A simple procedure for the synthesis of γ-hydroxy-α,β-(E)- alkenoic esters: Formal synthesis of (+)-macrosphelides a and B

Article abstract of DOI:10.1016/j.tetlet.2005.02.004

A highly trans-selective conjugate reduction of γ-hydroxy-α, β-alkynoic esters to produce γ-hydroxy-α,β-(E)-alkenoic esters using LiAlH₄ is reported. The application of this methodology is demonstrated by a formal synthesis of the potent cell-cell adhesion inhibitors (+)-macrosphelides A and B.

Full text of DOI:10.1016/j.tetlet.2005.02.004

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2287–2290
A simple procedure for the synthesis of
c-hydroxy-a,b-(E)-alkenoic esters: formal synthesis
of (+)-macrosphelides A and Bq
K. Srinivasa Rao,a,b K. Mukkanti,b D. Srinivasa Reddy,a Manojit Pala and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
Received 24 December 2004; revised 25 January 2005; accepted 1 February 2005
Abstract—A highly trans-selective conjugate reduction of c-hydroxy-a,b-alkynoic esters to produce c-hydroxy-a,b-(E)-alkenoic
esters using LiAlH4 is reported. The application of this methodology is demonstrated by a formal synthesis of the potent cell–cell
adhesion inhibitors (+)-macrosphelides A and B.
Ó 2005 Elsevier Ltd. All rights reserved.
F
OEt
OEt
c-Hydroxy-a,b-alkenoic esters are versatile building
blocks in the synthesis of complex natural products
and heterocycles.1 However, there are only limited meth-
ods available to access this important group of com-
pounds.2 The most popular is the Wittig method for
the synthesis of c-hydroxy-a,b-alkenoic esters but it suf-
fers fromthe limitation that the starting a-hydroxy alde-
hydes are prone to epimerization under basic
conditions.2
O
O
OH
OH
2 (85%)
1 (75%)
OMe
OEt
MeO
MeO
OEt
O
O
OH
OH
3 (62%)
4 (60%)
In this letter, we disclose a general method for the effi-
cient and highly trans-selective conjugate hydride addi-
tion on c-hydroxy-a,b-alkynoic esters using LiAlH4 as
the hydride source (Scheme 1).3,4 The potential use of
OEt
OEt
O
O
OH
OH
6 (72%)
5 (62%)
OEt
OEt
LiAlH4
OEt
O
O
OEt
R
R
O
0 oC to RT
THF
O
OH
OH
OH
OH
(>95% E-selectivity)
8 (65%)
7 (58%)
A
B
Scheme 1.
OEt
O
Keywords: Conjugate reduction; c-Hydroxy-a,b-alkenoic esters;
Macrosphelide.
q DRL publication no. 456A.
OH
9 (58%)
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail: javediqbaldrf@hotmail.com
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.004

2288
K. Srinivasa Rao et al. / Tetrahedron Letters 46 (2005) 2287–2290
the resulting c-hydroxy-a,b-alkenoic esters in complex
natural product synthesis was demonstrated by a formal
synthesis of (+)-macrosphelides A and B, which are po-
tent, orally bioavailable, inhibitors of cell–cell adhesion.
in a similar hydride mediated reduction.3,4 In another
example (conversion of 10 to 1), we showed that
c-keto-a,b-alkynoic esters7 can be directly reduced to
c-hydroxy-a,b-alkenoic esters without effecting the
selectivity (Scheme 3).
Initially, we chose a phenyl substituted acetylene sub-
strate and carried out LiAlH4 reduction to produce
the corresponding (E)-alkenoic ester 1 in 75% yield with
>95% (E)-selectivity. After a few attempts, we found
that the use of one equivalent of LiAlH4 in dry THF
or diethyl ether at 0 °C to rt were the optimum condi-
tions for this method.5 Next we generalized the method
for other substrates. All the starting c-hydroxy-a,b-alky-
noic esters (A) were synthesized fromthe corresponding
aldehydes by coupling with ethyl propiolate in the pres-
ence of LDA as previously described.6 We found that
our procedure worked well with a variety of R groups,
which include phenyl, alkyl, and vinyl groups (see 2–8
in Scheme 2). Stereoelectronic factors had little or no ef-
fect on this reaction and it is worth mentioning that the
product 9 could be readily obtained fromthe corre-
sponding tertiary alcohol in good yield (Scheme 2). In
spite of the moderate yields in these reactions, we did
not observe significant amounts of over-reduced by-
products.
The utility of the c-hydroxy-a,b-alkenoic esters was
readily demonstrated by a formal synthesis of (+)-mac-
rosphelides A and B via OmuraÕs advanced intermediate
(+)-21. Macrosphelides are novel 16-membered macro-
lides isolated from Microspheraeropsis sp. FO-5050
and have been reported to inhibit strongly the adhesion
of human leukemia HL-60 cells to human-umbilical-
vein endothelial cells (HUVETC). Thus, these macro-
lides may serve as valuable leads for the development
of anticancer drugs.8 In addition to their biological pro-
file, the presence of three lactone moieties along with
four stereogenic centers offers an attractive synthetic
OEt
OEt
LiAlH4
O
Ph
Ph
O
0 oC to RT
THF
OH
O
> 95% E-selectivity
~ 70%
10
1
The excellent E-stereoselectivity (>95%) in these reac-
tions may arise due to reasons reported earlier by others
Scheme 3.
OH
COOEt
OH
(-)-11
i. TBSCl, imid.
CHO
OTBS
LDA, HMPA
COOR
OR
O
(+)-13 R = tBu (65%)
(+)-14 R = Et (55%)
OTBS
ii. DIBAL- H,
-78oC
60-65%
(-)-12
OMEM
OH
LiAlH4
OR
OR
DIEA
0 oC to RT
THF
MEMCl
OTBS
O
OTBS
O
(-)-17 R = tBu (95%)
(-)-18 R = Et (90%)
(+)-15 R = tBu (75%)
(+)-16 R = Et (70%)
OMEM
OtBu
OH
TBAF
(+)-17
(+)-18
OH
O
95%
DCC, DMAP
CSA 62%
(-)-19
OMEM
aq.NaOH
78%
OTBS
(-)-20
O
O
O
Me
OH
O
Me
OMEM
O
ref. 9
X
MEMO
Me
O
Me
Me
O
O
O
OTBS ButO
(+)-21
O
X = α-OH (+)-macrosphelide A
X = O (+)-macrosphelide B
Scheme 4.

K. Srinivasa Rao et al. / Tetrahedron Letters 46 (2005) 2287–2290
2289
(f) Noda, M.; Ibuka, T.; Habashita, H.; Fujii, N. Chem.
Pharm. Bull. 1997, 45, 1259–1264; (g) Zheng, W.; De-
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Org. Chem. 1993, 58, 6177–6179; (j) Ibuka, T.; Taga, T.;
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Org. Chem. 1993, 58, 1207–1214.
challenge as demonstrated earlier during the first synthe-
sis by the combined effort of Omura and co-workers and
Smith and co-workers.9,10
Our synthesis commenced from the known aldehyde
(À)-12,11 which was prepared from commercially avail-
able ethyl lactate (À)-11. The c-hydroxy-a,b-alkynoic
esters (+)-13 and (+)-14 were prepared by the coupling
of aldehyde (À)-12 with t-butyl and ethyl propiolates,
respectively, in the presence of LDA.6 The desired major
erythro isomers were cleanly separated by column chro-
matography of the resulting mixture (Cram selectivity
erythro:threo ꢀ 5:1). As expected, conjugate reduction
of (+)-13 and (+)-14 using the present protocol fur-
nished cleanly c-hydroxy-a,b-alkenoic esters (+)-15
and (+)-16, respectively.12 Compound (+)-15 was trans-
formed to (À)-19 via protection of the free alcohol with
MEMCl and deprotection of the TBS ether. The carbox-
ylic acid (À)-20 obtained from(+)- 16 after MEM pro-
tection and hydrolysis, was coupled with (À)-19 under
KeckÕs conditions9,13 to furnish the advanced intermedi-
ate (+)-21 for the synthesis of macrosphelides A and B.
The spectral data (1H and 13C NMR and optical
rotation) of (+)-21 were compared with that of the
OmuraÕs intermediate9 and they were found to be iden-
tical (Scheme 4).
2. (a) Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443–
445; (b) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem.
Soc. 1997, 124, 7922–7924, and references cited therein; (c)
Koenig, S. G.; Lowe, R. S.; Austin, D. J. Synth. Commun.
2002, 32, 1379–1383; (d) Harcken, C.; Martin, S. F. Org.
Lett. 2001, 3, 3591–3593; (e) Chen, C.; Tagami, K.; Kishi,
Y. J. Org. Chem. 1995, 60, 5386–5387; (f) Tanikaga, R.;
Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983, 134–
135.
3. Very recently, while this work was in progress, a similar
method was reported by KoideÕs group using NaBH4 and
Red-Al. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785–
1787.
4. See, for related references using other reducing agents: (a)
Roulland, E.; Monneret, C.; Florent, J.-C. J. Org. Chem.
2002, 67, 4399–4406; (b) Kucera, D. J.; OÕConnor, S. J.;
Overman, L. E. J. Org. Chem. 1993, 58, 5304–5306; (c)
Tsuda, T.; Yoshida, T.; Kawamoto, T.; Saegusa, T. J.
Org. Chem. 1987, 52, 1624–1627; (d) Marshall, J. A.;
DeHoff, B. S. J. Org. Chem. 1986, 51, 863–872; (e)
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5. General procedure: To a suspension of lithiumaluminum
hydride (1 equiv) in dry THF or diethyl ether was added
the hydroxy acetylene ester in THF (or ether) dropwise at
0 °C, which was then allowed to stir at roomtemperature.
After the starting material had disappeared (TLC; 0.5–
2 h), the reaction was quenched with saturated ammonium
chloride solution, diluted with ether, filtered over Celite
and the organic layer was dried over Na2SO4. The residue
obtained after removal of the solvent was purified by
column chromatography to furnish the desired (E)-alke-
noate ester as a colorless liquid.
In short, we have developed a simple procedure for the
synthesis of c-hydroxy-a,b-(E)-alkenoic esters fromthe
corresponding acetylenic esters using LiAlH4 as the hy-
dride source. As a direct application of this method, we
have demonstrated a formal synthesis of (+)-macrosphe-
lides A and B through one of OmuraÕs advanced inter-
mediate. The synthesis of other related natural
products using this procedure will be the subject of
future work.
Acknowledgements
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We thank Dr. ReddyÕs Laboratories for the financial
support, and our analytical department for their help
with spectral data. Help fromDr. Vairamani, IICT,
Hyderabad in obtaining HRMS analysis is highly
appreciated.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.02.004.
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