Catalytic asymmetric dihydroxylation of enamides and application to the total synthesis of (+)-tanikolide

Article abstract of DOI:10.1002/anie.201004328

Asymmetric dihydroxylation of β,β- disubstituted enamides afforded chiral tertiary-alcohol-containing α-hydroxyaldehydes and 1,2-diols with high enantioselectivity (see scheme). This method was applied to the total synthesis of the antifungal natural prod

Full text of DOI:10.1002/anie.201004328

Angewandte
Chemie
DOI: 10.1002/anie.201004328
Asymmetric Catalysis
Catalytic Asymmetric Dihydroxylation of Enamides and Application to
the Total Synthesis of (+)-Tanikolide**
Benoit Gourdet and Hon Wai Lam*
Asymmetric transformations of 1,1-disubstituted alkenes
provide important building blocks for chemical synthesis,
but are often plagued with low stereoselectivities because it
can be difficult for a chiral reagent or catalyst to discriminate
between the enantiotopic faces of these substrates.[1] Among
the available methods, asymmetric dihydroxylation (AD)
stands out as one of the more successful, and can provide high
enantioselectivities in certain cases (Scheme 1, 1!2).[2,3]
However, low enantioselectivities are usually observed
when the two alkene substituents are of similar steric
demand.[4,5]
silanes involving carbocupration[10a] or carboalumination[10b]
of terminal alkynes, oxidation of the resulting alkenylmetal
species using a metal tert-butyl peroxide, and trapping of the
resulting enolate with an acylating or silylating agent.[10]
Furthermore, asymmetric dihydroxylation of enol benzoates
containing methyl substitution on the alkene was demonstra-
ted.[10b] Nevertheless, improvements with these approaches
can be envisaged. In the carbocupration procedure,[10a,11] the
organocopper reagents are generated from organolithium or
Grignard reagents, which pose restrictions on the functional
groups that may be present in the organometallic reagent.
Although functionalized organocopper reagents may be
obtained from the corresponding organozinc halides, these
reagents are poorly reactive towards unactivated terminal
alkynes.[12] In addition, because only alkylcopper reagents
exhibit sufficient reactivity in alkyne carbocupration, the
introduction of important groups such as (hetero)aryl sub-
stituents is usually not possible. In the carboalumination
procedure,[10b,13] only methyl groups can be transferred.
Therefore, full exploration of asymmetric dihydroxylation of
enol derivatives 3 to access chiral a-hydroxyaldehydes 4 and
diols 2 is compromised by these limitations.
Scheme 1. Asymmetric dihydroxylation (AD) routes to tertiary-alcohol-
containing terminal 1,2-diols 2.
A possible solution to this problem is to employ b,b’-
disubstituted enol derivatives 3 as the substrates, where
discrimination of the enantiotopic faces is expected to be
more straightforward (Scheme 1, 3!2). An additional bene-
fit of this approach is that asymmetric dihydroxylation results
in chiral a-hydroxyaldehydes 4, which are themselves val-
uable compounds, and which can be reduced to 1,2-diols 2 if
required. To ensure high enantioselectivity in the dihydrox-
ylation event, the substrate 3 must be obtained in high
stereoisomeric purity.[6] Unfortunately, existing methods to
prepare these compounds typically proceed with poor E/Z
stereoselectivity,[7–9] and the resulting geometric isomers can
be difficult to separate.
Our research group has recently developed rhodium-
catalyzed carbometalation reactions that offer solutions to
many of these drawbacks.[14] Instead of providing enol
derivatives 3, these reactions furnish b,b’-disubstituted enam-
ides 6[15] from the corresponding ynamides 5[16] (Scheme 2).
Collectively, these processes enable the introduction of alkyl,
Partial solutions to these problems have been described
recently.[10] Ready and co-workers have developed stereocon-
trolled syntheses of b,b’-disubstituted enol esters and enol
Scheme 2. Asymmetric dihydroxylation of enamides prepared by rho-
dium-catalyzed carbometalation of ynamides.
[*] B. Gourdet, Dr. H. W. Lam
School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings
West Mains Road, Edinburgh EH9 3JJ (UK)
Fax: (+44)131-650-6453
E-mail: h.lam@ed.ac.uk
Homepage: http://homepages.ed.ac.uk/hlam/index.html
alkenyl, aryl, heteroaryl, benzyl, and alkynyl groups, and the
presence of sensitive functional groups such as esters[14a–c] and
ketones[14c] on the organometallic reagent is permitted.
Accordingly, asymmetric dihydroxylation of enamides 6
should provide access to a much wider range of chiral
products than is possible using comparable methods.[10b] To
our knowledge, there are only limited reports of Sharpless
asymmetric dihydroxylation of enamides, where cyclic sub-
strates were oxidized with modest (ꢀ 77% ee) enantioselec-
tivities.[17] Herein, we report highly enantioselective dihy-
[**] This work was supported by the European Commission (Project
No. MEST-CT-2005-020744) and the University of Edinburgh. We
thank the EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea, for providing high-resolution mass
spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004328.
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droxylations of b,b’-disubstituted enamides, and the applica-
rhodium-catalyzed ynamide carbometalation procedures we
have described recently.[14] The enamides 6a, 6b, and 6d–6g
have been reported previously,[14] whereas enamides 6c, 6h,
and 6i are new compounds.[19] Highly enantioselective
dihydroxylation of these substrates was readily accomplished
using commercially available AD-mix-b without the addition
of MeSO2NH2.[3] After dihydroxylation was complete, addi-
tion of NaBH4 to the reaction mixture resulted in formation
of the 1,2-diols 2. The sense of enantiofacial selectivity by
AD-mix-b in these reactions is consistent with the Sharpless
mnemonic.[3] Enamides 6a–6c containing a phenyl substitu-
ent at the R1 position were effective substrates, with a 2-
thienyl group at R2 (entry 3) providing a higher enantiose-
lectivity than a methyl (entry 1) or an ethyl group (entry 2).
Enamides 6d–6i containing aliphatic groups (simple alkyl,
oxygenated alkyl) at R1 and (hetero)aryl groups (phenyl, p-
tolyl, 3-carboethoxyphenyl, 2-thienyl) at R2 proved to be
especially competent substrates, providing products in gen-
erally good yields with uniformly high enantioselectivities
(entries 4–9). Comparison of the present method with asym-
metric dihydroxylation of 1,1-disubstituted alkenes is infor-
mative. While diol 2a was obtained from enamide 6a with
slightly lower enantioselectivity (90% ee; entry 1) and as the
opposite enantiomer compared with asymmetric dihydroxy-
lation of a-methylstyrene under comparable reaction con-
ditions (ꢁ94% ee),[2c] the present method afforded diol 2b
with improved selectivity (87% ee; entry 2) compared with
that obtained from the corresponding 1,1-disubstituted
alkene (ꢁ78% ee).[2c] Interestingly, diol 2d was obtained
favoring the R enantiomer from both enamide 6d and alkene
1d, but the enantioselectivity was far superior in the case of
the enamide (95% ee; entry 4) compared with the alkene
[41% ee; Eq. (1)].
tion of this method in the total synthesis of (+)-tanikolide.[18]
The enamide employed in the initial part of this study are
shown in Table 1, and were prepared according to one of the
Table 1: Catalytic asymmetric dihydroxylation of enamides.[a]
Entry Enamide
Product
Yield [%][b] ee [%][c]
1
2
6a
6b
2a 72
90 (ꢁ94)[d]
87 (ꢁ78)[d]
2b 84
2c 61
2d 68
3
4
6c
6d
94
95
5
6
7
6e
6 f
6g
2e 70
2 f 83
2g 82
97
97
97
The reaction of b,b’-diarylenamide 6j[19] with AD-mix-b
was sluggish and did not proceed to completion, but
dihydroxylation using increased loadings of K2OsO2(OH)4
and the chiral ligand (DHQD)2PHAL (hydroquinidine 1,4-
phthalazinediyl diether), which is present in AD-mix-b, gave
improved results and afforded diol 2j in 98% ee [Eq. (2)].
Scheme 3 illustrates application of this method to the
concise preparation of a-hydroxyaldehyde 4k, a known
intermediate in the synthesis of (S)-oxybutynin (7),[20,21]
which is widely used in the treatment for urinary problems.[22]
In this case, rhodium-catalyzed carbozincation of ynamide 5a
8
9
6h
6i
2h 86
94
96
2i 68
[a] Reactions were conducted using 6a–6i (0.20 mmol) and AD-mix-b
(280 mg; 0.4 mol% of Os and 1 mol% of (DHQD)2PHAL) in tBuOH
(2 mL) and H2O (1 mL) for 7–24 hours, and subsequent addition of
NaBH4 (6 equiv) and stirring for an additional 1 hour. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] Values in parentheses refer to ee values obtained from asymmetric
dihydroxylation of the corresponding 1,1-disubstituted alkene using the
same chiral ligand (DHQD)2PHAL that is present in AD-mix-b, see
Ref. [2c]. TBS=tert-butyldimethylsilyl.
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Scheme 3. Synthesis of a-hydroxyaldehyde 4k, a precursor to (S)-
oxybutynin (7). THF=tetrahydrofuran.
with Cy2Zn (prepared from CyMgBr and ZnCl2; Cy = cyclo-
hexyl) according to our reported method[14a,b] did provide
enamide 6k, but in low yield owing to the formation of (Z)-3-
(2-styryl)oxazolidin-2-one as a major side product resulting
from undesired hydrozincation.[14b] However, improved
results were obtained from copper-catalyzed carbomagnesia-
tion of 5a using CyMgBr and [Cu(acac)2] (acac = acetylacet-
onate), which provided 6k in 74% yield.[23] In similar fashion
to 6j [Eq. (2)], asymmetric dihydroxylation of 6k with AD-
mix-b was sluggish, but dihydroxylation using increased
loadings of K2OsO2(OH)4 and (DHQD)2PHAL afforded a-
hydroxyaldehyde 4k in 80% yield and 91% ee. It should be
noted that dihydroxylation of a-cyclohexylstyrene using
(DHQD)2PHAL provides the corresponding diol as the
opposite R enantiomer in only 57% ee[2c,24]—once again
illustrating that use of b,b’-disubstituted enamides in place
of 1,1-disubstituted alkenes can prove advantageous in
asymmetric dihydroxylation reactions.
As a further exemplification of asymmetric enamide
dihydroxylation, we applied this method to a concise total
synthesis of the antifungal natural product (+)-tanikolide
(14).[18,25] First, bromoalkyne 9 was prepared from commer-
cially available tridecyne 8 using NBS/AgNO3 (Scheme 4).[26]
By using the method of Hsung and co-workers,[27] copper-
catalyzed coupling of 9 with oxazolidin-2-one then afforded
ynamide 10. Rhodium-catalyzed carbozincation of 10 using
commercially available 4-ethoxy-4-oxobutylzinc bromide[14a,b]
proceeded smoothly and provided enamide 11 in 56% yield.
Unfortunately, dihydroxylation of 11 using AD-mix-b was
poorly selective, and after reduction of the initially formed
aldehyde with NaBH4, diol 12 was produced in 58% ee.
However, use of (DHQD)2AQN (hydroquinidine anthraqui-
none-1,4-diyl diether)[28] as the chiral ligand in place of
(DHQD)2PHAL led to 12 being obtained in a much improved
88% ee.[29] Basic hydrolysis of 12, and subsequently heating
the resulting acid 13 in CDCl3 at reflux led to smooth
lactonization and provided (+)-tanikolide (14). Overall, the
route to (+)-tanikolide (14) presented in Scheme 4 is com-
petitive with previous syntheses.[25]
Scheme 4. Total synthesis of (+)-tanikolide (14). cod=cycloocta-l,5-diene,
NBS=N-bromosuccinimide.
the diversity of b,b’-disubstituted enamide derivatives avail-
able using recently reported rhodium-catalyzed ynamide
carbometalation protocols,[14] and offering often superior
enantioselectivity compared with asymmetric dihydroxyla-
tion of the corresponding 1,1-disubstituted alkenes, this
strategy serves as a versatile method for the preparation of
important 1,2-dioxygenated compounds. Many of these
tertiary-alcohol-containing building blocks 2 and 4 would be
difficult to access efficiently using alternative methods.
Application of this process to the concise syntheses of the
natural product (+)-tanikolide (14) and a-hydroxyaldehyde
4k, an intermediate en route to (S)-oxybutynin (7), has been
demonstrated.
Received: July 15, 2010
Published online: September 30, 2010
Keywords: asymmetric catalysis · dihydroxylation · enamides ·
.
total synthesis · ynamides
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alcohol. See the Supporting Information for details.
Angew. Chem. Int. Ed. 2010, 49, 8733 –8737
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8737