Enantioselective prophenol-catalyzed addition of 1,3-diynes to aldehydes to generate synthetically versatile building blocks and diyne natural products

Article abstract of DOI:10.1021/ja910656b

A highly enantioselective method for the catalytic addition of terminal 1,3-diynes to aldehydes was developed using our dinuclear zinc ProPhenol (1) system. Furthermore, triphenylphosphine oxide was found to interact synergistically with the catalyst to substantially enhance the chiral recognition. The generality of this catalytic transformation was demonstrated with aryl, α,β-unsaturated and saturated aldehydes, of which the latter were previously limited in alkynyl zinc additions. The chiral diynol products are also versatile building blocks that can be readily elaborated; this was illustrated through highly selective trans-hydrosilylations, which enabled the synthesis of a β-hydroxyketone and enyne. Additionally, the development of this method allowed for the rapid total syntheses of several biologically important diynol-containing natural products.

Full text of DOI:10.1021/ja910656b

Published on Web 03/22/2010
Enantioselective ProPhenol-Catalyzed Addition of 1,3-Diynes
to Aldehydes to Generate Synthetically Versatile Building
Blocks and Diyne Natural Products
Barry M. Trost,* Vincent S. Chan, and Daisuke Yamamoto
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received December 17, 2009; E-mail: bmtrost@stanford.edu
Abstract: A highly enantioselective method for the catalytic addition of terminal 1,3-diynes to aldehydes
was developed using our dinuclear zinc ProPhenol (1) system. Furthermore, triphenylphosphine oxide was
found to interact synergistically with the catalyst to substantially enhance the chiral recognition. The generality
of this catalytic transformation was demonstrated with aryl, R,ꢀ-unsaturated and saturated aldehydes, of
which the latter were previously limited in alkynyl zinc additions. The chiral diynol products are also versatile
building blocks that can be readily elaborated; this was illustrated through highly selective trans-
hydrosilylations, which enabled the synthesis of a ꢀ-hydroxyketone and enyne. Additionally, the development
of this method allowed for the rapid total syntheses of several biologically important diynol-containing natural
products.
Introduction
2). This rapid approach would set the stereocenter of the
secondary alcohol and introduce the diyne moiety in a single
Conjugated diynes are potentially intriguing building blocks
due to the unique behavior of acetylenes, especially in transition
metal-catalyzed processes.1 The unique juxtaposition of two
acetylene units in a 1,3-diyne begets unusual properties, both
from a chemical as well as biological point-of-view. Diyne
carbinols are of particular interest because of the additional
reactivity imparted by the propargyl alcohol, as well as its
presence in many fascinating bioactive, fatty acid-derived
polyacetylenic natural products (Figure 1).2,3 These optically
active propargyl alcohols exhibit a broad array of important
biological properties, ranging from antifungal to anticancer
activity.2
In spite of the growing recognition of the therapeutic potential
of these secondary metabolites, the conventional synthetic routes
to these classes of molecules are limited and lengthy. The most
common strategy employed in the total syntheses of these
molecules relies upon asymmetric ynone reductions to form the
chiral alcohol, followed by copper-catalyzed Cadiot-Chodkiewicz
cross-coupling to introduce the second acetylene unit (eq 1).3
chemical operation. While there are many effective catalyst
systems for the asymmetric nucleophilic addition of alkynes into
aldehydes,4 no known protocols exist for which the analogous
transformation can be performed with a diyne. In spite of the
structural similarities between an alkyne and 1,3-diyne, due to
hyperconjugative effects5 the two acetylenic species possess
inherently differential reactivity. Notably, the uniqueness of the
1,3-diyne was observed in practice by Carreira and co-workers:
use of their Zn(OTf)2/N-methylephedrine6a system allows for
the catalytic asymmetric synthesis of chiral propargyl alcohols,6b
however, for the coupling of diynes, a superstoichiometric
quantity (4 equiv each) of both zinc and chiral inducing agent
were required.7
Stimulated by our interest in exploring the synthetic potential
of diyne carbinols as building blocks, their presence as key
structural elements in biological metabolites and the difficulties
associated with their asymmetric syntheses, we set out to
determine if our ProPhenol (1) catalyst, which has been
successfully employed in the alkynylation of aldehydes,8 could
also effect a catalytic asymmetric addition of terminal 1,3-diynes
to carbonyl groups. Moreover, we wanted to identify a modular
(4) For a recent review, see: Trost, B. M.; Weiss, A. H. AdV. Synth. Catal.
2009, 351, 963–983.
(5) Jarowski, P. D.; Wodrich, M. D.; Wannere, C. S.; Schleyer, P. v. R.;
Houk, K. N. J. Am. Chem. Soc. 2004, 126, 15036–15037.
(6) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687–9688.
A complementary strategy for accessing a chiral diynol is
the direct addition of a terminal 1,3-diyne into an aldehyde (eq
(7) Reber, S.; Kno¨pfel, T. F.; Carreira, E. M. Tetrahedron 2003, 59, 6813–
6817.
(8) (a) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem.
Soc. 2006, 128, 8–9. (b) Trost, B. M.; Weiss, A. H. Org. Lett. 2006,
8, 4461–4464. (c) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed.
2007, 46, 7664–7666. (d) Trost, B. M.; O’Boyle, B. M. J. Am. Chem.
Soc. 2008, 130, 16190–16192. (e) Trost, B. M.; O’Boyle, B. M.; Hund,
D. J. Am. Chem. Soc. 2009, 131, 15061–15074.
(1) Stang, P. J., Diederich, F., Eds. Modern Acetylene Chemistry; VCH:
Weinheim, Germany, 1995.
(2) Minto, R. E.; Blacklock, B. J. Prog. Lipid Res. 2008, 47, 233–306.
(3) Shun, A. L. K. S.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006, 45,
1034–1057.
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5186 J. AM. CHEM. SOC. 2010, 132, 5186–5192
10.1021/ja910656b  2010 American Chemical Society

A R T I C L E S
Figure 1. Several polyacetylenic natural products with chiral diynol moiety.
Scheme 1. Proposed Mechanism for the ProPhenol (1)-Catalyzed Diynylation
diyne nucleophile which could serve as a 1,3-butadiyne
equivalent. This would provide access to a lynchpin approach
to rapidly generate both stereo- and structural complexity about
both ends of the diyne. Herein, we report the details of our
efforts to develop a catalytic asymmetric diynylation reaction
and the synthetic utility of this transformation.
however, penta-2,4-diynyl ethanoate (2b) furnished the corre-
sponding product 3b with significantly better selectivity (62%
ee).
Results and Discussion
Proposed Catalytic Cycle. It is believed that a dinuclear zinc
ProPhenol (1)-catalyzed terminal 1,3-diyne addition would
proceed in a fashion similar to the known alkynylation (Scheme
1).8a The chiral ligand 1 could react with 2 equiv of a
diynylmethylzinc species to generate the dinuclear zinc acetylide
A. We hypothesize that in intermediate A the Zn acetylide is
also coordinated to the nitrogen of the prolinol moiety and
oxygen of the phenol. These hypervalent interactions serve to
give the acetylide more anionic character, that is the nucleophile
is an activated diynyl zincate species.9 Furthermore, the active
catalyst contains a Lewis acidic Zn alkoxide which can bind
an aldehyde (B). Preorganization of the diyne and aldehyde
allows for a directed addition reaction to form the propargyl
zinc alkoxide C. Transmetalation between C and another
molecule of diynylmethylzinc liberates the desired product and
turns over the catalytic cycle.
Reaction Optimization. To establish that our dinuclear zinc
ProPhenol (1) catalyst system could facilitate the addition of a
terminal 1,3-diyne to an aldehyde, we evaluated the reaction of
protected penta-2,4-diyn-1-ols with octanal (eq 3). Under the
previously developed conditions,8a when tert-butyldimethyl-
(penta-2,4-diynyloxy)silane7 (2a) was used as the donor, pro-
pargyl alcohol 3a was isolated in 48% ee and 68% yield;
Since the nonreactive terminus of the 1,3-diyne is far removed
from the active site of the catalyst (see Scheme 1), it was
surprising that such a subtle substituent change impacted the
selectivity so significantly. Given that 3 equiv of donor was
used, we postulated perhaps the Lewis basic acetate of diyne
2b could be interacting with the Zn catalyst. This observation
is consistent with previous outcomes where methyl propiolate
was shown to be a more effective nucleophile than (trimethyl-
silyl)acetylene in alkynylations with the ProPhenol (1) catalyst.8a,b
Based on these results we sought to identify an exogenous,
substoichiometric Lewis base additive that could enhance the
enantioselectivity of the diynylation.
In the evaluation of Lewis base additives for the ProPhenol-
catalyzed diynylation, we chose to employ buta-1,3-diynyltri-
isopropylsilane (4) as the nucleophile. The reason for doing so
was two-fold: this particular diyne lacked any Lewis basic sites
which could potentially interfere with the action of the additive,
and furthermore, the cleavable TIPS group could allow for
further functionalization of the diynol product. Diyne 4 was
reacted with octanal using 10 mol % ProPhenol ligand 1, 3 equiv
of Me2Zn and a catalytic amount of an additive (eq 4). Working
under the assumption that our active catalyst was a dinuclear
zinc species, we added an equivalent of Lewis base per Zn atom
(Table 1).
(9) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc.
1986, 108, 6071–6072.
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A R T I C L E S
Table 1. Evaluation of Catalytic Lewis Bases in the Diynylationa
Table 2. Optimization of the Phosphine Oxidea
a Reaction as shown in eq 4 with 1 equiv of octanal, 3 equiv of diyne
4, 10 mol % 1, and 3 equiv of Me2Zn. b Isolated yield of diynol 5.
c Enantiomeric excess of 5 determined by chiral HPLC. d TDMPPO )
tris(2,6-dimethoxyphenyl)phosphine oxide. e BINAPO ) 2,2′-bis(diphenyl-
phosphoryl)-1,1′-binaphthyl.
Table 3. Optimization of TPPO Stoichiometrya
a Reaction run with 3 equiv of diyne 4. b Isolated yield. c Enantio-
meric excess determined by chiral HPLC. d Amount of molecular sieves
added based on 100 mg/mmol of octanal.
entry
mol % TPPO
% yieldb
% eec
1
2
3
4
10
20
50
65
63
66
57
73
79
77
77
In the absence of any additive, the catalytic coupling of 4
with octanal yielded propargyl alcohol 5 in only 50% ee (entry
1). The use of 4 Å molecular sieves, a common practice in the
ProPhenol/dinuclear zinc aldol reactions,10 proved detrimental
to the enantioselectivity (entry 2). Since the acetate moiety of
diyne 2b had a unique effect on the enantioselectivity, carbonyl-
type Lewis bases were primarily examined. Although ethyl
acetate and ethylene carbonate gave only modest improvements
in the selectivity of the diyne addition (entries 4 and 5,
respectively), they proved that a catalytic additive could enhance
the reaction. The Trost10a,11 and Shibasaki12 groups previously
demonstrated that oxidized phosphines could significantly
impact both the reactivity and diastereoselectivity, respectively,
of dinuclear zinc-catalyzed aldol reactions. Moreover, Shibasaki
and co-workers have repeatedly exploited this phenomenon for
1,2-additions of various nucleophiles to aldehydes with poly-
metallic catalysts.13 When triphenylphosphine sulfide, which
should have a high affinity for zinc, was evaluated, diynol 5
was isolated in only 58% ee (entry 6); however, with only 20
mol % triphenylphosphine oxide (TPPO) the enantioselectivity
of the diynylation improved to 79% ee (entry 7).
100
a Reaction as shown in eq 4 with 1 equiv of octanal, 3 equiv of diyne
4, 10 mol % 1, and 3 equiv of Me2Zn. b Isolated yield of diynol 5.
c Enantiomeric excess of 5 determined by chiral HPLC.
Figure 2. (a) Top-down, quadrant view of proposed TPPO coordination
to the dinuclear zinc catalyst. (b) Side view of the dinuclear zinc/TPPO
catalyst with diyne and aldehyde substrates bound.
evaluated, however, they were also found to be suboptimal
cocatalysts (entries 5-7), giving enantioselectivities similar to
the diynylation with no additive. Thus, triphenylphosphine oxide
was found to be the most effective cocatalyst for this
transformation.
Once TPPO was identified as a beneficial cocatalyst, an array
of tertiary phosphine oxides were subsequently examined in the
addition of TIPS diyne 4 to octanal (Table 2). Tri(2-furyl)phos-
phine oxide, which has multiple Lewis basic sites, proved to
be less effective than TPPO in the diynylation (68% ee, entry
2). The sterically demanding tris(2,6-dimethoxyphenyl)phos-
phine oxide, which the Shibasaki group has utilized quite
successfully,13 furnished diynol 5 in only 57% ee (entry 3). A
trialkylphosphine oxide was examined, but did not perform as
well as TPPO (entry 4). Bidentate phosphine oxides were
Next, optimization of the triphenylphosphine oxide stoichi-
ometry was performed (Table 3). In the coupling of TIPS diyne
4 with octanal, only 20 mol % TPPO (relative to 10 mol %
ProPhenol ligand) was required to maximize the enantioselec-
tivity (entry 2). Decreasing the cocatalyst loading led to a
marginally less selective diynylation (entry 1), while increasing
the amount of TPPO beyond 20 mol % did not further enhance
the enantioselectivity (entries 3 and 4).
The optimal 2:1 ratio of TPPO:ProPhenol suggests that each
zinc atom in the active catalyst is coordinated by a single
phosphine oxide. Based on this observation, as well as crystal-
lographic data of the dinuclear zinc catalyst,14 where a molecule
of THF is bound to each Zn atom, we hypothesize that the
triphenylphosphine oxides are “trans” to one another (Figure
2a). This proposed structure also explains why bidentate
phosphine oxides, which cannot achieve the necessary binding
geometry, were not beneficial (Table 2, entries 5-7). Further-
more, illustrated in Figure 2b is the putative TPPO/dinuclear
(10) For the seminal publication, see: (a) Trost, B. M.; Ito, H. J. Am. Chem.
Soc. 2000, 122, 12003–12004. For a recent example and references
therein: (b) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572–
4573.
(11) (a) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497–2500.
(b) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338–
339.
(12) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.;
Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466–2467.
(13) For leading references: Yamagiwa, N.; Abiko, Y.; Sugita, M.; Tian,
J.; Matsunaga, S.; Shibasaki, M. Tetrahedron: Asymmetry 2006, 17,
566–573.
(14) Xiao, Y.; Wang, Z.; Ding, K. Chem.sEur. J. 2005, 11, 3668–3678.
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A R T I C L E S
Table 4. Asymmetric Addition of TIPS Diyne 4a
Table 5. Diyne Scope in the Asymmetric Addition to Aldehydesa
a Reaction performed with 1 equiv of aldehyde and 3 equiv of diyne
donor. b Isolated yields. c Enantiomeric excess determined by chiral
HPLC. d Reaction was performed with 2 equiv of diyne and Me2Zn.
e Catalyst loading was increased to 20 mol % 1 and 40 mol % TPPO.
a Reaction run with 1 equiv of aldehyde and 2 equiv of diyne 4;
unreacted equivalents of
4
could be recovered. b Isolated yields.
R,ꢀ-unsaturated aldehyde by the dinuclear zinc catalyst was less
effective (entry 9).
c Enantiomeric excess determined by chiral HPLC. d Reaction performed
with 3 equiv each of 4 and Me2Zn.
Saturated aldehydes were also suitable electrophiles in the
enantioselective diynylation (Table 4, entries 10-12). The
coupling of 4 with 4-(4-methoxybenzyloxy)butanal using 10 mol
% (S,S)-1, 20 mol % TPPO and 3 equiv of Me2Zn furnished
the chiral alcohol in up to 80% ee (entry 10). Even bulky
R-substituted aldehydes proceeded with interesting levels of
enantiomeric excess: cyclohexane carboxaldehyde furnished the
corresponding diynol in 67% ee, while 2,2-dimethyl-4-pentenal
reacted with 4 in 83% ee (entries 11 and 12, respectively).
zinc catalyst with the diyne and aldehyde substrates bound. It
is likely the improved enantioselectivity is a result of the
triphenylphosphine oxides reinforcing the chiral pocket created
by the diphenylprolinol scaffold.
Scope of the Diyne Addition. Having identified optimal
conditions for the asymmetric diyne addition, we then set out
to investigate the scope of this transformation (Tables 4 and
5). In the diynylation of R,ꢀ-unsaturated aldehydes, it is
noteworthy that utilization of the TPPO cocatalyst allowed for
reduction of the amount of diyne and dimethylzinc used from
3 to 2 equiv without impacting either the reactivity or enanti-
oselectivity. Although excess diyne is still required for good
reactivity, the unreacted equivalents could be recovered.
Under the standard catalytic conditions (10 mol % ProPhenol
ligand 1 and 20 mol % TPPO), aromatic aldehydes were suitable
electrophiles; for instance TIPS diyne 4 reacted with 2-furfural
in 98% ee and 95% yield (Table 4, entry 2). Acrolein, a typically
difficult substrate, was a competent acceptor, furnishing prop-
argyl alcohol 6c in up to 86% ee and 89% yield (entry 3).
Substitution at either the R- or ꢀ-positions of the aldehyde was
also well-tolerated. In spite of the increased steric congestion
at the R-position, the diynylation of methacrolein provided
alcohol 6d in 87% ee and 94% yield (entry 4). Sensitive
functional groups such as a vinylcyclopropane (6e: 97% ee, entry
5) and allylic dimethylacetal (6f: 95% ee, entry 6) were
unperturbed under the reaction conditions. The coupling of diyne
4 with a simple trans-unsaturated aldehyde such as trans-2-
decenal led to diynol 6h being formed in 97% ee (entry 8);
however, discrimination of the enantiotopic π-faces of a cis-
Having demonstrated the effectiveness of TIPS diyne 4 as a
nucleophile in the asymmetric addition, we then examined the
substitution tolerated on the donor (Table 5). As previously
shown (eq 3), the presence of primary propargyl ethers was
tolerated. While the enantiomeric excesses were vastly improved
with the addition of 20 mol % triphenylphosphine oxide, the
selectivity was still highly dependent on the protecting group
used. The tert-butyldimethylsilyl-protected diyne 2a now coupled
with octanal in 65% ee and 76% yield (3a, entry 1), whereas
the analogous reaction with penta-2,4-diynyl ethanoate 2b
proceeded in 82% ee and 73% yield (3b, entry 2). More
importantly, the mild nature of the reaction conditions allows
for the presence of an activated ester with no side effects. Use
of an R,ꢀ-unsaturated aldehyde was also successful: the reaction
of trans-2-nonenal with acetate-protected diyne 2b furnished
diynol 7a in 97% ee and 93% yield (entry 3). More elaborate
linear saturated aldehydes were also suitable acceptors for the
diyne addition: donor 2b was used to quickly access chiral
propargyl alcohols 7b and 7c, precursors to strongylodiols A
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A R T I C L E S
Scheme 2. Selective Synthetic Manipulations of the Chiral Diynol
and B, with good reactivity and enantioselectivity (entries 4 and
5, respectively).
Given the trans-selectivity of the ruthenium-catalyzed hy-
drosilylation, we also envisioned employing this as a method
for the partial reduction of alkynes to trans-olefins (Scheme 2,
eq 6).18 Treatment of diynol 7d with benzyldimethylsilane
(BDMS-H) and 2 mol % [Cp*Ru(MeCN)3][PF6] furnished the
resulting vinylsilane 10 exclusively. Replacing the bulky tri-
isopropylsilyl group on the diyne terminus (see eq 5 in Scheme
2) with a smaller cyclohexyl substituent did not impact the
chemoselectivity, suggesting the hydrosilylation is indeed
directed by the propargyl alcohol. Facile protodesilylation was
achieved by treatment of 10 with tetrabutylammonium fluoride
in THF to afford enyne 11 in 75% yield over two steps.
Unfunctionalized 1,3-diynes were also viable donors with our
dinuclear zinc catalyst system. Buta-1,3-diynylcylclohexane
reacted with an R,ꢀ-unsaturated aldehyde to furnish diynol 7d
in 91% ee (entry 6) and octanal to afford 7e in 73% ee (entry
7). The electronic nature of the diyne was varied by extending
the conjugation of the π-system; addition of a cyclohexenediyne
into trans-4-methyl-2-pentenal afforded propargyl alcohol 7f
quantitatively in 88% ee (entry 8).
Selective Functionalization of the Diynols. Given the versatile
nature of the alkyne, we envisioned our optically active diyne
carbinols could be useful synthetic building blocks. Previous
studies in the Trost group demonstrated the use of [Cp*Ru-
(MeCN)3][PF6] (Cp* ) pentamethylcyclopentadienyl) as a
catalyst for the regioselective trans-hydrosilylation of propargyl
alcohols.15 Furthermore, the resulting vinylsilane is a useful
functional handle; in particular, it can be rendered to a ketone.16
Given the highly selective nature of this ruthenium catalyst, we
were interested in using it to exploit the directing ability of the
propargyl alcohol to distinguish between the two alkynyl units
and chemoselectively functionalize the proximal alkyne (Scheme
2).
Natural Product Synthesis. The versatility of the asymmetric
diynylation was also established through the total syntheses of
a variety of optically active polyacetylenic natural products.
Strongylodiols A (12) and B (13) were isolated from an
Okinawan marine sponge of the genus and exhibited micromolar
activity against several human cancer cell lines.19 As shown
earlier, penta-2,4-diynyl ethanoate (2b) was an effective nu-
cleophile for the coupling with saturated aldehydes and offered
quick access to two strongylodiol precursors (Table 5, entries
4 and 5). While these strongylodiols have been previously
synthesized,7,20 the overall efficiency of the ProPhenol-catalyzed
transformation allows for a more atom-economical21 approach.
Following the key diynylation step, strongylodiol A (12) was
isolated in quantitative yield from 7b through a base-mediated
cleavage of the primary propargyl acetate (Scheme 3, eq 7);
strongylodiol B (13) was also synthesized in a similar manner
(eq 8 in Scheme 3).
As previously mentioned, we chose to use TIPS diyne 4
because it is a surrogate for 1,3-butadiyne. We sought to
demonstrate the versatility of this nucleophile in the total
synthesis of panaxytriol (14), an active component of red
ginseng which is commonly used in traditional Asian medi-
cine.22 Aside from its well-known analeptic and erythropoietic
properties, panaxytriol is also cytotoxic against a variety of
Subjection of a diynol to a hydrosilylation/oxidation sequence
would furnish the corresponding aldol adduct, a ꢀ-hydroxy
ynone. The direct aldol reaction with methyl ynones was
previously accomplished using the ProPhenol dinuclear zinc
catalyst,17 however, the addition was limited to R,R-disubstituted
aldehydes. Moreover, conventional aldol reaction methods
involving electron-deficient aldehydes give competing elimina-
tion to form the unsaturated ketone. In the context of the
asymmetric addition, our diyne nucleophile would serve as a
methyl ynone surrogate for a challenging class of aldol reactions
(eq 5 in Scheme 2). Treatment of furyl diynol 6b with
ethoxydimethylsilane and 5 mol % [Cp*Ru] afforded the cyclic
1
vinylsiloxane 8 quantitatively as observed by H NMR spec-
troscopy. It is of note that this hydrosilylation proceeded with
exquisite chemo- and regioselectivity; the other possible isomers
were not observed. Subsequent Tamao-Fleming oxidation of
intermediate 8 with KHF2 and mCPBA furnished the desired
ꢀ-hydroxyketone 9 in 70% overall yield from diyne 6b.
(18) Trost, B. M.; Ball, Z. T.; Jo¨ge, T. J. Am. Chem. Soc. 2002, 124, 7922–
7923.
(19) Watanabe, K.; Tsuda, Y.; Yamane, Y.; Takahashi, H.; Iguchi, K.;
Naoki, H.; Fujita, T.; Van Soest, R. W. M. Tetrahedron Lett. 2000,
41, 9271.
(15) (a) Trost, B. M.; Ball, Z. T.; Jo¨ge, T. Angew. Chem., Int. Ed. 2003,
42, 3415–2418. (b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005,
127, 17644–17655.
(20) (a) Yadav, J. S.; Mishra, K. Tetrahedron Lett. 2002, 43, 1739–1741.
(b) Kirkham, J. E. D.; Courtney, T. D. L.; Lee, D.; Baldwin, J. E.
Tetrahedron Lett. 2004, 45, 5645–5647. (c) Kirkham, J. E. D.;
Courtney, T. D. L.; Lee, V.; Baldwin, J. E. Tetrahedron 2005, 61,
7219–7232.
(16) Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc.
2005, 127, 10028–10038.
(17) (a) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004,
126, 2660–2661. (b) Trost, B. M.; Frederiksen, M. U.; Papillon,
J. P. N.; Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem.
Soc. 2005, 125, 3666–3667.
(21) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281. (c) Trost, B. M.
Acc. Chem. Res. 2002, 35, 695–705.
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Scheme 3. Total Syntheses of Strongylodiols A and B
Figure 3. Structural similarity of 17 and falcarindiol.
Scheme 5. Total Synthesis of (3S,8S)-17a
Scheme 4. Total Synthesis of (3R,9R,10R)-Panaxytriol (14)a
a Conditions: (a) 1) Ac2O, Et3N, 10 mol % DMAP, CH2Cl2; 2) Bu4N+F-,
AcOH, THF, 0 °C, 70% over 2 steps; (b) decyl aldehyde, 20 mol % (R,R)-
1, 40 mol % TPPO, 3 equiv Me2Zn, toluene, 4 °C, 67%.
also interested in constructing a molecule using sequential
asymmetric diynylations. 8-Hydroxyheptadeca-1-en-4,6-diyn-
3-yl ethanoate (17), an unnamed natural product, was an ideal
target with which to demonstrate this principle (Figure 3).
Isolated from the Tanzanian medicinal plant Cussonia zimmer-
mannii, polyacetylene 17 exhibited potent antiprotozoal activity
and also cytotoxicity.27 Although the structure was elucidated
by NMR spectroscopy, no stereochemical assignment was
reported. As this molecule had not been previously synthesized,
a total synthesis would serve to confirm the structural assignment
and establish the absolute and relative stereochemistry. Given
the structural similarity of 17 with (3S,8S)-falcarindiol,28 we
hypothesized the target compound also possesses the (3S,8S)-
configuration.
Since (S,S)-ProPhenol (1) affords the (R)-diynol, use of the
(R,R)-enantiomer was required to prepare ent-6c with the correct
stereochemistry (Scheme 5). The absolute configuration of the
diyne addition was verified by the O-methylmandelate ester
method.29,30 Treatment of ent-6c with acetic anhydride, followed
by cleavage of the TIPS group with TBAF, furnished 18 in 70%
yield. The resulting terminal diyne was then utilized in a
subsequent ProPhenol-catalyzed diynylation; this double-bar-
reled approach allows for the rapid construction of two
challenging stereocenters. Under the reaction conditions with
catalytic (R,R)-1 and TPPO, diyne 18 coupled with decyl
aldehyde to furnish polyacetylene 17 in 67% yield.
a Conditions: (a) Bu4N+F-, THF, 0 °C, >99%; (b) 1) BuLi, THF, -78
°C, then BF3 ·Et2O; 2) 16, THF; 3) Bu4N+F-, 70%.
cancer cell lines.23 Furthermore, recent studies have shown that
the anticancer properties of 14 are a result of a cytoprotective
mechanism.24,25 Due to its important biological properties, many
total syntheses of panaxytriol have been accomplished,26 where
the C3 stereocenter has been derived from sugar degradation,26a,b,e
enzymatic resolution,26d or asymmetric ynone reduction,26f,g but
not through direct asymmetric diyne addition (Scheme 4).
Treatment of diynol 6c, formed in 86% ee from the addition
of TIPS diyne 4 into acrolein, with TBAF revealed terminal
diyne 15. Next, double deprotonation of 15 with BuLi generated
the dianion which was complexed with BF3 ·Et2O to form the
diynyl borate. The reaction of this acetylide with siloxy epoxide
16 led to regioselective ring-opening of the epoxide. An in situ
quench of the ring-opened intermediate with TBAF furnished
(3R,9R,10R)-panaxytriol in 70% yield. This lynchpin diynylation
strategy not only allowed for rapid enantioselective construction
of the diyne carbinol, but also facile coupling of two chiral
fragments without the need to discretely preactivate either piece.
Through our sequence, (3R,9R,10R)-panaxytriol was prepared
in 70% yield over three steps from acrolein.
In the synthesis of panaxytriol, a chiral diynol was coupled
with a fragment containing its own chirality; however, we were
The measured optical rotation of the synthetic natural product
was consistent with the literature report, confirming our
hypothesis that naturally occurring 17 is of the (3S,8S)-
configuration. Furthermore, the stereochemistry of the propargyl
alcohol at C8 was verified using the O-methylmandelate ester
method;30 this derivitization also revealed the diastereoselectivity
(>8.2:1 dr) of the second addition. Also of note is that the chiral
acetoxy group in diyne 18 did not appear to interfere with the
stereoselectivity of the second diynylation. Since the formation
of the two stereogenic centers was catalyst controlled, the other
(22) (a) Kitagawa, I.; Yoshikawa, M.; Yoshihara, M.; Hayashi, T.;
Taniyama, T. Yakugaku Zasshi 1983, 103, 612–622. (b) Kitagawa, I.;
Taniyama, T.; Shibuya, H.; Noda, T.; Yoshikawa, M. Yakugaku Zasshi
1987, 107, 495–505.
(23) (a) Katano, M.; Yamamoto, H.; Matsunaga, H.; Mori, M.; Takata,
K.; Nakamura, M. Gan to Kagaku Ryoho 1990, 17, 1045–1049. (b)
Matsunaga, H.; Saita, T.; Naguo, F.; Mori, M.; Katano, M. Cancer
Chemother. Pharmacol. 1995, 35, 291–296. (c) Saita, T.; Katano, M.;
Matsunaga, H.; Kouno, I.; Fujito, H.; Mori, M. Biol. Pharm. Bull.
1995, 18, 933–937. (d) Kim, J. Y.; Lee, K.-W.; Kim, S.-H.; Wee,
J. J.; Kim, Y.-S.; Lee, H. J. Planta Med. 2002, 68, 119–122.
(24) Halim, M.; Yee, D. J.; Sames, D. J. Am. Chem. Soc. 2008, 130, 14123–
14128.
(25) Ng, F.; Yun, H.; Lei, X.; Danishefsky, S. J.; Fahey, J.; Stephenson,
K.; Flexner, C.; Lee, L. Tetrahedron Lett. 2008, 49, 7178–7179.
(26) (a) Lu, W.; Zheng, G.; Cai, J. Synlett 1998, 737–738. (b) Lu, W.;
Zheng, G.; Gao, D.; Cai, J. Tetrahedron 1999, 55, 7157–7168. (c)
Gurjar, M. K.; Kumar, V. S.; Rao, B. V. Tetrahedron 1999, 55, 12563–
12576. (d) Mayer, S. F.; Steinreiber, A.; Orru, R. V. A.; Faber, K. J.
Org. Chem. 2002, 67, 9115–9121. (e) Yadav, J. S.; Maiti, A.
Tetrahedron 2002, 58, 4955–4961. (f) Yun, H.; Danishefsky, S. J. J.
Org. Chem. 2003, 68, 4519–4522. (g) Yun, H.; Chou, T.-C.; Dong,
H.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Org. Chem. 2005, 70,
10375–10380. (h) Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257–259.
(27) (a) Baur, R.; Simmen, U.; Senn, M.; Se´quin, U.; Sigel, E. Mol.
Pharmacol. 2005, 68, 787–792. (b) Senn, M.; Gunzenhauser, S.; Brun,
R.; Se´quin, U. J. Nat. Prod. 2007, 70, 1565–1569.
(28) Bernart, M. W.; Cardellina, J. H., II; Balaschak, M. S.; Alexander,
M. R.; Shoemaker, R. H.; Boyd, M. R. J. Nat. Prod. 1996, 59, 748–
753.
(29) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec,
J. M. J. Org. Chem. 1986, 51, 2370–2374.
(30) See the Supporting Information for analysis of the O-methylmandelate
esters.
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A R T I C L E S
diastereomers of 17 can be rapidly accessed simply by inter-
changing the ProPhenol ligand.
lectivities, they were still effective substrates as exemplified in
the expedient total synthesis of the antifungal (3S,8S)-8-
hydroxyheptadeca-1-en-4,6-diyn-3-yl ethanoate (17), where we
verified the structure and assigned the stereochemistry of the
natural product. Most importantly, use of this lynchpin approach
allowed for the direct and facile generation of molecular
complexity around the butadiyne moiety.
Conclusion
In conclusion, a catalytic and enantioselective process for
terminal 1,3-diyne additions to aldehydes has been developed.
Notably, in combination with the ProPhenol (1) catalyst,
triphenylphosphine oxide served to enhance the chiral recogni-
tion of the dinuclear zinc acetylide species, a unique effect that
was not previously observed in our aldol additions. The
ProPhenol-catalyzed diynylation exhibited good generality with
a variety of silyl- and alkyl-substituted diyne nucleophiles.
Furthermore, we evaluated a range of aldehydes and demon-
strated that aryl, R,ꢀ-unsaturated, and the potentially enolizable
saturated aldehydes are all well-tolerated by the dinuclear zinc
catalyst system.
The chiral diynols formed were also used as synthetic building
blocks; by taking advantage of the directing effect of the
propargyl alcohol, the proximal alkyne moiety could be
manipulated in a highly chemo- and regioselective fashion.
Through a hydrosilylation/Tamao-Fleming oxidation sequence,
we showed that the diyne carbinol is a ꢀ-hydroxy-ynone
surrogate. Additionally, the 1,3-diyne could be partially reduced
to the olefin in a trans-selective manner to furnish highly
functionalized allylic alcohols.
Experimental Section
Typical Procedure for Asymmetric Diyne Addition into
Aldehydes. A flame-dried microwave vial equipped with a stir bar
was charged with triphenylphosphine oxide (8.7 mg, 0.031 mmol,
0.2 equiv), ProPhenol ligand 1 (10 mg, 0.016 mmol, 0.1 equiv),
and toluene (1.0 mL) under argon. The TIPS diyne 4 (77 µL, 0.31
mmol, 2 equiv) was added via syringe, followed by dimethylzinc
(261 µL, 0.31 mmol, 2 equiv, 1.2 M in toluene). The alkynyl zinc
solution was stirred at room temperature for 30 min, and then the
reaction solution was cooled to 0 °C and the appropriate aldehyde
added (0.16 mmol, 1 equiv). The reaction was left to proceed under
argon at 4 °C. After 24 h, the reaction solution was quenched with
aqueous, saturated NH4Cl (2 mL) and stirred vigorously for 10 min.
The toluene phase was separated, and the aqueous phase was
extracted with Et2O (4 × 2 mL). The combined organic fractions
were dried over sodium sulfate, filtered, and concentrated on a rotary
evaporator. The crude product was then purified by flash column
chromatography on silica gel.
The synthetic utility of this method was further demonstrated
in the total syntheses of four biologically active polyacetylenic
natural products. The cytotoxic strongylodiols A and B (12 and
13, respectively) were synthesized in a straightforward manner
using a catalytic asymmetric addition of diyne 2b into the
corresponding saturated aldehydes with good levels of enanti-
oselectivity. Employment of a lynchpin strategy, where si-
lyldiyne 4 served as a 1,3-butadiyne surrogate, enabled the rapid
preparation of (3R,9R,10R)-panaxytriol (14) in only six steps
in the longest linear sequence. Although the diynylation with
saturated aldehydes did not always yield the highest enantiose-
Acknowledgment. We thank the NSF and the NIH (GM 33049)
for their generous support of our programs. We also thank Sigma-
Aldrich for donating ProPhenol ligand. V.S.C. acknowledges Dr.
J. P. Lumb for insightful discussions.
Supporting Information Available: Detailed experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA910656B
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5192 J. AM. CHEM. SOC. VOL. 132, NO. 14, 2010