Enantioselective total synthesis of eicosanoid and its congener, using organocatalytic cyclopropanation, and catalytic asymmetric transfer hydrogenation reactions as key steps

Article abstract of DOI:10.1021/jo800631z

(Chemical Equation Presented) An enantioselective unified strategy for the syntheses of the oxylipin class of natural products was accomplished. Our strategy relies on three catalytic steps: (a) organocatalytic cyclopropanation, (b) the catalytic asymmetr

Full text of DOI:10.1021/jo800631z

Enantioselective Total Synthesis of Eicosanoid
and Its Congener, Using Organocatalytic
Cyclopropanation, and Catalytic Asymmetric
Transfer Hydrogenation Reactions as Key Steps
Gullapalli Kumaraswamy* and Mogilisetti Padmaja
Organic DiVision III, Fine Chemicals Laboratory, Indian
Institute of Chemical Technology,
Hyderabad-500 607, India
gkswamy_iict@yahoo.co.in
FIGURE 1. Oxylipin family.
ReceiVed March 24, 2008
SCHEME 1. Retrosynthesis
An enantioselective unified strategy for the syntheses of the
oxylipin class of natural products was accomplished. Our
strategy relies on three catalytic steps: (a) organocatalytic
cyclopropanation, (b) the catalytic asymmetric transfer
hydrogenation (CATHy) reaction, and (c) the Nozaki-
Hiyama-Kishi reaction.
The trans-cyclopropane motif is a prevalent structural unit
in a number of marine oxylipin family members, such as
constanolactones 1a,b, halicholactone 2, solandelactones 3a,b,
and eicosanoid 4a.1 Primarily two subfamilies of oxylipins,
constanolactones 1a,b and solandelactones 3a,b (Figure 1), have
been identified based on the absolute configuration of the
cyclopropane ring.
The solandelactones 3a,b possess a (R,R)-cyclopropyl motif
linked to saturated or unsaturated eight-membered lactone and
a C22 aliphatic carbon chain, whereas constanolactone 1a,b
possess a δ-lactone, a dodecadiendiol side chain, and a (S,S)-
cyclopropyl motif. The halicholactone 2 possesses a (R,R)-
cyclopropyl motif as solandelactones but differs from it at C8,
C12, and C15. The intriguing biogenetic route proposed for
constanolactone is via a 12-lipoxygenase pathway, which leads
to intermediates such as arachidonic acid and an eicosanoid 4a.
Support for this pathway is provided by the isolation of 4a from
acetone powder of the Caribbean soft coral Plexaura homoma-
lla.2 The halicolactone is presumably derived from an eicosanoid
with a C20 carbon chain, while solandelactones might originate
from docosanoid containing a C22 carbon chain. The oxylipin
family displays a moderate to low inhibitory activity against
5-lipoxygenase and also acts as inhibitors of farnesyltransferase,
which is found in many types of cancer cells.3 Due to significant
(2) (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. (c) Lopez, A.;
Gerwick, W. H. Tetrahedron Lett. 1988, 29, 1505. (d) Moghaddam, F. M.;
Gerwick, W. H.; Ballantine, D. L. Prostaglandins 1989, 37, 303. (e) Solem,
M. L.; Jiang, Z. D.; Gerwick, W. H. Lipids 1989, 24, 256. (f) Corey, E. J., Jr.;
Yamada, Y. Tetrahedron Lett. 1985, 26, 4171. (g) Corey, E. J.; d’Alarcao, M.;
Matsuda, S. P.; Lansbury, P. T., Jr.; Yamada, Y. J. Am. Chem. Soc. 1987, 109,
289.
(3) Lee, S. H.; Kim, M.-J.; Bok, S. H.; Lee, H.; Kwon, B.-M.; Shin, J.; Seo,
Y. J. Org. Chem. 1998, 63, 7111.
(4) (a) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6621. (b)
Pietruszka, J.; Wilhelm, T. Synlett 2003, 1698. (c) Pietruszka, J.; Rieche,
A. C. M.; Schone, N. Synlett 2007, 2525. (d) Miyaoka, H.; Shigemoto, T.;
Yamada, Y. Heterocycles 1998, 47, 415. (e) Silva, C. B.-D.; Benkouider, A.;
Pale, P. Tetrahedron Lett. 2000, 41, 3077. (f) Yu, J.; Lai, J.-Y.; Ye, J.; Balu, N.;
Reddy, M. L.; Duan, W.; Fogel, B. R.; Capdevila, J. H.; Falck, J. R. Tetrahedron
Lett. 2002, 43, 3939. (g) Mohapatra, D. K.; Dutta, A. J. Org. Chem. 1998, 63,
642. (h) S. Varadarajan, S.; Mohapatra, D. K.; Dutta, A. Tetrahedron Lett. 1998,
39, 1075. (i) Da Silva, C. B.; Pale, P. Tetrahedron: Asymmetry 1998, 9, 3951.
(j) Nagasawa, T.; Onoguchi, Y.; Matsumoto, T.; Suzuki, K. Synlett 1995, 1023.
(k) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.;
Takemoto, Y. J. Org. Chem. 2001, 66, 81.
* Address correspondence to this author. Phone: + 91-40-27193154. Fax: +
91-40-27193275.
(1) (a) Gerwick, W. H. Chem. ReV. 1993, 93, 1807. (b) Baertschi, S. W.;
Brash, A. R.; Harris, T. M. J. Am. Chem. Soc. 1989, 11, 5003. (c) Niwa, H.;
Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989, 30, 4543. (d) Kigoshi, H.;
Niwa, H.; Yamada, K.; Stouck, T. J.; Clardy, J. Tetrahedron Lett. 1991, 32,
2427. (e) Seo, Y.; Cho, K. W.; Rho, J.-R.; Kwon, B.-M.; Bok, S.-H.; Song, J.-I.
Tetrahedron Lett. 1996, 52, 10583.
5198 J. Org. Chem. 2008, 73, 5198–5201
10.1021/jo800631z CCC: $40.75 2008 American Chemical Society
Published on Web 06/05/2008

SCHEME 2. Catalytic Cyclopropanation
SCHEME 3. Catalytic Asymmetric Transfer Hydrogenation
Reaction
activity coupled with unique stereogenic variations within
subfamilies of oxylipins, they have attracted the attention of
synthetic organic chemists toward their synthesis.4 The pioneer-
ing biomimetic synthesis initiated by White et al.5 produced
the first synthetic evidence of the intermediate of eicosanoid
4a. Following this, the same group reported the syntheses of
constanolactones 1a,b and solandelactones 3a,b.6 Martin et al.7
also successfully synthesized solandelactone 3a and unambigu-
ously assigned the absolute configuration. With our continued
interest in developing catalytic enantioselective routes to strained
small molecules,8 we were attracted to the enantioselective total
synthesis of eicosanoid 4a and its congener 4b (Figure 1).
Our strategy relies on three catalytic steps: (a) organocatalytic
cyclopropanation, (b) the catalytic asymmetric transfer hydro-
genation (CATHy) reaction, and (c) the Nozaki-Hiyama-Kishi
reaction. Our retrosynthetic approach is shown in Scheme 1.
At the outset, we envisioned that all the members of the
oxylipin family could be synthesized, in principle, by varying
chirality inducing ligands of the above pivotal reactions with
perfect stereocontrol and a predictable absolute stereochemistry.
For the proposed unified synthetic strategy, the ideal advanced
intermediate could be cyclopropyl δ-lactone aldehydes 17a-d
and vinyl iodide 18. We planned to exploit the enantioselective
organocatalytic cyclopropanation protocol of Gaunt et al.9 The
synthesis began with the monoprotected pentanediol 5 as its
benzyl ether, followed by oxidation to yield aldehyde 6. Addition
of vinylmagnesium bromide at 0 °C for 12 h afforded an allyl
alcohol, which on further oxidation furnished vinyl ketone 7.
tertButyl bromoacetate reacted with enone 7 in the presence of
10 mol % of L1 (DHQD)2Pyr and Cs2CO3 as base upon heating
furnished cyclopropane 8 in 85% isolated yield.
It was anticipated that the use of dimeric ligand L1′
(DHQ)2Pyr would generate the enantiomer 9. Nevertheless,
subjecting tert-butyl bromoacetate and enone 7 in the presence
of 10 mol % of L1′ (DHQ)2Pyr under identical conditions led
to the product 9 with decreased enantioselectivity. After
considerable experimentation,10 it was found that the benzyl
ether of quinine ligand L2 gave approximately equal magnitude
of rotation as 8 but opposite in sign (Scheme 2). An effort to
resolve the racemic cyclopropane product 8 on the chiral
stationary phase (Chiralpak AD-H) was not successful. At this
juncture, the enantioselectivity and relative configuration were
assigned based upon analogy9 and advanced further.
(5) (a) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1995, 117, 6224. (b)
White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1993, 115, 2970–2971.
(6) (a) White, J. D.; Martin, W. H. C.; Lincoln, C.; Yang, J. Org. Lett. 2007,
9, 3481. (b) White, J. D.; Lincoln, C. M.; Yokochi, A. F. T. Chem. Commun.
2004, 2846.
(7) (a) Davoren, J. B.; Martin, S. F. J. Am. Chem. Soc. 2007, 129, 510. (b)
Davoren, J. B.; Harcken, C.; Martin, S. F. J. Org. Chem. 2008, 73, 391.
(8) (a) Kumaraswamy, G.; Padmaja, M.; Markondaiah, B.; Jena, N.; Sridhar,
B.; Udaya Kiran, M. J. Org. Chem. 2006, 71, 337. (b) Kumaraswamy, G.;
Markondaiah, B. Tetrahedron Lett. 2007, 48, 1707. (c) Kumaraswamy, G.;
Markondaiah, B. Tetrahedron Lett. 2008, 49, 327. (d) Kumaraswamy, G.;
Ankamma, K.; Pitchaiah, A. J. Org. Chem. 2007, 72, 9822.
(10) The methoxy analogue of quinidine was found to be inferior to the benzyl
analogue. Additionally, the benzyl analogue can be prepared easily in multigram
quantities.
(9) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J.
Angew. Chem., Int. Ed. Engl. 2004, 43, 4641.
J. Org. Chem. Vol. 73, No. 13, 2008 5199

SCHEME 4. Synthesis of Cyclopropyl δ-Lactone Aldehyde
SCHEME 5. Synthesis of Eicosanoid and Its Congener
ether 14a. Hydrogenation over 10% Pd-C in MeOH under
balloon pressure led to the deprotection of the TES and benzyl
ether to furnish diol 15a.13a It was proposed to selectively
oxidize the primary alcohol and subject it to Yamaguchi
lactonization7b to synthesize cyclopropyl δ-lactone 16a. How-
ever, the Parikh-Doering13b oxidation proved problematic,
showing a multitude of products on tlc. Consequently, we opted
for the Ley14 oxidation. To our delight, diol 15a when subjected
to Ley’s conditions, afforded cleanly lactone 16a by selective
oxidation of the primary hydroxyl, hemiacetal formation, and
further oxidation. Exposure of 16a to TBAF in THF at rt and
further oxidation using the Ley14 protocol yielded aldehyde 17a
as a single isomer in 76% yield. The spectral and chirooptical
data were in agreement with data reported in the literature.5
Thus, the absolute configuration of the newly formed streogenic
centers in 17a was assigned as 5S, 6R, and 8R. Similarly, 17b,
17c, and 17d were synthesized employing the same sequence
of steps starting from 10b, 11c, and 11d, respectively (Scheme
4). Since 17b is a diastereomer of 17a, the absolute configuration
was assigned as 5R, 6R, 8R. Compound 17c is an advanced
intermediate used in the synthesis of constanolactone 1a,b, and
Next, we evaluated Noyori’s11a catalytic asymmetric transfer
hydrogenation reaction for the reduction of the keto group. The
reduction of compound 8 by using 1 mol % of chiral Ru catalyst
L3 and 7 mol % of KOH in 2-propanol at 80 °C for 6 h
proceeded cleanly to afford product 10a in a 9:1 diastereomeric
mixture.12 The major diastereomer 10a was isolated in 65%
yield by column chromatography. Without KOH or with K2CO3
and below 60 °C, no product formation was observed.
Using L4 as the ligand, under otherwise identical conditions,
led to the alcohol 10b with the same selectivity (9:1, dr)11b in
69% isolated yield. However, in the case of 9, using L3 as ligand
under similar conditions, the product 11c was obtained with
decreased selectivity (8:2, dr). This problem was circumvented
by using K2CO3 as the base and maintaining the reaction
temperature at 60 °C. The isolated product 11c showed excellent
facial selectivity (9.5:0.5, dr)12 in 87% yield. Similarly, employ-
ing L4 as ligand, the diastereomer 11d was successfully obtained
with the same level of efficiency in 86% isolated yield (Scheme
3). The assignment of the stereochemistry of the newly formed
hydroxyl group was based on Noyori’s protocol,11a i.e., S,S-
diamine-Ru catalyst induces the S-configuration (10a and
11c),while R,R-diamine-Ru generates the R-configuration (10b
and 11d). The results indicate that the asymmetric reduction
proceeded with good facial selectivity, as a result of reagent
control with little or no influence due to the substrate.
comparison of sign of rotation ([R]23 +78.0 (c 0.25, CHCl3)
D
{lit.4c [R]23D +73.0 (c 2.4, CHCl3}) helped to assign its absolute
configuration as 5R, 6S, and 8S.
Finally, the stage was set for the synthesis of eicosanoid 4a
by a Nozaki-Hiyama-Kishi coupling reaction of 17a and 18.
The vinyliodo segment 18was prepared by the Takai-Utimoto
reaction.15,5b
Initially, we have evaluated a catalytic version of the
Nozaki-Hiyama-Kishi coupling reaction.16 The reaction of 17a
with 18, using Mn (2 equiv), LiCl (2 equiv), TMSCl (1 equiv),
1 mol% of 4,4′-di-tert-butyldipyridyl-CrCl3, and 0.2 mol % of
4,4′-di-tert-butyldipyridyl-NiCl2 in DME at rt, for 4 h followed
by workup afforded a mixture of alkenyl alcohols. This mixture
on oxidation with the Dess-Martin periodinane yielded the
target compound 4a in 35% yield. Eventually, we selected a
stoichiometric version of this same reaction to improve the yield
of the final compound. The coupling of 17a with 18, using CrCl2
in the presence of catalytic NiCl2 in DMSO at rt, for 4 h
followed by oxidation of crude product with Dess-Martin
periodinane led to the target compound 4a in 65% isolated yield.
Having prepared the cyclopropyl alcohols 10a, 10b, 11c, and
11d, we next proceeded to synthesize eicosaniod 4a. To this
end, the secondary hydroxy group in 10a was protected as TES-
ether 12a, and subsequent exposure to DIBAL-H in DCM at
-78 °C yielded alcohol 13a, which was protected as its TBDPS-
(11) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738. (b) To estimate the enantioselectivity, the 10b was
converted to (S)-methoxymandelate ester. The 1H NMR spectrum of correspond-
ing ester showed >95% ee in coparision with (S)-methoxymandelate ester of
racemic 10b (please see the Supporting Information).
(13) (a) Rotulo-Sims, D.; Prunel, J. Org. Lett. 2002, 4, 4701. (b) Parikh,
J. R.; von E. Doering, W. J. J. Am. Chem. Soc. 1967, 89, 5505.
(14) (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639. (b) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6623.
(15) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
(16) Namba, K.; Wang, J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7, 5421.
(12) (a) The diastereomeric ratio was estimated by the 1H NMR spectrum
of crude product of 10 and 11. (b) Reduction of 8 with NaBH4 in MeOH led 1:1
mixture of 10a and 10b.
5200 J. Org. Chem. Vol. 73, No. 13, 2008

9.0, 6.0, 3.7 Hz), 2.07-1.99 (1H, m), 1.75-1.54 (4H, m), 1.39
(9H, s), 1.30 (2H, ddt, J ) 8.3, 6.0, 2.2 Hz); 13C NMR (50 MHz,
CDCl3) δ 207.4, 171.0, 138.4, 128.2, 127.5, 127.4, 81.0, 72.8, 69.7,
43.3, 29.0, 28.6, 27.9, 24.9, 20.4, 16.7; MS (ES) m/z 355 (M +
Na)+; HRMS (ES) m/z 355.1889 (calcd for C20H28O4Na 355.1885).
(1R,2R)-tert-Butyl-2-((S)-5-(benzyloxy)-1-hydroxypentyl)cy-
clopropane Carboxylate (10a). To a solution of 8 (2.0 g, 6.02
mmol) in anhydrous 2-propanol (84 mL) under argon was added
catalyst L3 (0.04 g, 0.065 mmol, 1.0 mol %), which was predis-
solved in CH2Cl2 (2 × 1 mL). To this reaction mixture was added
KOH (25 mg, 7.5 mol %), and the resulting reaction mixture was
heated to 80 °C for 6 h. After the reaction mixture was cooled to
rt, the solvent was evaporated under reduced pressure. The crude
residue was purified by column chromatography (8% EtOAc in
The spectral and optical data of 4a were in full agreement with
that reported in the literature5,4j ([R]23D -30.0 (c 0.15, CHCl3)
{lit. [R]23 -27.4 (c 0.46, CHCl3)}). The congener 4b was
D
synthesized in 62% yield from 17b following the above-
mentioned conditions (Scheme 5). The overall yield of the 11-
step synthesis was 20% from 8 to 4a.
In conclusion, we have succeeded in developing a catalytic
enantioselective unified strategy for the synthesis of the oxylipin
class of natural products. The salient features of this concise
convergent synthesis are (i) the genesis of chirality through an
organocatalytic reaction, (ii) the production of cyclopropanes
as either enantiomer employing a catalytic quantity of quinine-
or quinidine-based alkaloids, and (iii) the application of Noyori’s
CATHy reaction that could lead to the synthesis of C(5)
epimeric alcohols, which in turn would facilitate the synthesis
of every representative member of the oxylipin family. Further
application of this strategy for the syntheses of halicholactones
and solandelactones is underway.
hexane) to give alcohol 10a (1.3 g, 65%) as a colorless liquid. [R]23
D
-45.6 (c 0.8, CHCl3); IR (KBr) 3431, 2923, 2854, 1718, 1366,
1
1153, 1099, 757 cm-1; H NMR (300 MHz, CDCl3) δ 7.33-7.18
(5H, m), 4.46 (2H, s), 3.44 (2H, t, J ) 6.0 Hz), 3.05 (1H, q, J )
12.8, 6.0 Hz), 1.88 (1H, OH, br s) 1.68-1.46 (8H, m), 1.43 (9H,
s), 1.07 (1H, dt, J ) 9.0, 4.5 Hz), 0.73 (1H, dddd, J ) 10.5, 8.3,
6.0, 3.7 Hz); 13C NMR (75 MHz, CDCl3) δ 173.0, 138.4, 128.2,
127.5, 127.4, 80.2, 73.8, 72.8, 70.1, 36.7, 29.6, 28.2, 28.0, 22.1,
18.9, 12.3; MS (ES) m/z 357 (M + Na)+; HRMS (ESI) m/z
357.2055 (calcd for C20H30O4Na 357.2041).
Experimental Section
(1R,2R)-tert-Butyl-2-(5-(benzyloxy)pentanoyl)cyclopropane Car-
boxylate (8). The catalyst L1 (0.85 g, 8.4 mmol, 0.1 equiv with
respect to alkene) was added to a stirred solution of Cs2CO3 (3.7
g, 1.2 equiv) in MeCN (42 mL, 0.23 M) and heated to 80 °C. A
solution of tert-butyl bromoacetate (1.82 g, 9.37mmol) and the
alkene 7 (2.5 g, 11.41 mmol) in MeCN (42 mL) was added over
20 h by means of a syringe pump. The syringe was rinsed with
MeCN (2 mL) and the reaction mixture was stirred for a further
4 h. The reaction mixture was filtered through a celite pad and
rinsed with EtOAc (20 × 4 mL) and the resulting contents were
concentrated under reduced pressure. The residue was purified by
column chromatography (5% EtOAc in hexane) to afford 8 (3.21
Acknowledgment. We are grateful to Dr. J. S. Yadav,
Director, IICT, for his constant encouragement. The DST, New
Delhi (Grant No. SR/SI/OC-12/2007) is also gratefully ac-
knowledged for their financial assistance. Thanks are also due
to Dr. T. K. Chakraborty for his support. M.P. is thankful to
UGC (New Delhi) for awarding the fellowship.
Supporting Information Available: Detailed experimental
procedures, characterization data, and copies of 1H, 13C, spectra
for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
g, 85%) as a colorless liquid. [R]23 -126.1 (c 3.1, CHCl3); IR
D
1
(KBr) 2929, 2857, 1725, 1702, 1367, 1214, 1155, 1114 cm-1; H
NMR (300 MHz, CDCl3) δ 7.31-7.27 (5H, m), 4.46 (2H, s), 3.44
(2H, t, J ) 6.0 Hz), 2.62 (2H, t, J ) 6.7 Hz), 2.31 (1H, ddd, J )
JO800631Z
J. Org. Chem. Vol. 73, No. 13, 2008 5201