Asymmetric catalytic alkynylation of acetaldehyde: Application to the synthesis of (+)-tetrahydropyrenophorol

Article abstract of DOI:10.1002/anie.201203035

In control: By controlling the kinetics of alkynylation over aldolization, the challenging asymmetric catalytic alkynylation of acetaldehyde has been realized. The resulting products are attractive synthons which are produced with good to excellent enanti

Full text of DOI:10.1002/anie.201203035

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DOI: 10.1002/anie.201203035
Synthetic Methods
Asymmetric Catalytic Alkynylation of Acetaldehyde: Application to
the Synthesis of (+)-Tetrahydropyrenophorol**
Barry M. Trost* and Adrien Quintard
Enantiopure propargylic alcohols are highly potent function-
alities present in a wide range of natural products or in pivotal
synthetic building blocks. This is especially true for the
propargylic alcohols where the substituent is a methyl
(Scheme 1). Because of the ability to effect the chemo-
unmet challenge arises from the propensity of acetaldehyde
to serve at the same time as an excellent nucleophile and
electrophile, thus leading to its rapid consumption by self-
aldolization. In addition, the difficulty of controlling the
relatively small steric difference between the methyl and
hydrogen atom typically results in decreased enantiocontrol.
Attracted by this daunting problem during our application of
our ProPhenol alkynylation methodology to the synthesis of
complex natural products,[3m,n] we wondered if one could solve
this problem by favoring the kinetics of alkynylation over the
self-aldolization.[5] Herein we disclose our discovery of such
a process and its implementation to natural products syn-
thesis.
Optimization of the asymmetric catalytic alkynylation of
acetaldehyde is summarized in Table 1. Given the low price
and ready availability of acetaldehyde and the late-stage
Table 1: Screening of reaction conditions for the addition to acetalde-
hyde.
Scheme 1. Challenge of the catalytic asymmetric alkynylation of acetal-
dehyde.
selective elaboration of the alkyne unit, this process is
potentially applicable to the innumerous targets bearing
a chiral methyl carbinol subunit. Methods allowing access to
these particularly attractive targets are relatively atom and
time consuming. They are often based upon alkynylation via
the lithiated alkyne and subsequent kinetic resolution or
asymmetric reduction (Scheme 1).[1] In addition, the use of
the lithiated alkyne suffers from substrate compatibility.
Alternatively, direct catalytic asymmetric alkynylation of
aldehydes has recently appeared as a direct method of choice
to access propargylic alcohols.[2]
Unfortunately, despite recent progress, the alkynylation of
enolizable aldehydes (aliphatic aldehydes) remains limited.[3]
This is especially true for the asymmetric alkynylation of
acetaldehyde. The rare examples on this problematic reaction
report low yields and ee values, narrow scope, and the
requirement of a stoichiometric amount of ligand.[4] This
Entry
Time for
addition of 1
t
[h]
T [8C]
Equiv L*/
P(O)Ph3
Yield
[%][a]
ee
[%][b]
1
2
3
4
5
0 min
16
15
1
4
4
À20
À40
À20
0.1:0.2
0.2:0.4
0.2:0.4
0.2:0.4
0.2:0.2
29
79
53
61
86
70
81
15 min
30 min
20 min
30 min
78
2
1
47[c]
75
[a] Yields of isolated product obtained from 0.2 mmol of the starting
alkyne. [b] Determined by HPLC. [c] Only 59% conversion observed.
employment of this process, the alkyne becomes the limiting
partner. In preliminary attempts to apply our ProPhenol
catalyst and add the aldehyde all at once, a low yield of the
alkynylation product was observed (entry 1). Instead, the
product arising from self-aldol condensation of the acetalde-
hyde was recovered as the major one. This aldol process, also
catalyzed by the zinc/ProPhenol system, is due to the high
propensity of the aldehyde to serve both as a powerful
electrophile and nucleophile.[5a] Understanding that this side
reaction was due to the relatively high concentration of
aldehyde, we envisaged distracting the aldehyde from its self-
condensation and directing it to the desired alkynylation
process by modulating the different kinetics. This goal should
be attained by playing on the relative concentration of the
[*] Prof. B. M. Trost, Dr. A. Quintard
Department of Chemistry, University of Stanford
Stanford, CA 94035-5080 (USA)
E-mail: bmtrost@stanford.edu
[**] We thank the National Science Foundation (CHE-0846427) and the
National Institutes of Health (GM-33049) for their generous
support of our programs. A.Q. is grateful to the Swiss National
foundation for a fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203035.
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different species. A slow addition of acetaldehyde should
keep its concentration low at any given moment in time
provided the rate of addition of the alkyne to the aldehyde is
faster than the rate of adding the aldehyde, a substantial
challenge.[3] Surprisingly, in contradiction to literature indi-
cators where a prolonged reaction time was required, slow
addition of the aldehyde over only 15 minutes gave a 79%
yield together with a promising 61% ee using the ProPhenol-
based catalyst (entry 2). A temperature of À208C and
addition time of 30 minutes was found to be optimal in
terms of enantiocontrol (entry 3). Under these reaction
conditions, the reaction yielded 78% of the desired product
with an 86% ee (93:7 e.r.). Further decrease in temperature
did not improve the enantioselectivity (entry 4). Interestingly,
compared to previous alkynylations,[3] the reaction was
impressively fast and was over at the end of the aldehyde
addition. Finally, changing the ProPhenol/P(O)Ph3 ratio from
1:2 to 1:1 only slightly decreased the selectivity of the reaction
(81% ee, entry 5). While the X-ray structure of the zinc
ProPhenol catalyst shows that two Lewis-basic THF mole-
cules bind to the dinuclear complex, the small impact of
reducing the ratio of phosphine oxide to catalyst supports the
notion that two phosphine oxides may not be coordinated in
the transition state.[6]
tivities of 71–86% ee. The application of electron-poor
alkynes led to adducts 3e–3g with enhanced enantioselectiv-
ities ranging from 90–98% ee. Equally important, the reaction
tolerated a more complex structure bearing an extra stereo-
center to give the adduct 3h in excellent yield (98% yield,
1.1:1 d.r.). Formation of the new stereocenter of the same
configuration in 78–86% ee, even when using the racemic
propargyl acetate as a donor demonstrates the preference for
catalyst control over substrate control and is promising for the
application of this highly tolerant system at a late stage in
a total synthesis.[7]
It is interesting to note that adducts such as 3c or 3g,
which are rapidly obtained by this approach, have already
found applications in complex natural product synthesis but
previously required lengthy preparations.[9]
Surprisingly, when applying the optimized alkynylation
conditions to the highly functionalized product 4, the complex
structure 8 arising from an unexpected alkynylation/aldoliza-
tion cascade was formed predominantly (Scheme 3). Gratify-
ingly, optimizing the reaction conditions by decreasing the
This promising reactivity was further confirmed when
applying electronically different alkynes (Scheme 2). As
already observed for related systems, the reaction was
dependent on the nature of the donor alkyne. As a result,
the temperature had to be adjusted to obtain an optimal
reactivity. In a general trend, electron-rich alkynes had good
reactivities, thus forming adducts 3a–3d with enantioselec-
Scheme 3. Addition of highly functionalized alkyne 4 and 6 to acetalde-
hyde.
amount of aldehyde and directly quenching the reaction at the
end of the addition allowed isolation of the isomerized
product 5, as well as 7 (from 6) with good enantiocontrol (88–
94% ee). Interestingly, this enantiocontrol is independent of
the preexisting stereocenter of the starting material which is
destroyed during the reaction (both enantiomers of 5 could be
obtained in equal stereocontrol simply by changing the
absolute configuration of the ProPhenol).[8] It should be
pointed out that the resultant elaborated products, readily
obtained in two steps from commercially available starting
materials, are the equivalent of an asymmetric addition of an
acylalkyne to acetaldehyde (i.e., by hydrolysis of the enol
ether liberating the free corresponding ketone).
In addition, the enantiomer of 3e, prepared in 78% yield
from 1 mmol of starting alkyne, could lead in two steps to
a known precursor of minquartynoic acid (10), a natural
Scheme 2. Scope of the prophenol catalyzed alkynylation of acetalde-
hyde. TIPS=triisopropylsilyl.
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polyacetylenic molecule with anti-HIV and cytotoxic proper-
ties (Scheme 4).[10]
To highlight the potential of this process, notably in terms
of its tolerance, we envisioned its application for the synthesis
Scheme 4. Formal synthesis of minquartynoic acid. a) (R,R)-ProPhenol
(20 mol%), P(O)Ph3 (40 mol%), acetaldehyde, Me2Zn, toluene, À208C,
78%, 94% ee. b) 1. MOMCl, DIPEA, CH2Cl2; 2. nBu4NF, AcOH, THF,
65% over two steps. DIPEA=diisopropylethylamine, MOM=methox-
ymethyl, THF=tetrahydrofuran.
Scheme 6. Synthesis of (+)-tetrahydropyrenophorol. a) (S,S)-ProPhenol
(20 mol%), P(O)Ph3 (40 mol%), acetaldehyde, Me2Zn, toluene, 48C,
77% yield, 98% ee. b) 2. LiOH aq, THF then CuCl, CH3CN; 2. BzCl,
DMAP, pyridine, 90% over 2 steps. c) (S,S)-ProPhenol (20 mol%),
P(O)Ph3 (40 mol%), 15, Me2Zn, toluene, 08C, 70% yield, 12:1 d.r.
d) 1. H2, Rh/C, iPrOH; 2. TBDMSCl, imidazole, CH2Cl2; 3. NaOH aq,
MeOH, 25% over 3 steps. e) (R,R)-ProPhenol (20 mol%), P(O)Ph3
(40 mol%), 15, Me2Zn, toluene, 08C, 75% yield, 9:1 d.r. f) 1. 3,4-
dihydropyran, PPTS, CH2Cl2; 2. H2, Rh/C, iPrOH; 3. NaOH aq, MeOH,
40% over 3 steps. g) 1. PPh3, DEAD, toluene/THF (10:1), À258C;
2. PPTS, MeOH, 58% over two steps. Bz=benzoyl, DMAP=4-(dime-
thylamino)pyridine, PPTS=pyridinium para-toluenesulfonate,
TBDMS=tert-butyldimethylsilyl.
of a more complex structure, namely the natural diolide
macrocycle (À)-tetrahydropyrenophorol 11 (Scheme 5).[11]
The synthetic challenge of pyrenophorol derivatives arises
12 could be isolated from the corresponding mixture (12 is
another natural metabolite related to tetrahydropyreno-
phorol isolated from the same endophytic Phoma sp).[11]
This failure led us to turn to a Mitsunobu-type cyclization
to form the cyclic diolide.[15] The flexibility of this alkyne
strategy allowed us to invert the stereochemistry at C4 from
the same precursor 13 by using the (R,R)-ProPhenol ligand.
Successive mild protection, subsequent hydrogenation, and
treatment with base successfully provided access to the
cyclization precursor 17. A Mitsunobu-type cyclization and
subsequent THP removal gratifyingly led to an efficient
synthesis of (+)-tetrahydropyrenophorol 11.[16]
Mechanistically, this study has revealed several interesting
features of the ProPhenol-catalyzed alkynylation. First, the
multicatalytic nature of the ProPhenol ligand allows an
impressively fast alkynylation, thus limiting side reactions.
Most importantly, the rate of addition seems to play an
important role on the enantioselectivity of the reactions, that
is, the slower addition improves the stereoselectivity as well as
the yield.[17] This crucial mechanistic aspect suggests that
when a slow addition is performed, the concentration of the
aldehyde is lower, and only one molecule of aldehyde
coordinates to the Lewis-acidic zinc atoms of the ProPhenol.
Restricting the number of bound acetaldehyde molecules
limits the number of possible diastereoisomeric transition
states, thus resulting in higher ee values.
Scheme 5. Retrosynthesic analysis of tetrahydropyrenophorol.
from the difficulty in controlling the two stereocenters at
remote positions (1,4-diols). This issue has led the literature
syntheses to be relatively lengthy.[12] Retrosynthetic discon-
nection of this structure by iterative alkynylation should
control in an independent manner the rapid introduction of
both stereocenters, thus considerably shortening the syn-
thesis.
Preliminary attempts at controlling the stereochemistry at
C4 first failed because of its particular instability.[13] This issue
led us to reverse our synthetic strategy by controlling the
stereochemistry at C7 first (Scheme 6). Applying the alkyny-
lation of acetaldehyde, ester removal, and alcohol protection
led to 13 (98% ee). This product underwent a highly efficient
second asymmetric alkynylation yielding 14 with good
diastereocontrol. Hydrogenation and subsequent protection
of the alcohol with TBDMS was then performed in the hope
of applying our recently disclosed acid-catalyzed macrocyc-
lization strategy.[14] Unfortunately, this failed due to the silyl
group lability. Indeed, deprotection of the two esters proved
infeasible and instead, only the dihydropyrenophorolic acid
In summary, thanks to the control of the relative rates of
aldolization versus alkynylation, we have been able to address
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Soc. 2001, 123, 9687; c) G. Lu, X. Li, W. L. Chan, A. S. C. Chan,
the challenge of asymmetric acetaldehyde alkynylation. This
simple process was additionally applied to the rapid and
efficient synthesis of a natural product, (+)-tetrahydropyr-
enophorol. As a result of its high practicality, the chemo-
selectivity of alkynylzinc intermediates, the catalyst rather
than substrate control, and the range of accessible molecules,
we believe that this methodology will find applications in the
late stages of syntheses of other complex natural products
where catalyst rather than substrate control becomes crucial.
The novel use of substrates 5 or 7 as acylalkyne equivalents is
also noteworthy. The combination of the unexpected mech-
anistic implications with the synthetic utility makes the
observations of particular importance.
Chem. Commun. 2002, 172; d) G. Gao, D. Moore, R.-G. Xie, L.
Pu, Org. Lett. 2002, 4, 4143; e) S. Reber, T. N. Knopfel, E. M.
Carreira, Tetrahedron 2003, 59, 6813; f) T. Xu, C. Liang, Y. Cai, J.
Li, Y.-M. Li, X.-P. Hui, Tetrahedron: Asymmetry 2009, 20, 2733;
g) Y. Yue, M. Turlington, X.-Q. Yu, L. Pu, J. Org. Chem. 2009, 74,
8681; h) B. M. Trost, V. S. Chan, D. Yamamoto, J. Am. Chem.
Soc. 2010, 132, 5186; i) Y. Du, M. Turlington, X. Zhou, L. Pu,
Tetrahedron Lett. 2010, 51, 5024; j) M. Turlington, Y. Du, S. G.
Ostrum, V. Santosh, K. Wren, T. Lin, M. Sabat, L. Pu, J. Am.
Chem. Soc. 2011, 133, 11780; k) N. Kojima, S. Nishijima, K.
Tsuge, T. Tanaka, Org. Biomol. Chem. 2011, 9, 4425; l) R.
Boobalan, C. Chen, G.-H. Lee, Org. Biomol. Chem. 2012, 10,
1625; m) B. M. Trost, M. J. Bartlett, Org. Lett. 2012, 14, 1322;
n) B. M. Trost, A. C. Burns, M. Bartlett, T. Tautz, A. H. Weiss, J.
Am. Chem. Soc. 2012, 134, 1474; o) M. Turlington, L. Pu, Synlett
2012, 23, 649.
Experimental Section
[4] For scarce examples of asymmetric acetaldehyde alkynylation all
requiring stochiometric amounts of ligand (three examples in
41–87% yield and 67–72% ee), see: a) B. J. Albert, A. Sivar-
amakrishnan, T. Naka, K. Koide, J. Am. Chem. Soc. 2006, 128,
2792; b) B. J. Albert, A. Sivaramakrishnan, T. Naka, N. L.
Czaicki, K. Koide, J. Am. Chem. Soc. 2007, 129, 2648; c) D.
Beatriz, PCT, WO2004092098, 2004.
[5] For the discovery of the ProPhenol system and its use in aldol
reaction, see: a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122,
12003; For the first use of the ProPhenol system in aldehyde
alkynylation: b) B. M. Trost, A. H. Weiss, A. J. von Wangelin, J.
Am. Chem. Soc. 2006, 128, 8.
[6] For the X-Ray structure of Zn/ProPhenol, see: Y. Xiao, Z. Wang,
K. Ding, Chem. Eur. J. 2005, 11, 3668. In a previous paper
(Ref [3h]), it was suggested that two Ph3PO might be coordi-
nated during the transition state. This statement seems rather
unlikely and an alternative where only one Ph3PO is present
during the alkynylation looks more plausible. The slight differ-
ence observed between a 1:2 and 1:1 L*/Ph3PO ratio might
better be explained by a Lewis base concentration effect playing
on its ability to compete with acetaldehyde coordination.
[7] Application of the same unprotected starting material consid-
erably decreased both reactivity and enantiocontrol (74% yield
by a 1 h20 addition, 1:1 d.r., 39/45% ee).
Typical procedure for the alkynylation of acetaldehyde: A microwave
vial equipped with a stir bar was charged with the corresponding
alkyne (0.2 mmol, 1 equiv), 25.1 mg of (S,S)-ProPhenol ligand
(0.04 mmol, 20 mol%), 21.9 mg of P(O)Ph3 (0.08 mmol, 40 mol%).
Dry toluene (0.3 mL) was then added and the mixture cooled to 08C
under N2. A Me2Zn solution (0.5 mL; 1.2m in toluene) was then
slowly added over 5 min and the mixture stirred at 08C for 25 min.
The mixture was then placed at the appropriate bath temperature
(À208C or 08C) in a cold room (48C). Acetaldehyde (50 mL;
0.8 mmol; 4 equiv) was then slowly added in small portions (4 mL)
over 30 min. The resulting mixture was then stirred at the appropriate
temperature for 2 h before being slowly quenched by slow addition of
3 mL of aqueous NH4Cl. After stirring for 15 min, this solution was
extracted four times each with 3 mL of diethyl ether, dried over
MgSO4, filtered, and the solvent evaporated. Purification by silica gel
chromatography (n-hexane/Et2O) afforded the corresponding alco-
hol.
Received: April 20, 2012
Revised: May 1, 2012
Published online: June 5, 2012
Keywords: alkynes · asymmetric catalysis ·
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natural product synthesis · synthetic methods · zinc
[8] It must be pointed out that NMR analysis did not allow us to
determine the geometry of the enol ether.
[9] See Refs. [4a,b] and: B. M. Trost, T. J. J. Muller, J. Martinez, J.
Am. Chem. Soc. 1995, 117, 1888.
[1] For selected examples of asymmetric methods to access such
enantioenriched propargylic alcohols containing a methyl group,
see: a) K. Matsumura, S. Hashguchi, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1997, 119, 8738; b) S. Hu, L. P. Hager, J. Am.
Chem. Soc. 1999, 121, 872; c) A. Ford, S. Woodward, Angew.
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Parenty, J.-M. Campagne, Tetrahedron: Asymmetry 2004, 15,
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i) Y. Xing, G. A. Doherty, Org. Lett. 2009, 11, 1107. For a review
dealing with the preparation of enantioenriched compound with
a methyl substituent, see: j) K. Endo, T. Shibata, Synthesis 2012,
DOI: 10.1055s-0031-1290869.
[10] See the Supporting Informatin for details. This precursor had
previously required an 11 step sequence for its synthesis: a) G.
Sabitha, C. S. Reddy, J. S. Yadav, Tetrahedron Lett. 2006, 47,
4513. For another shorter synthesis of this natural product:
b) B. W. Gung, H. Dickson, Org. Lett. 2002, 4, 2517.
[11] K. Krohn, U. Farooq, U. Florke, B. Schulz, S. Draeger, G.
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2007, 3206, and references herein.
[12] For the precedented syntheses of pyrenophorol in 14 to 21 steps,
see: a) F. J. Dommerholt, L. Thijs, B. Zwanenburg, Tetrahedron
Lett. 1991, 32, 1499; b) N. Machinaga, C. Kibayashi, Tetrahedron
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B. V. Subba Reddy, Tetrahedron Lett. 2009, 50, 5984; e) J. S.
Yadav, G. M. Reddy, T. S. Rao, B. V. S. Reddy, A. Al Khazim Al
Ghamdi, Synthesis 2012, 783; For the synthesis of pyrenophorol
(15 steps) and tetrahydropyrenophorol (16 steps), see: f) H.-S.
Oh, H.-Y. Kang, Bull. Korean Chem. Soc. 2011, 32, 2869. For an
early approach to chiral 1,4-diols through aldehyde asymmetric
alkynylation, see: g) M. Amador, X. Arisa, J. Garcia, J. Ortiz,
Tetrahedron Lett. 2002, 43, 2691.
[2] For a recent review, see: B. M. Trost, A. H. Weiss, Adv. Synth.
Catal. 2009, 351, 963.
[3] For recent selected examples of catalyzed alkynylation of easily
enolizable aldehydes (aldehydes with
a contiguous CH2):
a) D. E. Frantz, R. Fassler, E. M. Carreira, J. Am. Chem. Soc.
2000, 122, 1806; b) N. K. Anand, E. M. Carreira, J. Am. Chem.
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[13] See the Supporting Information for details. Derivatization of 7
also led to an advanced precursor of tetrahydropyrenophorol.
Unfortunately, the difficulty at separating the obtained diaste-
reoisomers prevented us from accomplishing the particularly
short six-step route to the natural diolide (see the Supporting
Information).
[14] B. M. Trost, J. D. Chisholm, Org. Lett. 2002, 4, 3743.
[15] H. Gerlach, K. Gertle, A. Thanann, Helv. Chim. Acta 1977, 60,
2860.
It is worth mentioning that 3-butyn-2-ol, easily obtained in two
steps by this sequence, is a rather expensive commercially
available compound (Alrich: 1 g (R) enantiomer= 142.5 USD,
1 g (S) enantiomer= 214.5 USD).
[17] This higher enantiocontrol when performing a slow addition was
also observed when using other aldehydes or when scaling up the
reactions (see the Supporting Information for details). This is in
agreement with the role of triphenylphosphine oxide in these
alkynylations. See Ref. [3h]).
[16] For the mild THP protection/removal method, see: M. Miya-
shita, A. Yoshikoshi, P. A. Grieco, J. Org. Chem. 1977, 42, 3772.
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