Chiral Propargylic Alcohols:
Accessibility and Applications
Andrew H. Weiss
Department of Chemistry, Stanford University, Stanford, California 94305-5080
ahweiss@stanford.edu
ABSTRACT
O
R
R2
+ M
R1
HO R2
L*
O
L*
R
O
R
[H]
R1
R1
OH
H
H
Ph
O
O
OTIPS
Me
•
nC4H9
Optically active propargylic alcohols have long been established as robust and versatile building blocks for the
synthesis of complex natural products. Recent efforts in enantioselective catalysis have yielded a growing number
of efficient and selective processes to form such compounds. Mirroring the development of these processes is the
exciting application of such adducts in new coupling and rearrangement reactions to rapidly increase molecular
complexity.
Enantioenriched propargylic alcohols are useful and
versatile building blocks in asymmetric synthesis.1 Their
utility can be seen directly by the prevelance of alkynols in
natural products, fine chemicals, and synthetic
pharmaceuticals (Figure 1).
Some examples include
Merck’s HIV reverse transcriptase inhibitor efavirenz (1) 2
and mifepristone (2),3 the active component of RU-486.
One of the most striking examples of a naturally occurring
alkynol is the HIV reverse transcriptase inhibitor
petrosynol (3) 4 which was isolated from the marine sponge
Petrosia and contains four propargyl alcohol units.
Optically active propargylic alcohols can also serve as
precursors for a wide variety of chiral materials, as both the
alcohol and alkyne serve as handles for further
transformations. For this reason, propargyl alcohols have
been used as starting materials in many efficient syntheses.
This review will present advances in the preparation of
enantioenriched alkynols as well as their exploitation to
access complex substructures.
1
Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
Weinheim, 1995.
2
Thompson, A. S.; Corley, E. G.; Huntington, M. F. Grabowski, E. J.
J. Tetrahedron Lett. 1995, 36, 8937.
3
Bertagna, X.; Bertagna, C.; Luton, J. P.; Husson, M. J.; Girard, F. J.
Clin. Endocr. Metab. 1984, 25.
4
Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K. Tetrahedron
Lett. 1983, 28, 1377-1380.
H
N
O
H3C
O
Cl
CH3
N
CH3 OH
F3C
CH3
H
H
O
mifepristone, 2
efavirenz, 1
OH
OH
OH OH
5
5
petrosynol, 3
Figure 1. Biologically significant propargylic alcohols.
The two most common methods to prepare optically
active propargylic alcohols are through i) asymmetric
reduction of an ynone (eq 1), and ii) asymmetric metal
catalyzed alkynylation of a carbonyl (eq 2).5
5
For reviews, see: (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Pu, L.;
Yu, H.-B. Chem. Rev. 2001, 101, 757. (c) Soai, K.; Niwa, S. Chem. Rev.
1992, 92, 833.
O
L*
R1
R
+ M
R
[1]
R
R1
asymmetric
reduction
O
2
OH
[H]
R
R1
While these stoichiometric reductants produce the
desired propargylic alcohols with high chemical and optical
yields, and are often recoverable, a more atom economical9
method was desirable.
Corey’s proline-derived oxazaborolidine10 provides a
reliable, catalytic enantioselective reduction of ynones11
using catecholborane as the stoichiometric reductant. One
of the greatest advances in the field of ynone reductions,
however, is the recent use of transfer hydrogenation
(Scheme 1). Using only 0.5 mol% of Noyori’s chiral Ru
complex, ynones can be reduced with extremely high
yields and ee’s under mild neutral conditions.12
HO
L*
R2
[2]
R
asymmetric
alkynylation
R1
One of the most reliable and extensively studied
methods to form chiral propargyl alcohols is the reduction
of prochiral ynones (eq 1). Facile access to a variety of
chiral boranes spurred the early development of this area.
Alpine-borane,6,7
and
later
DIP-Cl8
(B-chlorodiisopinocampheylborane) were found to enantioselectively
reduce ynones (Figure 2). These reagents are easily
prepared from α-pinene (eq 3) and can be recovered from
the reaction mixture. Alpine-borane achieves high
enantioselectivity for sterically unhindered ynones, but
does not reduce sterically demanding ynones such as α-tBu
(eq 4). In contrast, DIP-Cl functions optimally with
sterically demanding ynones, while enantioselectivity
degrades with less sterically hindered substrates (eq 5).
BCl
1. BH3 SMe2
2
B
9-BBN
[3]
2. HCl
Alpine-Borane
(+)-pinene
DIP-chloride
Alpine-Borane: Reduces sterically unhindered ynones
O
OH
Alpine-Borane
R
[4]
R
8 hr, rt
R = iPr: 78% (91% ee)
R= tBu: no product
DIP-Chloride: Reduces sterically hindered ynones
O
OH
DIP-Cl
2-8 hr, -25 oC
R
Ph
R = Me:
Et:
iPr:
tBu:
[5]
R
92%, 21% ee
90%, 28% ee
85%, 53% ee
80%, 98% ee
Ph
Figure 2. Pinene-derived chiral reducing agents.
Scheme 1. Noyori’s asymmetric yransfer hydrogenation.12
Ph
O
Ru Ar
N
H
Ar = n6 - Mesityl, p-cymene
Ph
R2
R1
R1 = alkyl, aryl, TMS
R2 = alkyl
(0.5 mol%)
i-PrOH
OH
R2
R1
[6]
11 examples
yield >90%, ee 94-99%
Although a tremendous amount of work has led to highly
enantioselective catalytic hydrogenations, application of
these methods is ultimately limited by the necessity of an
ynone starting material. Ynones are accessible, however
the functional group suffers from a propensity to
decompose, to isomerize to allenyl ketones, or to react as
potent Michael acceptors. Also, by virtue of hydrogen
addition, reduction cannot give access to tertiary alkynols.
One solution to this problem is the application of alkyl
additions to an ynone. There has been a great deal of
fruitful research addressing this problem,13 but alkyl
additions are often complicated by ynone instability as well
and the high reactivity of the metalated alkyl group.
The addition of a terminal acetylide to an aldehyde5 (eq
2) alleviates both of these strategic concerns. There is no
necessity for an ynone or ynal as the carbonyl partner; any
aldehyde or ketone can be attacked to furnish a propargylic
alcohol. Also, the high kinetic acidity of terminal alkynes
(pKa = 25 in organic solvents) allows for their facile
deprotonation and metalation under mild conditions.
Alkynylation of a ketone (eq 2, R2 ≠ H) grants access to
tertiary carbinol centers. Also, the addition of an acetylide
has the possibility to yield a convergent synthesis,
adjoining two complex pieces while forming a stereocenter.
9
Trost, B. M. Science, 1991, 254, 1471.
Corey, E. J.; Bakshi, R.; K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J.
Am. Chem. Soc. 1987, 109, 7925.
11
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153.
12
Matsumura, K.; Hashigushi, S.; Ikarya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
13
Jeon, S.-J.; Li., H.; Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J.
Org. Chem. 2005, 70, 448 and references therein.
10
6
Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J.
Am. Chem. Soc. 1980, 102, 867.
7
Midland, M. M.; Tramontano, A.; Bazubski, A.; Graham, R. S.; Tsai,
D. J. S.; Cardin, D. B. Tetrahedron, 1984, 40, 1371.
8
Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539.
Ts
N
Scheme 2. Zn-catalyzed asymmetric alkynylation.16
nBu2N
OH
Me
Ph
OH
O
R2
R2
R1
Zn Et
2.0 equiv
H
= alkyl, aryl
R1
R2
R1
(5 mol%)
23 oC
= alkyl, aryl
[7]
R1=R2= Ph 95% (40% ee)
Numerous methods for diastereoselective14 and
enantioselective5 alkynylation of carbonyls have been
reported. The first enantioselective addition of a terminal
acetylide to an aldehyde catalyzed by a chiral amino
alcohol was reported by the Mukaiyama group15 in 1979.
Because a lithium acetylide was used, the reaction had to
be carried out at extremely low temperatures (-123 oC) to
avoid the ligandless, racemic background reaction. By
switching to Zn alkynylides (Scheme 2), the Soai group
was able to carry out enantioselective alkynylations at
room temperature without observing the racemic
background reaction.16 These important experiments paved
the way for a wealth of protocols to alkynylate aldehydes.5
Although capable of forming secondary propargylic
alcohols in high yield and ee, these processes are limited by
sensitivity to air and water, the necessity for a large excess
of metalated alkyne, and by the inability to alkynylate
ketones. These three limitations are currently being
addressed in this active area of research.
Table 1. Carreira’s ephedrine mediated alkynylation.17
sensitive dialkyl zinc species, metalation with Zn(OTf)2
and an amine base is tolerant to air and moisture (Table 1,
entry 1 vs 2). Complexation of the alkyne with Zn(OTf)2
increases the acidity of the alkyne, allowing deprotonation
with simple alkyl amine bases.
Furthermore, this
methodolgy allows a nearly 1:1 ratio of aldehyde:alkyne to
be used, and in an impressive feat of atom economy, the
reaction can be performed neat (Table 1, entry 6).17c These
conditions show broad scope with respect to aliphatic
aldehydes, however, unsaturated aldehydes are not ideal
substrates
due
to
a
competitive
Cannizzaro
disproportionation reaction (Table 1, entry 5). Ketones are
unreactive under these conditions.
Additionly, the
catalytic version of this process is not as tolerant to
moisture or varied substrate scope.
Table 2. Indium catalyzed alkynylation.18
OH
OH
O
+
R1
(10 mol%)
OH
R
InBr3 (10 mol%)
R1
Cy2NMe (50 mol%)
1-2 days, CH2Cl2
Time
yield
ee
entry
R
R1
(h)
(%)
(%)
1
Ph
Ph
24
84
95
2a
Ph
Ph
24
85
94
b
3
Ph
Ph
24
85
96
4
Cy
Ph
9
95
98
5
iBu
-(CH2)2 Ph
48
46
98
6
iBu
Ph
25
85
96
7
Cy
-(CH2)2 Ph
36
77
>99
a
b
Reaction was performed under air. InBr 3 (2 mol%), R-BINOL (2
mol%) and Cy2NMe (10 mol%) were used.
R
H
2.0 equiv
NMe2
CH3
O
R
H
+
R1
1.1 equiv
OH
OH
(1.2 equiv)
Et3N (1.2 equiv)
Zn(OTf)2 (1.1 equiv)
R
R1
yield
ee
entry
R
R1
(%)
(%)
1
iPr
-(CH2)2 Ph
88
99
2a
iPr
-(CH2)2 Ph
90
99
3a
Ph
Ph
82
93
4
Cy
TMS
93
98
5
PhCH=CH-(CH2)2 Ph
39
80
b
6
Cy
TES
87
91
a) undistilled toluene was used. b) catalytic conditions used: Zn(OTf)2
(20 mol%), Et3N (50 mol%), amino alcohol (22 mol%), reaction run neat.
A major contribution to this field came from the Carreira
group and was based on a new method for the metalation of
terminal acetylenes (Table 1).17 Alleviating the need for
14
Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudrechy, A. Chem.
Rev. 2006, 106, ASAP.
15
Mukaiyama, T.; K. Suzuki, K.; Soai, K.; Sato, T. Chem Lett. 1979,
447.
16
Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937.
17
(a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
1999, 121, 11245. (b) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 1806. (c) Anand, N. K.; Carriera, E. M. J. Am.
Recently, the alkynylation of aldehydes with high yields
and ee’s was demonstrated with an indium(III)-BINOL
complex (Table 2).18 While a variety of aliphatic and
aromatic alkynes and aldehydes were compatible, silylprotected alkynes were not tolerated. A major advantage to
this protocol is the robust nature of the catalyst, with
efficiency not affected by air (Table 2, entry 2), nor by
catalyst loadings as low as 2 mol% (Table 2, entry 3).
Alkyne additions to carbonyl compounds remain an
active area of research in the preparation of optically active
propargylic alcohols. Methods to alkynylate ketones19 as
well as utilizing particularly challenging propiolate20,21
donors have been recently reported. Substrate scope and
Chem. Soc. 2001, 123, 9687. (d) Boyall, D. Frantz, D. E.; Carreira, E. M.
Org. Lett. 2002, 4, 2605.
18
Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 13760.
19
(a) Cozzi, P. G. Angew. Chem. Int. Ed. 2003, 42, 2895. (b) Lu, G.;
Li, X. S.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem. Int. Ed.
2003, 42, 5057. (c) Chen, C.; Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R. Org.
Lett. 2006, 8, 2277, and references therein.
20
Gao, G.; Wang, Q.; Yu, X-Q.; Xie, R-G.; Pu, L. Angew. Chem. Int.
Ed. 2006, 45, 122.
21
Trost, B. M.; Weiss, A. H.; von Wagelin, A. J. J. Am. Chem. Soc.
2006, 128, 8.
catalyst loadings are improving rapidly making
alkynylations of carbonyls a practical synthetic method.
Scheme 3. Ru-catalyzed Alder-ene with propargyl alcohols.
Trost's Ancepsenolide Synthesis
[CpRu(COD)Cl]
(10 mol%)
MeOH, reflux
OH
4
CO2Et
(2 equiv)
O
OH
OEt
H3C
5
7
(75%)
7
6
is interesting to note that the gold-catalyzed process has a
high selectivity for the acetylenic Claisen (eq 9) while the
thermal process26 has the opposite selectivity (eq 10).
The Toste group reported27 a Au(I)-catalyzed
Rautenstrauch rearrangement, resulting in the synthesis of
chiral 2-cyclopentenones from pivaloate ester adducts
readily available from the enantioselective alkynylation of
α,β-unsaturated aldehydes (Scheme 4, eq 11). The chiral
information at the oxygen stereocenter was transferred
cleanly to the carbon stereocenter with high yield. Using
mild conditions, a wide variety of substituted
cyclopentenones can be efficiently prepared.
O
O
H3C
CH3
7
O
[(Ph3P)3RhCl]
O
O
O
Scheme 4. Au-catalyzed rearrangements.
H3C
H2
(93%)
O
CH3
8
(+)-ancepsenolide
O
O
OTBS
nC4H9
I
OEt
9
O
CpRu(MeCN)3PF6
(5 mol%)
CSA
(52%)
then NaBH4
OH
OH
OH
O
10
O
OEt
Ph
Acetylenic Claisen
(racemic)
O
11
[9]
•
80%
Ph
thermal
Allylic Claisen
Bipinnatin J
H
then NaBH4
O
I
O
[8]
nC4H9
OH
[(Ph3PAu)3O]BF4
(1 mol%)
OH
12
Ph
OTIPS
•
81%, 94% ee, >20:1 dr
I
O
O
H
Ph
Trauner's Bipinnatin Synthesis
OH
HO
[(Ph3PAu)3O]BF4
(1 mol%)
O
22
For a review, see: Trost, B. M.; Frederiksen, M. U.; Rudd, M. T.
Angew. Chem. Int. Ed. 2005, 44, 6630.
23
Trost, B. M.; Muller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995,
117, 1888.
24
Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345.
25
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
Ph
O
O
With improved access to chiral propargylic alcohols has
come the development of numerous approaches to exploit
these useful building blocks. One such process is the Rucatalyzed alkene-alkyne coupling to give Alder-ene type
products (Scheme 3).22 When alkyne 4 and diene 5 are
heated in methanol in the presence of a ruthenium catalyst,
the bis-butenolide 7 is formed in 75% yield. This was
used to rapidly access ancepsenolide23 (8) and has been
used to install butenolides in several natural products
including the biologically relevant (±)-bipinnatin J (12)
(Scheme 3). 24 In this synthesis, both distal stereocenters
were set diastereoselectively from the chirality of the
propargyl alcohol. Thus, this elegant 9-step synthesis
could be rendered enantioselective by using optically pure
starting alkynol 9.
Adducts from the enantioselective alkynylation of α,βunsaturated aldehydes are particularly useful intermediates
for the construction of complex molecules. They have
been shown to propagate their chiral information through
Pd-catalyzed allylic alkylation21 to form a tertiary
stereocenter, or through a gold-catalyzed Claisen
rearrangment25 to yield chiral allenes (Scheme 4, eq 8). It
[10]
HO
Ph3PAuSbF6
O
(5 mol%), 12 hrs
[11]
H
93% ee
86%, 91% ee
Chiral propargylic alcohols are incredibly versatile,
useful, and important building blocks in modern organic
chemistry.
They are available through catalytic
asymmetric reductions of ynones or directly by
alkynylations of carbonyl compounds. Although advances
in asymmetric catalysis have led to the ready access of
enantioenriched secondary propargylic alcohols, research
into the efficient and operationally facile preparation of
tertiary carbinols19 is ongoing. In addition, the necessity
for excess alkyne in most systems has hindered the
employment of alkynylations in late-stage couplings of
advanced intermediates.
The recent development of coupling reactions and
rearrangements of propargylic alcohols to obtain adducts
with increased molecular complexity has both fueled the
drive to efficiently prepare chiral alkynols and emphasized
the general value of methods for their synthesis.
26
27
Bancel, S.; Cresson, P. C. R. Acad. Sci., Ser. C 1970, 270, 2161.
Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802.