Catalytic asymmetric direct henry reaction of ynals: Short syntheses of (2S,3R)-(+)-xestoaminol C and (-)-codonopsinines

Article abstract of DOI:10.1002/anie.201004072

Triple for all: Various optically active anti-β-nitro propargylic alcohols are synthesized by the catalytic stereoselective addition of nitroalkanes to ynals (the direct Henry reaction of ynals). The utilization of the rich chemistry of carbon-carbon triple bond allows rapid access to three natural products.

Full text of DOI:10.1002/anie.201004072

Communications
DOI: 10.1002/anie.201004072
Asymmetric Synthesis
Catalytic Asymmetric Direct Henry Reaction of Ynals: Short Syntheses
of (2S,3R)-(+)-Xestoaminol C and (À)-Codonopsinines**
Daisuke Uraguchi, Shinji Nakamura, and Takashi Ooi*
Optically active propargylic alcohols are versatile building
blocks for the asymmetric synthesis of various biologically
relevant complex molecules owing to the rich chemistry of the
carbon–carbon triple bond, which allows its conversion into
numerous other functional groups.[1] There are three principal
approaches to the catalytic enantioselective construction of
this important class of compounds: 1) the reduction of
ynones,[2,3] 2) the addition of terminal alkynes to aldehydes,[4]
and 3) the addition of an appropriate nucleophile to ynals.[5,6]
Although the first two methods have been studied exten-
sively, efforts for exploring the potential of the third approach
have been rather limited despite the inherent flexibility in the
structure of the nucleophilic component used in this method.
Nitroalkanes appear to be an attractive candidate as nucle-
ophiles for addressing this issue because their coupling
Scheme 1. Catalytic asymmetric direct Henry reaction of ynals medi-
reaction with ynals, namely the direct Henry reaction of
ated by 1·Cl, and natural products concisely assembled from Henry
adducts.
ynals,[7–9] provides a straightforward entry to optically active
b-nitro propargylic alcohols. These alcohols are extremely
valuable intermediates that can be converted into various
functionalized b-amino alcohols and a-hydroxy carbonyls. In
particular, if the relative stereochemistry could be rigorously
controlled, this unprecedented transformation would serve as
a useful yet reliable process for the synthesis of anti- or syn-b-
amino alcohols with structures that are not readily accessible
by existing catalytic asymmetric methodologies. Herein, we
report the first catalytic asymmetric direct Henry reaction of
ynals efficiently mediated by a chiral tetraaminophospho-
nium salt 1d·Cl with excellent anti-selectivity and enantiose-
lectivity.[10,11] Furthermore, the synthetic utility of this new
procedure is clearly demonstrated by its application in the
short syntheses of (2S,3R)-(+)-xestoaminol C (5), (À)-codo-
nopsinine (6a), and (À)-2-epi-codonopsinines (6b;
Scheme 1).
and KOtBu in tetrahydrofuran at À788C for 30 minutes, the
desired Henry adduct anti-4a was obtained almost exclusively
in 86% ee, but in only 22% yield (Table 1, entry 1). Although
the stereoselectivity was promising, a substantial amount of
2a remained unreacted. Analysis of the crude mixture
revealed that the low conversion was primarily a result of
the decomposition of 1a during the initial stage of the
reaction. As the aminophosphonium cation 1 was fairly stable
Table 1: Effect of N,N-dimethylformamide concentration and catalyst
structure.[a]
We began our studies by examining the reaction of 3-
phenylpropynal (2a) with nitroethane (3a) using 1a·Cl, which
contains para-trifluoromethylphenyl moieties, as the catalyst
precursor.[10,12] When 2a was treated with 3a (10 equiv) under
the influence of the iminophosphorane generated from 1a·Cl
Entry
1·Cl
DMF
[v/v %]
Yield
[%][b]
anti/syn[c]
ee
[%][d]
1
2
3
4
5
6
7
1a
1a
1a
1b
1c
1d
1e
0
5
22
49
>99
82
93
94
>20:1
14:1
12:1
>20:1
11:1
>20:1
11:1
86
82
83
98
94
98
97
10
10
10
10
10
[*] Dr. D. Uraguchi, S. Nakamura, Prof. Dr. T. Ooi
Department of Applied Chemistry, Graduate School of Engineering
Nagoya University, Furo-cho B2-3(611)
Chikusa, Nagoya 464-8603 (Japan)
>99
[a] The reaction was performed with 0.20 mmol of 2a and 2.0 mmol of 3a
in the presence of 1·Cl/KOtBu (5 mol%) in THF/DMF (2.0 mL) at
À788C under an argon atmosphere. [b] Yield of isolated product.
[c] Diastereomeric ratio (d.r.) was determined by 1H NMR (400 MHz)
spectroscopic analysis of an aliquot of the crude reaction mixture.
[d] Enantiomeric excess was determined by HPLC on a chiral stationary
phase. Absolute and relative configurations were assigned by analogy to
4b and 4h.
Fax: (+81)52-789-3338
E-mail: tooi@apchem.nagoya-u.ac.jp
[**] This work was supported by grants from the JSPS for Scientific
Research, the Global COE program in Chemistry of Nagoya
University, and the Asahi Glass Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004072.
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Chemie
in the reactions with aromatic or aliphatic aldehydes under
similar conditions,[10] we assumed that the origin of this
decomposition would be the relatively low pKa of the in situ
generated secondary propargylic alkoxide,[13] which might
prevent the facile proton abstraction from the aminophos-
phonium cation. Rather, the intermediate would attack the
cationic phosphorus center, thus triggering the collapse of 1a.
To gain information about this presumably unique behavior
of the b-nitro secondary propargylic alkoxide, we prepared
the Henry adduct of 2a and 2-nitropropane, 4-methyl-4-nitro-
1-phenylpent-1-yn-3-ol, and treated it with the iminophos-
phorane preformed from 1c·Cl and KOtBu in tetrahydro-
furan. 31P NMR spectroscopic analysis of the resulting
mixture at À988C revealed that the original sharp signal of
iminophosphorane at d = 47.2 ppm had disappeared and a
new broad signal was observed upfield (d = 37.7 ppm),
corresponding to the tetraaminophosphonium cation,[10,12]
which confirmed the formation of the corresponding amino-
phosphonium alkoxide by an acid–base reaction.[14] This
observation is quite different to the result obtained with the
benzaldehyde-derived Henry adduct, 2-methyl-2-nitro-1-phe-
nylpropan-1-ol,[15] and supports our assumption regarding the
influence of pKa of the product 4. Interestingly, our attempts
to tackle this problem found that the catalyst decomposition
pathway could be suppressed by adding N,N-dimethylform-
amide as a co-solvent and that the conversion of the starting
ynal 2a improved gradually as the concentration of N,N-
dimethylformamide was increased, at the slight expense of
stereoselectivity (Table 1, entries 2 and 3). This trend is
probably because the overall polarity of the solvent system
has a beneficial effect on the stabilization of the amino-
phosphonium alkoxide intermediate.[16] These optimized
condition allowed us to investigate the effect of the aromatic
substituents of 1 (Ar) on the diastereo- and enantioselectiv-
ities (Table 1, entries 4–7), and steric bulk, rather than the
electronic effects of a para substituent on the aromatic
groups, seemed to be important. Eventually, the use of
1d·Cl, which contains para-tolyl groups, afforded quantitative
formation of 4a with an anti/syn ratio of greater than 20:1; the
enantiomeric excess of the anti isomer was determined to be
98% (Table 1, entry 6).
Further experiments were then conducted to probe the
substrate scope. The representative results listed in Table 2
show not only the generality of this reaction but also the
intriguing relationship between the structures of the reactants
and the concentration of N,N-dimethylformamide required
for efficient catalysis. In the reactions of aromatic ynals, the
electronic properties of the terminal aromatic substituents
affected the estimation of the suitable amount of N,N-
dimethylformamide, which again agrees with our conjecture
that the pKa of the in situ generated secondary propargylic
alkoxide is related to the decomposition of 1. For instance, the
amount of N,N-dimethylformamide can be reduced in the
coupling of para-anisyl-substituted ynal 2b with 3a, and
should be increased when electron-withdrawing para-chloro-
phenyl-substituted ynal 2c is employed (Table 2, entry 1
versus 2). In both cases, high levels of diastereo- and
enantioselectivities were maintained. On the other hand,
the addition of 5% (v/v) of N,N-dimethylformamide was
generally sufficient for facilitating a smooth reaction with
aliphatic ynals, and excellent stereoselectivities were uni-
formly obtained irrespective of their steric demands (Table 2,
entries 3–6). In addition to nitroethane (3a), other nitro-
alkanes were used as the nucleophilic component by simply
tuning the N,N-dimethylformamide concentration according
to their polarity (Table 2, entries 7 and 8).
The synthetic utility of this catalytic, highly anti-selective
and enantioselective direct Henry reaction of ynals was
demonstrated by its application to the concise asymmetric
syntheses of several naturally occurring, biologically active
compounds (Scheme 2). The treatment of 2-dodecynal (2h)
and nitroethane (3a) with 5 mol% of ent-1d·Cl/KOtBu in
tetrahydrofuran/N,N-dimethylformamide (95:5) at À788C for
30 minutes resulted in the predominant formation of anti-b-
nitro propargylic alcohol 4h (anti/syn = > 20:1) in 94% yield
and 98% ee. Subsequent simultaneous reduction of the triple
Table 2: Substrate profile.[a]
Entry
R (2)
R’ (3)
DMF
[v/v %]
Yield
[%][b]
anti/syn[c]
ee
4
[%][d]
1
2
3
4
5
6
7
8
p-MeO-C6H4 (2b)
p-Cl-C6H4 (2c)
Me(CH2)5 (2d)
cyclohexyl (2e)
PhCH2O(CH2)2 (2 f)
tBuMe2SiO(CH2)2 (2g)
Ph (2a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
H (3b)
5
15
5
5
5
5
5
15
>99
94
>99
89
>99
98
92
>20:1
16:1
>20:1
>20:1
14:1
>20:1
–
10:1
99
95
98
98
98
>99
88
93
4b
4c
4d
4e
4 f
4g
4i
Ph (2a)
Et (3c)
92
4j
[a] The reaction was performed with 0.20 mmol of 2 and 2.0 mmol of 3 in the presence of 1d·Cl/KOtBu (5 mol%) in THF/DMF (2.0 mL) at À788C
under an argon atmosphere. [b] Yield of isolated product. [c] Diastereomeric ratio (d.r.) was determined by 1H NMR (400 MHz) spectroscopic analysis
of an aliquot of the crude reaction mixture. [d] Enantiomeric excess was determined by HPLC on a chiral stationary phase. Absolute and relative
configurations of 4b were determined from the establishment of the total synthesis (Scheme 2) and others were assigned by comparison to 4b and
4h.
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Communications
Scheme 2. Short catalytic asymmetric syntheses of (2S,3R)-(+)-xestoaminol C (5) and (À)-codonopsinines (6). THF=tetrahydrofuran,
DMF=N,N-dimethylformamide, Boc=tert-butoxycarbonyl, PMP=para-methoxyphenyl, Red-Al=sodium bis(2-methoxyethoxy)aluminum hydride,
mCPBA=meta-chloroperbenzoic acid.
bond and the nitro functionality under the hydrogenation
conditions enabled the two-step, catalytic asymmetric syn-
thesis of the long-chain vicinal amino alcohol (2S,3R)-(+)-
xestoaminol C (5),[17,18] which displays a reverse transcriptase
inhibition. Attaining high anti selectivity in the asymmetric
direct Henry reaction of aliphatic aldehydes remains an
important problem to be solved in view of making a short
synthetic route to saturated anti-vicinal amino alcohols, such
as 5. As such, Henry reaction is particularly desirable for
accessing this class of chiral building blocks. Furthermore, the
exposure of para-methoxyphenyl-substituted anti-4b (99%
ee; Table 2, entry 1) to hydrochloric acid in the presence of
indium metal gave rise to N-Boc-anti-amino propargylic
alcohol 7, leaving the triple bond intact, and it can be
exclusively converted into the corresponding E-allylic alcohol
(E)-8 with Red-Al. Meanwhile, the use of zinc powder with a
catalytic amount of cupric chloride in methanol followed by
protection of the nitrogen atom with (Boc)2O selectively
afforded Z-allylic alcohol (Z)-8 in good yield. These simple
procedures allow for the facile synthesis of various E- and Z-
configured anti-amino allylic alcohols and thus offer a unique
opportunity for rapidly constructing the structural and
stereochemical frameworks of poly-functionalized molecules.
Indeed, (E)-8 and (Z)-8 were effectively transformed into
(À)-codonopsinine (6a)[19–21] and (À)-2-epi-codonopsinine
(6b),[20b,c] respectively, where the olefin geometry of 8 was
reflected in the C2 stereochemistry of the pyrrolidine
skeleton. To the best of our knowledge, this is the first
example of a catalytic asymmetric synthesis of these pyrro-
lidine alkaloids, which exhibit antibiotic and hypotensive
activities without affecting the central nervous system.[22]
In conclusion, we have achieved the first efficient, highly
anti-selective and enantioselective direct Henry reaction of
ynals through the identification of N,N-dimethylformamide as
a crucial co-solvent for facilitating the catalysis of chiral
tetraaminophosphonium chlorides of type 1·Cl. Moreover, we
have clearly shown that the synthetic potential of this new
method relies on the usefulness of optically active anti-b-nitro
propargylic alcohols as a precursor for the preparation of a
range of stereochemically uniform, saturated, and unsatu-
rated anti-vicinal amino alcohols, including the accomplish-
ment of the short syntheses of (2S,3R)-(+)-xestoaminol C (5)
and (À)-codonopsinines (6). We believe this study greatly
expands the potential of this approach, through the addition
of an appropriate nucleophile to ynals, toward the prepara-
tion of synthetically valuable, optically active propargylic
alcohols.
Experimental Section
Tetraaminophosphonium chloride 1d·Cl (0.011 mmol, 6.90 mg) was
treated with a solution of KOtBu (1.0m in THF; 0.010 mmol, 10.0 mL)
in the presence of nitroethane (3a) (2.0 mmol, 145.0 mL) in 2.0 mL of
THF contaminating DMF (5%) at À788C for 30 min. A 0.67m
solution of 2a in THF/DMF (95:5; 0.20 mmol, 320 mL) was slowly
added to the catalyst solution and allowed to stir for 30 min.
Introduction of a 0.5m toluene solution of trifluoroacetic acid
(100 mL) at À788C was followed by pouring the reaction mixture
into a saturated aqueous solution of NH4Cl. Extractive workup with
ethyl acetate was performed and the resulting organic phase was dried
over Na2SO4. Evaporation of the volatiles gave a crude residue and
the diastereomeric ratio was analyzed by 400 MHz 1H NMR spec-
troscopy. Purification of the residue by column chromatography on
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Angewandte
Chemie
silica gel (n-hexane/ethyl acetate = 4:1) afforded 4a in quantitative
yield. Enantiomeric excess of the anti isomer was determined to be
98% ee by HPLC on a chiral stationary phase (Daisel Chiralpak AD-
H, n-hexane/2-propanol/EtOH = 90:4.5:5.5, flow rate 1.0 mLminÀ1).
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Received: July 3, 2010
Published online: August 31, 2010
Keywords: amino alcohols · Henry reaction · organocatalysis ·
.
phosphonium salts · total synthesis
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