Stereoselective synthesis of the densely functionalized C1-C9 fragment of amphidinolides C and F

Article abstract of DOI:10.1016/j.tetlet.2009.09.001

The synthesis of the C1-C9 subunit of amphidinolides C and F is described. Key steps include tandem Sharpless asymmetric dihydroxylation-S_N2 cyclization reaction, Lewis acid-mediated epoxide opening, Wittig reaction, and Wacker oxidation.

Full text of DOI:10.1016/j.tetlet.2009.09.001

Tetrahedron Letters 50 (2009) 6276–6279
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the densely functionalized C1–C9 fragment
of amphidinolides C and F
a
b
b
Debendra K. Mohapatra a,b, , Pavankumar Dasari , Hasibur Rahaman , Rita Pal
*
a Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
b Organic Chemistry Division, National Chemical Laboratory (CSIR), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the C1–C9 subunit of amphidinolides C and F is described. Key steps include tandem
Sharpless asymmetric dihydroxylation-SN2 cyclization reaction, Lewis acid-mediated epoxide opening,
Wittig reaction, and Wacker oxidation.
Received 26 January 2009
Revised 27 August 2009
Accepted 1 September 2009
Available online 4 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amphidinolide C and F
Cytotoxic
Tandem dihydroxylation-SN2
Wittig reaction
Wacker oxidation
O
17
O
14
Amphidinolides are a group of structurally unique macrolides
isolated to date from laboratory-cultured dinoflagellates of the
Amphidinium sp.1 Many such amphidinolides exhibit potent anti-
tumor activity against lymphoma L1210 and human carcinoma
KB cells. Despite their common origin and uniformly high cytotox-
icity against various cancer cell lines, the amphidinolides possess a
high degree of structural diversity and incorporation of many
interesting molecular scaffolds. Our target amphidinolide C (1),
isolated from the marine dinoflagellates Amphidinium sp. (Y-5), is
a 25-membered macrolide having two tetrahydrofuran rings deco-
rated with vicinally juxtaposed one-carbon branches.2 The gross
structure of 1 was elucidated by 2D NMR data. Amphidinolide C
(1) showed extremely potent in vitro cytotoxic activity against
murine lymphoma L1210 and apidermoid carcinoma KB cells3
21
Me
Me
19
22
OH
38
OH
27
31
H
O
OH
Me
34
H
H
H
37
1
O
O
Me
41
2
40
36
O
OH
5
Me 35
Amphidinolide C (1)
O
17
O
14
21
Me
Me
OH
19
22
OAc
38
27
31
H
O
OH
Me
34
H
H
H
37
1
O
O
Me
41
(IC50 = 0.0058 and 0.0046 l
g mLꢀ1); the structurally related C2
2
40
36
O
OH
O
(2) and F (3) display significantly reduced activities against these
cell lines, suggesting that the C25–C34 side chain plays a crucial
role in the bioactivity of amphidinolides C, C2, and F. The structural
complexity and scant availability from natural resources, has made
amphidinolide C (1) an attractive target for us. Recently, we re-
ported the synthesis of C19–C34 fragment of amphidinolide C;4
we now report the synthesis of the C1–C9 fragment (7). During
the course of our work, Roush and co-workers reported the first
synthesis of C1–C9 fragment of amphidinolide C5 (see Fig. 1).
5
Me 35
Amphidinolide C2 (2)
17
O
14
21
Me
Me
Me
OH
19
22
27
H
O
OH
H
H
H
9
1
O
O
2
O
OH
5
Me
Amphidinolide F (3)
* Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail addresses: mohapatra@iict.res.in, dkm_77@yahoo.com (D.K. Mohapatra).
Figure 1. Structures of amphidinolide C, C2 and F.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.001

D. K. Mohapatra et al. / Tetrahedron Letters 50 (2009) 6276–6279
6277
O
17
O
14
21
Me
Me
19
22
OH
38
OH
27
31
H
O
H
OH
Me
34
H
H
37
1
O
O
Me
41
2
40
36
OH
O
5
Me 35
Amphidinolide C (1) R = H
Amphidinolide C2 (2) R = Ac
O
S
17
I
19
S
OP
Me
OH
H
Me
Me
O
H
+
34
OH
Me
4
5
SnBu3
+
OPMB
H
O
OP
O
H
1
TfO
H
H
OH
O
9
BnO
OBn
O
36
OP
Me
H
7
Me
6
OPMB
OH
H
O
H
O
H
H
O
OBn
O
O
BnO
OBn
10
Me
9
8
Scheme 1. Retrosynthetic analysis of amphidinolide C.
Our retro-synthetic analysis of 1 depicted in Scheme 1 sug-
gested that the target could be assembled from fragments 4, 5,
and 6 via a late-stage-cross esterification and coupling sequence.
The keto functionality of 7 was envisaged to be generated from a
vinyl group by the Wacker oxidation of 8. The olefin intermediate
8 would be obtained by Lewis acid-mediated opening of vinyl
epoxide 9 with benzyl alcohol. The vinyl epoxide 9, in turn could
be obtained from 10 via stereoselective alkylation, tandem Sharp-
less asymmetric dihydroxylation-SN2 cyclization on an ,b-unsatu-
a
rated ester followed by Sharpless asymmetric epoxidation. The
tandem Sharpless asymmetric dihydroxylation-SN2 cyclization to
construct a tetrahydrofuran ring was particularly appealing to us,
since an internal SN2 displacement in a pre-organized substrate
would be expected to be completely and predictably stereospecific
and install correct stereochemistry at the ring junctions.
The preparation of (S)-5-hydroxyl methyl butyrolactone 10 was
achieved in 60% overall yield from commercially available L-glu-
LDA, MeI, -78 ºC
THF, 4 h, 85%
TBSCl, TEA
tamic acid by a published procedure.6 The hydroxyl group of 10
was protected as its TBS-ether 11; stereoselective methylation6
of the lactone 11 with LDA and MeI in THF at ꢀ78 °C afforded 12
in 85% yield. The trans relationship between the two substituents
on the five-membered ring was confirmed by NOESY experiment
at a later stage of the synthesis. Lactone 12 was reduced by DI-
BAL-H at ꢀ78 °C; the corresponding hemiacetal was quickly ex-
posed to ethoxycarbonylmethylene-triphenylphosphorane6 in
O
O
O
CH2Cl2, 0 ºC-rta
8 h, 96%
O
O
H
H
H
OTBS
OH
11
10
MsCl, TEA
CH2Cl2, 0 ºC
DIBAL-H, CH2Cl2
-78 ºC, 2 h
HO
O
Ph3PCHCOOEt
benzene, 55 oC
OTBS
4 h, 94%
OTBS
EtO
O
13
12
20 h, 87% (2 steps)
CS2, MeI, NaH,
SAD
HO
THF, 0 ºC, 2 h
94%
0 ºC-rt, 36 h
93%
O
H
H
O
MsO
OTBS
OTBS
H
H
EtO
EtO
O
15
14
Me
5
4
Me
8
H
3
TBTH, AIBN, toluene
reflux, 8 h, 95%
6
7
XanthO
EtO
O
O
O
H
H
O
H
H
H
H
OTBS
OTBS
OTBS
EtO
O
1
EtO
O
x
17
16
Scheme 2. Synthesis of 17.
Figure 2. Selected NOE correlations of 17.

6278
D. K. Mohapatra et al. / Tetrahedron Letters 50 (2009) 6276–6279
furnished the 2-deoxy derivative 17.11 The NOE correlations for
OBn
OBn
compound 17 observed for H3/H8, H3/H5, H6/H4, and H6/H5, indi-
cated the relative stereochemistries between H3 and H6 and be-
tween H3 and H4, respectively, to be trans-oriented (Fig. 2).
Compound 17 was then treated with LiAlH4 in anhydrous
diethyl ether at 0 °C to afford the alcohol 18 in 92% yield. The pri-
mary hydroxyl moiety of 18 was protected as its benzyl ether to
provide 19 in 95% yield. The TBS ether of 19 was cleaved by treat-
ment with 1 M solution of Bu4N+Fꢀ in THF to afford the alcohol 20.
The Swern oxidation12 of 20 followed by the Wittig-Horner reac-
tion on the crude aldehyde with triethylphosphonoacetate and
NaH at 0 °C afforded the desired E-isomer 22 as the only product.
Reduction of ester 22 using DIBAL-H in dichloromethane at
ꢀ78 °C furnished the allylic alcohol derivative 23. The Sharpless
asymmetric epoxidation of the E-allylic alcohol 23 with L(+)-DET,
Ti(iPrO)4, and TBHP in CH2Cl2 at ꢀ20 °C provided the correspond-
ing epoxy alcohol 2413 with excellent diastereoselectivity (95% ee
confirmed by spectroscopic analysis).14 To assign the absolute ste-
reochemistry of the epoxide, compound 24 was converted to its
benzoate derivatives to obtain single crystal that was not success-
ful. We then transformed compound 24 to 27 following a standard
protocol of iodination, followed by a reductive opening of the iodo-
epoxide with Zn/NaI in refluxing methanol.15 Following modified
Mosher’s method,16 the newly created stereogenic center of com-
pound 27 bearing the hydroxyl group was assigned and found to
be an R-configuration (Fig. 3), which established the absolute ste-
reochemistry of the epoxide of 24. The alcohol derivative 24 was
efficiently oxidized with IBX in DMSO/THF at ambient temperature
to provide the aldehyde 25; exposure to methylene- triphenyl-
phosphorane (generated in situ from CH3P+Ph3Brꢀ and NaHMDS)
in THF gave Wittig methylenation to the requisite vinyl-substi-
tuted epoxide intermediate 917 (Scheme 3).
OH
O
O
H
H
O
H
H
OH
24
27
OMTPA
Me-83
-43
-56
Ph
O
-32
-30
+172
+35
C
H
O
H
H
Figure 3.
D
d = (dS ꢀ dR) ꢂ 103 for (R)-and (S)-MTPA esters of compound 27.
benzene at 55 °C to provide the corresponding a,b-unsaturated es-
ter as a mixture of geometrical isomers (9.5:0.5 by 1H NMR). The
minor (Z)-isomer was separated from the major (E)-isomer 13 by
silica gel column chromatography. The 1H NMR spectrum of
(E)-isomer 13 revealed
a
characteristic coupling constant
(J = 15.6 Hz) for the olefinic protons. The hydroxyl group of 13
was converted into its mesylate7 ester 14 with MeSO2Cl, Et3N
and DMAP (catalytic) in CH2Cl2. The mesyl ester was to play a dual
role as a protecting group and a leaving group at a later stage. The
mesylate derivative 14 was subjected to the Sharpless asymmetric
dihydroxylation8 (Scheme 2) with ligand (DHQD)2 PHAL,
K3Fe(CN)6, K2CO3, MeSONH2, and OsO4 in t-BuOH/H2O (1:1) for
36 h to afford the trans,syn-tetrahydrofuran 159 in 93% yield (no
traces of the other isomer was detectable by NMR and HPLC)
(Scheme 2). Our next objective was to deoxygenate the hydroxyl
group at C2 using Barton’s radical deoxygenation protocol.10 The
hydroxyl group of 15 was converted to its corresponding xanthate
derivative 16 with NaH/CS2/MeI in THF at 0 °C. Compound 16 when
treated with TBTH in presence of AIBN in refluxing toluene for 8 h
The epoxide 9 was treated with BnOH in the presence of
BF3ꢁEt2O18 in anhydrous dichloromethane to furnish b-hydroxy al-
lyl ether 26.19 The secondary hydroxyl group of 26 was converted
OBn
BnBr, NaH
TBAF, THF
rt, 4 h, 96%
LAH, Et2O,
o
HO
O
DMF, 0 C, 3 h
O
O
H
H
H
O
H
0 oC, 2 h, 92%
H
H
H
95%
OTBS
OTBS
OH
OTBS
EtO
19
18
17
OBn
OBn
OH
(COCl)2, DMSO
(EtO)2POCH2COOEt,
OBn
OEt
O
O
NaH, THF, 0 oC, 6 h
85% (two steps)
O
CH2Cl2, -78 oC, 2 h
H
O
H
H
O
H
H
22
21
SAE, CH2Cl2
-20 oC, 48 h, 90%
20
IBX, DMSO,
OBn
DIBAL-H, CH2Cl2
-78 oC, 1.5 h, 96%
OBn
Py, THF, rt, 4 h
OH
O
O
O
H
H
H
H
H
24
23
Ph3P+CH3Br-
NaHMDS
BF3-Et2O, CH2Cl2,
O
BnO
O
THF, 0 oC-rt
BnOH, rt, 30 min
75%
BnO
O
O
H
H
H
O
12 h, 73% (2 steps)
9
25
OBn
OBn
OBn
OBn
Cu(OAc)2
OBn
OBn
PMB-Cl, NaH
O
O
PdCl2, O2, DMA
H2O, 16 h, 84%
o
O
DMF, 0 C, 10 h
H
H
H
H
O
OPMB
H
H
OPMB
94%
OH
7
8
26
Scheme 3. Synthesis of the C1–C9 fragment 7.

D. K. Mohapatra et al. / Tetrahedron Letters 50 (2009) 6276–6279
6279
65.5, 69.9, 80.2, 86.0, 173.3; Anal. Calcd for C16H32O5Si: C, 57.79; H, 9.70.
Found: C, 57.66; H 9.61.
to its PMB-ether using PMBCl and NaH in DMF to provide 8
(Scheme 3). Finally, compound 8 was subjected to a modified Wac-
ker oxidation protocol20 with Cu(OAc)2ꢁH2O (0.2 equiv) and
10 mol % of PdCl2 in a mixture of DMA:H2O (7:1) under oxygen
atmosphere at ambient temperature for 16 h to afford 721 in 84%
yield.
We have thus achieved a stereoselective linear synthesis of the
C1–C9 segment of amphidinolides C (1) and F (3). The construction
of trans-2,5-disubstituted tetrahydrofuran ring was accomplished
by a tandem dihydroxylation-SN2 cyclization sequence. Synthesis
of other fragments required for the total synthesis of amphidino-
lide C is in progress in our laboratory.
10. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
11. Analytical and spectral data of 17: ½a D25
ꢀ14.6 (c 1.05, CHCl3); IR (neat): 2956,
ꢃ
2929, 2858, 1739 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.05 (s, 6H), 0.89 (s, 9H),
;
1.03 (d, J = 6.6 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.39–1.55 (m, 1H), 1.85–2.01 (m,
1H), 2.04–2.19 (m, 1H), 2.36–2.57 (m, 2H), 3.54–3.65 (m, 2H), 3.83 (ddd, J = 4.7,
7.6, 8.7 Hz, 1H), 3.97–4.09 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H); 13C NMR (50 MHz,
CDCl3): d ꢀ5.4, 14.2, 16.3, 18.3, 25.9, 37.0, 39.4, 39.9, 60.3, 65.9, 78.6, 81.7,
171.3; Anal. Calcd for C16H32O4Si: C, 60.72; H, 10.19. Found: C, 60.10; H, 11.80.
12. Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329.
13. Analytical and spectral data of 24: ½a D25
ꢀ21.82 (c 1.1, CHCl3); IR (neat): 3430,
ꢃ
3063, 2957, 2929, 2871 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.97 (d, J = 6.6 Hz,
;
3H), 1.32–1.42 (m,1H), 1.58–1.68 (m, 1H), 1.80–1.88 (m, 2H), 2.09–2.17 (m,
1H), 2.95–2.99 (m, 2H), 3.43–3.59 (m, 4H), 3.83–3.90 (m, 2H), 4.44 (s, 2H),
7.19–7.33 (m, 5H); 13C NMR (50 MHz, CDCl3): d 16.1, 34.0, 37.3, 39.6, 56.5,
57.1, 61.3, 67.5, 72.9, 76.4, 82.9, 127.4, 127.6, 128.2, 138.4; Anal. Calcd for
C17H24O4: C, 69.84; H, 8.27. Found: C, 69.71; H, 8.17.
Acknowledgments
14. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974; (b) Hanson, R.
M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922; (c) Pfenninger, A. Synthesis
1986, 89.
P.D., H.R, and R.P. thank CSIR, New Delhi, India, for the financial
assistance in the form of fellowships. We are thankful to the Direc-
tor, IICT, Hyderabad, and the Director, NCL, Pune, for their constant
support and encouragement.
15. (a) Schomaker, J. M.; Reddy, P. V.; Babak, B. J. Am. Chem. Soc. 2004, 126, 13600;
(b) Kermadec, D. D.; Prudhomme, M. Tetrahedron Lett. 1993, 34, 2757.
16. (a) Ohtani, I.; Kusumi, J.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092; (b) Yoshida, W. Y.; Bryan, P. J.; Baker, B. J.; McClintock, J. B. J. Org. Chem.
1995, 60, 780.
17. Analytical and spectral data of 9: ½a D25
ꢀ26.1 (c 1.15, CHCl3); IR (neat): 2960,
ꢃ
Supplementary data
2928, 2871 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.97 (d, J = 6.6 Hz, 3H), 1.31–
;
1.41 (m, 1H), 1.59–1.67 (m, 1H), 1.79–1.88 (m, 2H), 2.08–2.17 (m, 1H), 2.84
(dd, J = 2.1, 4.5 Hz, 1H), 3.13 (dd, J = 2.1, 7.5 Hz, 1H), 3.45–3.59 (m, 3H), 3.86
(ddd, J = 4.6, 6.6, 9.0 Hz, 1H), 4.44 (s, 2H), 5.20 (dd. J = 1.4, 10.3 Hz, 1H), 5.39
(dd, J = 1.4, 17.2 Hz, 1H), 5.48–5.57 (m, 1H), 7.17–7.26 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 16.2, 34.1, 37.3, 39.8, 56.7, 61.7, 67.7, 73.0, 76.7, 82.9, 119.4,
127.5, 127.6, 128.3, 135.1, 138.5; Anal. Calcd for C18H24O3: C, 74.97; H, 8.39.
Found: C, 74.88; H, 8.28.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.001.
References and notes
18. Prestat, G.; Baylon, C.; Heck, M.-P.; Mioskowski, C. Tetrahedron Lett. 2000, 41,
3829.
1. For recent reviews: (a) Kobayashi, J.; Ishibashi, M. Chem. Rev. 1993, 93, 1753;
(b) Chakraborty, T.; Das, S. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 131; (c)
Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pure. Appl. Chem. 2003, 75, 337;
(d) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93.
2. Kobayashi, J.; Saski, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490.
3. Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu, T.; Hirota, H.;
Saski, T. J. Antibiot. 1991, 44, 1259.
4. Mohapatra, D. K.; Rahman, H.; Chorghade, M. S.; Gurjar, M. K. Synlett 2007, 567.
5. Bates, R. H.; Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 10, 4343.
6. (a) Tomioka, K.; Cho, Y.-S.; Sato, F.; Foga, K. J. Org. Chem. 1988, 53, 4094; (b)
Nishida, Y.; Konno, M.; Fukushima, Y.; Ohrui, H.; Meguro, H. Agric. Biol. Chem.
1986, 50, 191.
19. Analytical and spectral data of 26: ½a D25
ꢀ4.4 (c 2.3, CHCl3); IR (neat): 3436,
ꢃ
3030, 2871 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.99 (d, J = 6.6 Hz, 3H), 1.51 (dd,
;
J = 6.7, 11.9 Hz, 1H), 1.61–1.69 (m, 1H), 1.81–1.90 (m, 2H), 1.95–1.99 (m, 1H),
2.21 (bs, 1H), 3.45–3.60 (m, 3H), 3.77 (t, J = 5.5 Hz, 1H), 3.81–3.86 (m, 1H),
3.93–3.99 (m, 1H), 4.32 (d, J = 7.9 Hz, 1H), 4.47 (s, 2H), 4.58 (d, J = 7.9 Hz, 1H),
5.29–5.36 (m, 2H), 5.81–5.90 (m, 1H), 7.22–7.32 (m, 10H); 13C NMR (50 MHz,
CDCl3): d 16.6, 34.5, 36.5, 40.1, 67.7, 70.2, 73.0, 74.8, 77.7, 81.4, 82.6, 119.7,
127.5, 127.6, 127.7, 128.3, 134.9, 138.3, 138.6; Anal. Calcd for C25H32O4: C,
75.73; H, 8.13. Found: C, 75.62; H, 8.01.
20. Smith, A. B.; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39, 8765.
21. Analytical and spectral data of 7: ½a D25
ꢃ
+9.52 (c 1.05, CHCl3); IR (neat): 3370,
7. Marshal, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819.
2927, 1719 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.86 (d, J = 6.6 Hz, 3H), 1.22–
;
8. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.;
Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J. Org.
Chem. 1992, 57, 2768; (b) Kolb, H. C.; Van-Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
1.36 (m, 2H), 1.50–1.65 (m, 1H), 1.70–1.87 (m, 2H), 2.07 (s, 3H), 3.23 (dt, J = 2.8,
9.0 Hz, 1H), 3.34–3.54 (m, 2H), 3.67–3.73 (m, 1H), 3.73 (s, 3H), 3.88 (d,
J = 3.2 Hz, 1H), 4.15 (q, J = 7.6 Hz, 1H), 4.34–4.49 (m, 4H), 4.50–4.63 (m, 2H),
6.77 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 7.17–7.25 (m, 10H); 13C NMR
(50 MHz, CDCl3): d 16.2, 27.4, 34.0, 38.0, 40.2, 55.2, 67.9, 72.5, 73.0, 73.2, 76.2,
(77.2), 82.1, 83.4, 83.6, 113.8, 127.5, 127.7, 127.9, 128.0, 128.3, 128.4, 129.8,
130.0, 131.9, 133.2, 137.6, 138.5, 141.9, 159.3, 209.6; Anal. Calcd for C33H40O6:
C, 74.41; H, 7.57. Found: C, 74.31; H, 7.48.
9. Analytical and spectral data of 15: ½a D25
ꢀ12.9 (c 1.65, CHCl3); IR (neat): 3478,
ꢃ
3018, 2930, 2858, 1738 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.03 (s, 6H), 0.88 (s,
;
9H), 1.09 (d, J = 6.6 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.43–1.59 (m, 1H), 2.05–2.18
(m, 1H), 2.36–2.53 (m, 1H), 3.55 (dd, J = 4.2, 11.0 Hz, 1H), 3.64 (dd, J = 4.2,
11.0 Hz, 1H), 1.73 (dd, J = 1.3, 9.2 Hz, 1H), 4.01–4.14 (m, 2H), 4.17–4.34 (m,
2H); 13C NMR (50 MHz, CDCl3): d ꢀ5.3, 14.2, 16.0, 18.3, 25.9, 34.8, 36.6, 61.6,