Stereodivergent construction of cyclic ethers by a regioselective and enantiospecific rhodium-catalyzed allylic etherification: Total synthesis of gaur acid

Article abstract of DOI:10.1002/anie.200460612

A dramatic enhancement of the stereospecificity of the title reaction was observed with trimethylphosphite-modified copper(I) alkoxide reagents. The combination of this reaction with ring-closing metathesis provides a direct approach to cis- and trans-dis

Full text of DOI:10.1002/anie.200460612

Communications
Cyclic Ethers
Stereodivergent Construction of Cyclic Ethers by
a Regioselective and Enantiospecific Rhodium-
Catalyzed Allylic Etherification: Total Synthesis
of Gaur Acid**
P. Andrew Evans,* David K. Leahy, William J. Andrews,
and Daisuke Uraguchi
The transition-metal-catalyzed intermolecular allylic ether-
ification is a fundamentally important cross-coupling strategy
for the construction of enantiomerically enriched allylic
ethers.[1] Although there are numerous examples of the use
of simple primary alcohols as nucleophiles, secondary or
tertiary alcohols have been used in relatively few studies,[2]
partially because of the poor nucleophilicity of these alcohols
and the high basicity of the corresponding alkali-metal
alkoxides. In response to these underlying problems, we
recently reported a regioselective and enantiospecific rho-
dium-catalyzed allylic etherification with copper(i) alkoxides
as nucleophiles.[3] The transmetalation of an alkali-metal
alkoxide served to diminish its basicity, thereby promoting the
etherification of a soft metal–allyl electrophile.[4]
Herein, we now describe a two-step stereodivergent
synthesis of cyclic ethers. The stereospecific etherification of
the acyclic enantiomerically enriched allylic carbonate I with
secondary alkenyl alcohols (R)- and (S)-II followed by ring-
closing metathesis (RCM) affords the cis- and trans-disub-
stituted cyclic ethers III and IV, respectively (Scheme 1; n =
0–3).[5–7] The inherent advantage of this approach is the ability
to vary both ring size and relative configuration as a direct
Scheme 1. General approach for the stereodivergent construction of
cyclic ethers. LG=leaving group.
[*] Dr. P. A. Evans, D. K. Leahy, W. J. Andrews, Dr. D. Uraguchi
Department of Chemistry
Indiana University
Bloomington, IN 47405 (USA)
Fax: (+1)812-855-8300
E-mail: paevans@indiana.edu
[**] We sincerely thank the National Institutes of Health (GM58877) for
generous financial support. We also thank Johnson and Johnson for
a Focused Giving Award, Pfizer GRD for the Creativity in Organic
Chemistry Award, and the Japan Society for the Promotion of
Sciences for a JSPS Research Fellowship for Young Scientists (D.U.).
We acknowledge Dr. James E. Oliver, who also recently completed a
total synthesis of gaur acid, for providing spectroscopic and optical-
rotation data for this compound.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460612
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Chemie
function of the alkenyl alcohol nucleophile employed in the
cross-coupling reaction.[8] This strategy was then applied to
the total synthesis of the natural product gaur acid to establish
its absolute configuration.[9,10]
modified with the additional trimethylphosphite, the reaction
was performed with the phosphite-ligated copper(i) alkoxides
in the presence of an unmodified Wilkinson catalyst (Table 1,
entry 6). This led to poor turnover and modest stereospeci-
ficity, thus indicating minimal transfer of trimethylphosphite
from the copper(i) alkoxide to the rhodium catalyst.
Table 1 outlines the development of the stereospecific
allylic etherification by using the secondary copper(i) alk-
oxides derived from (R)-2 (n = 1). Although we had demon-
strated previously that primary copper(i) alkoxides derived
from copper(i) chloride facilitate the enantiospecific ether-
ification, the allylic etherification with the secondary copper(i)
alkoxide proved problematic irrespective of the copper(i)
halide employed (Table 1, entries 1 and 2).[3] Hence, we
decided to screen a variety of rhodium catalysts with the
expectation that the stereospecificity could be improved by
either a decrease in the rate of p–s–p isomerization or an
increase in the rate of nucleophilic attack.
Preliminary screening of the catalyst derived from m-
dichlorotetraethylene dirhodium(i), in which there is no free
triphenylphosphane from the in situ ligand exchange, with
trimethylphosphite demonstrated slightly diminished stereo-
specificity. This result was intriguing given that the same
catalyst is presumably formed through its in situ modification
as that formed with the Wilkinson catalyst.[11] We reasoned
that the difference could be attributed to the absence of
residual triphenylphosphane from the in situ ligand exchange
in the latter case; the triphenylphosphane presumably
modifies and thereby activates the copper(i) alkoxide. To
test this hypothesis, the copper(i) alkoxide derived from (R)-2
(n = 1) was treated with an equimolar amount of triphenyl-
phosphane, with the expectation that this would improve the
stereospecificity. Gratifyingly, an increase in the specificity
was observed (Table 1, entry 4), which prompted the screen-
ing of additional ligands. This study demonstrated trimethyl-
phosphite to be the optimal ligand in terms of the regiose-
lectivity and enantiospecificity of the catalyst (Table 1,
entry 5). Thus, it appears that the phosphite ligand activates
the copper(i) alkoxide so that it alkylates the rhodium–allyl
electrophile stereospecifically prior to p–s–p isomerization.
To rule out the possibility that the rhodium catalyst is further
The rhodium-catalyzed allylic etherification with the
copper(i) alkoxide derived from the alkenyl alcohols (R)-
and (S)-2 was studied in combination with subsequent ring-
closing metathesis to furnish the cis- and trans-disubstituted
cyclic ethers 5 and ent-6 (Table 2).[5–7] This study demonstrates
that excellent regioselectivity and enantiospecificity is
observed irrespective of which enantiomer of the alkenyl
copper(i) alkoxide is employed (Table 2, entries 1–8). More-
over, ring-closing metathesis with the Grubbs catalyst pro-
ceeds to furnish the cyclic ethers in good to excellent yield.
However, the construction of the oxocine 5d and ent-6d
required the use of the Grubbs N-heterocyclic carbene
catalyst and very high dilution for efficient cyclization
(Table 2, entries 7–8). Overall, the ability to form cyclic
ethers in this manner is impressive not only in terms of the
excellent stereospecificity, but also because of the minimal
conformational bias present for the formation of medium-ring
ethers.[12]
Gaur acid (7) was recently isolated from the oily secretion
of the gaur (B. frontalis), a wild ox in Asia, by Oliver et al.[9,10]
This 18-carbon acid is thought to serve as a landing and
feeding deterrent for the yellow-fever mosquito (Aedes
aegypti). Although the relative configuration of 7 was
assigned, the absolute configuration of this agent had not
been established. We envisaged that the rhodium-catalyzed
allylic etherification in conjunction with ring-closing meta-
thesis would provide a stereospecific route to the trans-2,5-
Table 1: Optimization of the rhodium-catalyzed allylic etherification with the copper(i) alkenyl alkoxide derived from (R)-2 (n=1).[a]
Entry
Catalyst
Additive
3/4[b,c]
d.r. 3a/3b[b]
Yield [%][d]
1
2
3
4
5
6
[RhCl(PPh3)3]/P(OMe)3
[RhCl(PPh3)3]/P(OMe)3
[{RhCl(C2H4)}2]/P(OMe)3
[RhCl(PPh3)3]/P(OMe)3
[RhCl(PPh3)3]/P(OMe)3
[RhCl(PPh3)3]
CuCl
CuI
CuI
CuI/PPh3
CuI/P(OMe)3
CuI/P(OMe)3
9:1
11:1
13:1
13:1
49:1
24:1
2:1
4:1
3:1
20
63
63
46
72
15
7:1
ꢀ99:1
10:1
[a] All reactions (0.25 mmol) were carried out with 10 mol% of the catalyst in tetrahydrofuran with 1.9 equivalents of the copper alkoxide.
[b] Diastereomeric ratios were determined by capillary GLC on aliquots of the crude reaction mixture. [c] Authentic standards were prepared
independently by using copper cyanide as an additive. [d] Yields of the isolated products. Bn=benzyl, HMDS=hexamethyldisilazide, PMP=p-
methoxyphenyl, RT=room temperature.
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Table 2: Scope of the rhodium-catalyzed allylic etherification with the
copper(i) alkenyl alkoxides 2 followed by ring-closing metathesis.[a,b]
Scheme 3. Preparation of the enantiomerically enriched allylic carbon-
ate electrophile. BOC-ON=2-(tert-butoxycarbonyloxyimino)-2-phenyl-
acetonitrile, DCHT=dicyclohexyl tartrate, MS=molecular sieves,
TBHP=tert-butyl hydroperoxide, TBS=tert-butyldimethylsilyl.
The stereospecific allylic etherification was carried out
under analogous reaction conditions to those outlined in
Table 2.[17] Treatment of the allylic carbonate 12 with the
trimethylphosphite-modified Wilkinson catalyst and the cop-
per(i) alkoxide derived from the allylic alcohol 10, afforded
the diene 13 in 69% yield with excellent regioselectivity and
enantiospecificity [ ꢀ 19:1 by NMR spectroscopy, Eq. (1)].
Entry
Config.
of 2
n
d.r.[c]
53:1
1:50
23:1
1:23
27:1
1:26
29:1
1:39
Yield of
addition
Cyclic
ether
Yield [%][d]
product [%][d]
1
2
3
4
5
6
7
8
R
S
R
S
R
S
R
S
0
0
1
1
2
2
3
3
74
78
77
76
77
77
77
77
5a
ent-6a
5b
ent-6b
5c
ent-6c
5d
94
99
85
98
85
93
73[e]
82[e]
ent-6d
[a] All allylic etherification reactions (0.25 mmol) were carried out with
10 mol% of the catalyst in tetrahydrofuran with 1.9 equivalents of the
copper alkoxide. The regioselectivity (28/18) observed for the addition of
the copper alkoxide was ꢀ99:1 in all cases. (Authentic standards were
prepared independently by using copper cyanide as an additive.) [b] All
ring-closing metathesis reactions were carried out on a 0.1-mmol scale
with 5–10 mol% of the Grubbs catalyst in dichloromethane (0.1m).
[c] Ratios of regio- and diastereoisomers were determined by capillary
GLC on aliquots of the crude reaction mixture. [d] Yields of the isolated
products. [e] The Grubbs N-heterocyclic carbene catalyst (0.001m) was
used at reflux.
The synthesis of gaur acid (7) was then completed as
illustrated in Scheme 4. Treatment of the diene 13 with the
Grubbs N-heterocyclic carbene catalyst at 408C gave the
disubstituted tetrahydrofuran present in this potentially bio-
logically important agent, and thereby enable the determi-
nation of the absolute configuration.
The allylic alcohol 10 was prepared by the three-step
sequence outlined in Scheme 2. Regioselective ring-opening
of the known epoxide 8 with the cuprate derived from n-
Scheme 4. Completion of the synthesis of gaur acid (7). DCE=1,2-
dichloroethane, DMF=N,N-dimethylformamide, NHC=N-heterocyclic
carbene, PDC=pyridinium dichromate.
Scheme 2. Preparation of the enantiomerically enriched allylic alcohol
nucleophile. CAN=cerium(iv) ammonium nitrate.
desired cyclic ether, which was reduced in situ and depro-
tected with acid to afford the primary alcohol 14 in 75%
overall yield.[18] The hydrogenation of the alkene in the
metathesis product was necessary at this juncture because of
its propensity to undergo oxidation. Oxidation of the primary
alcohol 14 by pyridinium dichromate,[19] followed by palla-
dium-catalyzed hydrogenation of the benzyl ether, furnished
gaur acid (7) in 79% yield (two steps). Although the
spectroscopic data of the synthetic sample of 7 is identical
in all respects to those of the natural substance (1H/13C NMR,
IR, and MS), the optical rotation has the opposite sign
([a]2D5À7.5 (c = 1.1, CDCl3); lit.:[9,10] [a]2D6+7.0 (c = 7.1,
heptyllithium and copper(i) cyanide at À788C, gave the
desired alcohol 9 in 71% yield.[13,14] Benzyl protection of the
secondary alcohol 9, followed by oxidative cleavage of the p-
methoxyphenyl group, furnished the allylic alcohol 10 in 76%
yield (two steps).[15] The enantiomerically enriched allylic
carbonate 12 was prepared by an initial Sharpless kinetic
resolution of the allylic alcohol rac-11, followed by acylation
of the product (R)-11 (ꢀ 99% ee) with BOC-ON
(Scheme 3).[16]
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[11] a) M. L. Wu, M. J. Desmond, R. S. Drago, Inorg. Chem. 1979, 18,
CDCl3)), thus indicating the absolute configuration of the
natural product to be 6S, 9R, 10R.[20]
679 – 686; b) L. A. Watson, D. K. Leahy, P. A. Evans, K. G.
Caulton, unpublished results.
In conclusion, the stereospecific rhodium-catalyzed allylic
etherification with secondary alkenyl alcohols in conjunction
with ring-closing metathesis provides a direct approach to cis-
and trans-disubstituted cyclic ethers. This study demonstrated
that a dramatic enhancement of the stereospecificity is
possible through the modification of the copper(i) alkoxide
with trimethylphosphite, which presumably promotes the
rapid nucleophilic attack of the rhodium–allyl intermediate
prior to the p–s–p isomerization. Finally, the potential of this
methodology was highlighted through a seven-step total
synthesis of gaur acid (7), whereby the absolute configuration
of 7 was established.
[12] a) J. S. Clark, J. G. Kettle, Tetrahedron Lett. 1997, 38, 127 – 130;
b) R. J. Linderman, J. Siedlecki, S. A. OꢀNeill, H. Sun, J. Am.
Chem. Soc. 1997, 119, 6919 – 6920; c) M. T. Crimmins, A. L.
Choy, J. Org. Chem. 1997, 62, 7548 – 7549.
[13] S. L. Schreiber, T. S. Schreiber, D. B. Smith, J. Am. Chem. Soc.
1987, 109, 1525 – 1529.
[14] P. A. Evans, J. Cui, S. J. Gharpure, A. Polosukhin, H.-R. Zhang,
J. Am. Chem. Soc. 2003, 125, 14702– 14703.
[15] T. Fukuyama, A. A. Laird, L. M. Hotchkiss, Tetrahedron Lett.
1985, 26, 6291 – 6292.
[16] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 – 2547.
[17] This rather demanding cross-coupling reaction required a higher
catalyst loading (30 mol%) for efficient and complete conver-
sion.
[18] J. Louie, C. W. Bielawski, R. H. Grubbs, J. Am. Chem. Soc. 2001,
123, 11312– 11313.
[19] E. J. Corey, G. Schmidt, Tetrahedron Lett. 1979, 20, 399 – 402.
[20] This result contradicts the original stereochemical assignment
made by Ito et al. for the same agent isolated from sheep wool,
by analogy with a C16 derivative.[9]
Received: May 10, 2004
Keywords: allylation · asymmetric synthesis · cyclic ethers ·
.
metathesis · rhodium
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[8] For an explanation of the effect of copper(i) halide salts on the
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