31; H, 7.82; N,
6.39. Found: C, 49.49; H, 7.94; N, 6.46.
13C NMR (D2O) d 79.9 (CH), 75.4 (CH), 72.2 (CH), 71.7 (CH), 67.5 (CH), 65.5 (CH),
61.8 (CH2), 61.7 (CH2), 39.4 (CH2).
11. Synthetic 5-epi-hyacinthacine C3 2b: ½a D22
ꢁ
+14.8 (c 0.3, H2O); IR (NaCl) 3312 (O–
H), 2928 (C–H), 1038 (C–O) cmꢀ1 1H NMR (D2O) d 4.46 (m, 1H, CH), 4.00 (t,
;
J = 4.2 Hz, 1H, CH), 3.81 (dd, J = 9.0, 4.2 Hz, 1H, CH), 3.62 (dd, J = 11.6, 3.9 Hz,