Stereoselective synthesis of the ABCD ring framework of azaspiracids

Article abstract of DOI:10.1016/j.tetlet.2007.05.021

A stereoselective synthesis of the ABCD ring framework of azaspiracid-1 and azaspiracid-3 has been achieved using a tandem bis-spiroketalization protocol in the presence of a mild proton source from 1,4-diketone precursor. A tetrahydrofuran intermediate w

Full text of DOI:10.1016/j.tetlet.2007.05.021

Tetrahedron Letters 48 (2007) 5335–5340
Stereoselective synthesis of the ABCD ring framework
of azaspiracidsI
J. S. Yadav,a,* Sipak Joyasawal,a S. K. Duttab and A. C. Kunwarb
aDivision of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bCentre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 March 2007; revised 23 April 2007; accepted 2 May 2007
Available online 10 May 2007
Abstract—A stereoselective synthesis of the ABCD ring framework of azaspiracid-1 and azaspiracid-3 has been achieved using a
tandem bis-spiroketalization protocol in the presence of a mild proton source from 1,4-diketone precursor. A tetrahydrofuran inter-
mediate with the correct stereochemistry for the D ring of azaspiracids-1 and 3 was then taken through a linear sequence of reactions
to afford the desired diketone precursor. The D-ring of azaspiracid-1 was then constructed by employing a Sharpless asymmetric
dihydroxylation followed by etherification using a homoallyl derivative. The structure of the ABCD ring framework with four
contiguous rings was established by extensive NMR analysis.
Ó 2007 Published by Elsevier Ltd.
Azaspiracid-1, a biotoxin isolated from European shell-
fish, was first found in 1995 when several individuals
became ill after eating mussels harvested off the west
coast of Ireland. Yasumoto et al. first isolated and pro-
posed a structure for azaspiracid-1,1a (Fig. 1). Five aza-
spiracids (AZA 1–5) have been isolated so far and their
structures elucidated by extensive NMR studies and
FABMS-MS experiments.1b,c Other azaspiracids (AZA
6–11) have been detected using a combination of liquid
chromatography and multi-tandem mass spectrometry
(LC–MSn).1d Recently Nicolaou et al. revised the struc-
tures of azaspiracids-1,2a–g 2,2h,i and 3,2h,i after immense
synthetic efforts and proposed new structures as shown
in Figure 1. The genesis of the error was believed to
be in the northern portion (the ABCDE rings) of the
molecule. The cytotoxicity and unique structural archi-
tecture of azaspiracids prompted us to investigate their
synthesis.3 Herein, we describe a stereoselective synthe-
sis of the revised ABCD ring fragment of azaspiracids-
1 and 3.
The initial disconnection of Aza-1 into fragments
ABCD (1) and EFGHI (2) is shown in Scheme 1. The
ABCD ring fragment 1 could in turn be derived from
3. As the ABCD ring framework 3 of azaspiracid-1
and azaspiracid-3 have the same stereochemistry, in
our discussion we refer only to azaspiracid-1.
Retrosynthetic analysis of the ABCD ring framework 3
of azaspiracid-1 is shown in Scheme 2. We envisaged
that this framework could be obtained from 1,4-dike-
tone precursor 4 via deprotection of the TBS group fol-
lowed by a tandem bis-spiroketalization in the presence
of a mild proton source.4 Precursor 4 could be obtained
from a trans-substituted tetrahydrofuran 5 (the source
of the D ring), which could be obtained from compound
6, via asymmetric Sharpless dihydroxylation of the dou-
ble bond followed by in situ cyclization.5 Compound 6
itself could be obtained from acetylenic alcohol 7. The
terminal acetylenic compound 7 could be obtained from
lactone 8 via a methodology developed in our group.6
Lactone 8 could be synthesized from epoxy alcohol 9.7
The stereoselective synthesis of acetylenic compound 7,
which fixes the C-14 azaspiracid-1 stereogenic center,
is presented in Scheme 3. Treatment of the readily avail-
able epoxy-alcohol 97 with triphenylphosphine (TPP),
I2, and imidazole afforded epoxy iodide 10, which upon
treatment with Zn/NaI in methanol produced the sec-
ondary allylic alcohol 11 via reductive opening of the
Keywords: Substituted tetrahydrofuran ring; 7-Membered acetonide;
Radical cyclization; Acetylenic alcohol.
q IICT Communication No. 060604.
*
Corresponding author. Fax: +91 40 27160387; e-mail: yadavpub@
iict.res.in
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.021

5336
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5335–5340
Name R1 R2 R3 R4
R1
8
9
Aza-1 : H Me
Aza-2 : Me Me
H
H
H
OH H
H
H
H
H
H
11
B
CO2H
7
6
8
12
9
1
H
OH Me
20
A
4
1
11
B
R2
18
CO2H
R3
7
6
12
O
C
H
H
OH
20
A
O
Aza-3 : H
Aza-4 : H
Aza-5 : H
H
H
H
4
O
18
10
O
C
H
O
5
D
O
H
R4
16
13
21
O
HO
D
O
10
5
H
E
21
16
Me
13
14
OH
H
HO
H
E
15
Me
O
H
Me
O
14
Aza-6 : Me H
H
15
Me
H
H
N
H
Aza-7 : H Me OH H
H
N
O
O
H
Aza-8 : H Me
Aza-9 : Me H
Aza-10: Me H
H
OH
OH H
OH
Me
I
H
O
O
G
Me
I
O
Me
F
H
G
H
O
Me
F
H
Me
Aza-11: Me Me OH H
H
Me
Originally proposed structure of azaspiracid-1
Revised structure of azaspiracids
Figure 1.
Aza-1 (revised structure)
Me
E
21
O
O
H
Me
8
CO2Et
9
11
B
7
6
1
1
H
N
H
1
A
O
H
O
H
+
O
Me
I
1
5
1
1
H
O
1
OP
C
D
O
H
O
G
1
O
Me
F
2
Me
H
H
1
Me
1
2
P = Protecting group
8
9
7
1
H
H
A
O
6
OBn
1
H
O
B
1
1
1
O
1
C
D
O
H
1
5
PMBO
2
Me
1
1
3
Scheme 1.
OTBS
8
9
O
18
11
7
6
12
15
11
14
O
9
H
17
D
O
A
18
19
O
B
OBn
13
16
OBn
12
H
O
10
19
H
O
10
C
Me
D
O
H
H
20
16
15
13
OTBS
5
PMBO
20
Me
14
8
H
7
6
OPMB
5
3
4
H
H
HO
Me
Me
D
O
OBn
OBn
H
O
OH
O
O
O
6
5
Me
Me
BnO
HO
BnO
OH
O
OH
O
O
7
8
9
Scheme 2.

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5335–5340
5337
BnO
b
c
BnO
X
BnO
O
O
OH
Br
9 X = OH
10 X = I
a
OEt
12
11
Me
Me
e
f
d
BnO
BnO
8
O
O
OEt
CCl2
13
14
Me
g
XO
OX
7 X = H
h
15 X = TBS
Scheme 3. Reagents and conditions: (a) TPP, I2, imidazole, CH3CN–Et2O (1:3), 0 °C to rt, 1 h, 81%; (b) Zn dust, NaI, methanol, reflux, 4 h, 82%; (c)
ethyl vinyl ether, NBS, CH2Cl2, 0 °C to rt, 1 h, 85%; (d) n-Bu3SnH, AIBN (cat.), benzene, reflux, 30 min, 36%; (e) Jones’ oxidation, CrO3, 8 N H2SO4,
acetone 0 °C to rt, 1 h, 83%; (f) TPP, CCl4, THF, reflux, 3 h, 82%; (g) Li sand, THF, reflux, 2 h, 80%; (h) TBDMSCl, imidazole, CH2Cl2, 0 °C to rt,
12 h, 84% (AIBN = azobis-isobutyronitrile; NBS = N-bromosuccinimide; TBDMS = TBS = tert-butyldimethyl silyl; TPP = triphenylphosphine).
epoxide7 in 67% yield over the two steps. Vinyl alcohol
11 was subsequently reacted with ethyl vinyl ether and
NBS to afford bromoacetal 12 as a (1:1) mixture of
diastereomers.
To synthesize the trans-substituted D ring of azaspir-
acid-1, the acetylenic compound 15 was converted to
the alkynyl borate complex12 by treatment with n-BuLi
and BF3ÆOEt2 in THF at ꢀ78 °C, which was then re-
acted with chiral epoxide13 19 to produce 16 (88% yield)
as shown in Scheme 4. Reduction of the triple bond of
compound 16 was investigated under different reaction
conditions. Unfortunately, several attempts using Red-
Al in refluxing THF, LAH in ether at room tempera-
ture, LAH in refluxing THF, LAH in a refluxing mix-
ture of THF:DME failed to produce the trans (E)-
homoallylic alcohol; moreover Birch reduction condi-
tions also failed to produce the desired product. After
careful experimentation, the triple bond in compound
16 was reduced at a high temperature (155 °C) using
LAH in diglyme and THF (8:1). Deprotection of the
TBS groups was also observed under these reduction
conditions to give the trans-homoallylic alcohol 17.14
The 1,4-diol component of compound 17 was then pro-
tected as a seven-membered acetonide15 using 2,2-DMP
and CSA as catalyst to furnish 6. The secondary hydr-
oxyl group of the homoallylic alcohol 6 was then sub-
jected to tosylation using p-toluenesulfonyl chloride
The diastereomeric mixture of bromoacetal 12 afforded
lactol ether 13 stereoselectively as a mixture of anomers
(1:1) via a radical cyclization8 using n-Bu3SnH in reflux-
ing benzene. The methyl group of the C ring was thus
introduced stereoselectively.8d,e Jones’ oxidation of com-
pound 13 (CrO3, 8 N H2SO4) furnished lactone 8 (92%
de, 61% yield over three steps).9 The preparation of acet-
ylenic compound 7 from lactone 8 requires a one carbon
homologation. Therefore, lactone 8 was converted into
the dichloromethylene derivative 14 following Chapl-
eur’s method10 (CCl4 and TPP). Reductive opening of
enol ether 14, using a methodology developed in our
group11 (active Li sand in refluxing THF), furnished
acetylenic compound 7 with concomitant removal of
the benzyl group (67% yield over the two steps). The
hydroxyl groups of acetylenic compound 7 were
protected as TBS ethers using TBSCl and imidazole to
afford silyl ether 15 in 84% yield.
Me
Me
OBn
a, then
b
15
HO
OBn
OH
OH
OH
OTBS
OTBS
OBn
O
19
16
17
Me
OBn
e
c
5
O
OX
O
6 X = H
18 X = Ts
d
Scheme 4. Reagents and conditions: (a) n-BuLi (1.5 M), BF3ÆOEt2, THE, ꢀ78 °C, 1 h, 88%; (b) LiAlH4, diglyme–THF (8:1), 155 °C, 6 h, 77%; (c)
2,2-DMP, acetone, CSA (cat.), 0 °C to rt, 1 h, 82%; (d) TsCl, Et3N, DMAP (cat.), CH2Cl2, 0 °C to rt, 12 h, 87%; (e) AD-mix-b, CH3SO2NH2,
t-BuOH–H2O (1:1), 0 °C, 12 h then rt, 12 h, 79%; AD-mix-b = (DHQD)2PHAL, K3Fe(CN)6, K2CO3, K2OsO4Æ2H2O; diglyme = diethyleneglycol
dimethyl ether.

5338
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5335–5340
(TsCl) and Et3N; the resulting product 18 was then
treated with AD-mix-b and methyl sulfonamide in
tert-butanol and water (1:1) at 0 °C to produce the
trans-substituted tetrahydrofuran 5 in a 44% overall
yield in four steps.
ded diol 27 (76% yield over the two steps). Diol 27
was subjected to partial hydrogenation using Lindlar’s
catalyst, quinoline, EtOH, and H2 to give cis-olefin 28.
The two secondary hydroxyl groups were oxidized
(DMP)18 to give 1,4-diketone 4, the precursor of the
ABCD ring of azaspiracid-1 (72% yield over the two
steps).
The final di-ketone precursor for the ABCD ring frame-
work of azaspiracid-1 was elaborated as shown in
Scheme 5. The secondary hydroxyl group of compound
5 was protected as its TBS ether using TBSOTf and 2,6-
lutidine to yield compound 20 and deprotection of the
acetonide under mild acidic conditions using catalytic
CSA in CH2Cl2:methanol (1:1) afforded 1,4-diol 21
(79% yield over the two steps). Diol 21 was then sub-
jected to IBX oxidation to furnish c-lactol 22 via the
Corey protocol,16 which after treatment with a one car-
bon Wittig ylide (Ph3PCH3I, NaNH2), produced the
homologated terminal olefin 23. Protection of the sec-
ondary hydroxyl group of 23 as its TES ether using
TESCl and imidazole yielded 24 (65% yield over the
three steps). Epoxidation of the terminal double bond
of 24 using m-CPBA produced epoxide 25 as a 1:1 dia-
stereomeric mixture (84% yield). Opening of epoxide 25
was achieved using the Yamaguchi protocol at ꢀ78 °C
with an alkynyl borate derived from 2917 (n-BuLi,
BF3ÆEt2O), to afford compound 26 as a mixture of dia-
stereomers. No attempts were made to separate these
since the hydroxyl group was eventually to be converted
into a keto group. Selective deprotection of the TES
group in 26 with CSA in CH2Cl2:methanol (4:1) affor-
Compound 4 was treated with CSA in methanol to effect
deprotection of both TBS groups and concomitant spi-
rocyclization4 to afford 319 (62% yield, Scheme 5), the
ABCD ring fragment of azaspiracid-1. The thermody-
namically controlled product was formed through inter-
mediate 30, with the anomeric effect favoring formation
of the desired ABCD ring fragment of azaspiracid-1.
The stereochemistry at the C-10 and C-13 carbon atoms
of 3 was confirmed by extensive NMR spectroscopic
studies (1H, DQFCOSY, TOCSY, NOESY).20 Charac-
teristic NOE correlations and the energy minimized
structure (drawn using Insight II (97.0)/Discover1 pro-
gram) are shown in Figures 2 and 3, respectively.
In conclusion, we have described a stereoselective syn-
thesis of the ABCD ring fragment of azaspiracid-1 and
azaspiracid-3. The C-14 Me stereogenic center was con-
structed by an exo-cyclic radical cyclization. The D ring
was constructed using a Sharpless asymmetric dihydr-
oxylation followed by in situ cyclization. The synthesis
of the ABCD ring of azaspiracid-1 and azaspiracid-3
was made in 24 linear steps starting from epoxide 9. Fur-
H
H
H
H
TBSO
Me
TBSO
Me
XO
Me
b
c
OBn
OBn
OBn
O
O
O
H
H
H
H
H
O
OH
O
OH
HO
O
5 X = H
20 X = TBS
a
22
21
H
H
OTBS
H
H
TBSO
Me
TBSO
Me
OX
HO
O
g
OBn
f
OBn
OBn
d
O
H
O
O
Me
OTBS
H
H
H
OTES
OX
PMBO
23 X = H
24 X = TES
e
25
OTBS
OPMB
29
26 X = TES
27 X = H
h
OH
O
OTBS
OH
O
OBn
HO
O
j
k
i
OBn
Me
H
H
O
3
OH
4
Me
OTBS
H
H
OPMB
OPMB
28
30
Scheme 5. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 30 min, 90%; (b) CSA (cat.), CH2Cl2–methanol (1:1), 0 °C to rt,
30 min, 88%; (c) IBX, DMSO, CH2Cl2, 0 °C to rt, 6 h, 84%; (d) Ph3PCH3I, NaNH2, diethyl ether, 0 °C to rt, 6 h, addition of lactol (22) at 0 °C,
20 min, 84%; (e) TESCl, imidazole, CH2Cl2, 0 °C to rt, 12 h, 92%; (f) m-CPBA, CH2Cl2, 0 °C to rt, 6 h, 84%; (g) 29, n-BuLi (1.5 M), BF3ÆOEt2, THE,
ꢀ78 °C, 10 min, then 25, 0 °C, 15 min, 86%; (h) CSA (cat.), CH2Cl2–methanol (4:1), 0 °C, 15 min, 86%; (i) Lindlar’s catalyst, quinoline (cat.),
ethanol, H2, rt, 10 min, 89%; (j) DMP, CH2Cl2, 0 °C to rt, 6 h, 81%; (k) CSA (cat.), methanol, 0 °C to rt, 1 h, 62%.

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5335–5340
5339
Bernal, F.; Frederick, M. O.; Qian, W.; Uesaka, N.;
Diedrichs, N.; Hinrichs, J.; Koftis, T. V.; Loizidou, E.;
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H
PMBO
O
H
O
H
H
H
H
O
H
Me
H
O
H
H
H
OBn
Figure 2. Characteristic NOE correlations in 3.
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Figure 3. Energy minimized structure of 3.
ther studies toward the total synthesis of azaspiracids are
currently underway and will be reported in due course.
Acknowledgements
S.J. and S.K.D. thank CSIR, New Delhi, India, for
providing fellowships.
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10. (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.;
Okawara, M. J. Am. Chem. Soc. 1982, 104, 5564–5566; (b)
Stork, G.; Mook, R., Jr.; Biller, S. A.; Rychnovsky, S. D.

5340
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5335–5340
J. Am. Chem. Soc. 1983, 105, 3741–3743; (c) Moriya, O.;
(dd, J = 10.1, 5.3 Hz, C-5Hpro-S, 1H), d 2.52 (dddd,
J = 17.5, 4.2, 2.4, 2.0 Hz, C-9Hpro-S, 1H), d 2.30 (ddd,
J = 12.3, 12.0, 7.7 Hz, C-12Hpro-S, 1H), d 2.14 (ddd, J =
12.5, 12.0, 7.3 Hz, C-11Hpro-S, 1H), d 2.12 (ddd, J = 17.5,
4.5, 1.4 Hz, C-9Hpro-R, 1H), d 2.07 (ddq, J = 12.6, 4.5,
6.7 Hz, C-14H, 1H), d 2.00 (dd, J = 12.5, 7.7 Hz, C-
Okawara, M.; Ueno, Y. Chem. Lett. 1984, 1437–1440; (d)
Ueno, Y.; Moriya, O.; Chino, K.; Watanabe, M.; Oka-
wara, M. J. Chem. Soc., Perkin Trans. 1 1986, 1351–1356.
11. Lakhrissi, M.; Chapleur, Y. Synlett 1991, 583–585.
12. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–
394.
11Hpro-R, 1H), d 1.94 (dd, J = 13.2, 6.2 Hz, C-18Hpro-R
,
13. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen,
E. N. Science 1997, 277, 936–938; (b) Furrow, M. E.;
Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
6776–6777.
14. Rossi, R.; Carpita, A. Synthesis 1977, 561–562.
15. Martin, D. D.; Kotecna, N. R.; Ley, S. V.; Mantegani, S.;
Menendez, J. C.; Organ, H. M.; White, A. D.; Banks, B. J.
Tetrahedron 1992, 48, 7899–7938.
1H), d 1.90 (ddd, J = 14.3, 4.5, 2.3 Hz, C-15Hpro-R, 1H), d
1.82 (ddd, J = 13.2, 9.6, 4.3 Hz, C-18Hpro-S, 1H), d 1.74
(ddd, J = 14.3, 12.6, 2.8 Hz C-15Hpro-S, 1H) d 1.66 (dd,
J = 12.3, 7.3 Hz, C-12Hpro-R, 1H), d 0.91 (d,J = 6.7 Hz, C-
14Me, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 138.4,
130.4, 129.1, 128.6, 128.2, 127.6, 127.4, 126.5, 123.6, 113.7,
110,0, 105.5, 77.1, 76.5, 73.2, 72.9, 72.8, 72.0, 71.9, 69.1,
55.2, 36.5, 36.1, 35.0, 32.1, 31.2, 29.5, 16.1; HR-MS (ESI+)
calculated for C32H40O7Na+ [M+Na]+: 559.2671; found
559.2660.
16. Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 7945–
7948.
17. Acetylenic compound 29 was prepared from D-(ꢀ)-tartaric
acid (a) Yadav, J. S.; Chander, M. C.; Joshi, B. V.
Tetrahedron Lett. 1988, 29, 2737–2740; (b) Takano, S.;
Samizu, K.; Sugihara, T.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1989, 1344–1345.
20. For the structural elucidation of 3, the coupling,
3
3JC-14H–C-15H(pro-S) = 12.6 Hz, JC-14H–C-15H(pro-R) = 4.5 Hz,
3
3JC-16H–C-15H(pro-S) = 2.8 Hz, JC-16H–C-15H(pro-R) = 2.3 Hz,
3
and JC-16H–C-17H = 2.6 Hz and strong 1,3-di-axial NOE
correlation between C-17H and C-15H(pro-S) are in the
16
18. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
C ring consistent with
C
13
chair conformation. This is
also consistent with cis-ring fusion geometry between
the C and D rings at C-16 and C-17. The presence of
strong NOE’s between C-14 Me and both the C-15H
protons supports the R configuration of the C-14 car-
19. Spectral data for 3: Viscous liquid; Rf = 0.45, ethyl
25
acetate–hexane (3:7); ½aꢁD 4.13 (c 0.47, CHCl3); IR (neat):
3033, 2976, 2855, 1610, 1513, 1457, 1362, 1449, 1173, 1099,
1029, 988, 871, 837, 740, 698, 583, 513, 403 cmꢀ1
;
1H
bon. The presence of JC-11H(pro-S)–C-12H(pro-S) = 12.0 Hz,
3
NMR (CDCl3, 500 MHz) d 6.84–7.36 (9H, aromatic
protons), d 5.80 (dddd, J = 10.4, 4.5, 2.0, 2.0 Hz, C-8H,
1H), d 5.76 (dddd, J = 10.4, 2.4, 1.4, 1.1 Hz, C-7H, 1H), d
3JC-11H(pro-R)–C-12H(pro-R) ꢂ 0 Hz and strong NOE’s, C-
12H(pro-S)/C-14Me, C-12H(pro-S)/C-14H, C-11H(pro-
S)/C-9H(pro-S) are consistent with a twisted geometry
for the five membered ring (B) with C-11 being endo to the
C ring oxygen. In the six-membered ring A, C-6H shows a
strong NOE correlation with the C-14 Me in the C-ring,
confirming a twisted conformation such that the dihedral
angles O–C6–C7–C8 has a negative magnitude whereas
C7–C8–C9–C10 has a positive value. The NOE correla-
tions and geometries of the A–D rings in the energy
minimized structure of 3 are shown in Figures 2 and 3,
respectively.
4.60 (d, J = 12.3 Hz, benzyl-CH2, 1H),
J = 12.3 Hz, benzyl-CH2, 1H), d 4.57 (m, C-6H, 1H), d
4.52 (d, J = 11.9 Hz, PMB-CH2, 1H), 4.51 (d,
d 4.58 (d,
d
J = 11.9 Hz, PMB-CH2, 1H), d 4.43 (dddd, J = 9.6, 6.2,
5.8, 3.6 Hz, C-19H, 1H), d 4.19 (dd, J = 4.3, 2.6 Hz, C-
17H, 1H), d 3.91 (ddd, J = 2.8, 2.6, 2.3 Hz, C-16H, 1H), d
3.81 (s, PMB-OMe, 3H), d 3.55 (dd, J = 10.1, 5.6 Hz, C-
5Hpro-R, 1H), d 3.52 (dd, J = 10.0, 3.6 Hz, C-20Hpro-R
,
1H), d 3.47 (dd, J = 10.0, 5.8 Hz, C-20Hpro-S, 1H), d 3.46