Synthetic studies on amphidinolides C and F: synthesis of the C18-C29 segment of amphidinolide F

Article abstract of DOI:10.1016/j.tetlet.2009.02.093

The C18-C29 segment of amphidinolide F is synthesised in 12 steps from 1,4-butanediol. Key steps include a mono-Sharpless dihydroxylation of a dienoate, iodocyclisation to construct the trans-THF ring and an E-selective Wittig reaction to introduce the C25-C26 olefin.

Full text of DOI:10.1016/j.tetlet.2009.02.093

Tetrahedron Letters 50 (2009) 3325–3328
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies on amphidinolides C and F: synthesis of the C18–C29
segment of amphidinolide F
*
Alan Armstrong , Constantina Pyrkotis
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The C18–C29 segment of amphidinolide F is synthesised in 12 steps from 1,4-butanediol. Key steps
include a mono-Sharpless dihydroxylation of a dienoate, iodocyclisation to construct the trans-THF ring
and an E-selective Wittig reaction to introduce the C25–C26 olefin.
Received 9 January 2009
Revised 3 February 2009
Accepted 11 February 2009
Available online 15 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Dihydroxylations
Iodine
Cyclisations
Wittig reactions
The amphidinolides1 are a structurally diverse family of cyto-
toxic marine compounds which occur naturally in only minute
amounts; total synthesis therefore becomes an important potential
source. Although successful routes to several members of the fam-
ily have been reported,1 this feat has not yet been accomplished
for the closely related amphidinolides C and F (Fig. 1). Amphidi-
nolide C, in particular, exhibits highly potent cytotoxic activity
against L1210 and KB cells in vitro (values of 0.0058 and
Wittig reaction to give 3 in 36% overall yield (E,E:E,Z = 92:8) from
4. The low yield is believed to be at least partly due to the volatility
and water miscibility of 5. A higher overall yield was obtained in a
6
sequential oxidation/olefination process using methodology re-
cently reported by Graham and co-workers. Thus, in situ MnO
monooxidation/olefination of diol 6 afforded 7, which was isolated
and purified before application of a second oxidation/olefination
step, this time using PCC as oxidant, to give 3 (65% overall) with sim-
ilar stereoselectivity (E,E:E,Z = 92:8).
,2
7
2
3
4
0
.0046 lg/ml, respectively), making a synthetic route to amphidi-
nolides of this class an important goal. To date, three groups have
With dienoate 3 in hand, we could now study the key conver-
sion to THF 2. Ideally, this would be effected directly via a novel
reported studies towards the synthesis of fragments of these com-
3
b,d,5
pounds.
Here we describe our own approach, leading to a con-
cise synthesis of the C18–C29 THF unit of amphidinolide F.
We envisaged key bond disconnections across the diene at C9–
C10 and the macrolactone, as well as at C17–C18. These led us to
require the THF fragment 1 (Scheme 1), which could be obtained
O
O
18
1
5
20
13
by appropriate manipulation of the
a-hydroxy-diester 2. Diester
2
3
OH
HO
H
O
2
could in principle be accessed directly via a desymmetrising
R29
H
mono-Sharpless AD/Michael reaction on symmetrical dienoate 3.
In the forward sense, this process would raise interesting questions
of regio- and stereocontrol (vide infra), but it would potentially
provide a highly concise route to the key intermediate 2.
We first required an efficient route for the synthesis of diene dio-
ate 3. Of several methods evaluated, the two proving most efficient
in our hands are shown in Scheme 2. Hydrolysis of 2,5-dimethoxy-
tetrahydrofuran 4 gave the dialdehyde 5 which underwent double
24
O
H
H
O
6
3
4
O
OH
OR'
nBu
R=
29
R=CH3
Amphidinolide C R'=H
Amphidinolide F
Amphidinolide C2 R'=Ac
*
Corresponding author. Fax: +44 0 20 75945804.
E-mail address: a.armstrong@imperial.ac.uk (A. Armstrong).
Figure 1. Structures of Amphidinolides C, C2 and F.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.093

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A. Armstrong, C. Pyrkotis / Tetrahedron Letters 50 (2009) 3325–3328
in a Michael reaction as part of his synthesis of the amphidinolide
3
d
C17–C29 fragment. While this was not encouraging, we hoped
that use of alternative cyclisation conditions would allow im-
proved stereocontrol. Application of standard Sharpless AD condi-
S
S
1
8
10
2
0
23
tions to 3 with 1 equivalent of AD-mix-b (Table 1, entry 1) in the
EtO C
CO Et
2
4
2
0
2
1
8
O
presence of methanesulfonamide effected complete reaction in
<2 h. The diol 8 was isolated in 85% yield together with 10% of
the THF 2, which was obtained as a 3:2 mixture of diastereoiso-
2
H
H
2
3
H
O
OH
29
2
H
2
4
26
1
mers according to H NMR analysis. The enantiomeric excess of
TBSO
1
diol 8 was determined by chiral HPLC and found to be 73%. For
comparison, AD was also carried out with AD-mix-
a (entry 2).
Interestingly, this gave diol ent-8 of lower ee (57% ee), despite
the fact that the quinidine and quinine-derived ligands in the
two AD-mixes usually behave as ‘pseudoenantiomers’, giving prod-
ucts of similar enantiomeric excess. We next attempted the AD
reaction in the presence of additional base in an attempt to pro-
mote the cyclisation reaction (entries 3 and 4). While conversion
was high and the THF 2 was now the major product, the yield
was low, suggesting base-mediated decomposition. Moreover,
the diastereoselectivity was consistently low (3:2). Since we had
been able to isolate only low amounts of THF 2, but good yields
of diol 8, we decided to investigate the cyclisation step separately.
Treatment of 8 with 1 equiv of EtONa in EtOH/THF for 2 h gave 2 in
50% yield, again as a 3:2 mixture of diastereoisomers. Aprotic con-
ditions (LHMDS in THF) gave very low conversion and an un-
changed stereoisomeric ratio. We were able to separate small
quantities of the two diastereomers, and resubmission of these to
base allowed us to tentatively conclude that the minor cis-diaste-
reomer was thermodynamically preferred. We therefore decided
to abandon the Michael addition and investigate alternative meth-
ods for THF formation.
EtO C
CO Et
2
2
3
Scheme 1.
a
O
O
MeO
O
4
OMe
5
b
EtO C
2
CO Et
2
3
d
c
HO
OH
HO
6
7
CO Et
2
Scheme 2. Reagents and Conditions: (a) HCl (aq), THF, reflux, 2 h; (b)
Ph P@CHCO Et, 3 Å MS, CH Cl , rt, 36 h, 36%; (c) MnO , Ph P@CHCO Et, 48 h,
5%; (d) PCC, imidazole, Ph P@CHCO Et, 19 h, 65%.
11
Iodocyclisation has been widely employed for THF synthesis
and was an attractive option. This was first attempted with the
3
2
2
2
2
3
2
9
3
2
‘
unnatural’ diol, ent-8 (Scheme 3), affording a 3:1 mixture of
trans- and cis- tetrahydrofurans ent-9b and ent-9a. Separation of
the two diastereoisomers using flash chromatography gave the
trans-diastereoisomer ent-9b as a pale yellow semi-crystalline so-
lid, recrystallisation of which resulted in enhanced ee (93%)
according to chiral HPLC analysis. X-ray crystallography12 verified
both the relative and the absolute configuration of ent-9b.
one-pot Sharpless AD/Michael reaction. Mono- versus bis-dihydr-
oxylation of the diene was a potential concern. While we could
not find direct literature precedent for selective mono-AD on
2
,6-dienoates, there was literature precedent for mono-dihydroxy-
8
lation of this type of substrate under Upjohn conditions. Addition-
ally, we hoped that in situ Michael reaction of the initially formed
AD product would remove the potentially reactive second alkene
before any second dihydroxylation could take place.
We repeated the iodocyclisation with 8 itself (Scheme 3) to ob-
tain 9b. Resolution during recrystallisation again resulted in
1
3
enrichment from 73% to over 93% ee. The improved cyclisation
diastereoselectivity (albeit in a still-moderate 3:1 ratio), the signif-
icantly increased overall yield and the opportunity to improve the
enantiomeric excess via resolution during the recrystallisation
meant that the iodocyclisation approach towards the synthesis of
this fragment was preferable to the earlier, base-mediated
cyclisation.
For the cyclisation step, we envisaged that the desired 5-exo-
trig cyclisation mode would be kinetically preferred over the
alternative possible 6-exo-trig.9 A further key question involved
stereoselectivity in the Michael reaction, given the lack of stereo-
centres in the linking chain between C20 and C23. In one relevant
precedent, Kobayashi observed non-diastereoselective cyclisation
Table 1
Dihydroxylation/Cyclisation of Dienoate 3
AD-mix (1 eq)
OH
CO Et
EtO C
2
CO
OH
2
Et
CH SO NH (1 eq)
+
3
2
2
3
O
2
t
EtO C
H
H
BuOH:H O (1:1), r.t.
2
HO
2
2
8
Entry
1
2
3
4
AD-mix
Additive
Time (h)
Yield 8 (%)
Yield 2 (%)
2 trans:cisa
b
a
b
b
—
—
2
2
18
8
85
82
—
10
12
35
40
3:2
3:2
3:2
3:2
b
DBU (2 equiv)
NaOH (2 equiv)
—
a
Determined by 1H NMR analysis. Major isomer is the trans-THF by correlation with products from the iodocyclisation route.
Ent-8 and ent-2 obtained in this experiment.
b

A. Armstrong, C. Pyrkotis / Tetrahedron Letters 50 (2009) 3325–3328
3327
1
2
O
I
2
, NaHCO
CH CN
3
2
0
EtO C
2
CO Et
2
ent-8
3
a
O
H
H
(57% ee)
4 h, 90% yield
I
OH
d.r.= 3:1 trans:cis
ent-9a α-H
2
2
0
0
6.11 ppm
4
.10 ppm
ent-9b β-H
HO H
O
H
OTBS
OTBS
H
H
H
H
I
2
, NaHCO
CH CN
3
6.73 ppm
H
EtO C
2
14
HO
3
CH3
+
4
h, 90% yield
EtO C
2
CO Et
8
2
O
H
OTBS
1
.82 ppm
(
73% ee) d.r.= 3:1 trans:cis
H
H
O
H
I
OH
6.56 ppm
6
5% (9b)
0% (9a)
O
H
15
H
2
9
a β-H
CO
2
Et 13
70%
2
2
0
0
EtO C
9
b α-H (93% ee)
2
14:15, 2:1
Scheme 3.
t
Scheme 5. (a) SeO
2
, BuOOH, CH
2
2
Cl , rt, overnight.
Having desymmetrised the diene dioate 3, we were now in a
position to install the required functionality at either side of the
THF unit (Scheme 4). Deiodination of 9b could be effected effi-
ciently using either tributyltin hydride/cat. AIBN in toluene at
could potentially result in a mixture of regioisomeric products. In
the event, 12 underwent SeO allylic oxidation to give, after chro-
matography, the desired allylic alcohol 13 (ca. 70%; E,E-configu-
2
2
1
14
ration confirmed by NOE analysis), along with a 2:1 mixture
5
4 3
0 °C or with indium hydride, generated from NaBH /cat. InCl .
1
assigned tentatively by H NMR as aldehyde 14 and regioisomeric
Differentiation of the two ethyl esters was now accomplished by
-hydroxy ester15 using BH
selective reduction of the /cat.
ꢀSMe
NaBH . Hydroxy group differentiation was achieved by bis-TBS
ether formation and selective primary deprotection, affording 11.
allylic alcohols 15. This key transformation potentially allows ac-
cess into amphidinolide C and analogues bearing unnatural side-
chains at C29.
In conclusion, we have achieved a synthesis of the C18–C29
fragment 1 of amphidinolide F in 12 steps starting from commer-
cially available butane-1,4-diol 6. We have also demonstrated po-
tential for further elaboration to amphidinolide C and analogues
via oxidation at C29. Further studies towards these targets are cur-
rently underway.
a
3
2
4
16
Dess-Martin oxidation in the presence of 1 equiv of H
2
O
afforded
an unstable aldehyde in 80% yield which was then subjected to an
17
E-selective olefination with a tributylphosphonium ylide to pro-
1
8
vide 12 (43% from alcohol 11; 87:13, E:Z). The E-isomer was dis-
tinguished from the minor Z-isomer by coupling constant analysis
(J H25–H26 = 15.1 vs 11.3 Hz). Reduction of the ethyl ester with DI-
BAL-H gave the corresponding aldehyde which was then converted
1
9
Acknowledgements
to the 1,3-dithiane 1. Use of BF
afforded 1 in only moderate yields due to competitive cleavage
of the TBS ether. However, use of the milder Lewis acid MgBr
2
3
ꢀOEt
2
as Lewis acid in this step
We thank Merck Sharpe and Dohme and Pfizer for support of
our work. C.P. thanks the A.G. Leventis Foundation for a fellowship.
2
ꢀOEt
solved this problem, leading to formation of 1 (87:13, E:Z) in 75%
yield (over two steps).
References and notes
Finally, we have performed preliminary studies demonstrating
the feasibility of converting the amphidinolide F side-chain into
that of amphidinolide C, via selective allylic oxidation at C29
1.
(a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93; (b) Kobayashi, J. J.
Antibiot. 2008, 61, 271–284; (c) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70,
451–460.
(
Scheme 5). We could find little literature precedent for SeO
2
-med-
20
2. For reviews, see: (a) Chakraborty, T. K.; Das, S. Curr. Med. Chem.-Anti-Cancer
Agents 2001, 1, 131–149; (b) Hiersemann, M. Nachr. Chem. 2006, 5, 534–537;
iated allylic oxidation of acyclic 1,3-dienes, and this process
(
c) Colby, E. A.; Jamison, T. F. Org. Biomol. Chem. 2005, 3, 2675–2684; (d)
Furstner, A.; Bouchez, L. C.; Funel, J. A.; Liepins, V.; Poree, F. H.; Gilmour, R.;
Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem. Int. Ed 2007, 46, 9265–9270.
and references therein..
EtO C
CO
2
Et
a
CO Et
b
3. (a) Kobayashi, J.; Ishibashi, M.; Walchli, M. R.; Nakamura, H.; Hirata, Y.;
Takuma, S.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490–494; (b) Ishiyama, H.;
Ishibashi, M.; Kobayashi, J. Chem. Pharm. Bull. 1996, 44, 1819–1822; (c) Kubota,
T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363–1366; (d) Kubota, T.; Tsuda,
M.; Kobayashi, J. Tetrahedron 2003, 59, 1613–1625; (e) Kubota, T.; Tsuda, M.;
Kobayashi, J. Tetrahedron 2001, 57, 5975–5977.
2
2
O
O
H
9
H
H
2
H
H
I
OH
EtO C
OH
2
b
d, e
2
4
4. Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu, T.; Hirota, H.;
Sasaki, T. J. Antibiot. 1991, 44, 1259–1261.
O
O
OH
H
H
H
EtO C
OTBS
5. (a) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865–3868; (b) Bates, R. H.;
Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 10, 4343–4346; (c) Mohapatra, D.
K.; Rahaman, H.; Chorghade, M. S.; Gurjar, M. K. Synlett 2007, 567–570;
Synthesis of an amphidinolide U fragment: Mohapatra, D. K.; Rahaman, H.
Synlett 2008, 837–840.
2
EtO C
OR
12
2
1
0 R=H
c
1
1 R=TBS
S
6
7
.
.
Sato, K.; Inoue, S.; Ota, S.; Fujita, Y. J. Org. Chem. 1972, 37, 462–464.
(a) Phillips, D. J.; Pillinger, S. K.; Li, W.; Taylor, A. E.; Graham, A. E. Chem.
Commun. 2006, 2280–2282; (b) Phillips, D. J.; Pillinger, S. K.; Li, W.; Taylor, A.
E.; Graham, A. E. Tetrahedron 2007, 63, 10528–10533.
Saito, S.; Morikawa, Y.; Moriwake, T. Synlett 1990, 523–524.
Guindon, Y.; Delorme, D.; Law, K. C.; Zamboni, R. J. Org. Chem. 1988, 53, 267–
275.
f, g
S
O
H
H
1
OTBS
8
9
.
.
Scheme 4. Reagents and Conditions: (a) AIBN, nBu
cat. InCl , NaBH , CH CN, 3 h, 73%; (b) (i) BH
ꢀSMe
TsOH, 60% (+18% starting material); (c) (i) TBSCl, imidazole DMF, rt, overnight, 81%;
3
SnH, toluene, reflux, 1 h, 95% or
10. Reviews: (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547; (b) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006, 1725–
3
4
3
3
2
/THF, rt; (ii) NaBH ; (iii) EtOH,
4
1756.
(
(
ii) HF.pyridine, pyridine, THF, rt, 8 h, 86%; (d) Dess-Martin periodinane, CH
2
Cl
Br , nBuLi (in hexanes), DMSO, toluene,
78 °C to 0 °C, 43% (over two steps), 87:13 E:Z; (f) DIBAL-H, THF, ꢁ78 °C, 1 h; (g)
HS(CH SH, MgBr , CH Cl , rt, 1 h, 75% (over two steps).
ꢀOEt
2
+
-
11. For examples of Sharpless AD/iodocyclization for THF synthesis, see: (a) Zhang,
H.; Mootoo, R. D. J. Org. Chem. 1995, 60, 8134–8135; (b) Zhang, H.; Seepersaud,
M.; Seepersaud, S.; Mootoo, R. D. J. Org. Chem. 1998, 63, 2049–2052.
2 2 3
wet), rt, 5–15 min; (e) Me C@CHCH P Bu
ꢁ
2
)
3
2
2
2
2

3
328
A. Armstrong, C. Pyrkotis / Tetrahedron Letters 50 (2009) 3325–3328
1
1
2. We thank Dr. A. J. P. White, Department of Chemistry, Imperial College, London,
for determination of this crystal structure.
1.77 (s, 3H), 1.65–1.38 (m, 2H), 1.28 (t, J 7.1 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H),
0.06 (s, 3H); 13C NMR (101 MHz, CDCl
): d 171.3, 137.0 (Z), 135.0 (E), 129.6 (E),
128.5 (Z), 127.5 (E), 125.7 (Z), 124.7 (E), 120.3 (Z), 82.3, 75.7, 75.1, 60.4, 40.9,
3
3. Data for 9b: pale yellow crystalline solid, mp = 58–60 oC, ee = 93% (chiral HPLC,
i
Chiralcel OD, 10% PrOH/hexane, 0.05 mL/min, 254 nm) 9b (153.8 min), ent-9b
31.9, 26.9, 26.0, 25.9 (3 ꢃ C), 18.2 (2 ꢃ C), 14.2, ꢁ4.7 (2 ꢃ C); HRMS (CI) m/z
2
0
+
(
(
164.0 min); 9b; R
f
0.75, (50% EtOAc/petrol); ½
a
ꢂ
ꢁ22.7 (c. 1.06, EtOH); IR
calcd for C21
19. Data for 1: R
max 1654, 1462, 1378, 1264, 1063 cm
H
f
42NO
4
Si (MNH
4
), 400.2883, found: 400.2883.
D
ꢁ
1
1
25
CHCl ): max 3436, 2982, 1736, 1281, 469 cm
3
m
;
H NMR (400 VHz, CDCl
3
): d
0.52 (10% EtOAc/petrol); ½
aꢂ ꢁ25.3 (c. 1.02, EtOH); IR (CHCl
3
):
): d 6.29
D
;
ꢁ
1
1
4
1
1
.43 (td, J 7.6, 2.0 Hz, 1H), 4.38–4.31 (m, 1H), 4.30–4.12 (m, 4H), 4.02 (d, J 2.0 Hz,
H), 2.93 (d, J 8.4 Hz, 1H), 2.44–2.36 (m, 1H), 2.17–2.01 (m, 2H), 1.87–1.78 (m,
H), 1.68 (br s, 1H), 1.27 (t, J 7.2 Hz, 3H), 1.25 (t, J 7.2 Hz, 3H); 1 C NMR (101 MHz,
m
H NMR (400 MHz, CDCl
3
(app t, J 14.3 Hz, 1H), 5.87 (br d, J 11.1 Hz, 1H), 5.50–5.37 (m, 1H), 4.34–4.26
(m, 1H), 4.24–4.19 (m, 1H), 4.18–4.11 (m, 1H), 4.10–4.00 (m, 1H), 2.95–2.73
3
CDCl
3
): d 172.5, 169.6, 80.84, 80.75, 72.4, 61.77, 61.75, 32.2, 27.5, 25.7, 14.1, 13.7;
(m, 4H), 2.70–2.55 (m, 2H), 2.14–1.77 (m, 4H), 1.80 (s, 3H), 1.78 (s, 3H), 1.62–
+
13
HRMS (CI) m/z calcd for C12
6
H23NO I (MNH
4
), 404.0570, found: 404.0574.
1.34 (m, 2H), 0.94 (s, 9H), 0.12 (s, 6H); C NMR (101 MHz, CDCl
3
): d 137.6 (C
Z
),
),
1
1
4. Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002, 124, 906–907.
5. (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.;
Moriwake, T. Chem. Lett. 1984, 1389–1392; (b) Saito, S.; Ishikawa, T.; Kuroda,
A.; Koga, K.; Moriwake, T. Tetrahedron 1992, 48, 4067–4086.
135.5 (C
122.9 (CH
E Z E E Z
), 129.9 (CH ), 129.2 (CH ), 128.0 (CH ), 125.3 (CH ), 124.4 (CH
E
Z
), 81.3, 80.5, 76.1, 44.4, 41.8, 37.4, 33.5, 31.3, 30.4, 26.0, 25.6, 23.9,
+
20.8, 18.5, ꢁ3.6; HRMS (ESI) m/z calcd for C16
H
25OS
2
(MꢁOTBS ), 297.1347,
found: 297.1374.
1
1
6. Meyer, D. S.; Schreiber, S. J. Org. Chem. 1994, 59, 7549–7552.
7. Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem. 1988, 53, 2723–
20. (a) McMurry, J. E.; Rico, J. G.; Shih, Y. Tetrahedron Lett. 1989, 30, 1173–1176; (b)
Ichige, T.; Okano, Y.; Kanoh, N.; Nakata, M. J. Am. Chem. Soc. 2007, 129, 9862–
9863; (c) Kim, M.; Kleckley, T. S.; Wiemer, A. J.; Holstein, S. A.; Holh, R. J.;
Wiemer, D. F. J. Org. Chem. 2004, 69, 8186–8193.
2
728.
8. Data for 12 (87:13, E:Z) R
IR (CHCl ): max 1739, 1659, 1463, 1430, 1379, 1254 cm
CDCl ): d 6.49 (dd, J 15.1, 11.1 Hz, 1Hmajor), 6.23 (app t, J 11.3 Hz, 1Hminor), 6.10
d, J 11.3 Hz, 1Hminor), 5.85 (d, J 10.8 Hz, 1Hmajor), 5.56 (dd, J 15.1, 5.5 Hz,
2
5
1
f
0.82 (20% EtOAc/petrol); ½
aꢂ
ꢁ32.0 (c. 1.04, EtOH);
ꢁ1 1
D
3
m
;
H NMR (400 MHz,
f 3
21. Data for 13: R ): d 6.56 (ddd,
0.76 (50% EtOAc/petrol); 1H NMR (400 MHz, CDCl
3
J 15.1, 11.1, 1.4 Hz, 1H), 6.11 (d, J 11.1 Hz, 1H), 5.73 (dd, J 15.1, 5.1 Hz, 1H),
4.37–4.27 (m, 2H), 4.17 (q, J 7.1 Hz, 2H), 4.11 (d, J 4.1 Hz, 2H), 4.06–4.00 (m,
1H), 2.61 (dd, J 15.0, 7.1 Hz, 1H), 2.45 (dd, J 15.0, 6.2 Hz, 1H), 2.12–1.84 (m, 2H),
1.82 (s, 3H), 1.83–1.72 (m, 1H), 1.58–1.36 (m, 2H), 1.29 (t, J 7.1 Hz, 3H), 0.93 (s,
9H), 0.09 (s, 3H), 0.07 (s, 3H).
(
1
4
2
Hmajor), 5.30 (app t, J 10.6 Hz, 1Hminor), 4.38–4.28 (m, 1H), 4.23 (t, J 5.5 Hz, 1H),
.15 (q, J 7.1 Hz, 2H), 4.00 (dt, J 7.1, 5.5 Hz, 1H), 2.61 (dd, J 15.0, 7.1 Hz, 1H),
.43 (dd, J 15.0, 6.3 Hz, 1H), 2.15–2.03 (m, 1H), 1.95–1.85 (m, 1H), 1.79 (s, 3H),