Enantioselective synthesis of 10-epi-anamarine via an iterative dihydroxylation sequence

Article abstract of DOI:10.1021/ol047322i

(Chemical Equation Presented) The enantioselective syntheses of 10-epi-anamarine and 5,10-epi,epi-anamarine have been achieved in 13 to 14 steps. The route relies upon an enantio- and regioselective Sharpless dihydroxylation of either dienoates or trienoates to establish the C-8 to C-11 stereochemistry. A diastereoselective Leighton allylation established the desired C-5 stereochemistry. The route also relies upon a ring-closing metathesis to establish the α,β-unsaturated lactones.

Full text of DOI:10.1021/ol047322i

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1069-1072
Enantioselective Synthesis of
10-epi-Anamarine via an Iterative
Dihydroxylation Sequence
Dong Gao and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received December 28, 2004
ABSTRACT
The enantioselective syntheses of 10-epi-anamarine and 5,10-epi,epi-anamarine have been achieved in 13 to 14 steps. The route relies upon
an enantio- and regioselective Sharpless dihydroxylation of either dienoates or trienoates to establish the C-8 to C-11 stereochemistry. A
diastereoselective Leighton allylation established the desired C-5 stereochemistry. The route also relies upon a ring-closing metathesis to
establish the
r,â-unsaturated lactones.
Anamarine (1)1 is a member of a growing class of polyac-
etate/pyranone-containing natural products, which display a
broad spectrum of biological activity. Other examples of this
class of natural products include spicigerolide (2),1b hyptolide
(3),1c and synrotolide (4)1d (Figure 1). All of these R,â-
shown significant medicinal properties.2 This array of
properties ranges from cytotoxicity against human tumor cells
to antibacterial and/or antifungal activity.
Due to their interesting biological activities, several
synthetic approaches to this class of molecules have been
reported.3 All of the previous syntheses derived their absolute
and relative stereochemistry from carbohydrate-based starting
materials.3 In contrast, we were interested in the possibility
of preparing various stereoisomers of anamarine via asym-
metric catalysis.4 Recently, we5 and others6 have demon-
strated that the selective oxidation/hydration of polyenoates
(1) (a) Alemany, A.; Marquez, C.; Pascual, C.; Valverde, S.; Martinez-
Ripoll, M.; Fayos, J.; Perales, A. Tetrahedron Lett. 1979, 20, 3583-3586.
(b) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-Rojas, C. M.
Tetrahedron 2001, 57, 47-53. (c) Achmad, S. A.; Hoyer, T.; Kjaer, A.;
Makmur, L.; Norrestam, R. Acta Chem. Scand. 1987, 41B, 599-609. (d)
Coleman, M. T. D.; English, R. B.; Rivett, D. E. A. Phytochemistry 1987,
26, 1497-1499.
(2) (a) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-Rojas,
C. M. Tetrahedron 2001, 57, 47-53. (b) Pereda-Miranda, R.; Hernandez,
L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P.; Chai, H.; Pezzuto, J. M. J.
Nat. Prod. 1993, 56, 583-593.
Figure 1. Anamarine-type pyranone polyacetates.
(3) (a) Diaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A.
Tetrahedron 2004, 60, 2979-2985. (b) Falomir, E.; Murga, J.; Ruiz, P.;
Carda, M.; Marco, J. A. J. Org. Chem. 2003, 68, 5672-5676. (c) Lorenz,
K.; Lichtenthaler, F. W. Tetrahedron Lett. 1987, 28, 6437-6440. (d)
Valverde, S.; Herradon, A.; Herradon, B.; Babanal, R. M.; Marrtin-Lomas,
M. Tetrahedron 1987, 43, 3499-3504. (e) Lichtenthaler, F. W.; Lorenz,
K.; Ma, W. Tetrahedron Lett. 1987, 28, 47-50.
unsaturated lactones were isolated from the leaves and
flowers of an unclassified Hyptis species and other botani-
cally related genera. In addition, the common structural
features of the members of this class of compounds have
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is a viable method for synthesis. In particular, we reported
an expedient and practical synthesis of C-6-substituted
galacto-sugars from simple achiral precursors with complete
stereocontrol (5a to 6, Scheme 1).7 This approach relies on
C-11 tetrol stereochemistry of 9 could be established by
applying two Sharpless AD reactions on either dienoate 5a
or trienoate 5b.7
We initially investigated the asymmetric synthesis of
aldehyde 9 from the commercially available ethyl sorbate
(5a) (Scheme 3). As we previously described, ethyl sorbate
Scheme 1. One-Step Synthesis of galacto-γ-Lactone
Scheme 3. Synthesis of Ester 13
the iterative use of an OsO4-catalyzed dihydroxylation
reaction on achiral dienoates such as 5a. To test the utility
of this methodology for natural product synthesis, we decided
to apply it toward the synthesis of various anamarine
analogues.4 Reported herein is our approach to two unnatural
analogues, 10-epi-anamarine and 5,10-epi,epi-anamarine,
which both rely upon the enantio- and regioselective use of
the Sharpless dihydroxylation,8 as well as a Leighton
asymmetric allylation9 and Grubbs metathesis.10
Retrosynthetically, we envisioned that the lactone rings
of 10-epi-anamarine and 5,10-epi,epi-anamarine could be
synthesized by employing a selective metathesis reaction10
of triene 8 (Scheme 2). The triene 8 could be prepared by
(5a) was enantioselectively dihydroxylated and the corre-
sponding diol was protected to give acetonide 10 in good
yield (74% for two steps) and enantiomeric excess (80% ee).7
Acetonide 10 was once again dihydroxylated in a diastereo-
merically matched sense,7 with the pseudoenantiomeric
reagent (2 mol % OsO4, 4 mol % (DHQD)2PHAL, 3 equiv
of K3Fe(CN)6, 3 equiv of K2CO3, and 1 equiv of MeSO2-
NH2) to diastereoselectively give a diol (dr ) 10:1), which
was protected as the acetonide 11 (66% yield for two steps).
As a result of performing the second dihydroxylation (10 to
11) with a diastereomerically matched chiral reagent system,
the acetonide 11 was isolated with greater enantiomeric purity
(>96% ee) than the initial acetonide 10.11
Scheme 2. Retrosynthetic Analysis of 10-epi-Anamarine
With the relative and absolute tetrol stereochemistry
established in 11, we next looked to extend ester 11 into
R,â-unsaturated ester 13. Exhaustive reduction of ester 11
an asymmetric allylation9 of aldehyde 9 followed by an
acylation. Finally, it was envisioned that the C-8 through
(9) Kubota, K.; Leighton, J. Angew. Chem., Int. Ed. 2003, 42, 946-
948.
(4) Migual Carda and Alberto Marco noted that various stereoisomers
of spicigerolide (2) have improved cytotoxicity against several cancer cell
lines; see ref 3b.
(5) (a) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447-4450.
(b) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959-1962. (c)
Garaas, S. D.; Hunter, T. J.; O’Doherty, G. A. J. Org. Chem. 2002, 67,
2682-2685. (d) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 2777-
2780. (e) Li, M.; O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 6407-
6411.
(10) For a review on ring-closing metathesis reactions, see: (a) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Deiters, A.; Martin,
S. F. Chem. ReV. 2004, 104, 2199-2238. For other uses of this pyranone
formation in synthesis, see refs 5b-e and: (c) Pradaux, F.; Bouzbouz, S.
Org. Lett. 2001, 3, 2233-2235. (d) Ghosh, A. K.; Wang, Y.; Kim, J. T. J.
Org. Chem. 2001, 66, 8973-8982. (e) Reddy, M. V. R.; Yucel, A. J.;
Ramachandran, P. V. J. Org. Chem. 2001, 66, 2512-2514. (f) Wang, Y.-
G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615-4618. (g) Mizutani, H.;
Watanabe, M.; Honda, T. Tetrahedron 2002, 58, 8929-8936. (h) Trost, B.
M.; Yeh, V. S. C. Org. Lett. 2002, 4, 3513-3516. (i) Falomir, E.; Murga,
J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44, 539-541.
(11) While the conversion of 10 to 11 is a diastereoselective matched
reaction with the (DHQD)2PHAL/OsO4 reagent system, the reaction occurs
at a significantly slower rate and, as a result, a higher catalyst loading is
required (2% OsO4 and 4% (DHQD)2PHAL, see Scheme 3).
(6) For a quite elegant use of this methodology in total synthesis, see:
Smith, A. B., III; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett. 2005,
7, 139-142.
(7) Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D. J.;
O’Doherty, G. A. Org. Lett. 2005, 7, 745-748.
(8) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
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Org. Lett., Vol. 7, No. 6, 2005

with DIBALH (3.0 equiv; 93%) followed by a Swern
oxidation (86%) provided aldehyde 12 in 82% yield for two
steps. A Wittig reaction of aldehyde 12 with corresponding
ylide (EtO2CCHdPPh3) provided the desired ester 13 in 81%
yield.
by a reduction/oxidation sequence. Exposure of a THF
solution of ester 13 with 3.0 equiv of DIBALH at -78 °C
provided allylic alcohol (Scheme 5), which without purifica-
In an effort to shorten the synthesis, as well as to further
test the iterative dihydroxylation methodology, we decided
to investigate a second approach to enoate 13 from trienoate
5b (Scheme 4). The starting trienoate 5b was easily prepared
Scheme 5. Synthesis of Aldehyde 9
Scheme 4. Alterative Synthesis of Acetonide 13
tion was oxidized with MnO2 to give aldehyde 9 in good
yield (82% for two steps).
Diastereoselective allylation of aldehyde 9 was achieved
by using either enantiomer of the easily prepared Leighton
allyl silane reagents (R,R)-16 and (S,S)-169 (Scheme 6).
Scheme 6. Diastereoselective Leighton Allylation
by a Wittig reaction of commercially available 2,4-hexadienal
and ylide (EtO2CCHdPPh3). As with the dienoate 5a, the
trienoate 5b was exposed to the Sharpless dihydroxylation
protocol, and the resulting diol was protected as the acetonide
to give dienoate 14 in a good yield (72% for two steps) and
enantiomeric excesses (90% ee). Again, the second Sharpless
AD reaction of dienoate 14 was preformed using the
stereochemically matched ligand system ((DHQD)2PHAL).
While the desired diol 15b was formed with excellent
diastereocontrol, to our surprise it was also formed with a
significant amount of the undesired regioisomer 15a.12 The
two regioisomers 15a and 15b were obtained in a 1:1 ratio.
Unfortunately, removing the acetonide protecting group had
no positive effect on the regioselectivity.13 The desired
regioisomer 15b was separated by chromatography and
protected as bis-acetonide 13 and proved to be spectroscopi-
cally identical to the bis-acetonide 13 prepared by the
previous route (Scheme 3).14
Simply adding a solution of aldehyde 7 to the chiral
allylsilane reagent (S,S)-16 (0.2 M in CH2Cl2) at -10 °C
gave allylic alcohol 17a in 92% with near complete stereo-
control (>99% ee and dr).15,16 Similarly exposing 9 to the
enantiomeric reagent (R,R)-16 provided a 95% yield of the
diastereomeric allylic alcohol 17b in equally high enantio-
meric and diastereomeric purity (>99% ee and dr).16
We next prepared the metathesis precursor triene 8
(Scheme 7). A DCC-promoted coupling (4 equiv of acrylic
acid/DCC in CH2Cl2) with allylic alcohol 17a provided a
triene 8 in a 78% yield. To address the formation of the
lactone ring, we turned to the use of a ring-closing meth-
To study the diastereoselective allylation reaction, ester
13 was converted into aldehyde 9. This was accomplished
(14) While this second route (Scheme 4) is shorter, we preferred the
first route (Scheme 3) because of the ease of isolation of all the intermediates
and the greater overall yield (33 vs 26%).
(12) To the best of knowledge, this loss of regiocontrol also occurs when
14 is dihydroxylated without (DHQD)2PHAL. When 14 was exposed to
OsO4/NMO in MeOH, four diastereotopic tetrol products were produced.
This result is inconsistent with an initial regioselective formation of diol
15b, because when diol 15b is exposed to OsO4/NMO in MeOH only a
single tetrol is produced.
(13) In contrast to our results for acetonide 14 and its corresponding
diol, Smith observed excellent regiocontrol (>10:1) in the dihydroxylation
of related substituted epoxy-trienoates. Similarly, they observed no signifi-
cant loss of stereocontrol in the mismatched (slower) case; see ref 6.
(15) Previous approaches to this class of pyranone natural products use
the Brown AllylBIpc2 reagent for this transformation; see refs 3a-d. We
have found that the Leighton reagent works equally well in terms of
stereochemical outcome and allows for a significantly simpler product
isolation procedure; see ref 9.
(16) All enantioexcesses were determined by examining the 1H NMR
of the corresponding Mosher esters, see: Sullivan, G. R.; Dale, J. A.;
Mosher, H. S. J. Org. Chem. 1973, 38, 2143-2147.
Org. Lett., Vol. 7, No. 6, 2005
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Scheme 7. Completion of the Synthesis of 10-epi-Anamarine
Scheme 8. Completion of the Synthesis of
5,10-epi,epi-Anamarine
7
athesis reaction. This was easily implemented by exposure
of a refluxing CH2Cl2 solution of the triene 8 to the Grubbs
catalyst 18 (10 mol %), resulting in a clean cyclization to
dihydropyran 19a in 82% yield.
All that remained to complete the synthesis was to
deprotect the acetonides and to acylate the resulting tetrol.
After some experimentation, we found that this was most
easily accomplished by heating 19a in 10% aqueous hydro-
chloric acid for 20 min at 65 °C. The crude tetrol product
was directly acylated by solvent removal and addition of
pyridine, acetic anhydride, and DMAP. This two-step, one-
pot protocol provided excellent yield of 10-epi-anamarine 7
(86% for two steps).
Similarly, the diastereomeric target molecule 20 was also
prepared from 17b by the same metathesis procedure
(Scheme 8). Acylation of 17b with DCC and acrylic acid
provided triene 8b in 76% yield, which similarly underwent
a ring-closing methathesis reaction to give pyranone 19b
(80%). Finally a two-step, one-pot, acid-catalyzed deprotec-
tion/acylation reaction sequence provided 5,10-epi,epi-an-
amarine (20) in 82% yield for the two steps.
been developed. This highly enantio- and diastereocontrolled
route illustrates the utility of an iterative AD reaction and
Leighton allylation sequence. This approach provided both
10-epi-anamarine and 5,10-epi,epi-anamarine in 14 and 13%
overall yields, respectively. It is also worth noting that this
route is significantly shorter than the previous carbohydrate-
based approaches to the anamarines, yet this new route starts
from achiral sources. Further application of this approach
to other members of this class of natural product synthesis
and biological testing is ongoing.
Acknowledgment. We are grateful to NIH (GM63150)
and NSF (CHE-0415469) for the support of our research
program and NSF-EPSCoR (0314742) for a 600 MHz NMR
spectrometer at WVU.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, two short and enantioselective syntheses
of 10-epi-anamarine (7) and 5,10-epi,epi-anamarine (20) have
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