Stereoselective synthesis of (-) - Pironetin by an iterative prins cyclisation and reductive cleavage strategy

Article abstract of DOI:10.1055/s-0029-1219810

A stereoselective synthesis of pironetin, a natural product which is highly immunosuppressive and shows remarkable plant growth regulatory and antitumoral activities, is described. The approach avails successfully the high stereoselection of Prins cyclisation. The route relies, in addition, on the reductive opening of cyclic ethers, olefin metathesis, and lithium acetylide displacement of tosylate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219810

LETTER
1205
Stereoselective Synthesis of (–)-Pironetin by an Iterative Prins Cyclisation and
Reductive Cleavage Strategy
S
tereosele
.
ctive
S
ynthe
S
sis of
(
–
)
-
Piron
.
etin Yadav,* Hissana Ather, N. Venkateswar Rao, M. Sridhar Reddy, A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 17 December 2009
tion was made on the retrosynthetic analysis (Scheme 1).
Abstract: A stereoselective synthesis of pironetin, a natural prod-
uct which is highly immunosuppressive and shows remarkable
plant growth regulatory and antitumoral activities, is described. The
approach avails successfully the high stereoselection of Prins cycli-
We first simplified the molecule to the intermediate 2
which has all the required stereochemistry and a homoal-
lylic 1,3-diol system. We envisaged that this intermediate
sation. The route relies, in addition, on the reductive opening of cy- could be easily drawn from pyran 3, by a reductive open-
clic ethers, olefin metathesis, and lithium acetylide displacement of
ing, which in turn was expected through Prins cyclisation
tosylate.
of acrolein and the intermediate 4. Intermediate 4, again a
Key words: natural products, Prins cyclisation, stereoselective
synthesis, reductive cleavage, olefin metathesis
homoallylic 1,3-diol system, was envisaged to be avail-
able from pyranyl methanol 5 by a reductive opening. Fi-
nally, pyranyl methanol 5 could be obtained from Prins
cyclisation of known homoallylic alcohol 6 and aldehyde
Pironetin (1) is an unsaturated d-lactone derivative, which 7.
was isolated independently by two research groups from
Streptomyces sp. NK10958 and from the fermentation
broths of Streptomyces prunicolor PA-48153, respective-
ly.1 Apart from plant growth regulatory and immunosup-
pressive activities, the biological effects of 1 and its
derivatives on cell-cycle progression and antitumor activ-
ities were reported.2 More importantly, the mode of action
of 1 is different from those established for the immuno-
suppressant cyclosporine A (CsA) and FK506 that inhibit
T cell activation.3 Pironetin showed suppressive effects on
the responses of T and B lymphocytes to mitogens. In-
spired by the biological properties and attracted by its
consecutive 1,3-anti-diol system flanked by 2- or 4-alkyl
groups for which we have recently established a method
via Prins cyclisation,4,5 we investigated a synthesis of
pironetin. Before the synthetic venture, a careful examina-
Our synthesis of pironetin is outlined in Scheme 2. Prins
cyclisation between known homoallylic alcohol 65h and
aldehyde 75e in the presence of TFA4a resulted in the tri-
fluoroacetate derivative of 5 which on direct treatment
with K2CO3 in MeOH gave tetrahydropyran diol 5, the
only isolable compound in 55% yield. The stereochemical
aspects of such Prins cyclisations and structurally very
close compounds of 5have been discussed in detail previ-
ously.4,5 Transformation of the primary hydroxyl group to
a tosylate using TsCl and triethylamine and protection of
the secondary hydroxyl group as its TBS ether using
TBSCl and imidazole resulted in fully protected interme-
diate 8. Substitution of the tosylate using NaI in acetone
followed by reductive opening5a of iodomethylpyran 9
produced alcohol 10.6 Alcohol 10 was converted to its me-
thyl ether and the key homologation with homoallyl piv-
OMOM
O
reductive
opening
OMe
acylation
OMe OAc
OH
metathesis
OMe OH
O
O
3
2
Prins
cyclisation
pironetin (1)
O
Me
OH
O
Prins
cyclisation
reductive
opening
OMe OH
HO
+
BnO
OH
BnO
O
OH
5
7
4
6
Scheme 1
SYNLETT 2010, No. 8, pp 1205–1208
x
x.
x
x.
2
0
1
0
Advanced online publication: 09.04.2010
DOI: 10.1055/s-0029-1219810; Art ID: D36609ST
© Georg Thieme Verlag Stuttgart · New York

1206
J. S. Yadav et al.
LETTER
OH
OTBS
O
Me
O
e
a
b, c
OH
+
R
HO
BnO
O
BnO
BnO
OR
5
OH
8 R = OTs
9 R = I
7
6
d
OMe OTBS
OMe OTBS
OH OTBS
i, j
f, g
RO
BnO
OPiv
BnO
11 R = Piv
12 R = H
13 R = Bn
14 R = H
10
i
h
k
OMe OTBS
OMe OTBS
o, p
m, n
l
TsO
16
15
OMOM
OMe OH
OMe
s, t
q, r
O
3
4
O
OMe OAc OMOM
OMe OAc
O
w, x
u, v
pironetin (1)
18
17
Scheme 2 Reagents and conditions: (a) TFA, CH2Cl2, 0 °C to r.t., 3 h then K2CO3, MeOH, r.t., 30 min, 55%; (b) Et3N, TsCl, CH2Cl2, 0 °C to
r.t., 6 h, 95%; (c) TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 3 h, 97%; (d) NaI, acetone, reflux, 24 h, 97%; (e) Zn, EtOH, NaHCO3, reflux, 2 h,
80%; (f) NaH, MeI, THF, 0 °C to r.t., 6 h, 98%; (g) i, Grubbs II cat., CH2Cl2, 40 °C, 6 h; (h) K2CO3, MeOH, r.t., 3 h, 68% (for 2 steps); (i) MsCl,
Et3N, DMAP, CH2Cl2, 0 °C to r.t., 30 min; (j) LiAlH4, THF, 0 °C to r.t., 4 h, 95% (for 2 steps); (k) Na, liq NH3, THF, 10 min, –33 °C, 95%; (l)
Et3N, TsCl, 0 °C to r.t., 6 h, 97%; (m) HC≡CLi·EDA, DMSO, r.t., 2 h, 82%; (n) n-BuLi, MeI, THF, –78 °C to r.t., 12 h, 98%; (o) CSA, MeOH,
0 °C to r.t., 15 min, 99%; (p) Na, liq NH3, THF, –33 °C, 6 h, 90%; (q) acrolein, TFA, CH2Cl2, 0 °C to r.t., 3 h then K2CO3, MeOH, r.t., 30 min,
58%; (r) MOMCl, DIPEA, CH2Cl2, r.t., 3 h, 97%; (s) Na, liq NH3, THF, –33 °C, 45 min, 94%; (t) Ac2O, DMAP, CH2Cl2, 0 °C to r.t., 2 h, 92%;
(u) Me3SiBr, CH2Cl2, –40 °C, 15 min, 76%; (v) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C to r.t., 30 min, 60%; (w) Grubbs II cat., CH2Cl2,
50 °C, 8 h, 32%; (x) 3 N HCl, MeOH, 60 °C, 6 h 74%.
alate was achieved using a cross-metathesis protocol7 to ing Na in ammonia followed by protection of the alcohol
yield 11. The pivalate group in 11 was removed using as an acetate resulted in 17 as a diastereomeric mixture.
K2CO3/MeOH, and the resulting alcohol 12 was convert- The MOM ether in 17 was cleaved using TMSBr,9 and the
ed to a mesylate before subjecting it to reductive elimina- resulting alcohol was transformed to its acrylate to pro-
tion to yield 13, suitable for homologation at the other duce key fragment 18. Ring-closing metathesis of 18 in
terminus. Thus, deprotection of the benzyl ether using Na/ the presence of Grubbs second-generation catalyst,10a–c,5g
liq NH3 followed by transformation of the resulting hy- followed by hydrolysis of the acetate group, produced
droxyl group 14 to tosylate using TsCl and triethylamine pironetin (1) in 53% yield. Of note was the failure of the
produced 15. Substitution of tosylate with lithium RCM reaction with Grubbs I10d catalyst; this may be at-
acetylide8 followed by methylation of the resulting termi- tributed to the presence of an internal double bond. Our
nal alkyne with MeI/n-BuLi in THF yielded homologated synthetic material showed spectroscopic and physical
16. The TBS ether in 16 was cleaved using CSA in data {1H NMR, 13C NMR, IR, Rf and [a]D} consistent with
MeOH, and the resulting alkynol was subjected to Birch the isolated sample.1,11
reduction to furnish key homoallylic alcohol 4.
In summary, we have described a stereoselective ap-
The stage was now set for a second Prins cyclisation to in- proach to pironetin using our recently developed synthetic
troduce the remaining stereochemical features. Thus, the sequence to access polyketide precursors via Prins cycli-
second Prins cyclisation was performed on 4 with ac- sation. This synthetic approach can provide a means for
rolein, and the resulting pyranol was protected as its probing the structure–activity relationships of these and
MOM ether to yield 3. Reductive opening5b of pyran 3 us- other related antifungal agents.
Synlett 2010, No. 8, 1205–1208 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of (–)-Pironetin
1207
Acknowledgment
100.4
23.6
25.1
7
HA, NVR, and MSR thank CSIR, New Delhi for the award of fel-
lowships and also thank DST for the financial assistance under J. C.
Bose Fellowship Scheme.
1) TBAF, THF,
O
3
O
5
OH OTBS
Me
0 °C to r.t.,
1 h
1
2
6
4
BnO
BnO
8
2) 2,2-DMP,
PTSA, r.t.
Me
Me
Me
References and Notes
Scheme 3
(1) (a) Kobayashi, S.; Tsuchiya, K.; Harada, T.; Nishide, M.;
Kurokawa, T.; Nakagawa, T.; Shimada, N.; Kobayashi, K.
J. Antibiot. 1994, 47, 697. (b) Kobayashi, S.; Tsuchiya, K.;
Kurokawa, T.; Nakagawa, T.; Shimada, N.; Iitaka, Y.
J. Antibiot. 1994, 47, 703. (c) Tsuchiya, K.; Kobayashi, S.;
Harada, T.; Nishikiori, T.; Nakagawa, T.; Tatsuta, K.
J. Antibiot. 1997, 50, 259.
1H NMR supported the stereochemistry of the 4-a-methyl
group.
(7) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.;
Ling, T.; Yamada, Y. M. A.; Tang, W.; Frederick, M. O.
Angew. Chem. Int. Ed. 2004, 43, 4318.
(2) Konodoh, M.; Usui, T.; Kobayashi, S.; Tsuchiya, K.;
Nishikawa, K.; Nishikiori, T.; Mayumi, T.; Osada, H.
Cancer Lett. 1998, 126, 29.
(3) For a paper about chemical modifications of pironetin to
reduce its toxicity, see: Yasui, K.; Tamura, Y.; Nakatani, T.;
Horibe, I.; Kawada, K.; Koizumi, K.; Suzuki, R.; Ohtani, M.
J. Antibiot. 1996, 49, 173.
(8) (a) Toshima, K.; Jyojima, T.; Miyamoto, N.; Katohno, M.;
Nakata, M.; Mastumura, S. J. Org. Chem. 2001, 66, 1708.
(b) Moune, S.; Niel, G.; Busquet, M.; Eggleston, I.; Jouin, P.
J. Org. Chem. 1997, 62, 3332.
(9) Imoto, H.; Matsumoto, M.; Odaka, H.; Sakamoto, J.;
Kimura, H.; Nonaka, M.; Kiyota, Y.; Momose, Y. Chem.
Pharm. Bull. 2004, 52, 120.
(4) For examples of the Prins cyclisation, see: (a) Barry, C. S. t.
J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429.
(b) Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem. 2001,
66, 739. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew.
Chem. Int. Ed. 2005, 44, 3485. (d) Barry, C. S.; Bushby, N.;
Harding, J. R.; Willis, C. S. Org. Lett. 2005, 7, 2683.
(e) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
12216. (f) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
G. D.; Willis, C. L. Org. Lett. 2002, 4, 3407. (g)Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett.
2002, 4, 3919. (h) Kozmin, S. A. Org. Lett. 2001, 3, 755.
(i) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem.
2001, 66, 4679. (j) Kopecky, D. J.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2001, 123, 8420. (k) Rychnovsky, S. D.;
Thomas, C. R. Org. Lett. 2000, 2, 1217. (l) Rychnovsky, S.
D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62,
3022. (m) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126,
2425. (n) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.;
Gunasekar, D. Synthesis 2001, 885. (o) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M. S.; Niranjan, N. J. Mol. Catal. A: Chem.
2004, 210, 99. (p) Yadav, J. S.; Reddy, B. V. S.; Reddy,
M. S.; Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003,
1779.
(5) For our previous applications of Prins cyclisation, see:
(a) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4397. (b) Yadav, J. S.; Reddy,
M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4937.
(c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2005, 46, 2133. (d) Yadav, J. S.; Reddy, M. S.; Prasad,
A. R. Tetrahedron Lett. 2006, 47, 4995. (e) Yadav, J. S.;
Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synlett 2007, 2049.
(f) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.; Prasad,
A. R. Tetrahedron Lett. 2007, 48, 1469. (g) Yadav, J. S.;
Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron
2006, 63, 2689. (h) Yadav, J. S.; Kumar Rao, P. P.; Reddy,
M. S.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 5427.
(6) As shown below, compound 10 was subjected to TBS ether
cleavage and then transformed to the corresponding
acetonide to confirm the anti relationship of hydroxyl groups
by examination of the 13C NMR spectrum. See:
(10) (a) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H.
J. Am. Chem. Soc. 2001, 123, 6543. (c) Shibahara, S.;
Fujino, M.; Tashiro, Y.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Org. Lett. 2008, 10, 2139. (d) Schwab, P.;
France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039; Angew. Chem. 1995, 107,
2179.
(11) Spectroscopic and Physical Data of Selected Compounds
(2R,3S,4R,6R)-2-[(S)-1-(Benzyloxy)propan-2-yl]-tetra-
hydro-6-hydroxymethyl)-3-methyl-2H-pyran-4-ol (5)
[a]D25 +18.5 (c 1.0, CHCl3); Rf = 0.3 (SiO2, 60% EtOAc in
hexane). IR (neat): 3390, 2926, 2859, 1359, 1158, cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.23–7.30 (m, 5 H), 4.39–4.55
(m, 2 H), 3.21–3.56 (m, 7 H), 2.02–2.11 (m, 1 H), 1.77–1.86
(m, 1 H), 1.22–1.44 (m, 2 H), 0.96 (d, 3 H, J = 6.64 Hz), 0.85
(d, 3 H, J = 6.64 Hz). 13C NMR (75 MHz, CDCl3): d =
138.53, 128.30, 127.48, 79.47, 75.50, 73.33, 73.12, 72.97,
65.83, 40.40, 36.77, 34.10, 12.04, 9.54. ESI-HRMS: m/z
[M + Na]+ calcd for C17H26NaO4: 317.1728; found:
317.1719.
(2S,3R,4R,5R)-1-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-2,4-dimethyloct-7-en-3-ol (10)
[a]D25 +13.9 (c 0.65, CHCl3); Rf = 0.6 (SiO2, 10% EtOAc in
hexane). IR (neat): 3500, 2930, 2855, 1461, 1063, 911 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30–7.27 (m, 5 H), 5.81–
5.67 (m, 1 H), 5.08–4.49 (m, 2 H), 4.45–4.56 (m, 2 H), 3.97–
3.92 (m, 1 H), 3.75 (d, 1 H, J = 9.82 Hz), 3.53–3.39 (m, 2 H),
2.37–2.20 (m, 2 H), 1.85–1.70 (m, 2 H), 1.46 (br, OH), 0.89–
0.87 (m, 12 H), 0.75 (d, 3 H, J = 6.8 Hz), 0.06 (s, 3 H), 0.09
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 138.60, 135.13,
128.24, 127.47, 127.36, 116.90, 116.67, 81.09, 73.86, 72.82,
71.15, 60.70, 40.55, 39.38, 35.30, 26.02, 18.2, 9.7, 9.1,
–3.17, –4.37. ESI-HRMS: m/z [M + Na]+calcd for
C23H40NaO3Si: 415.2644; found: 415.4635.
(3E,6R,7S,8R,9S,11E)-8-Methoxy-7,9-dimethyltridec-
3,11-dien-6-ol (4)
[a]D25 +4.0 (c 1.3, CHCl3); Rf = 0.5 (SiO2, 20% EtOAc in
hexane); IR (neat): 3420, 2966, 2931, 1715, 1457, 1083, 971
cm–1; 1H NMR (300 MHz, CDCl3): d = 5.62–5.29 (m, 4 H),
3.90–3.83 (m, 1 H), 3.48 (s, 3 H), 2.98 (m, 1 H), 2.57 (br, 1
H, OH), 2.27–1.75 (m, 8 H), 1.67 (d, 3 H, J = 6.40 Hz), 0.98
(t, 3 H, J = 7.34 Hz), 0.92 (d, 3 H, J = 7.9 Hz), 0.89 (d, 3 H,
J = 7.8 Hz). 13C NMR (75 MHz, CDCl3): d = 134.69, 129.18,
126.58, 125.63, 89.80, 70.6, 61.63, 38.10, 37.8, 37.2, 36.05,
(a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 39, 7099; One broad coupling
(J = 9.0 Hz) of 3-H of the acetonide in Scheme 3 in its
Synlett 2010, No. 8, 1205–1208 © Thieme Stuttgart · New York

1208
J. S. Yadav et al.
LETTER
25.63, 17.93, 14.57, 13.8, 10.91. ESI-HRMS: m/z [M +
Na]+calcd for C16H30NaO2: 277.1987; found: 277.1977.
(2R,3S,4R,6R)-3-Ethyl-tetrahydro-6-[(E,2S,3R,4S)-3-
methoxy-4-methyloct-6-en-2-yl]-2-vinyl-2H-pyran-4-ol
(3a)
J = 5.28 Hz), 1.75–1.50 (m, 4 H), 1.45–1.28 (m, 2 H), 0.92–
0.79 (m, 9 H). 13C NMR (75 MHz, CDCl3): d = 170.40,
134.51, 132.50, 125.50, 125.5, 96.30, 88.51, 66.99, 68.30,
58.0, 55.62, 49.06, 39.52, 36.42, 35.50, 33.75, 23.65, 21.20,
19.53, 19.35, 15.30, 12.42, 10.25. ESI-HRMS: m/z [M +
Na]+ calcd for C23H24NaO5: 421.2929; found: 421.2923.
(5R,6R)-5-Ethyl-5,6-dihydro-6-[(E,2R,3S,4R,5S)-2-
hydroxy-4-methoxy-3,5-dimethylnon-7-enyl]pyran-2-
one (1)
[a]D25 –27.6 (c 0.65, CHCl3). IR (neat): 3427, 2967, 2929,
1718, 1457, 1089, 759 cm–1. 1H NMR (300 MHz, CDCl3):
d = 5.88–5.71 (m, 1 H), 5.49–5.36 (m, 2 H), 5.26–5.11 (m, 2
H), 3.69–3.45 (m, 3 H), 3.33 (s, 3 H), 3.05 (dd, 1 H, J = 9.55,
2.94 Hz), 2.32–2.27 (m, 1 H), 2.08–1.95 (m, 2 H), 1.76–1.41
(m, 7 H), 1.25–1.14 (m, 1 H), 1.02–0.75 (m, 11 H). 13C NMR
(75 MHz, CDCl3): d = 130.65, 130.44, 128.71, 126.13, 84.8,
80.25, 74.34, 73.43, 70.67, 50.97, 49.21, 40.54, 38.99,
38.25, 35.49, 19.41, 17.96, 11.86, 10.18. ESI-HRMS: m/z
[M + Na]+ calcd for C19H34NaO3: 333.2405; found:
333.2409.
[a]D25 –139.5 (c 0.35, CHCl3); Rf = 0.3 (SiO2, 50% EtOAc in
hexane); IR (neat): 3479, 2965, 2931, 1718, 1459, 1384,
1088 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.04 (dd, 1 H,
J = 9.82, 6.04 Hz), 6.04 (d, 1 H, J = 9.82 Hz), 5.50–5.32 (m,
2 H), 4.76 (m, 1 H), 4.23 (br d, 1 H), 3.47 (s, 3 H), 3.39 (br,
OH), 2.36–2.27 (m, 1 H), 3.00–2.97 (m, 1 H), 2.13–2.06 (m,
1 H), 1.97–1.63 (m, 6 H), 1.67 (d, 3 H, J = 5.27 Hz), 1.56–
1.45 (m, 1 H), 1.01 (t, 3 H, J = 7.18 Hz), 0.97 (d, 3 H,
J = 7.18 Hz), 0.95 (d, 3 H, J = 6.70 Hz). 13C NMR (75 MHz,
CDCl3): d = 164.1, 144.8, 121.5, 96.1, 75.2, 69.7, 55.4, 41.8,
29.4, 20.1.164.75, 150.77, 130.08, 126.91, 120.72, 90.2,
77.73, 67.17, 61.55, 39.16, 39.05, 37.32, 36.73, 35.96,
20.76, 17.91, 15.1, 11.88, 10.96. ESI-HRMS: m/z [M + Na]+
calcd for C19H32NaO4 347.2198; found: 347.2205.
(4R,5R,7R,8S,9R,10S,12E)-4-Ethyl-9-methoxy-5-
(methoxymethoxy)-8,10-dimethyltetradeca-2,12-dien-7-
yl acetate (17)
IR (neat): 2929, 2855, 1740, 1244, 1097, 966 cm–1. 1H NMR
(300 MHz, CDCl3): d = 5.51–5.03 (m, 5 H), 4.63–4.59 (m, 2
H), 3.56–3.41 (m, 1 H), 3.39 (s, 3 H), 3.37 (s, 3 H), 2.84–2.77
(m, 1 H), 2.03 (s, 3 H), 2.17–1.91 (m, 3 H), 1.66 (d, 6 H,
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