Asymmetric, organocatalytic, three-step synthesis of α-hydroxy-(E)- β,γ-unsaturated Esters

Article abstract of DOI:10.1021/ol100615j

Figure presented An efficient and enantiocontrolled three-step synthesis of α-hydroxy-(E)-β,γ-unsaturated esters is reported. Enantioenriched α-selenyl aldehydes, prepared in one step by asymmetric, organocatalytic α-selenylation of aldehydes, were direct

Full text of DOI:10.1021/ol100615j

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2120-2122
Asymmetric, Organocatalytic, Three-Step
Synthesis of r-Hydroxy-(E)-ꢀ,γ-
unsaturated Esters
Lindsey C. Hess and Gary H. Posner*
Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles Street,
Baltimore, Maryland 21218
ghp@jhu.edu
Received March 15, 2010
ABSTRACT
An efficient and enantiocontrolled three-step synthesis of r-hydroxy-(E)-ꢀ,γ-unsaturated esters is reported. Enantioenriched r-selenyl aldehydes,
prepared in one step by asymmetric, organocatalytic r-selenylation of aldehydes, were directly subjected to a Wittig reaction followed by
allylic selenide to selenoxide oxidation and final spontaneous [2,3]-sigmatropic rearrangement to yield the target compounds in 43-65%
overall yield and in 94-97% ee.
Asymmetric synthesis utilizing organoselenium compounds
has become increasingly popular in recent years.1 Selenium
incorporation can be done in either a nucleophilic or an
electrophilic fashion.2 Once selenium is introduced into the
molecule, many different chemical transformations can occur
including oxidations leading to either syn-elimination3 or,
in the case of an allylic selenide, [2,3]-sigmatropic rear-
rangement to give an allylic alcohol.4 Pursuing our recently
published work preparing chiral nonracemic γ-hydroxy-(E)-
R,ꢀ-unsaturated sulfones and esters,5 we have developed a
complementary asymmetric synthetic method producing
R-hydroxy-(E)-ꢀ,γ-unsaturated esters.
R-Hydroxy esters and their corresponding acids are key
structural units of valuable synthetic intermediates as well
as natural products.1,6 On the basis of the utility of these
structural units, we set out to design a simple, asymmetric
general strategy for their synthesis. Suprisingly, most reports
of selenium oxidation and [2,3]-sigmatroptic rearrangements
have been done utilizing chiral oxidants as opposed to
installing chirality prior to oxidation.7 There have been a
few reports involving diastereoselective oxidations of se-
lenides containing chiral moieties,8 but the scope is quite
(6) Tamura, Y.; Yakura, T.; Haruta, J. I.; Kita, Y. Tetrahedron Lett.
1985, 26, 3837. (b) Tamura, Y.; Annoura, H.; Yamamoto, H.; Kondo, H.;
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Tokoro, H.; Kato, D. I.; Nishiyama, S.; Sugai, T. Tetrahedron Lett. 2005,
46, 3291. (d) Hong, Y. T.; Cho, C. W.; Skucas, E.; Krische, M. Org. Lett.
2007, 9, 3745. (e) Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1973,
95, 553. (f) Masamune, T. I.; Ono, M.; Matsue, H. Bull. Chem. Soc. Jpn.
1975. (g) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantio-
(1) Wirth, T. Tetrahedron 1999, 55, 1.
(2) (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697.
(b) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947. (c) Grieco,
P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485. (d) Tomoda,
S.; Nomura, Y. Chem. Lett. 1981, 1069.
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(b) Nicalaou, K. C.; Lysenko, Z. J. Am. Chem. Soc. 1977, 99, 3185. (c)
Friedrich, L. E.; Lam, P. Y. S. J. Org. Chem. 1981, 46, 306. (d) Scarborough,
R. M.; Smith, A. B. Tetrahedron Lett. 1977, 18, 4361. (e) Liotta, D.;
Markiewicz, W.; Santiesteban, H. Tetrahedron Lett. 1977, 18, 4365.
(4) (a) Reich, H. J. J. Org. Chem. 1975, 40, 2570. (b) Clive, D. L.;
Chittattu, G.; Curtis, N. J.; Menchen, S. M. J. Chem. Soc., Chem. Commun.
1978, 770.
selectiVe Synthesis; VCH: Weinheim, 1997.
(7) (a) Davis, F. A.; Stringer, O. D.; McCauley, J. P. Tetrahedron 1985,
41, 4747. (b) Reich, H. J.; Yelm, K. E. J. Org. Chem. 1992, 57, 5672. (c)
Davis, F. A.; Reddy, R. T. J. Org. Chem. 1992, 57, 2599. (d) Komatsu, N.;
Nishibayashi, Y.; Sugita, T.; Uemura, S. J. J. Chem. Soc., Chem. Commun.
1992, 46. (e) Komatsu, N.; Matsunaga, S.; Sugita, T.; Uemura, S. J. Org.
Chem. 1993, 58, 3697. (f) Komatsu, N.; Nishibayashi, Y.; Sugita, T.;
Uemura, S. J. Am. Chem. Soc. 1993, 115, 5847. (g) Komatsu, N.;
Nishibayashi, Y.; Uemura, S. Tetrahedron Lett. 1993, 34, 2339.
(5) Petersen, K. S.; Posner, G. H. Org. Lett. 2008, 10, 4685.
10.1021/ol100615j  2010 American Chemical Society
Published on Web 04/08/2010

limited, with low to moderate yields and only modest
diastereomeric excess (de). Other methods have also been
reported using conformationally locked ring systems to
induce stereocontrol.9
Table 1. Reaction Results from Scheme 1
compound
A
B
Recent reports on the organocatalytic, asymmetric R-se-
lenenylation of aldehydes in high yields (>85%) and high
enantiomeric excess (>95%)10,11 gave an excellent method
for controlling the absolute stereochemistry of our R-hy-
droxy-(E)-ꢀ,γ-unsaturated target systems.
We chose a variety of aldehydes (3-phenylpropanal,
2-cyclohexylethanal, N-Boc-4-piperidineethanal, hexadeca-
nal, and 6-benzyloxyhexanal) as well as three different ester
functional groups (OMe, O-t-butyl, and O-benzyl) to deter-
mine the generality of this reaction. R-Selenyl aldehydes
3a-e, prepared according to an Italian protocol,11 were
immediately subjected in situ to a Wittig reaction to give
the enantiomerically enriched compounds 5-11 (Scheme 1,
(A,B)
R
R′
yield, % yield, % ee (%)a
5, 12
6, 13
7, 14
8, 15
Bn (1a)
Bn (1a)
Bn (1a)
OMe (4a)
O(t-Bu) (4b)
OBn (4c)
73
73
81
79
87
63
70
67
95
95
95
95
cyclohexyl (1b) OBn (4c)
N-Boc-piperidine
9, 16
10, 17
(1c)
OBn (4c)
83
48
77
67
90
83
94
97
95
BnO(CH2)4 (1d) OBn (4c)
11, 18b CH3(CH2)13 (1e) OBn (4c)
a ee values determined using chiral HPLC and racemic standards.
b Catalyst (2R)-2 was used.
of solvents (e.g., THF, CHCl3, CH3CN, and hexanes) at room
temperature they were stable to racemization (as determined
via chiral HPLC) for at least 24 h. We also used mCPBA as
an oxidant of selenium, and we obtained a comparable yield
and ee when compared to hydrogen peroxide (system tested
was hexadecanal). The preferred method of oxidation
remained hydrogen peroxide due to the convenience of the
reaction conditions (nonanhydrous).
Scheme 1. Preparation of R-Hydroxy-(E)-ꢀ,γ-unsaturated Esters
To illustrate the utility of this method for natural product
synthesis, we completed a formal total synthesis of (+)-
symbioramide (20), a naturally occurring bioactive ceramide
composed of D-erythro-dihydrosphingosine and (2R,3E)-2-
hydroxy-3-octadecenoic acid.12 We prepared key intermedi-
ate (-)-19 that had been used in a recent synthesis13 of this
biologically active ceramide (Scheme 2). Intermediate (-)-
Scheme 2
.
Previously Published Synthesis of (+)-Symbioramide
(20) Using Key Intermediate (-)-19
A; Table 1) in 48-83% yields. Oxidation of the γ-seleneyl-
(E)-R,ꢀ-unsaturated esters to the selenoxide using hydrogen
peroxide caused spontaneous [2,3]-sigmatropic rearrangement
to give the final enantioenriched R-hydroxy-(E)-ꢀ,γ-unsatur-
ated esters (Scheme 1, B) in 63-90% yields and excellent
ee’s(g94%).Theexclusive(E)-geometryofthecarbon-carbon
double bond in intermediates 5-11 as well as the final
1
products 12-18 was confirmed by H NMR spectroscopy
(J ) 14-16 Hz). It is important to note that when R-hydroxy
ester final products 12, 13, and 14 were dissolved in a variety
19 had been prepared in seven steps and 11.8% overall yield
from L-serine.13a Using the new method described here, we
prepared this intermediate monoprotected diol (-)-19 in only
5 steps and in 28% overall yield and 95% ee (Scheme 3). It
is important to note that, in order to achieve the natural
stereochemistry at the chiral 2-position, we employed the
(8) (a) Nishibayashi, Y.; Singh, J. D.; Fukuzawa, S.; Uemura, S. J. Org.
Chem. 1995, 60, 4114. (b) Davoren, J. E.; Harcken, C.; Martin, S. F. J.
Org. Chem. 2008, 73, 391
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J. Org. Chem. 1985, 50, 2981. (b) Koprowski, M.; Krawczyk, E.;
Skowronska, A.; McParlin, M.; Choi, N.; Radojevic, S. Tetrahedron 2001,
57, 1105
.
(12) Kobayashi, J. J. Nat. Prod. 1989, 52, 225.
(13) (a) Azuma, H.; Takao, R.; Niiro, H.; Shikata, K.; Tamagaki, S.;
Tachibana, T.; Ogino, K. J. Org. Chem. 2003, 68, 2790. (b) Yoshida, J.;
Masako, N.; Seki, H.; Hino, J. J. Chem. Soc., Perkin Trans. 1 1992, 3,
343.
(10) (a) Sunden, H.; Rios, R.; Cordova, A. Tetrahedron Lett. 2007, 48,
7865
.
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Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46, 6882
Org. Lett., Vol. 12, No. 9, 2010
.
2121

Scheme 3
.
Formal Total Synthesis of (+)-Symbioramide (20)
Scheme 4
.
Synthesis of a 23-(E)-ene-25(S)-hydroxy Vitamin D3
Chiron
opposite proline-derived catalyst in the asymmetric R-sele-
nenylation of hexadecanal. This formal total synthesis of (+)-
symbioramide (20) allowed us to confirm the absolute
stereochemistry of our final R-hydroxy carbonyl products.
Previously published characterization of monoprotected diol
(-)-19 indicates that the absolute stereochemistry at the 2
position is R, with [R]D ) -77°, matching our experimental
data for intermediate (-)-19 prepared via Scheme 3.
In one final example, we prepared also a vitamin D3 chiron
that incorporated a side chain with the structural motif
generated via this synthetic method. An SN2 displacement
of iodide 2214 using allylmagnesium bromide yielded
terminal olefin 23. Oxidative cleavage afforded aldehyde 24.
Using the method described here (Scheme 4), we were able
to prepare R-hydroxy-(E)-ꢀ,γ-unsaturated benzyl ester 26 as
a single diastereomer. This fragment can be easily modified
to prepare final C,D-ring side-chain modified vitamin D
analogues.
(E)-ꢀ,γ-unsaturated esters in high enantiomeric purities. This
three-step synthesis works with a variety of substrates, in
good overall yields (46-65%), and with excellent control
of absolute stereochemistry (ee values g94%). We have
proven the utility of this method through a formal total
synthesis of natural product (+)-symbioramide (20) as well
as through the preparation of a 23-(E)-ene-25(S)-hydroxy
building block useful for the synthesis of new vitamin D
side-chain analogues.15
Acknowledgment. We thank the NIH (CA 93547) for
support.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we report an efficient, generalized, asym-
metric, organocatalytic procedure for synthesis of R-hydroxy-
OL100615J
(14) Posner, G. H.; Lee, J. K.; White, M. C.; Hutchings, R. H.; Dai, H.;
Kachinski, J. L.; Dolan, P.; Kensler, T. W. J. Org. Chem. 1997, 62, 3299.
(15) Bouillon, R.; Okamura, W. H.; Normon, A. W. Endocr. ReV. 1995,
16, 200.
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