Enantioselective synthesis of α-methylene-β-hydroxy carboxylic acid derivatives via a diastereoselective aldol/β-elimination sequence: Application to the C(15)-C(21) fragment of tedanolide C

Article abstract of DOI:10.1021/ol1006955

An enantioselective synthesis of α-methylene-β-hydroxy carboxylic acid derivatives via a highly diastereoselective, one-pot syn-aldol and β-elimination sequence utilizing the chiral β-(phenylselenyl) propionyl imide 15 is described. This new method, which constitutes an alternative to the Baylis-Hillman reaction, has been applied to the synthesis of the C(15)-C(21) fragment of tedanolide C.

Full text of DOI:10.1021/ol1006955

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2342-2345
Enantioselective Synthesis of
r-Methylene-ꢀ-hydroxy Carboxylic Acid
Derivatives via a Diastereoselective
Aldol/ꢀ-Elimination Sequence:
Application to the C(15)-C(21)
Fragment of Tedanolide C
Roland Barth and William R. Roush*
Department of Chemistry, The Scripps Research Institute, Scripps Florida,
130 Scripps Way, Jupiter, Florida 33458
roush@scripps.edu
Received March 24, 2010
ABSTRACT
An enantioselective synthesis of r-methylene-ꢀ-hydroxy carboxylic acid derivatives via a highly diastereoselective, one-pot syn-aldol and
ꢀ-elimination sequence utilizing the chiral ꢀ-(phenylselenyl)propionyl imide 15 is described. This new method, which constitutes an alternative
to the Baylis-Hillman reaction, has been applied to the synthesis of the C(15)-C(21) fragment of tedanolide C.
Tedanolide C (1) is the newest member of a family of marine
natural products which include tedanolide (2), 13-deoxy-
tedanolide (3), and the candidaspongiolides (4, Figure 1).1-4
Tedanolide C was isolated from a Papua New Guinea marine
sponge of the Ircinia species, and its structure and relative
stereochemistry were assigned by NMR methods in conjunc-
tion with molecular modeling and DFT calculations. Tedano-
lide C displays an IC50 value of 0.057 µg/mL (95 nM) against
HCT-116 cells (colorectal cancer cell line), and also arrests
growth of HCT-116 cells in the S-phase after 24 h exposure
at 0.2 µg/mL. It has been suggested that tedanolide C, like
13-deoxytedanolide (3), may be a protein synthesis inhibitor.1
(1) Tedanolide C (1): Chevallier, C.; Bugni, T. S.; Feng, X.; Harper,
M. K.; Orendt, A. M.; Ireland, C. M. J. Org. Chem. 2006, 71, 2510
.
In planning a synthesis of tedanolide C (1), we elected to
target the enantiomeric structure 5 (Scheme 1). The
C(10)-C(23) fragment has been identified as the key
pharmacophoric unit of 13-deoxytedanolide,5 but the stereo-
chemistry of the corresponding fragment has been given the
enantiomeric configuration (except for the epoxide) in the
(2) Tedanolide (2): Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.;
Bilayet Hossain, M.; Van Der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251
(3) 13-Deoxytedanolide (3): Fusetani, N.; Sugawara, T.; Matsunaga, S.;
Hirota, H. J. Org. Chem. 1991, 56, 4971
.
.
(4) Candidaspongiolide (4): Meragelman, T. L.; Willis, R. H.;
Woldemichael, G. M.; Heaton, A.; Murphy, P. T.; Snader, K. M.; Newman,
D. L.; van Soest, R.; Boyd, M. R.; Cardellina, J. H., II; McKee, T. C. J.
Nat. Prod. 2007, 70, 1133
.
10.1021/ol1006955  2010 American Chemical Society
Published on Web 04/20/2010

Scheme 2. Rationale of Applying Aldol Chemisty for the
Preparation of Baylis-Hillman-Type Products
Figure 1. Family of tedanolide natural products.
proposed structure of tedanolide C (1);1 the absolute con-
figuration of tedanolide C has not been assigned. Therefore,
we selected the enantiomeric stucture 5 as the synthetic target
in anticipation that this will lead to the biologically active,
naturally occurring enantiomer.
Our retrosynthetic analysis (Scheme 1) of target 5 focuses
on the formation of the tertiary hydroxy group at C(16) by
a dihydroxylation reaction of alkene 7. To synthesize 7, we
considered using the Baylis-Hillman reaction between
epoxyaldehyde 8 and methyl acrylate (9).6,7 However, this
reaction failed (Scheme 1), presumably because the valuable,
synthetically advanced aldehyde intermediate 8 could not be
used in large excess;as is generally required for bimolecular
Baylis-Hillman reactions.6,7
anticipated that the phenylselenyl group, as in 15, would
satisfy these criteria.8 Accordingly, acyl oxazolidinone 15
was synthesized in high yield by 1,4-addition of PhSeH to
known acryloyl imide 14 and subsequent recrystallization.10
Oxazolidinone 15 was readily converted into the corre-
sponding boron enolate upon treatment with Bu2BOTf and
NEt3 under standard conditions (c ) 0.2 M in CH2Cl2, -78
°C).9a Addition of isobutyraldehyde to the enolate solution
at -78 °C to promote the aldol reaction (6 h at up to 0 °C),
followed by oxidative workup with H2O2 and pyridine at 0
°C resulted in the oxidation of the phenylselenide to the
selenoxide, which underwent a subsequent ꢀ-elimination to
give the allylic alcohol 13a in 81% yield.
A wide variety of aldehydes are compatible with this
methodology (Table 1). Simple aliphatic aldehydes such as
isobutyraldehyde and propionaldehyde gave R-methylene-
ꢀ-hydroxy imides 13a and 13b in 81-93% yield (entries 1
and 2). Use of the stereochemically demanding pivaldehyde
as substrate gave product 13c in 56% yield after conversion
to the TBS ether (entry 3).
Various aromatic aldehydes were excellent substrates:
aldol-elimination reactions of benzaldehyde, 2-furaldehyde,
4-methylthiazole-5-carboxaldehyde, and 3-pyridinecarbox-
aldehyde gave products 13d (86%), 13e (86%), 13f (84%),
and 13g (88%), respectively (entries 4-7). Due to the mild
We therefore considered the possibility of using an aldol
reaction to prepare Baylis-Hillman-type products in an
enantioselective fashion.7 Specifically, we anticipated that
an acyl oxazolidinone like 10, equipped with a leaving group
at C(3) of the propionyl fragment, would be a suitable
substrate for a boron-mediated Evans syn-aldol reaction
(Scheme 2).8,9 This approach would have the advantage that
both the masked Michael acceptor 10 and the aldehyde could
be used in stoichiometric amounts.
As additional design criteria, the leaving group “X” in 10
was required to be stable under the aldol reaction conditions
but to undergo ꢀ-elimination during reaction workup. We
Scheme 1. Retrosynthetic Anaylsis of the C(15)-C(23) Fragment of Tedanolide C (Synthetic Target 5)
Org. Lett., Vol. 12, No. 10, 2010
2343

aldehydes such as 1712 could also be used as substrate (76%
yield; entry 9); unsaturated aldehydes are typically avoided
in Baylis-Hillman reactions.6 The only substrate that worked
poorly in our hands was acrolein, which gave a multitude
of side products that were difficult to separate (data not
shown). In all cases, the isolated allylic alcohols 13a-i were
obtained as single diasteromers.
Table 1. Synthesis of R-Methylene-ꢀ-hydroxy Acyl
Oxazolidinones 13a-i via an Aldol/Elimination Sequencea
We expected from the outset that acyl oxazolidinone 15
would undergo aldol reaction via the corresponding Z(O)-
boron-enolate 11 (X ) SePh) and provide syn-aldol products
prior to oxidative workup. This was confirmed in the case
of aldol 18, which was isolated from an aldol reaction of 15
and isobutryraldehyde following mild basic (but nonoxida-
tive) workup. Treatment of 18 with LiBH4 and protection
of the resulting 1,3-diol gave p-methoxyphenyl (PMP) acetal
19. The Ha-Hb coupling constant of 19 (3J ) 1.9 Hz) as
1
well as H NOE data provide the basis for this assignment
(Scheme 3).
Scheme 3. Stereochemical Assignments
a General procedure for the aldol/elimination sequence: Formation of
the boron enolate from imide 15 (1.0 equiv), Bu2BOTf (1.2 equiv), and
NEt3 (1.8 equiv) in CH2Cl2 (c ) 0.2 M) at -78 °C; addition of aldehyde
(1.1 equiv) at -78 °C; oxidation of the aldol product in CH2Cl2 and pyridine
(2.0 equiv) at 0 °C with H2O2 (approximately 3-5 equiv); all products
were isolated by column chromatography. b Xp ) (4S)-(4-benzyloxazoli-
dinone)-5-yl. c dr >20:1. d Isolated yields of the indicated products. e 13a
was isolated after protection as the TBS ether.
The absolute configuration of aldol 18 was determined
independently via the advanced Mosher ester method,13 as
well as by reduction of the derived allylic alcohol 13a to
the known diol 20 upon treatment with NaBH4 in the
presence of CeCl3·7H2O.14,15
Application of this new methodology to the synthesis of
the C(15)-C(21) fragment 27 of tedanolide C is presented
in Scheme 4. Aldehyde 8 was synthesized starting from the
known aldehyde 21. Thus, the standard Wittig reaction of
21 with Ph3PdCHCO2Et followed by DIBAL reduction of
the ester provided allylic alcohol 22 (80%). Subjection of
22 to the Sharpless asymmetric epoxidation conditions16
oxidative workup conditions, pyridine-N-oxide formation was
not observed in the latter case.
Finally, the silyl-protected R-hydroxyaldehyde 1611 gave
13h in 88% yield (entry 8). In addition, R,ꢀ-unsaturated
(5) Nishimura, S.; Matsunaga, S.; Yoshida, S.; Nakao, Y.; Hirota, H.;
Fusetani, N. Bioorg. Med. Chem. 2005, 13, 455.
(6) (a) Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, 1972. For
reviews of the Baylis-Hillman reacdtion, see: (b) Ciganek, E. Org. React.
1997, 51, 201. (c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV.
2003, 103, 811. (d) Krishna, P. R.; Sachwani, R.; Reddy, P. S. Synlett 2008,
2897. (e) Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y. Chem. Commun. 2009,
5496.
(7) For reports of enantioselective Baylis-Hillman reactions with chiral
acylate derivatives: (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am.
Chem. Soc. 1997, 119, 4317, and references cited therein. (b) Brzezinski,
L. J.; Rafel, S.; Leahy, J. W. Tetrahedron 1997, 53, 16423.
(8) For previous syntheses of racemic Baylis-Hillman adducts from
aldol reactions of ꢀ-selenophenyl enolboranes see: (a) Leonard, W. R.;
Livinghouse, T. J. Org. Chem. 1985, 50, 730. (b) Leonard, W. R.;
Livinghouse, T. Tetrahedron Lett. 1985, 26, 6431.
(11) Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.;
Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G.
J. Am. Chem. Soc. 1995, 117, 634.
(12) Ramachandran, P.; Burghardt, T. E.; Reddy, M. V. R. J. Org. Chem.
2005, 70, 2329.
(13) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(b) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451.
(14) (a) The reductive cleavage of the auxiliary with LiBH4 gave a
mixture of the 1,2- and the 1,4-reduced products in a 1:1 ratio. (b) Luche,
(9) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997,
30, 3.
J.-L. J. Am. Chem. Soc. 1978, 100, 2226
.
(15) Enders, D.; Voith, M. Synthesis 2002, 1571
.
(10) Miyashita, M.; Yoshikoshi, A. Synthesis 1980, 664.
(16) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
Org. Lett., Vol. 12, No. 10, 2010
2344

Finally, asymmetric dihydroxylation of 26 by using Sharp-
less’ AD-mix ꢀ17 gave diol 27 (75%, 95% b.r.s.m.) as the
major component of a 4.5:1 mixture of diastereomers.18,19
In summary, we developed an efficient and highly ste-
reoselective procedure for synthesis of R-methylene-ꢀ-
hydroxy acyl oxazolidinones;so-called Baylis-Hillman
adducts;via an enantioselective syn-aldol/ꢀ-elimination
sequence using ꢀ-(phenylselenyl)propionyl imide 15 as the
key reagent. This method allows for the use of 15 and the
aldehyde reaction partner in stoichiometric amounts;which
is not possible in conventional Baylis-Hillman reactions.
This new sequence has been applied to the synthesis of the
C(15)-C(21) fragment 27 of tedanolide C (target structure
5). Further elaborations of 27 toward tedanolide C will be
reported in due course.
Scheme 4
.
Synthesis of the C(15)-C(21) Fragment 27 of
Tedanolide C
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) is gratefully
acknowledged. R.B. thanks the Austrian Science Fund (FWF)
for a Schro¨dinger fellowship.
Supporting Information Available: Experimental pro-
1
cedures and copies of H NMR and 13C NMR spectra of
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1006955
followed by a Parikh-Doering oxidation of epoxyalcohol
23 provided the epoxyaldehyde 8 in 79% yield from 22. Use
of epoxyaldehyde 8 as the substrate for aldol reaction with
15, followed by oxidative workup, provided allylic alcohol
24 in 79% yield with >20:1 distereoselectivity. Treatment
of 24 with NaBH4 and CeCl3·7H2O14b and subsequent
protection of the bis-allylic alcohol 25 with 2 equiv of TESCl
gave the bis-silyl ether 26 in 91% yield for the two steps.
(17) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483
.
(18) The stereochemistry of the C(16) hydroxy group was assigned
based on the usual sense of asymmetric induction in Sharpless
asymmetric dihydroxylation reactions, and was not rigorously determined
at this stage.
(19) The two diastereomers were inseparable by standard column
chromatography. Purification of the major diastereomer was performed by
HPLC.
Org. Lett., Vol. 12, No. 10, 2010
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