Efficient two-step conversion of α,β-unsaturated aldehydes to optically active γ-oxy-α,β-unsaturated nitriles and its application to the total synthesis of (+)-patulolide C

Article abstract of DOI:10.1021/ol034944f

(Matrix presented) An efficient two-step conversion of α,β -unsaturated aldehydes into optically active γ-oxy-α,β -unsaturated nitriles is described. First, catalytic asymmetric cyanation-ethoxycarbonylation using (S)-YLi₃tris(binaphthoxide) (Y

Full text of DOI:10.1021/ol034944f

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ORGANIC
LETTERS
2003
Vol. 5, No. 17
3021-3024
Efficient Two-Step Conversion of
r,â-Unsaturated Aldehydes to Optically
Active γ-Oxy-r,â-unsaturated Nitriles
and Its Application to the Total
Synthesis of (+)-Patulolide C
Jun Tian, Noriyuki Yamagiwa, Shigeki Matsunaga, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received May 29, 2003
ABSTRACT
An efficient two-step conversion of r,â-unsaturated aldehydes into optically active γ-oxy-r,â-unsaturated nitriles is described. First, catalytic
asymmetric cyanation−ethoxycarbonylation using (S)-YLi3tris(binaphthoxide) (YLB) afforded chiral allylic cyanohydrin carbonate. Second, a
[3,3]-sigmatropic rearrangement proceeded without racemization under thermal conditions to give γ-oxy-r,â-unsaturated nitriles. Lewis acids
were also effective for the rearrangement, and the reaction proceeded smoothly under mild conditions. To demonstrate the utility of the
conversion, concise catalytic enantioselective total synthesis of (+)-patulolide C was performed.
Optically active cyanohydrins serve as important precursors
of many useful organic compounds, and there are various
reports of catalytic asymmetric syntheses of cyanohydrins
using (CH3)3SiCN and/or HCN as a cyanide source.1 As a
part of our ongoing research program on asymmetric
cyanation reactions,2 we recently reported a novel catalytic
asymmetric cyanation-ethoxycarbonylation reaction of al-
dehydes with ethyl cyanoformate (2) promoted by a YLi3-
tris(binaphthoxide) (YLB, 1) complex (Figure 1).3 Ethyl
cyanoformate (2) serves a combined role as an in situ source
of cyanide ions and an ethoxycarbonylating reagent, thus
affording atom-economical4 one-pot access to optically active
Figure 1. Structure of (S)-YLi3tris(binaphthoxide) [(S)-YLB: 1]
and ethyl cyanoformate (2).
(1) Recent reviews: (a) North, M. Tetrahedron: Asymmetry 2003, 14,
147. (b) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649 and references therein.
(2) Recent reviews: (a) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem.
Commun. 2002, 1989. (b) Gro¨ger, H. Chem. Eur. J. 2001, 7, 5246. (c)
Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511.
(3) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2002, 41, 3636.
cyanohydrin carbonates.5 When utilizing chiral cyanohydrins
in the synthesis, transformations of cyanohydrins should be
10.1021/ol034944f CCC: $25.00 © 2003 American Chemical Society
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performed under racemization-free conditions. Many race-
mization-free transformations of trimethylsilyl cyanohydrins
and cyanohydrins themselves have been reported;1 however,
transformations from chiral cyanohydrin carbonates have not
been adequately investigated, despite their potential as unique
chiral building blocks distinct from trimethylsilyl cyanohy-
drins. Based on a few reports of useful transformations of
racemic allylic cyanohydrin carbonates,6 we investigated a
[3,3]-sigmatropic rearrangement of chiral allylic cyanohydrin
carbonates. Herein, we report an efficient two-step conversion
of R,â-unsaturated aldehydes: catalytic asymmetric cyana-
tion-ethoxycarbonylation reactions of R,â-unsaturated al-
dehydes 3 (step 1) and a chiral transmission of allylic
cyanohydrin carbonate intermediate 4 via the [3,3]-sigma-
tropic rearrangement (step 2), which provides easy access
to optically active γ-oxy-R,â-unsaturated nitriles (Scheme
1). The concise catalytic enantioselective total synthesis of
(+)-patulolide C using this method is also described.
completion within 2-3 h at -78 °C to afford the products
in good yield (96-100%) and enantiomeric excess (91-
93%), with no 1,4-addition product. Thus, the allylic cyano-
hydrin carbonates 4 were obtained in one step in a highly
atom-economical process.
First, [3,3]-sigmatropic rearrangement of 4a was examined
under thermal conditions. As summarized in Table 2, the
Table 2. [3,3]-Sigmatropic Rearrangement of 4a under
Thermal Conditions
time yieldb
entry
solvent
o-xylene
T (°C) (h)
(%)
trans/cisb
1a
2
180
180
200
36
16
5
>95
>95
>95
60/40
75/25
86/14
1,2-dichlorobenzene
Scheme 1. Two-Step Conversion of R,â-Unsaturated
Aldehyde into γ-Oxy-R,â-unsaturated Nitrile
3
1,2,4-trichlorobenzene
a Reaction was done using a sealed tube. b Yield and trans/cis ratio were
determined by NMR analysis.
rearrangement proceeded smoothly to afford thermodynami-
cally favorable R,â-unsaturated nitriles 5a in quantitative
yield as stereochemical mixtures. The trans/cis ratio changed
depending on the reaction conditions. Rearrangement in
o-xylene (180 °C, sealed tube) afforded 5a in trans/cis )
60/40 after 36 h (entry 1). 5a was obtained in trans/cis )
75/25 with dichlorobenzene (reflux, 180 °C) after 16 h (entry
2). The reaction proceeded faster in more polar trichloroben-
zene (200 °C), and 5a was obtained in quantitative yield
after 5 h. The trans/cis ratio was improved to 86/14. The
exposure of isolated pure cis-5a to the reaction conditions
for 6 h (trichlorobenzene, 200 °C) resulted in the recovery
of pure cis-5a, and there was no trans/cis isomerization. The
result suggested that the rearrangement is irreversible under
the reaction conditions, probably due to the thermodynamic
stability of R,â-unsaturated nitrile against allylic cyanohydrin
carbonate. The trans-5a is kinetically favored in the rear-
rangement. The enantiomeric excess of 4a (92% ee) and
those of trans-5a (92% ee) and cis-5a (92% ee) were the
same. The absolute configuration at the γ-position of trans-
5a was R and that of cis-5a was S.8 On the basis of the
absolute configurations of the products, the proposed transi-
tion states to afford the trans adducts (chair) and cis adducts
(boat) are shown in Figure 2. Under the optimized conditions,
rearrangements of 4a-d were performed to afford 5a-d in
As shown in Table 1, chiral allylic cyanohydrin carbonates
were efficiently synthesized from R,â-unsaturated aldehydes
Table 1. Catalytic Asymmetric
Cyanation-Ethoxycarbonylation of R,â-Unsaturated Aldehydes
entry
aldehyde (R)
product time (h) yieldb (%) eec (%)
1a
2
3
4a
3a , CH3(CH2)2
3b, Ph (CH2)2
3c, c-C6H11
3d , Ph
4a
4b
4c
4d
3
2
3
3
100
96
98
92
92
93
91
100
a Reported results, see ref 3. b Isolated yield. c Determined by chiral
HPLC and chiral GC analysis.
in one step using 10 mol % of (S)-YLB, 30 mol % of H2O,
10 mol % of BuLi, 10 mol % of [2,6-(CH3O)2C6H3]3P(O),
and 1.2 equiv of ethyl cyanoformate.7 The reaction reached
(6) Thermal [3,3]-sigmatropic rearrangement (a) Hu¨nig, S.; Reichelt, H.
Chem. Ber. 1986, 119, 1772. Palladium-catalyzed allylic substitution: (b)
Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J.
Org. Chem. 1985, 50, 1523. (c) Deardorff, D. R.; Taniguchi, C. M.; Tafti,
S. A.; Kim, H. Y.; Choi, S.-Y.; Downey, K. J.; Nguyen, T. V. J. Org.
Chem. 2001, 66, 7191 and references therein.
(4) Trost, B. M. Science 1991, 254, 1471.
(5) For other examples of catalytic asymmetric cyanation reaction using
cyanoformate, see: (a) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195.(b) Casas, J.; Baeza, A.; Sansano, J. M.; Naje´ra, C.; Saa´, J. M.
Tetrahedron: Asymmetry 2003, 14, 197.
(7) For the optimization of the catalytic asymmetic cyanation-ethoxy-
carbonylation reaction of aldehydes, see ref 3.
(8) Absolute configuration of trans-5a and cis-5a were determined after
conversion to a known compound. See the Supporting Information.
3022
Org. Lett., Vol. 5, No. 17, 2003

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ratio was excellent with Pd catalysis (entry 1, >98/2; entry
2, 96/4); however, partial racemization was observed, and
the enantiomeric excess of trans-5a was decreased to 89%
and 86%, depending on the reaction conditions (entries 1
and 2). These results were probably due to the strong affinity
of a nitrile moiety to Pd, enabling deprotonation at the
R-position of 4 under mild conditions. Slightly lower
reactivity of 4a compared with simple allylic carbonate can
also be attributed to the nitrile group. Various hard Lewis
acids were also examined to produce a charge-induced
concerted rearrangement.11 As shown in Table 4, (CH3)3-
SiOTf and Sc(OTf)3 were effective for the rearrangement
of 4. The rearrangement proceeded at room temperature in
good yield (entries 3-5, yield 76-86%), although stoichio-
metric amounts of Lewis acids were necessary for good
yields. There was no racemization with (CH3)3SiOTf in
toluene, (entry 3). The trans/cis ratio of 5a was slightly better
than that obtained under thermal conditions (entry 3, 89/
11). Both Sc(OTf)3 and (CH3)3SiOTf afforded 5a in good
yield in CH2Cl2 (entries 4 and 5). Partial racemization,
however, occurred in CH2Cl2 (entries 3 and 4, 75% ee). Other
Lewis acids gave less satisfactory results in terms of
reactivity and enantiomeric excess of the product.12
Figure 2. Supposed transition-state model to afford trans- and cis-
5.
good isolated yield (93-99%) as summarized in Table 3. In
all cases, there was no racemization.
Table 3. [3,3]-Sigmatropic Rearrangement under Thermal
Conditions
substrate
(ee, %)
time yielda
ratiob
eec (%)
The present two-step conversion efficiently afforded
optically active γ-oxy-R,â-unsaturated nitriles in good yield
and ee, starting from readily available R,â-unsaturated
aldehydes. The γ-oxy-R,â-unsaturated nitrile should be a
useful chiral building block.
entry
product
(h)
(%)
trans/cis trans/cis
1
2
3
4
4a (92)
4b (91)
4c (93)
4d (91)
5a
5b
5c
5d
12
12
12
12
99
93
95
99
86/14
76/24
77/23
75/25
92/92
91/91
92/93
91/90
To demonstrate the utility of the present two-step conver-
sion, we examined a catalytic enantioselective total synthesis
of (+)-patulolide C. Patulolide C is an antifungal and
antibacterial macrolide isolated from the culture broth of the
Penicillium urticae mutant S11R59.13 Although several
enantioselective approaches have been reported for its
syntheses,14 all of them are rather lengthy, especially the
schemes for the enantiocontrolled synthesis of a γ-hydroxy-
R,â-unsaturated ester unit. Our catalytic enantioselective
approach is summarized in Scheme 2. Starting from aldehyde
3e, catalytic asymmetric cyanation-ethoxycarbonylation
using (R)-YLB (4e, yield 92%, 87% ee) followed by the
rearrangement gave γ-oxy-R,â-unsaturated nitrile 5e in good
yield (yield 99%, trans: 87% ee). After exchange of the
protective group, 7 was subjected to a diastereoselective
a Isolated yield. b Determined by NMR analysis of crude mixture.
c Determined by chiral GC and HPLC analysis.
There are several excellent examples of cyclization-
induced rearrangement of allylic esters and carbamate by
Pd(II) catalysis,9 which led us to examine the Lewis acid-
promoted rearrangement of 4a. As shown in Table 4, the
Table 4. [3,3]-Sigmatropic Rearrangement Promoted by Lewis
Acid
(9) Review: (a) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23,
3, 579. (b) Nubbemeyer, U. Synthesis 2003, 961. For leading references,
see: (c) Overman, L. E.; Knoll, F. M. Tetrahedron Lett. 1979, 20, 321. (d)
Oehlschlager, A. C.; Mishra, P.; Dhami, S. Can. J. Chem. 1984, 62, 791.
(10) PdCl2(CH3CN)2 was less reactive.
(11) Oxophilic Eu(fod)3 efficiently catalyzes [3,3]-sigmatropic rearrange-
ment of allylic esters at room temperature, although the substrate is limited
to allylic alkoxyacetate. (a) Shull, B. K.; Sakai, T.; Koreeda, M. J. Am.
Chem. Soc. 1996, 118, 11690. (b) Dai, W.-M.; Mak, W. L.; Wu, A.
Tetrahedron Lett. 2000, 41, 7101 and references therein.
(12) Only trace 5 was obtained with Sc(OTf)3 in toluene. In toluene,
only (CH3)3SiOTf was effective for good conversion. Reaction proceeded
in CH2Cl2 using other Lewis acids such as TiCl4 (yield ca. 60%), BF3‚
Et2O (yield 19%), Zn(OTf)2 (yield <5%), Sn(OTf)2 (yield <5%), and so
on; however, partial racemization occurred.
Lewis acid
(mol %)
T
time yielda trans/cis ee (%)c
entry
solvent (°C) (h)
(%)
ratiob
trans
1
2
3
4
5
PdCl2(PhCN)2 (5) THF
PdCl2(PhCN)2 (5) THF
(CH3)3SiOTf (100) toluene rt
(CH3)3SiOTf (100) CH2Cl2 rt
rt
24
32
90
82
74
86
>98/2
96/4
89
86
92
75
75
50 24
48
36
36
89/11
88/12
89/12
Sc(OTf)3 (100)
CH2Cl2 rt
a Isolated yield. b Determined by NMR analysis of crude mixture.
c Determined by chiral GC and HPLC analysis.
(13) Rodphaya, D.; Sekiguchi, J.; Yamada, Y. J. Antibiot. 1986, 39, 629.
(14) (a) Mori, K.; Sakai, T. Liebigs Ann. Chem. 1988, 13. (b) Leemhuis,
F. M. C.; Thijs, L.; Zwanenburg, B. J. Org. Chem. 1993, 58, 7170 and
references therein. (c) Yang, H.; Kuroda, H.; Miyashita, M.; Irie, H. Chem.
Pharm. Bull. 1992, 40, 1616. (d) Takano, S.; Murakami, T.; Samizu, K.;
Ogasawara, K. Heterocycles 1994, 39, 67.
rearrangement proceeded at room temperature using 5 mol
% of PdCl2(PhCN)2 in THF (entry 1, yield 32%).10 At 50
°C, 5a was obtained in 90% yield (entry 2). The trans/cis
Org. Lett., Vol. 5, No. 17, 2003
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at this stage by chiral HPLC analysis. The diastereomeric
ratio (10/11-epi-10) was 81/19. These results suggested that
statistical asymmetric amplification of the enantiomeric
excess was achieved using two catalytic asymmetric reac-
tions.17 Removal of the TBS group afforded (+)-patulolide
C, [R]23 ) +5.0 (c 0.32 EtOH) [lit.12a [R]25 ) +5.4 (c
Scheme 2. Concise Catalytic Enantioselective Total Synthesis
of (+)-Patulolide Ca
D
D
0.57 EtOH); lit.12d [R]30D ) +5.6 (c 0.22 EtOH)] from 3e in
nine steps with an overall yield of 33%.
In summary, we developed an efficient two-step conver-
sion of R,â-unsaturated aldehydes to optically active γ-oxy-
R,â-unsaturated nitriles. First, catalytic asymmetric cyanation-
ethoxycarbonylation afforded allylic cyanohydrin carbonate
in good ee (87-93%) and excellent yield (92-100%).
Second, [3,3]-sigmatropic rearrangement proceeded smoothly
under thermal conditions (yield 93-99%) and/or under Lewis
acid-promoted conditions. The utility of the present method
was demonstrated by a concise catalytic enantioselective total
synthesis of (+)-patulolide C. Further studies to realize the
racemization-free rearrangement with catalytic amount of
hard Lewis acids as well as other conversions of chiral allylic
cyanohydrin carbonates are underway in our group.
a (a) (R)-YLB (10 mol %), H2O (30 mol %), BuLi (10 mol %),
[2,6-(CH3O)2C6H3]3P(O) (10 mol %), ethyl cyanoformate (1.2
equiv), -78 °C, 5 h, y. 92%, 87% ee; (b) 1,2,4-trichlorobenzene,
190 °C, 6 h, yield 99%; trans/cis ) 85/15, trans: 87% ee; (c)
K2CO3, CH3OH/H2O (1/1), rt, 2 h; (d) TBSCl, imidazole, DMF,
rt, 8 h, yield 92% (two steps); (e) (S)-CBS (30 mol %), catechol-
borane (2 equiv), toluene, -78 °C, 20 h, yield 95%; (f) DIBAL,
toluene, -78 °C, 3 h; (g) NaClO2, NaH2PO4, 2-methyl-2-butene,
t-BuOH-H2O, rt, 5 h, yield 72% (two steps); (h) 2-methyl-6-
nitrobenzoic anhydride (1.2 equiv), DMAP, rt, 16 h (slow addition),
yield 84%, dr ) 81/19 (10/11-epi-10); (i) HF-pyridine, 0 °C, THF,
yield 99%.
Acknowledgment. We acknowledge financial support by
RFTF and Grant-in-Aid for Encouragements for Young
Scientists (B) (for S.M.) from JSPS.
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and
determination of the absolute configuration of 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
reduction with (S)-CBS (30 mol %) and catecholborane15 to
afford 8 as an inseparable mixture in 95% yield. The
enantiomeric excess and diastereomeric ratio (desired/11-
epi) of the product was determined at a later stage of the
synthesis. After conversion of the nitrile to carboxylic acid,
macrolactonization of 9 proceeded smoothly with 2-methyl-
6-nitrobenzoic anhydride16 at room temperature to give 10
in 84% yield. The desired diastereomer 10 was isolated from
its 11-epimer by silica gel flash column chromatography.
The enantiomeric excess of 10 was determined to be 98%
OL034944F
(17) Selectivity in the reduction of 7 with (S)-CBS was C11-R/S ) 86/
14 (72% ee), which was calculated from dr and ee value of 10. In the model
study using 2-octanone and 30 mol % of (S)-CBS, 2-octanol was obtained
in 75% ee at -78 °C after 20 h. The calculated ee value for the reduction
of 7 (72% ee) matched well with that in the model study. For detailed
calculations and discussion of statistical asymmetric amplification, see the
Supporting Information. For a recent application of statistical asymmetric
amplification in the total synthesis, see: (a) Huo, S.; Negishi, E. Org. Lett.
2001, 3, 3253 and references therein. For a leading reference, see: (b)
Vigneron, J. P.; Dhaenens, M.; Horeau, A. Tetrahedron 1973, 29, 1055.
(15) Review: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998,
37, 7, 1986.
(16) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535.
3024
Org. Lett., Vol. 5, No. 17, 2003