De novo synthesis of a galacto-papulacandin moiety via an iterative dihydroxylation strategy

Article abstract of DOI:10.1016/j.tetlet.2005.04.073

A short and highly efficient route to both the pyranose and furanose forms of a galacto-papulacandin ring system has been developed. The key to the overall transformation is the sequential two osmium-catalyzed dihydroxylation reactions of substituted 2,4-

Full text of DOI:10.1016/j.tetlet.2005.04.073

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4151–4155
De novo synthesis of a galacto-papulacandin moiety via an iterative
dihydroxylation strategy
Md. Moinuddin Ahmed and George A. OꢀDoherty*
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Received 17 April 2005; accepted 18 April 2005
Abstract—A short and highly efficient route to both the pyranose and furanose forms of a galacto-papulacandin ring system has
been developed. The key to the overall transformation is the sequential two osmium-catalyzed dihydroxylation reactions of
substituted 2,4-dienone. The resulting tetrol can be efficiently transformed into the two spiroketal moieties of galacto-papulacandin,
which can also be inter-converted via acid catalyzed equilibration.
Ó 2005 Elsevier Ltd. All rights reserved.
The papulacandins are a class of naturally occurring gly-
colipids with potent antifungal activity against Candida
albicans and several other yeasts.1 They are also found
to be active against P. carinii pneumonia, a most preva-
lent opportunistic infection that is a frequent cause of
death in AIDS patients.1 The papulacandins were iso-
lated from the fermentation broths of Papularia sphero-
sperma2 and Dictyochaeta simplex.3 The mechanism of
action for the papulacandins is believed to be the inhibi-
tion of 1,3-a-D-glucan synthase, which is essential for
cell wall construction in fungal cells but not exist in
human cells.4
tose disaccharide with the gluco-sugar converted to a
spirocyclic arylglycoside. On each sugar there is an
unsaturated fatty acid, linked at the C-3 and C-60 hydro-
xyl groups. The simplest member, papulacandin D,
lacks the C-4 galactose with the C-60 acyl group.
The high degree of selective toxicity and the fascinating
molecular structure of the papulacandins have stimu-
lated a significant amount of both biological5 and syn-
thetic research by a number of research groups.6 So
far, only one member of the papulacandins has ceded
to total synthesis that being by the efforts of Barrett
et al.7 Hitchcock and his group at Lilly have completed
a semi-synthesis of papulacandin D by attaching the
more readily available papulacandin A side chain to
the papulacandin D ring system.8 These two routes,
when taken together, can be used to assign the absolute
stereochemistry of the C-3 acyl side chain for both pap-
ulacandin A and papulacandin D.
Of the papulacandins A–D, papulacandin C is the most
active member (Fig. 1). Papulacandin C contains a lac-
O
O
HO
HO
HO
With the exception of the work from the Danishefsky
group6a and our own,9 all other routes to the papulacan-
dins derived their asymmetry from D-glucose. Danishef-
sky used a Diels–Alder strategy to construct the
spiroketal portion of the papulacandins, in which the
asymmetry was derived from a combination of chiral
auxiliary and chiral Lewis acid.6a Our group has devel-
oped an approach to the mannose, allose and glucose
stereoisomers of the papulacandin ring system via an
asymmetric dihydroxylation of 5-aryl-2-vinyl furans
(1a–c from 2, Scheme 1), followed by an Achmatowicz
rearrangement.10 The route initially generated a mixture
OH
O
HO
O
O
O
OH
HO
O
OH
O
OH
Figure 1. Papulacandin C.
*
Corresponding author. Tel.: +1 304 293 3435x6444; fax: +1 800 293
4904; e-mail: george.odoherty@mail.wvu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.073

4152
M. M. Ahmed, G. A. O’Doherty / Tetrahedron Letters 46 (2005) 4151–4155
PO
TBSO
OP
HO
PO
OP
BnO
HO OBn
O
OAc OAc
O
O
HO
OP
O
OBn
HO
5
HO
OAc OAc OBn
HO
O
BnO
OBn
O
O
OP'
2
1a: manno
1d
4
1b: allo
1c: gluco
TBSO
TBSO
O
OH
P'O
PO
HO OP
O
O
OP
OBn
OH OBn
OP
BnO
OBn
BnO
OBn
HO
5
3
HO
PO
OP
O
3
1d: galacto
TBSO
O
O
P
H
OMe
OMe
Scheme 1. De novo approaches to various papulacandins.
3
+
O
OBn
BnO
OBn
7
6
of manno- and allo-papulacandins (1a/b) and using an
oxidation/reduction strategy, converted the manno-iso-
mer to the gluco-isomer (1a to 1c).9
Scheme 2. Retrosynthetic analysis of galacto-papulacandin.
exposed to the typical Sharpless AD-mix procedure
(4% OsO4/4.1% (DHQD)2 PHAL, 3 equiv of
K3Fe(CN)6/K2CO3, 1 equiv of MeSO2NH2) to give diol
5 in a good yield (60%) and high enantiomeric excess
(90% ee).15 As we found with the dienoates,12 this dou-
ble bond selectivity in the dihydroxylation of dienone 3
can be explained in terms of electron density of the p-
system; where as, the second double bond does not react
under the reaction conditions because of a mismatch be-
tween the reagent ((DHQD)2PHAL/OsO4) and sub-
strate (5).12
In the context of a research program aimed at the synthe-
sis and biological study of the papulacandins and various
analogues, we have been looking for an easy entry into
the spiroketal moiety of a galacto-papulacandin. In par-
ticular, we desired a galacto-papulacandin 1d to examine
it as both a potential glycosidase and a glycosyl transfer-
ase inhibitor. While in theory 1d could be prepared from
the gluco-isomer 1c, in practice this would require too
many additional steps. Thus we decided to investigate
an alternative de novo approach to a galacto-papulacan-
din 1d. Ultimately we hoped that a galacto-isomer like 1d
would lead to the formation of disaccaride papulacan-
dins via an SN2-type inversion at C-4.
The mismatch between the substrate and reagent was
also seen when the ligand ((DHQD)2PHAL) was re-
moved from the AD-mix reaction condition (Scheme
4).16 Thus, when diol 5 were exposed to the typical Up-
john procedure (OsO4/NMO in t-BuOH/acetone), it re-
acted with achiral OsO4 to afford tetrol product with
good conversion, which was isolated as their corre-
sponding tetra-acetate 4 (70% yield in two steps) with
4:1 diastereomeric ratio.17 Once the minor diastereomer
was removed by silica gel chromatography the tetra-ace-
tate 4 was obtained with essentially complete enantio-
meric and diastereomeric purity.
For some time, we have been exploiting the efficiency of
the Sharpless asymmetric dihydroxylation of various
2,4-dienoates for synthesis.11 Quite recently we disclosed
our discovery that various galacto-sugars can be easily
prepared from 2,4-dienoates iteratively using the Sharp-
less asymmetric dihydroxylation.12 Herein we would like
to describe a new strategy for construction of the spiro-
ketal moiety of galacto-papulacandin 1d via a similar
iterative osmium-catalyzed dihydroxylation reaction of
substituted 2,4-dienone 3 (Scheme 2).
Deprotection of TBS group from tetra-acetate 4 using
3 M HCl/MeOH afforded the mixed ketal 11 in excellent
yield (90%). Exposure of 11 to the global acetate
deprotection (5 equiv LiOH/MeOH), followed by spiro-
Retrosynthetically, we envisioned constructing the de-
sired dienone 3 by an HWE-olefination of b-keto
phosphonate 6 with the known aldehyde 7. The b-keto
phosphonate 6 was easily prepared from the 3,5-dibenz-
yloxy benzyl alcohol 8 in four steps and excellent overall
yield 56% (Scheme 3). The benzylic alcohol 8 was selec-
tively iodinated with NIS and then protected to form
TBS ether 9 in excellent overall yield (91%). Carbonyl-
ation of 9 with catalytic palladium in methanol gave
10 in 82% yield, which upon exposure to a lithiated tri-
methylphosphate gave b-keto phosphonate 6 in 75%
yield.
TBSO
HO
PdCl2, PPh3
CO, MeOH
I
1) NIS, DMF
2) TBSCl
91% in 2 steps
10
82%
BnO
OBn
BnO
OBn
O
9
8
TBSO
TBSO
O
P
O
O
P
OMe
OMe
OMe
Li
OMe
THF, 75%
With ample supplies of phosphonate 6, we next investi-
gated the synthesis of dienone 3 and its subsequent bis-
dihydroxylation (Scheme 4). Exposure of 6 and 7 to
OMe
OBn
BnO
BnO
OBn
6
10
Cs2CO3 in i-propanol gave a good yield of the desired
13,14
Scheme 3. Synthesis of b-keto phosphonate.
dienone 3 (70% yield).
The 2,4-dienone 3 was

M. M. Ahmed, G. A. O’Doherty / Tetrahedron Letters 46 (2005) 4151–4155
4153
TBSO
O
O
P
OMe
OMe
H
Cs2CO3, IPA
70%
3
+
O
BnO
TBSO
OBn
OBn
7
6
TBSO
O
O
OH
AD-β*
t-BuOH/H2O
60%
OBn
OH OBn
BnO
OBn
BnO
OBn
3
5
TBSO
TBSO
O
O
OH
OAc OAc
1) OsO4/NMO
t-BuOH/acetone
2) Ac2O/Py
70% in 2 steps
OH OBn
OAc OAc OBn
BnO
OBn
BnO
OBn
5
4; dr = 4:1
AD-β* = 4% OsO4, 4.1% (DHQD)2PHAL, 3 eq K3Fe(CN)6, 3 eq K2CO3, 1 eq MeSO2NH2
Scheme 4. Regio- and diastereoselective dihydroxylation.
TBSO
OMe
O
OAc OAc
O
OAc OAc
3M HCl
MeOH
90%
OAc OAc OBn
OAc OAc OBn
OBn
11
BnO
OBn
4
BnO
BnO
O
BnO
H
1) LiOH
HO OBn
HO
HO
MeOH
2) 3M HCl
O
O
OBn
11
OBn
BnO
HO
80% in 2 steps
OH
HO
+
O
H
2:1
1d
12
Scheme 5. Deprotection and spiroketalization.
ketalization of the crude material using 3 M HCl affor-
ded galacto-pyrano papulacandin 1d and galacto-furano
papulacandin 12 as 2:1 ratio and good yield (80%;
Scheme 5).18
by 6 equiv of HCl (3 M) gave the same 2:1 mixture of 1d
and 12 in an improved overall yield (80%).
To establish whether 1d and 12 were formed via thermo-
dynamically controlled process the two isomers were
separately equilibrated under mildly acidic conditions
until identical ratios were achieved. Thus, the galacto-
pyrano-papulacandin 1d and galacto-furano-papulacan-
din 12 were separately exposed to a catalytic amount of
PyÆTsOH (10%) in methanol. After 36 h, crude 1H NMR
By simply keeping track of the exact amounts of acid
and base used in the deprotection/spiroketalization steps
an improved one-pot procedure was achieved (Scheme
6). Thus exposing a MeOH solution of tetra-acetate 4
to 1 equiv of HCl (3 M), then 5 equiv of LiOH, followed
BnO
HO OBn
O
OBn
HO
HO
O
1d
+
a) 3M HCl
TBSO
b) LiOH
O
OAc OAc
2
:
c) 3M HCl
1
MeOH
80%
OAc OAc OBn
BnO
BnO
OBn
H
HO
O
4
OBn
BnO
HO
OH
O
H
12
Scheme 6. One-pot deprotection and spiroketalization.

4154
M. M. Ahmed, G. A. O’Doherty / Tetrahedron Letters 46 (2005) 4151–4155
Nollstadt, K.; Schmatz, D.; Schwartz, R.; Hammond,
BnO
HO OBn
M.; Balkovec, J.; Van Middlesworth, F. L. Antimicrob.
Agent Chemother. 1992, 36, 1648–1657.
O
OBn
Py•TsOH
HO
+
1d 12
HO
H
4. (a) Baguley, B. C.; Rommele, G.; Gruner, J.; Wehrli, W.
Eur. J. Biochem. 1979, 97, 345–351; (b) Perez, P.; Varona,
R.; Garcia-Acha, I.; Duran, A. FEBS Lett. 1981, 129,
249–252; (c) Varona, R.; Perez, P.; Duran, A. FEMS
Microbiol. Lett. 1983, 20, 243–247; (d) Rommele, G.;
Traxler, P.; Wehrli, W. J. Antibiot. 1983, 36, 1539–
1542.
5. (a) Kaneto, R.; Chiba, H.; Agematu, H.; Shibamoto, N.;
Yoshioka, T.; Nishida, H.; Okamoto, R. J. Antibiot. 1993,
46, 247–250; (b) Chiba, H.; Kaneto, R.; Agematu, H.;
Shibamoto, N.; Yoshioka, T.; Nishida, H.; Okamoto, R.
J. Antibiot. 1993, 46, 356–358; (c) Aoki, M.; Andoh, T.;
Ueki, T.; Masuyoshi, S.; Sugawara, K.; Oki, T. J. Antibiot.
1993, 46, 952–960; (d) Okada, H.; Nagashima, M.; Suzuki,
H.; Nakajima, S.; Kojiri, K.; Suda, H. J. Antibiot. 1996,
49, 103–106; (e) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter,
W. J. J. Antibiot. 1980, 33, 967–978.
MeOH
95%
O
1d
2:1
BnO
HO
Py•TsOH
O
OBn
+
1d 12
BnO
HO
MeOH
95%
2:1
OH
O
12
H
Scheme 7. Spiroketal equilibration.
analysis indicated that both solutions had equilibrated
to the original 2:1 ratio. It is important to note that
these equilibrated mixtures of isomers were re-isolated
in excellent yields (95% yield, Scheme 7); therefore, indi-
cated that neither isomer was being selectively destroyed
under the reaction conditions.
6. For other approaches to the papulacandin ring system see:
(a) Danishefsky, S.; Philips, G.; Ciufolini, M. Carbohydr.
Res. 1987, 171, 317–327; (b) Parker, K. A.; Georges, A. T.
Org. Lett. 2000, 2, 497–499; (c) Friesen, R. W.; Sturino, C.
F. J. Org. Chem. 1990, 55, 5808–5810; (d) Friesen, R. W.;
Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994, 72, 1262–
1272; (e) Friesen, R. W.; Daljeet, A. K. Tetrahedron Lett.
1990, 31, 6133–6136; (f) Dubois, E.; Beau, J.-M. Tetrahe-
dron Lett. 1990, 31, 5165–5168; (g) Dubois, E.; Beau,
J.-M. Carbohydr. Res. 1992, 223, 157–167; (h) Rosenblum,
S.; Bihovsky, M. J. Am. Chem. Soc. 1990, 112, 2746–2748;
(i) Czernecki, S.; Perlat, M. C. J. Org. Chem. 1991, 56,
6289–6292; (j) McDonald, F. E.; Zhu, H. Y. H.; Holm-
quist, C. R. J. Am. Chem. Soc. 1995, 117, 6605–6606; (k)
Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163–
7169; (l) Carretero, J. C.; Eugenio de Diego, J.; Hamdou-
chi, C. Tetrahedron 1999, 55, 15159–15166.
In summary, we have developed a concise de novo
approach to both the pyranose and furanose forms of a
galacto-papulacandin (1d and 12) from 2,4-dienone 3 in
four steps and 33% overall yield. The complete synthesis
requires only nine total steps from commercially avail-
able 3,5-dibenzyloxybenzyl alcohol 8, which has pro-
vided significant quantities (ꢀ500 mg in three batch) of
material for both biological study and further synthetic
efforts toward papulacandin C.
Acknowledgements
7. Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Org.
Chem. 1996, 61, 1082–1100.
We are grateful to NIH (GM63150) and NSF (CHE-
0415469) for the support of our research program and
NSF-EPSCoR (0314742) for a 600 MHz NMR at
WVU.
8. (a) Hitchcock, S. A.; Gregory, G. S.; Kraynack, E. A.;
Mayhugh, D. R. 218th ACS National Meeting, New
Orleans, August 22–26, 1999; (b) Hitchcock, S. A. In
Frontiers of Biotechnology & Pharmaceuticals; Science:
New York, 2002; Vol. 3, pp 229–242.
9. (a) Balachari, D.; OꢀDoherty, G. A. Org. Lett. 2000, 2,
863–866; (b) Balachari, D.; OꢀDoherty, G. A. Org. Lett.
2000, 2, 4033–4036.
Supplementary data
10. An Achmatowicz reaction is the oxidative rearrangement
of furfuryl alcohols to 2-substituted 6-hydroxy-2H-pyran-
3(6H)-ones. For examples see: (a) Achmatowicz, O.;
Bielski, R. Carbohydr. Res. 1977, 55, 165–176; (b) Grap-
sas, I. K.; Couladouros, E. A.; Georgiadis, M. P. Pol. J.
Chem. 1990, 64, 823–826; For its use in de novo
carbohydrate synthesis see: Ref. 9, and (c) Harris, J. M.;
Keranen, M. D.; OꢀDoherty, G. A. J. Org. Chem. 1999, 64,
2982–2983; (d) Harris, J. M.; Keranen, M. D.; Nguyen,
H.; Young, V. G.; OꢀDoherty, G. A. Carbohydr. Res. 2000,
328, 17–36.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.04.073.
References and notes
1. (a) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.;
Schwartz, R. E.; Fromtling, R. A.; Nollstadt, K. H.; Van
Middlesworth, F. L.; Wilson, K. E.; Turner, M. J. Proc.
Natl. Acad. Sci. U.S.A. 1990, 87, 5950–5954; (b) Kovacs,
J.; Masur, H. J. Infect. Dis. 1988, 158, 254–259.
11. (a) Hunter, T. J.; OꢀDoherty, G. A. Org. Lett. 2001, 3,
1049–1052; (b) Hunter, T. J.; OꢀDoherty, G. A. Org. Lett.
2002, 4, 4447–4450; (c) Smith, C. M.; OꢀDoherty, G. A.
Org. Lett. 2003, 5, 1959–1962.
2. Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiot. 1977,
30, 289–296.
3. (a) Van Middlesworth, F.; Omstead, M. N.; Schmatz, D.;
Bartizal, K.; Fromtling, R.; Bills, G.; Nollstadt, K.;
Honeycutt, S.; Zweerink, M.; Garrity, G.; Wilson, K. J.
Antibiot. 1991, 44, 45–51; (b) Jabri, E. D. R.; Quigley, M.;
Alders, M.; Hrmova, M.; Taft, C. S.; Phelps, P.; Selitren-
nikoff, C. P. Curr. Microbiol. 1989, 19, 153–161; (c)
Bartizal, K.; Abruzzo, G.; Trainor, C.; Krupa, D.;
12. Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D.
J.; OꢀDoherty, G. A. Org. Lett. 2005, 7, 745–
748.
13. It is worth noting that the use of i-propanol was critical to
prevent polymerization of enal 7, see: Ref. 14.
14. Narkunan, K.; Nagarajan, M. J. Org. Chem. 1994, 59,
6386–6390.

M. M. Ahmed, G. A. O’Doherty / Tetrahedron Letters 46 (2005) 4151–4155
4155
15. (a) The enantioexcesses of diol 5 was determined by
examining the 1H NMR of Mosher ester 13b; (b) Sullivan,
G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143–2147.
(d, J = 12 Hz, 1H), 4.19 (ddd, J = 6.0, 4.2, 1.2 Hz, 1H),
4.14 (ddd, J = 7.2, 4.2, 1.2 Hz, 1H), 3.87 (ddd, J = 9.0, 4.2,
4.2 Hz, 1H), 3.80 (dd, J = 10.2, 6.0 Hz, 1H), 3.73 (dd,
J = 10.2, 4.8 Hz, 1H), 2.83 (d, J = 3.6 Hz, 1H), 2.65 (d,
J = 6.0 Hz, 1H), 1.89 (d, J = 7.8 Hz, 1H); 13C NMR
(150 MHz, CDCl3) d 162.1, 154.9, 143.4, 137.8, 136.5,
136.4, 128.6 (2C), 128.5 (2C), 128.4 (2C), 128.1, 127.8,
127.7 (2C), 127.6, 127.4 (2C), 126.9 (2C), 118.2, 110.8,
100.5, 98.4, 73.6, 73.0, 72.5, 70.9, 70.4, 70.3, 70.2, 70.0,
69.9; CIHRMS: Calculated for [C34H34O8+Na]+:
593.2151, found: 593.2125.
TBSO
O
OR
(Cl CO) CO, Py/CH Cl
2
1)
2)
3
2
2
5
0.5% Pd2(DBA)3•CHCl3
OBn
1% PPh3, HCOOH/Et3N
BnO
OBn
60% in 2 steps
13a: R= H
13b: R=
O
(+)-R-Mosher acid
DCC/DMAP/CH2Cl2
25
CF3
Minor Isomer (12): Rf (EtOAc) = 0.27; ½aꢁD ꢂ9.9 (c 1,
CH2Cl2); IR (thin film, cmꢂ1) 3480, 2957, 2921, 2851,
2360, 1637, 1540, 1494, 1456, 1418, 1338, 1154, 1114, 1092,
1064, 980, 731; 1H NMR (600 MHz, CDCl3) d 7.39 (m,
15H), 6.51 (d, J = 1.2 Hz, 1H), 6.38 (d, J = 1.8 Hz, 1H),
5.18 (d, J = 12.6 Hz, 1H), 5.11 (d, J = 12 Hz, 1H), 5.08 (d,
J = 12 Hz, 1H), 5.02 (s, 2H), 4.96 (d, J = 12.6 Hz, 1H),
4.77 (dd, J = 9.0, 8.4 Hz, 1H), 4.56 (d, J = 12.6 Hz, 1H),
4.53 (d, J = 12.6 Hz, 1H), 4.29 (dd, J = 8.4, 7.2 Hz, 1H),
3.95 (dd, J = 7.2, 4.8 Hz, 1H), 3.91 (ddd, J = 6.6, 6, 4.8 Hz,
1H), 3.60 (dd, J = 9.6, 6.6 Hz, 1H), 3.53 (dd, J = 9.6,
7.2 Hz, 1H), 2.93 (d, J = 1.2 Hz, 1H), 2.81 (d, J = 6.0 Hz,
1H), 2.49 (d, J = 10.2 Hz, 1H); 13C NMR (150 MHz,
CDCl3) d 162.3, 155.1, 143.3, 137.7, 136.4, 136.2, 128.7
(2C), 128.6 (2C), 128.4 (2C), 128.1,128.0, 127.8, 127.7
(2C), 127.4 (2C), 127.0 (2C), 116.0, 114.2, 100.4, 98.1, 81.3,
78.6, 76.2, 73.5, 72.8, 71.4, 70.4, 70.3, 69.9; CIHRMS:
calculated for [C34H34O8+Na]+: 593.2151, found:
593.2109.
MeO Ph
16. When diol 5 was dihydroxylated with the matched reagent
system ((DHQ)2PHAL/OsO4) gave the same selectivity as
the OsO4/NMO reaction but in a lower overall yield (44%).
17. (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett.
1983, 24, 3943–3946; For a review of diastereoselection in
the osmium catalyzed dihydroxylation reaction see: (b)
Cha, J. K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761–
1795.
25
18. Major Isomer (1d): Rf (EtOAc) = 0.32; mp 151 °C; ½aꢁD
12.7 (c 1, CH2Cl2); IR (thin film, cmꢂ1) 3480, 2957, 2921,
2873, 2360, 1637, 1540, 1494, 1456, 1418, 1338, 1154, 1092,
1064, 980; H NMR (600 MHz, CDCl3) d 7.39 (m, 15H),
1
6.51 (d, J = 1.2 Hz, 1H), 6.42 (d, J = 1.8 Hz, 1H), 5.15 (d,
J = 12 Hz, 1H), 5.11 (d, J = 11.4 Hz, 1H), 5.09 (d,
J = 11.4 Hz, 1H), 5.07 (d, J = 12 Hz, 1H), 5.03 (s, 2H),
4.65 (dd, J = 9.0, 8.4 Hz, 1H), 4.57 (d, J = 12 Hz, 1H), 4.52