Synthesis of a lactone diastereomer of the cembranolide uprolide D

Article abstract of DOI:10.1021/ol101776e

Figure Presented. A convergent stereoselective synthesis of a C1/C14 bis-epimer of uprolide D is described in which an intramolecular Barbier-type reaction was employed for macrocyclization with concomitant introduction of the C1 and C14 stereocenters of a fused α-methylene lactone ring through an anti-Felkin-Anh transition state. Unlike previous examples of allyl chromium additions, none of the Felkin-Anh derived adduct could be detected.

Full text of DOI:10.1021/ol101776e

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4328-4331
Synthesis of a Lactone Diastereomer of
the Cembranolide Uprolide D
James A. Marshall,*,† Ce´line A. Griot,† Harry R. Chobanian,§,† and
William H. Myers‡
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904, and
Department of Chemistry, UniVersity of Richmond, Richmond, Virginia 27173
jam5x@Virginia.edu
Received July 30, 2010
ABSTRACT
A convergent stereoselective synthesis of a C1/C14 bis-epimer of uprolide D is described in which an intramolecular Barbier-type reaction was
employed for macrocyclization with concomitant introduction of the C1 and C14 stereocenters of a fused r-methylene lactone ring through
an anti-Felkin-Anh transition state. Unlike previous examples of allyl chromium additions, none of the Felkin-Anh derived adduct could be
detected.
Since the isolation of eupalmerin acetate from Eunicea
succinea in 1972, soft corals of the genus Eunicea have
proven to be a rich source of cembranolide natural products.
In their ongoing investigations of Caribbean soft coral related
to Eunicea mammosa indigenous to the waters of Puerto
Rico, Rodr´ıguez and co-workers isolated a number of
structurally novel cytotoxic cembranolides, the uprolides,
possessing an embedded tetrahydrofuran ring at C4/C7.1
Figure 1. Proposed biosynthesis of uprolide D and E acetates.
Biogenetically, the uprolides are thought to arise from
epimeric epoxide derivatives of eupalmerin acetate (Figure
1). Intrigued by the structure and possible biological activity
of these unusual cembranolides, we formulated plans for a
synthesis of uprolide D that revolved around two metal-
initiated cyclization reactions. The first of these involved a
vinyl tetrahydrofuran cascade sequence (B f C),2 and the
second employed a type of Barbier macrocyclization (D f
E), analogous to that reported by Semmelhack3 and Chan4
for fused-ring R-methylene lactones (Scheme 1).
The requisite precursor A for this approach was prepared
by a convergent sequence in which two main segments, 2
and 4 (Scheme 2), were combined by a Wittig condensation
(Scheme 3).
The aforementioned condensation of phosphonium ylide
2 and aldehyde 4 afforded the (E) conjugated ester 5 as the
sole detectable isomer (Scheme 3). The first of the two
epoxides required for precursor B of the tetrahydrofuran
† University of Virginia.
‡ University of Richmond.
§ Current address: Department of Medicinal Chemistry, Merck Research
Laboratories, Merck & Co, Rahway, New Jersey 07065.
(1) Rodr´ıguez, A. D.; Soto, J. J.; Pina, I. C. J. Nat. Prod. 1995, 58,
1209.
(3) (a) Semmelhack, M. F.; Wu, E. S. C. J. Am. Chem. Soc. 1976, 98,
3384. (b) Semmelhack, M. F.; Tomesch, J. C.; Czarny, M.; Boettger, S. J.
Org. Chem. 1978, 43, 1259.
(2) Marshall, J. A.; Chobanian, H. R. Org. Lett. 2003, 5, 1931.
(4) Bryan, V. J.; Chan, T. H. Tetrahedron Lett. 1996, 37, 5341.
10.1021/ol101776e  2010 American Chemical Society
Published on Web 08/26/2010

drofuran 10 as a 4:1 mixture of diastereomers in 82% yield.
Our previous studies have shown that the foregoing Zn
cascade route to 2-vinyltetrahydrofurans is highly stereose-
lective.2 Hence, we surmise that the mixture of tetrahydro-
furan diastereomers must result from the Shi epoxidation.
For further elaboration of the side chain segment, alcohol
10 was transformed to alcohol 11 after alcohol protection
and selective DPS ether cleavage.
Scheme 1. Synthetic Plan for Uprolide D
Aldehyde 12, obtained from alcohol 11 by Dess-Martin
oxidation, afforded the acrylic ester 13 as a 1:1 mixture of
diastereoisomers upon Baylis-Hillman condensation with
methyl acrylate (Scheme 4).6 Treatment of this alcohol
Scheme 4. Synthesis of Aldehyde 15
Scheme 2. Syntheses of Intermediates 2 and 4
intermediate C was introduced with excellent enantiomeric
purity by Sharpless epoxidation of the allylic alcohol 6,
obtained through reduction of ester 5 with DIBALH. The
remaining double bond was epoxidized by Shi’s methodol-
ogy5 after conversion of the epoxy alcohol 7 to the bromide
8. Treatment of the resulting bromo epoxide intermediate 9
with Zn and TBAI in refluxing ethanol afforded the tetrahy-
mixture with methanesulfonic anhydride and lithium bromide
led to the (Z)-R-bromomethyl acrylate 14 as the sole
stereoisomeric product. We assume that this conversion
proceeds by way of an intermediate mesylate, which
undergoes in situ displacement with bromide to form the
thermodynamically preferred (Z) isomer. Methanesulfonic
anhydride rather than the chloride was selected for this
conversion to avoid a possible competing reaction leading
to the chloromethyl analogue of 14. Aldehyde 15 was
obtained by selective cleavage of the PMB ether 14 and
Dess-Martin oxidation.
Scheme 3. Synthesis of 11
With the bromo aldehyde 15 in hand, we had arrived at a
critical step in our planned synthesis, the intramolecular
Barbier reaction. In a previously reported study of such
reactions,3,4 zinc or indium was used to prepare fused-ring
R-methylene γ-butyrolactones from ω-formyl allylic bro-
mides. The use of CrCl2 for intramolecular additions of allylic
bromides was reported as early as 1983 by Still and Mobilio7
in their synthesis of the cembrane asperdiol and later by
Paquette and co-workers8 for the pseudopterolide, gorgi-
(5) (a) Tu, Y.; Frohn, M.; Wang, Z.-X.; Shi, Y. Org. Synth. 2003, 80,
1. (b) Wang, Z.-X.; Shu, L.; Frohn, M.; Tu, Y.; Shi, Y. Org. Synth. 2003,
80, 9.
(6) (a) Drewes, S. E.; Hoole, R. F. A. Synth. Commun. 1985, 15, 1067.
(b) Hoffmann, H. R. M.; Rabe, J. J. Org. Chem. 1985, 50, 3849.
(7) Still, C. W.; Mobilio, D. J. Org. Chem. 1983, 48, 4785.
(8) Rayner, C. M.; Astles, P. C.; Paquette, L. A. J. Am. Chem. Soc.
1992, 114, 3926.
Org. Lett., Vol. 12, No. 19, 2010
4329

acerone. However, neither of these applications involved
R-halomethyl acrylates or aldehydes with R stereocenters.
For the present application, the proposed intramolecular
Barbier reaction raises two stereochemical issues. The first
of these, the relative stereochemistry of the lactone ring, can
be predicted from the well-precedented cyclic transition state
for additions of Lewis acidic allylmetal reagents to aldehydes
in which the (E)/(Z) stereochemistry of the double bond
correlates to the anti/syn stereochemistry of the adduct.9 The
second issue concerns the diastereoselectivity of additions
to R-chiral aldehydes, usually referred to as Felkin-Anh
control. With R-oxygenated aldehydes, Cram-chelate control
is also possible. As only a few studies of additions to
aldehydes such as 15 could be found,9 we decided to conduct
a model study utilizing the aldehyde 16 and the bromomethyl
ester 17, obtained by Baylis-Hillman homologation of
isovaleraldehyde by a sequence analogous to that described
in Scheme 4 (see Supporting Information).
Scheme 6. Intramolecular Barbier Reaction
+76.0, differed in both magnitude and sign from that reported
for the natural product ([R]D ) -19.9). As NOE data
supported a cis fused lactone ring, we surmise that the
synthetic product must have the syn, anti, cis arrangement,
epimeric with uprolide D at C1 and C14 and corresponding
to the minor product (19) of our model studies.11 Treatment
of the minor fraction of the foregoing mixture with p-
toluenesulfonic acid afforded a complex mixture of lactone
and other products. The proton NMR spectrum of this
mixture lacked several of the signals reported for uprolide
D. Thus while the outcomes of the intermolecular and
intramolecular Barbier reactions are comparable, insofar as
both afford cis lactones, they differ considerably in the degree
of Felkin-Anh selectivity.
Scheme 5. Intermolecular Barbier Reaction
A possible explanation for this discrepancy can be
constructed from an examination of Newman formulas
representing possible transition states for the additions.
Previous studies of Felkin-Anh versus chelation control,
unlike the present examples, employed (E) allylmetal re-
agents (Figure 2).9,12 In these reactions the chelating ability
The model Barbier addition (Scheme 5) was first examined
with excess indium in refluxing THF, which afforded a
complex mixture of at least three isomeric lactones in 40%
yield. With zinc as the initiating metal most of the aldehyde
was recovered along with decomposition byproducts. The
use of CrCl2 in THF proved the most promising, resulting
in a 4:1 mixture of lactones 18 and 19 in 55% yield after
treatment of the reaction mixture with p-TsOH to lactonize
the initially formed hydroxy ester intermediates.10
In accord with the results of these model studies we elected
to employ CrCl2 in THF for the cyclization of bromo
aldehyde 15, whereupon a mixture of hydroxy esters,
separable into two major fractions by flash chromatography,
was obtained (Scheme 6). Treatment of the major fraction
with p-toluenesulfonic acid effected both lactonization and
cleavage of the MOM ethers affording the lactone 20 as the
only identifiable product in 54% yield based on the bromo
aldehyde. The proton and carbon spectra of this lactone
closely resembled the published spectral data for uprolide
D, but the optical rotation of our synthetic material, [R]D )
Figure 2. Chelation transition states for allylmetal additions.
of MXn would play a major role in the diastereoselectivity
of the addition. However, with (Z) allylmetal reagents,
chelation control suffers from the necessity of the R2
(11) Lactone 20 was submitted to NCI for biological evaluation, but
after preliminary screening, it was not selected for futher testing.
(9) Review: Denmark, S. E., Almstead, N. G. Allylation of Carbonyls:
Methodology and Stereochemistry. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; pp 369-370, 376, 386-388.
(10) For the structure determination of these lactones, see Supporting
Information.
(12) Paquette and co-workers have studied indium-initiated Barbier
reactions of methyl (Z)-2-bromomethylpropenoate to various R-silyloxy and
benzyloxy aldehydes in aqueous media. These additions also proceed by
anti-Felkin-Anh transition states. Isaac, M. B.; Paquette, L. A. J. Org.
Chem. 1997, 62, 5333
.
4330
Org. Lett., Vol. 12, No. 19, 2010

substituent to occupy a position directly over the chelate ring.
Therefore chelation control is deemed extremely unlikely for
additions involving (Z) allylmetal reagents in reactions
proceeding through cyclic transition states.
The differing outcomes of the inter- and intramolecular
allylchromium additions relating to aldehydes 16 and 15 can
thus be considered in the light of four possible nonchelating
transition state arrangements. Two of these conform to
Felkin-Anh (Figure 3, FA 1 and FA 2), and two have the
uents. Both of the anti-Felkin-Anh arrangements a-FA 1
or a-FA 2 are free of syn-pentane interactions and predomi-
nance of one or the other would depend on the stereoelec-
tronic preference for an antiperiplanar OR or R1 group and
the relative magnitude of interactions between the attacking
allylmetal nucleophile and R1, in a-FA 1 or the OR
substituent in a-FA 2.
For the intramolecular addition leading from aldehyde 15
to the syn, anti, cis adduct 20, the substituents represented
by R1 and R2 in Figure 3 are connected by a tether of 10
atoms, including a tetrahydrofuran ring. We believe that the
closer proximity of R1 and R2 in the Felkin-Anh orientation
FA 1 leading to the observed anti, syn adduct 20 permits
greater flexibility of this connecting tether and thereby
engenders fewer steric interactions than the corresponding
Felkin-Anh FA 2 or anti-Felkin-Anh alternatives. Thus
while FA 1 is disfavored for intermolecular additions, it is
the preferred arrangement for intramolecular additions.
The present synthesis is noteworthy for the high degree
of stereoselection of the key tetrahydrofuran cascade se-
quence and the Cr-initiate Barbier cyclization reaction. In
fact, except for the Shi epoxidation, all stereochemically
defining steps proceed with 90% or higher selectivity.
Regrettably an unforeseen conformational control element
in the allylchromium ring-forming reaction resulted in a C1/
14 diastereoisomer of uprolide D as the only identifiable
lactone product. Conceivably, the present approach would
be well suited to cembranoid natural products with this syn,
anti, cis array at C12/C13/C14/C1.14 However, incorporation
of the present allylmetal strategy in a future synthesis of the
currently known uprolide natural products would best be
confined to intermolecular applications.
Acknowledgment. This work was supported by NSF
Grant CHE-0320669 (University of Richmond). We are
indebted to Professor Abimael Rodr´ıguez (University of
Puerto Rico) for sharing his original NMR spectra and Dr.
Jason Chruma (University of Virginia) for helpful disscus-
sions on transition states.
Figure 3. Non-chelation transition states for allylmetal additions.
so-called anti-Felkin-Anh arrangement (a-FA 1 and a-FA
2). For the intermolecular addition the FA 1 array would
expectedly be highly disfavored by a syn-pentane interaction
between R1 and R2.13 The FA 2 arrangement would likewise
suffer from an interaction between the R2 and OR substit-
Supporting Information Available: Experimental details
and spectra data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101776E
(13) Roush, W. R. J. Org. Chem. 1991, 56, 4151. Review: Roush, W. R.
Allylorganometallics. In ComprehensiVe Organic Synthesis; Heathcock,
C. H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1, pp
24-27.
(14) A likely precursor to an uprolide analogue of structure 20, bis-
12,13-epi-eupalmerin acetate, was isolated in 1993 by Rodr´ıguez and
Dhasmana: Rodr´ıguez, A. D.; Dhasmana, H. J. Nat. Prod. 1993, 56, 564.
Org. Lett., Vol. 12, No. 19, 2010
4331