Synthesis of marine oxylipins constanolactones C and D

Article abstract of DOI:10.1055/s-2007-986647

After providing the marine oxylipins constanolactones A and B, the next two members of this family were synthesized for the first time. Key to the success was a highly enantioselective and Z-selective reagent-controlled allyl addition (>99%) en route to t

Full text of DOI:10.1055/s-2007-986647

LETTER
2525
Synthesis of Marine Oxylipins Constanolactones C and D
Synthesis
ö
of Marine
O
r
gConstanolactones
C
P
and
D
ietruszka,* Anja C. M. Rieche, Niklas Schöne
Institut für Bioorganische Chemie, Heinrich-Heine-Universität Düsseldorf, Forschungszentrum Jülich, Stetternicher Forst Geb. 15.8,
52428 Jülich, Germany
Fax +49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
Received 19 July 2007
Dedicated to Professor Dr. Volker Jäger on the occasion of his 65th birthday
O
Abstract: After providing the marine oxylipins constanolactones A
and B, the next two members of this family were synthesized for the
first time. Key to the success was a highly enantioselective and Z-
selective reagent-controlled allyl addition (>99%) en route to the al-
iphatic side chain.
OH
O
ω-3
ω-6
R1 R2
Key words: allylation, asymmetric synthesis, boron, natural prod-
ucts, total synthesis
R1 = OH, R2 = H;
R1 = H, R2 = OH;
R1 = OH, R2 = H;
R1 = H, R2 = OH;
ω-6
1a constanolactone A
1b constanolactone B
1c constanolactone C
1d constanolactone D
ω-6
ω-3, ω-6
ω-3, ω-6
Constanolactones1 1 as well as the related solandelac-
tones,2 or the halicho- and neohalicholactone3 are meta-
bolites of unsaturated fatty acids, e.g. arachidonic acid, of
marine origin. All these marine oxylipins4 contain a cy-
clopropyl lactone moiety; however, they differ in the ring
size of the lactones and configurations of the stereogenic
units. Seven constanolactones A–G were isolated from the
red alga Constatinea simplex by Gerwick et al. between
1989 and 1993. The structures were elucidated shortly
after their isolation.1a,b A number of synthetic efforts cul-
minated in the total syntheses of constanolactones A and
B (1a and 1b)1c–f and the isomeric natural product con-
stanolactone E.1g–i The common feature in all the cases
was the absence of the w-3-double bond (see Figure 1). As
a matter of fact, the same holds true for the solandelac-
tones that bear the identical acyclic side chains. Herein we
report the first total synthesis of constanolactones C and D
(1c and 1d). Since they were originally isolated as their
acetates only, our efforts have culminated in the first
characterization of the actual natural products.
O
OH
ω-3
ω-6
O
I
ω-6
3,
4,
OHC
ω-3, ω-6
2
Figure 1 Constanolactones A–D (1a–d)
O
OH
O
I
OHC
4
2
ref. 1f:
11 steps,
28% yield
B*
EtO2C
OHC
OPMB
Ph
OH
7
5
6
The retrosynthetic strategy for the constanolactones A–D
(1a–d) is straightforward: a late Cr(II)-catalyzed5 cou-
pling, between the known aldehyde 2 and the correspond-
ing iodides 3 or 4, proved to be efficient in various cases.
Recently, during the course of the total synthesis of con-
stanolactones A and B (1a and 1b) we demonstrated that
aldehyde 2 is reliably formed in 11 steps from cinnamyl
alcohol (5) in 28% overall yield (Scheme 1).1f,6 Again,
while the acyclic side chain 3 was known prior to our stud-
ies (see e.g. ref.1f and references therein), a route to triene
4 was still elusive. We envisaged using allylboronate 6, a
reagent whose synthesis was just established via a [3,3]-
sigmatropic rearrangement.7 Highly enantioselective allyl
addition to aldehyde 78 should lead to a Z-configured
Ph Ph
O
O
OMe
OMe
–B* :
B
Ph Ph
Scheme 1 Constanolactones C and D: retrosynthesis of main
fragments
homoallylic alcohol; elaboration of the functional groups
should ultimately give the coupling partner 4.
As expected, on a large scale, the allyl addition worked
well and gave the homoallylic alcohol 8 in quantitative
yield (Scheme 2). The enantiomeric excess as determined
by HPLC (Chiracel OD-H, hexane–i-PrOH, 9:1) was 99%.
The outcome can be readily rationalized by assuming a
chair-like transition state 9, with the substituent a to the
boron moiety being preferentially located in axial posi-
SYNLETT 2007, No. 16, pp 2525–2528
0
1
.1
0
.2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986647; Art ID: D22107ST
© Georg Thieme Verlag Stuttgart · New York

2526
J. Pietruszka et al.
LETTER
OTBS
tion, and the result that a Z double bond is formed. Since
the boronic ester itself is obviously bulky, the observation
is in full agreement with those previously established by
Hoffmann et al.9 In three high-yielding steps (88% overall
yield: protection of the secondary alcohol followed by
reduction of the ester functionality to a primary alcohol
and selective oxidation with Dess–Martin periodinane10)
aldehyde 10 was formed. For the consecutive Z-selective
Wittig reaction, low temperatures and the use of sodium
hexamethyldisilazide as base were essential to assure
complete selectivity and highest yields (68%). Best results
for the deprotection of the PMB ether were achieved with
DDQ furnishing alcohol 11 in up to 60% yield.
OH
11
a
b
c
88%
59%
91%
OH
I
4
d
62%, dr 60:40
O
O
1c (R = H)
89%
OR
O
O
e
B*
EtO2C
OHC
OPMB
B*
12 (R = Ac)
1d (R = H)
OR
7
6
O
PMBO
a
quant., 99% ee
OH
CO2Et
OR
e
93%
9
13 (R = Ac)
EtO2C
OPMB
OR
8
95%
98%
94%
Scheme 3 Reagents and conditions: (a) SO3–pyridine, Et3N,
CH2Cl2–DMSO, 0 °C; (b) CrCl2, CHI3, THF, 0 °C; (c) 5% HF in
MeCN–H2O, r.t.; (d) 2, CrCl2, cat. NiCl2, DMSO, r.t.; (e) Ac2O, pyri-
dine, r.t.
b
c
d
OTBS
In conclusion, a first convergent total synthesis of con-
stanolactones C and D (1c and d) has been completed. The
reported structures were not only confirmed, but spectro-
scopic data of natural products could be provided. A key
feature of the synthesis was the utilization of triene 4 via
the new reagent 6. The highly selective key step allowed
for the straightforward elaboration of the final products.
OHC
OPMB
10
e
68%
60%
f
OTBS
OH
11
Acknowledgment
Scheme 2 Reagents and conditions: (a) CH2Cl2, r.t.; (b) TBSCl,
imidazole, CH2Cl2, r.t.; (c) LiAlH4, THF, 0 °C to r.t.; (d) DMP,
CH2Cl2, r.t.; (e) n-PrPPh3Br, NaN(SiMe3)2, THF, –110 °C; (f) DDQ,
CH2Cl2, r.t.
This work was supported by the Deutsche Forschungsgemeinschaft
(PI 263/4-1 to 4-3) and through grants from the Degussa Stiftung
(for A.C.M.R.), the Landesgraduiertenförderung Baden-Württem-
berg (for N.S.), and the Heinrich-Heine Universität Düsseldorf
(‘Rektoratsstipendium’ for A.C.M.R.).
The synthesis of the final coupling partner 4 was com-
pleted in yet another three-step sequence (Scheme 3).
Selective oxidation using modified Swern conditions11
furnished an aldehyde (88%) that was directly converted
into the corresponding (E)-vinyl iodide by a Takai–
Utimoto reaction (59%).12 Cleavage of the silyl ether with
HF–MeCN yielded the acyclic side chain (91%). It should
be emphasized that the same side chain could be used for
the first syntheses of solandelactones C, D, G and H by
applying the identical strategy. The final coupling was not
optimized; however, the natural products constanolac-
tones C and D (1c and d) were isolated (62%; dr 60:40)
and separated by preparative HPLC for the first time. The
diastereoselectivity as well as the retention order correlate
very well with those previously observed for constano-
lactones A and B (1a and b). The structures were finally
confirmed by conversion into the known acetates 12 and
13, respectively.13
References and Notes
(1) For isolation and structure elucidation, see: (a) Nagle, D.
G.; Gerwick, W. H. Tetrahedron Lett. 1990, 31, 2995.
(b) Nagle, D. G.; Gerwick, W. H. J. Org. Chem. 1994, 59,
7227. For complete total syntheses of constanolactones A
and B, see: (c) White, J. D.; Jensen, M. S. J. Am. Chem. Soc.
1995, 117, 6224. (d) Barloy-Da Silva, C.; Benkouider, A.;
Pale, P. Tetrahedron Lett. 2000, 41, 3077. (e) Yu, J.; Lai, J.-
Y.; Ye, J.; Balu, N.; Reddy, L. M.; Duan, W.; Fogel, E. R.;
Capdevila, J. H.; Falck, J. R. Tetrahedron Lett. 2002, 43,
3939. (f) Pietruszka, J.; Wilhelm, T. Synlett 2003, 1698.
Constanolactone E: (g) Miyaoka, H.; Shigemoto, T.;
Yamada, Y. Tetrahedron Lett. 1996, 37, 7407.
(h) Miyaoka, H.; Shigemoto, T.; Tamura, M.; Yamada, Y.
Heterocycles 1998, 40, 205. (i)Miyaoka, H.; Shigemoto, T.;
Yamada, Y. Heterocycles 1998, 47, 415.
Synlett 2007, No. 16, 2525–2528 © Thieme Stuttgart · New York

LETTER
Synthesis of Marine Oxylipins Constanolactones C and D
2527
(2) (a) For isolation and structure elucidation: Seo, Y.; Cho, K.
W.; Rho, J.-R.; Shin, J.; Kwon, B.-M.; Bok, S.-H.; Song,
J.-I. Tetrahedron 1996, 52, 10583. (b) For a complete total
synthesis of solandelactone E (and structure revision), see:
(c) Davoren, J. E.; Martin, S. F. J. Am. Chem. Soc. 2007, 129,
510.
(3) For isolation and structure elucidation, see: (a) Niwa, H.;
Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989, 30,
4543. (b) Kigoshi, H.; Niwa, H.; Yamada, K.; Stout, T. J.;
Clardy, J. Tetrahedron Lett. 1991, 32, 2427. For a
completed syntheses of halicholactone, see: (c) Critcher, D.
J.; Connolly, S.; Wills, M. Tetrahedron Lett. 1995, 36,
3763. (d) Critcher, D. J.; Connolly, S.; Wills, M. J. Org.
Chem. 1997, 62, 6638. (e) Takemoto, Y.; Baba, Y.; Saha,
G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T. Tetrahedron
Lett. 2000, 41, 3653. (f) Baba, Y.; Saha, G.; Nakao, S.;
Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y.
J. Org. Chem. 2001, 66, 81. (g) Takahashi, T.; Watanabe,
H.; Kitahara, T. Heterocycles 2002, 58, 99. (h) For neohali-
cholactone, see ref. 3c and 3d.
(C-6¢), 199.8 (CHO). HRMS (ESI, 70 eV): m/z calcd for
C9H12O3: 168.0786; found: 168.0790.
Iodide 4: Rf 0.19 (PE–EtOAc, 90:10); [a]20D –25 (c = 0.90,
CHCl3). 1H NMR (600 MHz, CDCl3): d = 0.98 (t, 3J11,10 = 7.5
Hz, 3 H, 11-H), 1.81 (d, 3JOH,3 = 4.3 Hz, 1 H, OH), 2.07
(qddt, 3J10,11 = 7.5 Hz, 3J10,9 = 7.2 Hz, 4J10,8 = 1.6 Hz, 5J10,7
0.8 Hz, 2 H, 10-H), 2.34 (mc, 2 H, 4-H), 2.80 (ddddtt, 3J7,6
=
=
=
7.4 Hz, 3J7,8 = 7.2 Hz, 4J7,9 = 1.7 Hz, 4J7,5 = 1.7 Hz, 5J7,10
0.8 Hz, 5J7,4 = 0.8 Hz, 2 H, 7-H), 4.15 (mc, 1 H, 3-H), 5.29
(dtt, 3J8,9 = 10.6 Hz, 3J8,7 = 7.2 Hz, 4J8,10 = 1.6 Hz, 1 H, 8-H),
5.39 (dtt, 3J5,6 = 10.8 Hz, 3J5,4 = 7.5 Hz, 4J5,7 = 1.7 Hz, 1 H,
5-H), 5.42 (dtt, 3J9,8 = 10.6 Hz, 3J9,10 = 7.2 Hz, 4J9,7 = 1.7 Hz,
1 H, 9-H), 5.59 (dtt, 3J6,5 = 10.8 Hz, 3J6,7 = 7.4 Hz, 4J6,4 = 1.6
Hz, 1 H, 6-H), 6.38 (dd, 3J1,2 = 14.5 Hz, 4J1,3 = 1.4 Hz, 1 H,
1-H), 6.60 (dd, 3J2,1 = 14.5 Hz, 3J2,3 = 5.9 Hz, 1 H, 2-H). 13
C
NMR (151 MHz, CDCl3): d = 14.2 (C-11), 20.6 (C-10), 25.7
(C-7), 34.6 (C-4), 73.8 (C-3), 77.3 (C-1), 123.6 (C-5), 126.5
(C-8), 132.4 (C-9), 132.5 (C-6), 147.7 (C-2). GC–MS (EI,
+ve ions): m/z (%) = 274(1) [M – H2O]+, 183 (100)
[C3H4IO+].
(4) Reviews: (a) Gerwick, W. H. Chem. Rev. 1993, 93, 1807.
(b) Gerwick, W. H.; Nagle, D. G.; Proteau, P. J. Top. Curr.
Chem. 1993, 167, 119.
(5) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 3179. (b) Hiyama, T.; Okude, Y.;
Kimura, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1982, 55, 561.
(c) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki,
H. Tetrahedron Lett. 1983, 24, 5281. (d) Review: Fürstner,
A. Chem. Rev. 1999, 99, 991.
(6) Enantiomerically pure cyclopropane building blocks were
synthesized via a chemoenzymatic sequence: Pietruszka, J.;
Rieche, A. C. M.; Wilhelm, T.; Witt, A. Adv. Synth. Catal.
2003, 345, 1273.
(7) (a) Pietruszka, J.; Schöne, N. Angew. Chem. Int. Ed. 2003,
42, 5638; Angew. Chem. 2003, 115, 5796. (b)Pietruszka,J.;
Schöne, N. Synthesis 2006, 24.
(8) Smith, A. B.; Fox, R. J. Org. Lett. 2004, 6, 1477.
(9) Hoffmann, R. W.; Weidmann, U. J. Organomet. Chem.
1980, 195, 137.
(10) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277. (b) Wavrin, L.; Viala, J. Synthesis 2002, 326.
(11) Nicolaou, K. C.; Ramphal, J. Y.; Abe, Y. Synthesis 1989,
898.
(12) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408.
(13) Spectroscopic data of 1c, 1d, 2, 4, 12 and 13:
Aldehyde 2: Rf 0.48 (EtOAc); [a]20D +73.0 (c = 2.4, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.15 (ddd, 3J3a,1 = 8.4 Hz,
Constanolactone C (1c): Rf 0.22 (EtOAc); separation of the
diastereomers 1c and 1d with semi-preparative HPLC
(Maxsil 5 mm, 250 × 10 mm; c = 6.4 mg/mL; flow = 3 mL/
min; l = 202 nm); [a]20D –5.8 (c = 0.70, CHCl3). 1H NMR
(600 MHz, CDCl3): d = 0.62 (ddd, 3J7a,8 = 8.6 Hz, 2J7a,7b = 5.2
Hz, 3J7a,6 = 5.2 Hz, 1 H, 7-Ha), 0.75 (ddd, 3J7b,6 = 8.8 Hz,
3J7b,8 = 5.6 Hz, 2J7b,7a = 5.2 Hz, 1 H, 7-Hb), 0.97 (t, 3J20,19
7.5 Hz, 3 H, 20-H), 1.00 (dddd, 3J6,7b = 8.8 Hz, 3J6,5 = 8.4 Hz,
3J6,7a = 5.2 Hz, 3J6,8 = 4.4 Hz, 1 H, 6-H), 1.15 (dddd, 3J8,7a
8.6 Hz, 3J8,9 = 7.4 Hz, 3J8,7b = 5.6 Hz, 3J8,6 = 4.4 Hz, 1 H,
8-H), 1.67 (dddd, 2J4a,4b = 13.9 Hz, 3J4a,3a = 10.6 Hz, 3J4a,5
=
=
=
10.1 Hz, 3J4a,3b = 4.9 Hz, 1 H, 4-Ha) 1.80 (ddddd, 2J3a,3b
=
13.6 Hz, 3J3a,4a = 10.6 Hz, 3J3a,2a = 8.7 Hz, 3J3a,2b = 7.1 Hz,
3J3a,4b = 4.8 Hz, 1 H, 3-Ha), 1.74 (br, 2 H, OH), 1.95 (ddddd,
2J3b,3a = 13.6 Hz, 3J3b,2a = 7.0 Hz, 3J3b,2b = 5.3 Hz, 3J3b,4b = 5.1
Hz, 3J3b,4a = 4.9 Hz, 1 H, 3-Hb), 2.01 (ddddd, 2J4b,4a = 13.9
3
Hz, J4b,3b = 5.1 Hz, 3J4b,3a = 4.8 Hz, 3J4b,5 = 3.5 Hz, 5J4b,2b
=
1.1 Hz, 1 H, 4-Hb), 2.07 (qddt, 3J19,20 = 7.5 Hz, 3J19,18 = 7.2
Hz, 4J19,17 = 1.6 Hz, 5J19,16 = 0.8 Hz, 2 H, 19-H), 2.33 (ddddt,
3
3
2J13a,13b = 14.4 Hz, J13a,14 = 7.1 Hz, J13a,12 = 5.9 Hz,
4J13a,15 = 1.6 Hz, 5J13a,16 = 0.8 Hz, 1 H, 13-Ha), 2.38 (ddddt,
2J13b,13a = 14.4 Hz, J13b,14 = 7.5 Hz, J13b,12 = 6.9 Hz,
4J13b,15 = 1.5 Hz, 5J13b,16 = 0.8 Hz, 1 H, 13-Hb), 2.45 (ddd,
2J2a,2b = 17.8 Hz, 3J2a,3a = 8.7 Hz, 3J2a,3b = 7.0 Hz, 1 H, 2-Ha),
2.56 (dddd, 2J2b,2a = 17.8 Hz, 3J2b,3a = 7.1 Hz, 3J2b,3b = 5.3 Hz,
5J2b,4b = 1.1 Hz, 1 H, 2-Hb), 2.81 (ddddtdd, 3J16,15 = 7.3 Hz,
3J16,17 = 7.3 Hz, 4J16,18 = 1.6 Hz, 4J16,14 = 1.6 Hz, 5J16,19 = 0.8
Hz, 5J16,13a = 0.8 Hz, 5J16,13b = 0.8 Hz, 2 H, 16-H), 3.70–3.74
(m, 1 H, 9-H), 3.72 (ddd, 3J5,4a = 10.1 Hz, 3J5,6 = 8.4 Hz,
3J5,4b = 3.5 Hz, 1 H, 5-H), 4.20 (mc, 1 H, 12-H), 5.30 (dtt,
3J17,18 = 10.6 Hz, 3J17,16 = 7.2 Hz, 4J17,19 = 1.6 Hz, 1 H, 17-H),
5.40 (dtt, 3J18,17 = 10.6 Hz, 3J18,19 = 7.2 Hz, 4J18,16 = 1.6 Hz, 1
3
3
3J3a,2 = 6.4 Hz, 2J3a,3b = 4.8 Hz, 1 H, 3-Ha), 1.37 (ddd, 3J3b,2
9.2 Hz, 3J3b,1 = 4.8 Hz, 2J3b,3a = 4.8 Hz, 1 H, 3-Hb), 1.71
=
(dddd, 2J3¢a,3¢b = 13.8 Hz, 3J3¢a,4¢a = 10.9 Hz, 3J3¢a,2¢ = 10.6 Hz,
3J3¢a,4¢b = 4.8 Hz, 1 H, 3¢-Ha), 1.79 (dddd, 3J2,3b = 9.2 Hz,
3J2,2¢ = 7.2 Hz, 3J2,3a = 6.4 Hz, 3J2,1 = 4.0 Hz, 1 H, 2-H), 1.85
(ddddd, 3J4¢a,3¢a = 10.9 Hz, 2J4¢a,4¢b = 9.9 Hz, 3J4¢a,5¢a = 9.1 Hz,
3J4¢a,5¢b = 7.0 Hz, 3J4¢a,3¢b = 4.7 Hz, 1 H, 4¢-Ha), 1.98 (ddddd,
3
H, 18-H), 5.43 (dtt, 3J14,15 = 10.7 Hz, J14,13 = 7.3 Hz,
4J14,16 = 1.6 Hz, 1 H, 14-H), 5.53 (dtdd, 3J15,14 = 10.7 Hz,
3J15,16 = 7.3 Hz, 4J15,13a = 1.6 Hz, 4J15,13b = 1.5 Hz, 1 H, 15-H),
5.79 (mc, 2 H, 10-H, 11-H). 13C NMR (151 MHz, CDCl3):
d = 7.5 (C-7), 14.2 (C-20), 18.3 (C-3), 20.4 (C-6), 20.6
(C-19), 23.4 (C-8), 25.7 (C-16), 27.8 (C-4), 29.5 (C-2), 35.0
(C-13), 71.6 (C-12), 74.2 (C-9), 83.6 (C-5), 124.8 (C-14),
126.9 (C-17), 131.3 (C-15), 132.0 (C-10), 132.2 (C-18),
133.6 (C-11), 171.5 (C-1). HRMS (ESI, +ve ions, solution
in MeOH): m/z calcd for C20H30NaO4: 357.2036; found:
357.2024.
2J4¢b,4¢a = 9.9 Hz, 3J4¢b,3¢b = 8.1 Hz, 3J4¢b,5¢a = 7.1 Hz, 3J4¢b,5¢b
4.8 Hz, 3J4¢b,3¢a = 4.8 Hz, 1 H, 4¢-Hb), 2.05 (ddddd, 2J3¢b,3¢a
=
=
13.8 Hz, 3J3¢b,4¢b = 8.1 Hz, 3J3¢b,4¢a = 4.7 Hz, 3J3¢b,2¢ = 3.4 Hz,
4J3¢b,5¢b = 1.1 Hz, 1 H, 3¢-Hb), 2.11 (dddd, 3J1,3a = 8.4 Hz,
3J1,3b = 4.8 Hz, 3J1,2 = 4.0 Hz, 3J1,CHO = 4.0 Hz, 1 H, 1-H),
2.48 (dddd, 2J5¢a,5¢b = 17.8 Hz, 3J5¢a,4¢a = 9.1 Hz, 3J5¢a,4¢b = 7.1
Hz, 4J5¢a,3 = 0.9 Hz, 1 H, 5¢-Ha), 2.60 (dddd, 2J5¢b,5¢a = 17.8 Hz,
3J5¢b,4¢a = 7.0 Hz, 3J5¢b,4¢b = 4.8 Hz, 4J5¢b,3¢b = 1.1 Hz, 1 H, 5¢-
Hb), 3.90 (ddd, 3J2¢,3¢a = 10.6 Hz, 3J2¢,2 = 7.2 Hz, 3J2¢,3¢b = 3.4
Constanolactone D (1d): Rf 0.22 (EtOAc); [a]20D –9.1 (c =
0.60, CHCl3). 1H NMR (600 MHz, CDCl3): d = 0.59 (ddd,
3J7a,8 = 8.8 Hz, 3J7a,6 = 5.3 Hz, 2J7a,7b = 5.3 Hz, 1 H, 7-Ha),
0.64 (ddd, 3J7b,6 = 8.7 Hz, 3J7b,8 = 5.5 Hz, 2J7b,7a = 5.3 Hz,
Hz, 1 H, 2¢-H), 9.38 (d, 3JCHO,1 = 4.0 Hz, 1 H, CHO). 13
C
NMR (151 MHz, CDCl3): d = 11.9 (C-3), 18.4 (C-4¢), 26.8
(C-2), 26.9 (C-1), 28.0 (C-3¢), 29.5 (C-5¢), 80.8 (C-2¢), 170.7
Synlett 2007, No. 16, 2525–2528 © Thieme Stuttgart · New York

2528
J. Pietruszka et al.
LETTER
1 H, 7-Hb), 0.97 (t, 3J20,19 = 7.5 Hz, 3 H, 20-H), 1.11 (dddd,
3J6,7b = 8.7 Hz, 3J6,5 = 8.1 Hz, 3J6,7a = 5.3 Hz, 3J6,8 = 4.4 Hz,
Hz, 5J16,13b = 0.8 Hz, 5J16,19a = 0.8 Hz, 2 H, 16-H), 3.80 (ddd,
3J5,4a = 10.6 Hz, 3J5,6 = 7.5 Hz, 3J5,4b = 3.2 Hz, 1 H, 5-H), 4.91
1 H, 6-H), 1.14 (dddd, 3J8,7a = 8.8 Hz, 3J8,9 = 7.3 Hz, 3J8,7b
5.5 Hz, 3J8,6 = 4.4 Hz, 1 H, 8-H), 1.69 (dddd, 2J4a,4b = 13.9
=
(dddd, 3J9,8 = 8.1 Hz, 3J9,10 = 5.8 Hz, 4J9,11 = 1.3 Hz, 5J9,12
=
0.7 Hz, 1 H, 9-H), 5.28 (dtt, 3J17,18 = 10.6 Hz, 3J17,16 = 7.3 Hz,
4J17,19 = 1.6 Hz, 1 H, 17-H), 5.30 (ddddd, 3J12,13b = 6.8 Hz,
3J12,13a = 6.3 Hz, 3J12,11 = 6.2 Hz, 4J12,10 = 1.2 Hz, 5J12,9 = 0.7
Hz, 1 H, 12-H), 5.34 (dddt, 3J14,15 = 10.7 Hz, 3J14,13b = 7.6 Hz,
3J14,134 = 7.1 Hz, 4J14,16 = 1.7 Hz, 1 H, 14-H), 5.39 (dtt,
3J18,17 = 10.6 Hz, 3J18,19 = 7.2 Hz, 4J18,16 = 1.6 Hz, 1 H, 18-H),
5.48 (dtt, 3J15,14 = 10.7 Hz, 3J15,16 = 7.4 Hz, 4J15,13 = 1.6 Hz, 1
H, 15-H), 5.70 (ddd, 3J10,11 = 15.7 Hz, 3J10,9 = 5.8 Hz,
4J10,12 = 1.2 Hz, 1 H, 10-H), 5.82 (ddd, 3J11,10 = 15.7 Hz,
3J11,12 = 6.2 Hz, 4J11,9 = 1.3 Hz, 1 H, 11-H). 13C NMR (151
MHz, CDCl3): d = 7.6 (C-7), 14.2 (C-20), 18.4 (C-3), 20.1
(C-8), 20.5 (C-19), 20.8 (C-6), 21.2, 21.3 (9-OAc, 12-OAc),
25.6 (C-16), 27.9 (C-4), 29.5 (C-2), 32.2 (C-13), 73.0 (C-
12), 75.3 (C-9), 82.3 (C-5), 123.8 (C-14), 126.8 (C-17),
129.1 (C-10), 130.9 (C-11), 131.3 (C-15), 132.2 (C-18),
170.3, 170.3 (9-OAc, 12-OAc), 171.0 (C-1). HRMS (ESI,
+ve ions, solution in MeOH): m/z calcd for C24H34NaO6:
441.2248; found: 441.2242.
Hz, 3J4a,3a = 10.9 Hz, 3J4a,5 = 10.5 Hz, 3J4a,3b = 5.1 Hz, 1 H, 4-
Ha), 1.81 (ddddd, 2J3a,3b = 13.6 Hz, 3J3a,4a = 10.9 Hz, 3J3a,2a
=
8.8 Hz, 3J3a,2b = 7.1 Hz, 3J3a,4b = 5.0 Hz, 1 H, 3-Ha), 1.87 (br,
2 H, OH), 1.96 (ddddd, 2J3b,3a = 13.6 Hz, 3J3b,2a = 7.1 Hz,
3J3b,2b = 5.2 Hz, 3J3b,4a = 5.1 Hz, 3J3b,4b = 4.8 Hz, 1 H, 3-Hb),
2.02 (ddddd, 2J4b,4a = 13.9 Hz, 3J4b,3a = 5.0 Hz, 3J4b,3b = 4.8
Hz, 3J4b,5 = 3.3 Hz, 5J4b,2b = 1.2 Hz, 1 H, 4-Hb), 2.07 (qddt,
3J19,20 = 7.5 Hz, 3J19,18 = 7.3 Hz, 4J19,17 = 1.6 Hz, 5J19,16 = 0.7
Hz, 2 H, 19-H), 2.33 (ddddt, 2J13a,13b = 14.3 Hz, 3J13a,14 = 7.1
Hz, 3J13a,12 = 5.7 Hz, 4J13a,15 = 1.6 Hz, 5J13a,16 = 0.7 Hz, 1 H,
13-Ha), 2.38 (ddddt, 2J13b,13a = 14.3 Hz, 3J13b,12 = 7.6 Hz,
3J13b,14 = 7.1 Hz, 4J13b,15 = 1.6 Hz, 5J13b,16 = 0.5 Hz, 1 H, 13-
Hb), 2.46 (ddd, 2J2a,2b = 17.7 Hz, 3J2a,3a = 8.8 Hz, 3J2a,3b = 7.1
Hz, 1 H, 2-Ha), 2.57 (dddd, 2J2b,2a = 17.7 Hz, 3J2b,3a = 7.1 Hz,
3J2b,3b = 5.2 Hz, 5J2b,4b = 1.2 Hz, 1 H, 2-Hb), 2.81 (ddddtdd,
3J16,15 = 7.4 Hz, 3J16,17 = 7.2 Hz, 4J16,14 = 1.7 Hz, 4J16,18 = 1.6
Hz, 5J16,19 = 0.7 Hz, 5J16,13a = 0.7 Hz, 5J16,13b = 0.5 Hz, 2 H,
3
16-H), 3.71 (mc, 1 H, 9-H), 3.73 (ddd, J5,4a = 10.5 Hz,
Acetate 13: Rf 0.34 (PE–EtOAc, 50:50); [a]20D –4.4 (c =
0.50, CHCl3). 1H NMR (600 MHz, CDCl3): d = 0.59 (ddd,
3J7a,8 = 8.6 Hz, 3J7a,6 = 5.7 Hz, 2J7a,7b = 5.4 Hz, 1 H, 7-Ha),
0.68 (ddd, 3J7b,6 = 8.7 Hz, 3J7b,8 = 5.4 Hz, 2J7b,7a = 5.4 Hz, 1
H, 7-Hb), 0.98 (t, 3J20,19 = 7.5 Hz, 3 H, 20-H), 1.17–1.23 (m,
2 H, 6-H, 8-H), 1.64 (dddd, 2J4a,4b = 13.7 Hz, 3J4a,3a = 10.6
Hz, 3J4a,5 = 10.1 Hz, 3J4a,3b = 5.0 Hz, 1 H, 4-Ha), 1.81 (ddddd,
2J3a,3b = 13.6 Hz, 3J3a,4a = 10.6 Hz, 3J3a,2a = 8.7 Hz, 3J3a,2b = 7.1
Hz, 3J3a,4b = 4.9 Hz, 1 H, 3-Ha), 1.94 (ddddd, 2J3b,3a = 13.6 Hz,
3J3b,2a = 7.0 Hz, 3J3b,2b = 5.3 Hz, 3J3b,4b = 5.1 Hz, 3J3b,4a = 5.0
Hz, 1 H, 3-Hb), 1.97 (ddddd, 2J4b,4a = 13.7 Hz, 3J4b,3b = 5.1
Hz, 3J4b,3a = 4.9 Hz, 3J4b,5 = 3.3 Hz, 4J4b,2b = 1.2 Hz, 1 H, 4-
Hb), 2.07 (qddt, 3J19,20 = 7.5 Hz, 3J19,18 = 7.2 Hz, 4J19,17 = 1.6
Hz, 5J19,16 = 0.8 Hz, 2 H, 19-H), 2.07, 2.09 (2 × s, 6 H, 9-
OAc, 12-OAc), 2.36 (ddddt, 2J13a,13b = 14.6 Hz, 3J13a,14 = 7.1
Hz, 3J13a,12 = 6.3 Hz, 4J13a,15 = 1.5 Hz, 6J13a,16 = 0.8 Hz, 1 H,
3J5,6 = 8.1 Hz, 3J5,4b = 3.3 Hz, 1 H, 5-H), 4.19 (mc, 1 H, 12-
H), 5.30 (dtt, 3J17,18 = 10.6 Hz, 3J17,16 = 7.2 Hz, 4J17,19 = 1.6
Hz, 1 H, 17-H), 5.40 (dtt, 3J18,17 = 10.6 Hz, 3J18,19 = 7.3 Hz,
4J18,16 = 1.6 Hz, 1 H, 18-H), 5.42 (dddt, 3J14,15 = 10.8 Hz,
3J14,13b = 7.3 Hz, 3J14,13a = 7.1 Hz, 4J14,16 = 1.7 Hz, 1 H, 14-H),
5.55 (dtt, 3J15,14 = 10.8 Hz, 3J15,16 = 7.4 Hz, 4J15,13 = 1.6 Hz, 1
H, 15-H), 5.79 (mc, 2 H, 10-H, 11-H). 13C NMR (151 MHz,
CDCl3): d = 6.6 (C-7), 14.2 (C-20), 18.4 (C-3), 20.6 (C-19),
21.2 (C-8), 23.4 (C-6), 25.7 (C-16), 27.9 (C-4), 29.5 (C-2),
35.2 (C-13), 71.5 (C-12), 73.8 (C-9), 83.3 (C-5), 124.7 (C-
14), 126.8 (C-17), 131.6 (C-15), 131.7 (C-10), 132.2 (C-18),
133.2 (C-11), 171.5 (C-1). HRMS (ESI, +ve ions, solution in
MeOH): m/z calcd for C20H30NaO4: 357.2036; found:
357.2024.
Acetate 12: Rf 0.34 (PE–EtOAc, 50:50); [a]20D –7.5 (c =
0.70, CHCl3). 1H NMR (600 MHz, CDCl3): d = 0.63 (ddd,
3J7a,8 = 8.6 Hz, 3J7a,6 = 5.3 Hz, 2J7a,7b = 5.3 Hz, 1 H, 7-Ha),
0.74 (ddd, 3J7b,6 = 8.9 Hz, 3J7b,8 = 5.5 Hz, 2J7b,7a = 5.3 Hz, 1
H, 7-Hb), 0.97 (t, 3J20,19 = 7.5 Hz, 3 H, 20-H), 1.04 (dddd,
3J6,7b = 8.9 Hz, 3J6,5 = 7.5 Hz, 3J6,7a = 5.3 Hz, 3J6,8 = 4.4 Hz,
13-Ha), 2.45 (ddd, 2J2a,2b = 17.7 Hz, 3J2a,3a = 8.7 Hz, 3J2a,3b
7.0 Hz, 1 H, 2-Ha), 2.45 (ddddt, 2J13b,13a = 14.6 Hz, 3J13b,14
=
=
7.5 Hz, 3J13b,12 = 6.8 Hz, 4J13b,15 = 1.6 Hz, 5J13b,16 = 0.8 Hz, 1
H, 13-Hb), 2.55 (dddd, 2J2b,2a = 17.7 Hz, 3J2b,3a = 7.1 Hz,
3J2b,3b = 5.3 Hz, 4J2b,4b = 1.2 Hz, 1 H, 2-Hb), 2.78 (ddddddt,
3J16,15 = 7.3 Hz, 3J16,17 = 7.2 Hz, 4J16,14 = 1.7 Hz, 4J16,18 = 1.7
Hz, 5J16,13a = 0.8 Hz, 5J16,13b = 0.8 Hz, 5J16,19 = 0.8 Hz, 2 H,
16-H), 3.82 (ddd, 3J5,4a = 10.1 Hz, 3J5,6 = 6.8 Hz, 3J5,4b = 3.3
1 H, 6-H), 1.23 (dddd, 3J8,7a = 8.6 Hz, 3J8,9 = 8.1 Hz, 3J8,7b
5.5 Hz, 3J8,6 = 4.4 Hz, 1 H, 8-H), 1.64 (dddd, 2J4a,4b = 14.0
=
Hz, 3J4a,3a = 11.0 Hz, 3J4a,5 = 10.6 Hz, 3J4a,3b = 5.2 Hz, 1 H, 4-
Ha), 1.81 (ddddd, 2J3a,3b = 13.8 Hz, 3J3a,4a = 11.0 Hz, 3J3a,2a
8.9 Hz, 3J3a,2b = 7.1 Hz, 3J3a,4b = 5.1 Hz, 1 H, 3-Ha), 1.93
(ddddd, 2J3b,3a = 13.8 Hz, 3J3b,2a = 7.1 Hz, 3J3b,4a = 5.2 Hz,
3J3b,2b = 5.1 Hz, 3J3b,4b = 4.5 Hz, 1 H, 3-Hb), 1.98 (ddddd,
=
Hz, 1 H, 5-H), 4.83–4.87 (m, 1 H, 9-H), 5.28 (dtt, 3J17,18
=
10.6 Hz, 3J17,16 = 7.2 Hz, 4J17,19 = 1.6 Hz, 1 H, 17-H), 5.28
(mc, 1 H, 12-H), 5.32 (dtt, 3J14,15 = 10.7 Hz, 3J14,13 = 7.3 Hz,
4J14,16 = 1.7 Hz, 1 H, 14-H), 5.40 (dtt, 3J18,17 = 10.6 Hz,
3J18,19 = 7.2 Hz, 4J18,16 = 1.7 Hz, 1 H, 18-H), 5.49 (dtt,
3J15,14 = 10.7 Hz, 3J15,16 = 7.3 Hz, 4J15,13 = 1.6 Hz, 1 H, 15-H),
5.68–5.74 (m, 2 H, 10-H, 11-H). 13C NMR (151 MHz,
CDCl3): d = 6.7 (C-7), 14.2 (C-20), 18.3 (C-3), 20.3 (C-6,
C-8), 20.6 (C-19), 21.2, 21.3 (9-OAc, 12-OAc), 21.7 (C-6,
C-8), 25.7 (C-16), 27.8 (C-4), 29.5 (C-2), 32.3 (C-13), 73.0
(C-12), 75.5 (C-9), 81.9 (C-5), 123.7 (C-14), 126.7 (C-17),
129.5 (C-10, C-11), 130.5 (C-11, C-10), 131.4 (C-15), 132.2
(C-18), 170.1, 170.5 (9-OAc, 12-OAc), 171.1 (C-1). HRMS
(ESI, +ve ions, solution in MeOH): m/z calcd C24H34NaO6:
441.2248; found: 441.2253.
2J4b,4a = 14.0 Hz, 3J4b,3a = 5.1 Hz, 3J4b,3b = 4.5 Hz, 3J4b,5 = 3.2
Hz, 4J4b,2b = 1.1 Hz, 1 H, 4-Hb), 2.07 (qddt, 3J19,20 = 7.5 Hz,
3J19,18 = 7.2 Hz, 4J19,17 = 1.6 Hz, 5J19,16 = 0.8 Hz, 2 H, 19-H),
2.07, 2.08 (2 × s, 6 H, 9-OAc, 12-OAc), 2.39 (ddddt,
3
3
2J13a,13b = 14.6 Hz, J13a,14 = 7.1 Hz, J13a,12 = 6.3 Hz,
4J13a,15 = 1.6 Hz, 6J13a,16 = 0.8 Hz, 1 H, 13-Ha), 2.45 (ddd,
2J2a,2b = 17.7 Hz, 3J2a,3a = 8.9 Hz, 3J2a,3b = 7.1 Hz, 1 H, 2-Ha),
2.46 (ddddt, 2J13b,13a = 14.6 Hz, 3J13b,14 = 7.6 Hz, 3J13b,12 = 6.8
Hz, 4J13b,15 = 1.6 Hz, 5J13b,16 = 0.8 Hz, 1 H, 13-Hb), 2.56
(dddd, 2J2b,2a = 17.7 Hz, 3J2b,3a = 7.1 Hz, 3J2b,3b = 5.1 Hz,
4J2b,4b = 1.1 Hz, 1 H, 2-Hb), 2.78 (ddddddd, 3J16,15 = 7.4 Hz,
3J16,17 = 7.3 Hz, 4J16,14 = 1.7 Hz, 4J16,18 = 1.6 Hz, 5J16,13a = 0.8
Synlett 2007, No. 16, 2525–2528 © Thieme Stuttgart · New York