Total synthesis of marine oxylipins constanolactone A and B

Article abstract of DOI:10.1055/s-2003-40986

A short, high-yielding synthesis of the marine oxylipins constanolactone A and B was reported. Starting from cinnamyl alcohol (3), the cylopropyl lactone moiety 2 was obtained in 28% yield (11 steps). The second coupling partner, vinyl iodide 1, was isolated in 7 steps and 32% yield. Chromium mediated addition yielded the natural products as a 2:1 mixture (74%).

Full text of DOI:10.1055/s-2003-40986

1698
LETTER
Total Synthesis of Marine Oxylipins Constanolactone A and B
Total
S
ynt
ö
hesis of Mar
r
ine Oxyl
g
ipins
C
onstanolac
t
P
one
A
and
B
ietruszka,* Thorsten Wilhelm
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)6854269; E-mail: joerg.pietruszka@po.uni-stuttgart.de
Received 5 June 2003
Abstract: A short, high-yielding synthesis of the marine oxylipins
constanolactone A and B was reported. Starting from cinnamyl al-
cohol (3), the cylopropyl lactone moiety 2 was obtained in 28%
yield (11 steps). The second coupling partner, vinyl iodide 1, was
isolated in 7 steps and 32% yield. Chromium mediated addition
yielded the natural products as a 2:1 mixture (74%).
Key words: natural products, total synthesis, asymmetric synthe-
sis, cyclopropane, ozonolysis
Marine oxylipins bearing a cyclopropyl lactone moiety
have attracted considerable interest in recent years. The
isolation of hybridalactone,1 solandelactones,2 halicholac-
tone,3 neohalicholactone,3 and constanolactones4 pro-
voked a synthetic response.5 In this communication, we
present a route to constanolactones A and B. Constanolac-
Figure 1 Retrosynthesis of constanolactone A and B.
tones A-G were isolated by Nagle and Gerwick from the
red alga Constantinea simplex – harvested off the Oregon
coast – in 1990.4 The structures were determined through
degradation and spectroscopic methods; a biosynthetic
pathway was proposed.6 Syntheses of constanolactone A
and B5f–h as well as constanolactone E5i,j were reported,
partly driven by the fact that despite the known biological
activity of cyclopropyl lactones, physiological data are
still scarce. Our own synthetic efforts first focussed on the
synthesis of constanolactones A and B with an attempt to
efficiently provide the key intermediates 1 and 2
(Figure 1) that should readily give the natural products by
a known chromium mediated addition.5f It is important to
note that the iodide 1 is also the common precursor for
several solandelactones.
of alcohol 6 using Dess–Martin periodinane 912 and a typ-
ical CBS-reduction13 with catalytic amounts of reagent 10
furnished exclusively diastereomer 7 in 81% yield. Direct
acylation to diene 8 was conveniently performed with
acryloyl chloride (96% yield). Next, a ring-closing meta-
thesis followed, using the modified protocol by Fürstner
and Langemann:14 In the presence of a Lewis acid and the
Grubbs catalyst 11,15 the envisaged model lactone 12 was
obtained in high yield (97%, Scheme 2).
A closer examination of the model compound 12 revealed
that only 4 steps were missing to finish the synthesis of the
key intermediate 2 for all constanolactones: Obviously,
the crucial step would be the hydrogenolysis of the double
bond, since ring-opening of the cyclopropane ring to com-
pound 13 would be expected. Indeed, when performing
the reaction at room temperature, this transformation is
the only one we found. Nevertheless, it was observed that
the addition to the double bond is considerable faster and
consequently lowering the reaction temperature should
disfavor the formation of the benzyl derivative 13. It
proved ideal to reduce the olefin at a temperature between
–20 to –10 °C thus minimizing the amount of 13 formed
and maximizing the yield of cyclopropyl lactone 14 (89%
yield). All that remained to be done was to oxidatively de-
grade the phenyl group in order to obtain a carbonyl
group. It was found that ozonolysis16 with a reductive
work-up conveniently furnished the carboxylic acid 15
(70%)17 along with some dicarboxylic acid 16 (20%;
formed during work-up). Strict absence of water was es-
sential in order to minimize the amount of 16. As a matter
of course, both derivatives could be converted to the acid
First, we thought to investigate the formation of the cyclo-
propyl lactone moiety by means of a model sequence
(Scheme 1). Starting from cinnamyl alcohol (3), we ob-
tained essentially enantiomerically pure cyclopropane 4
by a combination of enantioselective catalytic cyclopro-
panation according to a Denmark protocol7 and a kinetic
enzymatic resolution.8 Oxidation under Ley’s conditions9
(90%) followed by an allyl addition with the Roush re-
agent 5,10 yielded the homoallyl alcohols 6 and 7 in 81%
as an easily seperable 19:81 diastereomeric mixture. The
minor diastereoisomer could be converted directly to the
desired acrylic ester 8 with acrylic acid under Mitsunobu
conditions,11 however, the yield was unsatisfactory
(40%). A two step procedure proved superior: Oxidation
Synlett 2003, No. 11, Print: 02 09 2003. Web: 05 08 2003.
Art Id.1437-2096,E;2003,0,11,1698,1700,ftx,en;D12903st.pdf.
DOI: 10.1055/s-2003-40986
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Marine Oxylipins Constanolactone A and B
1699
chloride in near quantitative yield, followed by a Rosen-
mund reduction18 to furnish aldehyde 2 [(65% yield over
two steps; 28% starting from cinnamyl alcohol (3)]. Alter-
native coupling strategies failed: no suitable precursors
for the natural products were formed via the acid chloride
or even the carboxylic acid.
Scheme 2 i Pd/C, H2, EtOAc, –20 to –10 °C (89% + 6% 13); ii a)
O3, CH2Cl2, 4 Å molecular sieves, 0 °C, b) Me2S, CH2Cl2, 4 Å mole-
cular sieves, –78 °C to r.t. (70% + 20% 16); iii SOCl2, –78 °C to r.t.;
iv a) i-Pr2NEt, Pd/BaSO4, 4 Å molecular sieves, H2, toluene, 0 °C, b)
reflux (65% over 2 steps).
Scheme 1 i n-Pr4NRuO4, N-methylmorpholine N-oxide, 4 Å mo-
lecular sieves, CH2Cl2, 0 °C to r.t. (90%); ii 5, toluene, –78 °C.
(94%, dr 6:7 19:81); iii 9, 4 Å molecular sieves, CH2Cl2, r.t. (81%);
iv cat. 10, 2 equiv catecholborane, toluene, –78 °C (quant., dr
7:6>98:2); v CH2=CHCOCl, i-Pr2NEt, 4-(dimethylamino)pyridine,
CH2Cl2, –78 °C (96%); vi 0.1 equiv 11, 0.3 equiv Ti(O-i-Pr)4,
CH2Cl2, 40 °C (97%).
The vinyl iodide 1 contains only one stereogenic center
that we introduced via the epoxide 17 (Scheme 3). After
the introduction of a silyl protecting group (94%), ring- Scheme 3 i Imidazole, TES-Cl, CH2Cl2, r.t. (94%); ii 1-heptyne,
BF3·OEt2, BuLi, THF, –78 °C to r.t. (91%); iii imidazole, TBS-Cl,
CH2Cl2, r.t. (86%); iv Lindlar-cat., H2, toluene, r.t. (90%); v a) 4 equiv
(COCl)2, 8 equiv DMSO, CH2Cl2, –78 °C, b) 19, CH2Cl2, –78 °C to
–20 °C, c) Et3N, –78 °C to r.t. (72%); vi 8 equiv CrCl3, 4 equiv
opening with lithiated heptyne in the presence of
BF3·OEt2 (91%) yielded pure secondary alcohol 18.19 For-
mation of a tert-butyldimethylsilyl ether under standard
conditions (86%) and syn-selective reduction of the triple
LiAlH4, 2 equiv CHI3, THF/dioxane (1:6) (77%); vii n-Bu4NF·3H2O,
bond led to Z-olefin 19 (90%). Under Swern conditions
the primary silyl protecting group was cleaved; consecu-
tive oxidation to the aldehyde occurred in the same step
(72%).19 The Takai–Utimoto20 reaction led to vinyl iodide
2021 (77%; 37% in 6 steps starting from epoxide 17).
THF, r.t. (88%); viii 6 equiv CrCl2, 4 Å molecular sieves, DMSO
(74%, dr 67:33).
Synlett 2003, No. 11, 1698–1700 © Thieme Stuttgart · New York

1700
J. Pietruszka, T. Wilhelm
LETTER
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For the high E-selectivity it was of vital importance to use
not less than 2 equivalents of iodoform: Under the same
conditions, but with 1.75 equivalents we obtained an also
highly reproducable 88% yield, however, the reaction fur-
nished an inseparable 80:20 mixture of E- and Z-olefin.
Deprotection with n-Bu4NF afforded the second essential
coupling partner. The final step of the constanolactone A
and B synthesis was the well established CrCl2-mediated
addition to aldehyde 2;5f in 74% yield the natural products
were obtained as a 67:33 mixture of diastereoisomers. The
spectroscopic data were in full agreement with those pub-
lished.5f
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0.96, CHCl3). IR(film): n = 2957 (br OH), 2861, 2622, 1729
(C=O), 1718 (C=O) cm–1. HRMS (CI, 70 eV) for [M + H+]
(C9H13O4): Calcd 185.0755. Found: 185.0808. 1H NMR
(500 MHz, CDCl3): d = 1.09 (ddd, 3J = 8.5 Hz, 3J = 6.8 Hz,
2J4a,4b = 4.7 Hz, 1 H, 4-Ha), 1.29 (ddd, 3J = 9.4 Hz, 3J = 4.7
Hz, 2J4b,4a = 4.6 Hz, 1 H, 4-Hb), 1.72 (1 H, dddd,
2J5¢a,5¢b = 13.8 Hz, 3J5¢a,4¢a = 11.7 Hz, 3J5¢a,6¢ = 10.6 Hz,
3J5¢a,4¢b = 5.0 Hz, 5¢-Ha), 1.75–1.79 (2 H, mc, 2-H, 3-H), 1.84
(ddddd, 2J4¢a,4¢b = 13.0 Hz, 3J4¢a,5¢a¢ = 11.7 Hz, 3J4¢a,3¢a = 9.0
Hz, 3J4¢a,3¢b = 7.0 Hz, 3J4¢a,5¢b = 4.7 Hz, 1 H, 4¢-Ha), 1.97
(ddddd, 2J4¢b,4¢a = 13.0 Hz, 3J4¢b,3a¢ = 7.1 Hz, 3J4¢b,3¢b = 5.0 Hz,
3J4¢b,5¢a = 5.0 Hz, 3J4¢b,5¢b = 4.7 Hz, 1 H, 4¢-Hb), 2.05 (1 H,
ddddd, 2J5¢b,5¢a = 13.8 Hz, 3J5¢b,4¢b = 4.7 Hz, 3J5¢b,4¢a = 4.7 Hz,
3J5¢b,6¢ = 3.3 Hz, 4J5¢b,3¢b = 1.3 Hz, 5¢-Hb), 2.48 (ddd,
2J3¢a,3¢b = 17.9 Hz, 3J3¢a,4¢a = 9.0 Hz, 3J3¢a,4¢b = 7.1 Hz, 3¢-Ha),
2.59 (dddd, 2J3¢b,3¢a = 17.9 Hz, 3J3¢b,4a¢ = 7.0 Hz, 3J3¢b,4b¢ = 5.0
Hz, 4J3¢b,5¢b = 1.3 Hz, 1-H, 3¢-Hb), 3.91 (1 H, ddd,
3J6¢,5¢b = 10.6 Hz, 3J6¢,3 = 6.7 Hz, 3J6¢,5¢b = 3.3 Hz, 6¢-H), 10.74
(1 H, b, COOH). 13C NMR (125 MHz, CDCl3): d = 12.1 (C-
4), 17.8 (C-3), 18.3 (C-4¢), 26.6 (C-2), 27.8 (C-5¢), 29.4 (C-
3¢), 80.9 (C-6¢), 171.4 (C-2¢), 179.0 (COOH).
(18) Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362.
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In conclusion, we succeeded to synthesize the two natural
products, constanolactone A and B via a convergent route
(longest linear chain: 12 steps, 21% yield). The building
blocks used, were synthesized in just a few, high yielding
steps.
Acknowledgment
The generous support of this project by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie, and the Otto-
Röhm-Gedächtnisstiftung is gratefully acknowledged. Donations
from the Boehringer Ingelheim KG, the Degussa AG, the Bayer
AG, the BASF AG, the Roche Diagnostics GmbH, the Wacker AG,
and the Novartis AG were greatly appreciated. We are also grateful
to the Institut für Organische Chemie der Universität Stuttgart for
their ongoing support.
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Synlett 2003, No. 11, 1698–1700 © Thieme Stuttgart · New York