Diastereoselective synthesis of syn-1,3-diols by titanium-mediated reductive coupling of propargylic alcohols

Article abstract of DOI:10.1021/ol902609k

(Figure presented) A titanium-mediated, hydroxy-directed reductive coupling reaction of propargylic alcohols and aldehydes/ketones Is described. Excellent diastereoselectivity and synthetically useful yields have been obtained for a range of substrates. This transformation has enabled a highly convergent three-component approach to syn-1,3-diols using (trimethylsilyl)acetylene as a C1 linchpin.

Full text of DOI:10.1021/ol902609k

ORGANIC
LETTERS
2010
Vol. 12, No. 2
288-290
Diastereoselective Synthesis of
syn-1,3-Diols by Titanium-Mediated
Reductive Coupling of Propargylic
Alcohols
Guo-Qiang Tian, Thomas Kaiser, and Jiong Yang*
Depeartment of Chemistry, Texas A&M UniVersity, College Station, Texas 77842-3092
yang@mail.chem.tamu.edu
Received November 13, 2009
ABSTRACT
A titanium-mediated, hydroxy-directed reductive coupling reaction of propargylic alcohols and aldehydes/ketones is described. Excellent
diastereoselectivity and synthetically useful yields have been obtained for a range of substrates. This transformation has enabled a highly
convergent three-component approach to syn-1,3-diols using (trimethylsilyl)acetylene as a C1 linchpin.
Homochiral 1,3-diols are ubiquitous in natural products of
polyketide origin. The synthesis of these structural motifs
normally relies on stereoselctive C-H or C-C bond forma-
tion of ꢀ-hydroxycarbonyl compounds or C-O bond forma-
tion of homoallylic alcohols (Figure 1).1 These ꢀ-hydroxy-
carbonyl compounds and homoallylic alcohols are in turn
prepared by stereoselective aldol or allylation reactions.
Theoretically, a 1,3-diol can be more convergently prepared
by sequential couplings of a 1,1-bismetallic C1 linchpin or
its functional equivalent with two aldehydes. We envisioned
terminal acetylenes to be such functional equivalents of 1,1-
bismetallic reagents. A synthetic sequence consisting of a
stereoselective alkynylation of the first aldehyde followed
by a diastereoselective reductive coupling of the propargylic
Figure 1. Synthesis of 1,3-diols.
alcohol intermediate with a second aldehyde would lead to
formation of a 1,3-diol. The enantio- and diastereoselective
alkynylations of aldehydes have been well documented, and
the alkyne-aldehyde reductive couplings by a number of
transition metal based systems are also known.2,3 While
(1) For a recent review: Bode, S. E.; Wolberg, M.; Mu¨ller, M. Synthesis
2006, 557–588.
(2) For the enantio- and diastereoselective alkynylations of aldehydes: (a)
Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151–3152. (b)
Tan, L.; Chen, C. Y.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew.
Chem., Int. Ed. 1999, 38, 711–713. (c) Frantz, D. E.; Fa¨ssler, R.; Carreira,
E. M. J. Am. Chem. Soc. 2000, 122, 1806–1807. (d) Anand, N. K.; Carreira,
E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688. (e) Xu, M. H.; Pu, L. Org.
Lett. 2002, 4, 4555–4557. (f) Trost, B. M.; Weiss, A. H.; von Wangelin,
A. J. J. Am. Chem. Soc. 2006, 128, 8–9. (g) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2004, 4095–4105. (h) Walsh, P. J.
Acc. Chem. Res. 2003, 36, 739–749. (i) Guillarme, G.; Ple, K.; Banchet, A.;
Liard, A.; Haudrechy, A. Chem. ReV. 2006, 106, 2355–2403. (j) Trost, B. M.;
Weiss, A. H. AdV. Synth. Catal. 2009, 351, 963–983.
(3) For some reviews: (a) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV.
2000, 100, 2835–2886. (b) Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000,
753–775. (c) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100,
2789–2834. (d) Sato, F.; Okamoto, S. AdV. Synth. Catal. 2001, 343, 759–
784. (e) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890–3908. (f)
Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1269–1279. (g) Moslin, R. M.;
Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441–4449. (h)
Montgomery, J.; Sormune, G. J. Top. Curr. Chem. 2007, 279, 1–23. (i)
Iida, H.; Krische, M. J. Top. Curr. Chem. 2007, 279, 77–104. (j) Ngai,
M.-Y.; Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063–1072.
(k) Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische, M. J. Angew. Chem.,
Int. Ed. 2009, 48, 34–46
.
10.1021/ol902609k  2010 American Chemical Society
Published on Web 12/04/2009

enantioselective variants of these reductive couplings have
been reported for limited sets of substrates,3 very few
examples exist for diastereoselective alkyne-aldehyde reduc-
tive couplings. One such precedent was from the lab of
Micalizio, which reported that ene-1,5-diols could be pre-
pared by the reductive coupling of homopropargylic alcohols
and aldehydes with moderate diastereoselectivity.4 Herein
we report the first highly diastereoselecitve hydroxy-directed
alkyne-aldehyde reductive coupling of propargylic alcohols
and aldehydes to syn-1,3-diols by Ti(Oi-Pr)4/i-PrMgCl.5
We chose the propargylic alcohols derived from (tri-
methylsilyl)acetylene for the investigation because the tri-
methylsilyl group had been reported to direct the titanium-
mediated reductive coupling with aldehydes to occur at the
acetylene carbon distal to the silyl group.6 In addition, the
silyl group can later be removed by protodesilylation or used
as a handle for additional transformations. An initial concern
was that ꢀ-elimination of the hydroxy group might compete
with the desired reductive coupling process because deriva-
tives of propargylic alcohols have been known to undergo
ꢀ-elimination under titanium-mediated reductive coupling
conditions to give rise to allenyltitanium species.7 However,
we speculated that the elimination reaction pathway could
be suppressed by initial formation of an alkoxide, which
had been shown to be compatible with the titanium-mediated
reductive coupling conditions.8,9 In addition, advantage could
be taken of the propargylic alkoxide for hydroxy-directed
reductive coupling to achieve diastereocontrol.10 To validate
these hypotheses, we used propargylic alcohol 1a, prepared
from (trimethylsilyl)acetylene and isobutyraldehyde, as the
test substrate. We were gratified to find that the desired
coupling did occur between 1a and cyclohexanecarboxal-
dehyde under the reductive conditions mediated by Ti(Oi-
Pr)4/i-PrMgCl, and diastereoselective (dr ) 18:1) formation
of the syn-1,3-diol 2a was unambiguously confirmed by
X-ray crystallographic analysis (Scheme 1). A major side
Experiments were carried out to optimize the reaction
conditions. Formation of 3a was minimized by conducting
the reaction at -40 to -50 °C (see Supporting Information).
Whereas Ti(Oi-Pr)4 and ClTi(Oi-Pr)3 gave similar results for
the reductive coupling, replacement of i-PrMgCl with
i-PrMgCl·LiCl or c-C5H9MgCl gave inferior yields and
diastereoselectivities. Similar results were obtained when the
reaction was carried out with toluene or THF as the solvent.
We probed the scope of the reaction using a range of
propargylic alcohols and aldehydes. Most of these substrates
showed excellent diastereoselectivity and synthetically useful
yields (Table 1). Notable exceptions are aromatic and R,ꢀ-
Table 1. Reductive Coupling of Propargylic Alcohols and
Aldehydes
entrya
1
R
R′
2
yield (%)b (syn/anti)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
i-Pr
Cy
i-Pr
Et
t-Bu 2d
Ph
2a
2b
2c
74 (18:1)
58 (18:1)
58 (18:1)
trace
2e
2fc
2g
2h
2i
2j
2k
2l
47 (7:1)
1bc PhCH2CH2 Cy
60 (>20:1)
78 (20:1)
57 (>20:1)
71 (>20:1)
58 (>20:1)
77 (4:1)
43 (10:1)
74 (11:1)
trace
1c
1c
1d
1d
1e
1f
n-Pr
Cy
i-Pr
Cy
Et
Cy
Cy
Cy
Cy
9
Et
10
11
12
13
14
Ph
PhCHCH
Cy
1g
1h
2m
2n
t-Bu
a Reaction conditions: 1.0 equiv of the propargylic alcohol, 1.6 equiv
of Ti(Oi-Pr)4 in diethyl ether, and 3.2 equiv of i-PrMgCl, -40 °C, 4 h;
then 3.5 equiv of the aldehyde, -78 to -40 °C, 18 h. b Isolated yield. c >94%
ee, determined by HPLC analysis with a CHIRALCEL IB column.
Scheme 1. Reductive Coupling of 1a
unsaturated aldehydes. For example, reductive coupling of
1a with benzaldehyde gave less than satisfactory yield as a
result of the competing pinnacol reaction (entry 5),11 and
cinnamaldehyde gave only a trace amount of the coupling
product (not shown). A remedy to these inefficient reductive
couplings with aromatic and R,ꢀ-unsaturated aldehydes was
to prepare the propargylic alcohols from these aldehydes
instead. Good diastereoselectivity and synthetically useful
yields were obtained from these propargylic alcohols (entries
11 and 12). The reactions could be carried out at a scale of
10 mmol of the propargylic alcohols with similar results
(entries 1 and 6). Enantiomeric purity of the propargylic
alcohol was maintained under the reductive coupling condi-
product was identified to be 3a, arising from regioisomeric
coupling of the titanocyclopropene intermediate with cyclo-
hexanecarboxaldehyde.
(4) (a) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc.
2005, 127, 3694–3695. (b) Bahadoor, A. B.; Micalizio, G. C. Org. Lett.
2006, 8, 1181–1184.
(5) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.; Pri-
tytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244–2245. (b) Kulinkovich, O. G.;
Sviridov, S. V.; Vasilevski, D. A. Synthesis 1991, 234.
(6) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203–
3206.
(9) For related hydroxy-directed hydrozirconation reactions: (a) Zhang,
D.; Ready, J. M. J. Am. Chem. Soc. 2007, 129, 12088–12089. (b) Liu, X.;
Ready, J. M. Tetrahedron 2008, 64, 6955–6960.
(7) (a) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995,
36, 3207–3210. (b) Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett.
1998, 39, 4551–4554.
(10) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307–1370.
(11) (a) Muramatsu, Y.; Harada, T. Angew. Chem., Int. Ed. 2008, 47,
1088–1090. (b) Matiushenkov, E. A.; Sokolov, N. A.; Kulinkovich, O. G.
Synlett 2004, 77–80.
(8) See ref 3a,b and Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39,
7329–7332
.
Org. Lett., Vol. 12, No. 2, 2010
289

tions (entry 6). The steric requirements of the tert-butyl
groups have been attributed to the low reactivities of entries
4 and 14.
Scheme 3. Reduction of syn-1,3-Diol 2f
The reductive coupling of propargylic alcohols was not
limited to aldehydes. While only a limited set of ketones
have been tested (Table 2), synthetically useful diastereo-
Table 2. Reductive Coupling of Propargylic Alcohols and
Ketones
the vinylsilane 2f was protodesilylated by TBAF-Cu(Ot-Bu)
to give diol 5.13 Reduction of 5 by the in situ prepared
diimide gave the anti,anti-stereotriad 6 with moderate
diastereoselectivity (dr ∼3:1). On the other hand, masking
the diol 5 as an acetonide prior to catalytic hydrogenation
by H2 and 10% Pd/C allowed its diastereoselective reduction
to generate the syn,syn-stereotriad 7 exclusively. Thus,
titanium-mediated reductive coupling of propargylic alcohols
and aldehydes followed by protodesilylation and diastereo-
selective reduction provides a convergent and highly efficient
entry to both the anti,anti- and syn,syn-stereotriads, which
are important structural motifs common to natural products
of polyketide origin.
entry
1
R
R′
R′′
2
yield (%)
1
2
3
4
5
1c
1c
1d
1d
1a
n-Pr
-(CH2)5-
Ph
n-Bu
Et
4a
4b
4c
4d
4e
66
Me
Me
Me
Me
17 (>20:1)
62 (11:1)
56 (2:1)
26 (4:1)
Et
i-Pr
vinyl
selectivity and yields were obtained for nonaromatic ketones
(entries 1 and 3). The stereochemistry of the major products
was assigned by analogy to that of the coupling products
with aldehydes. Interestingly, only the 1,2-addition product
(4e) was obtained when methyl vinyl ketone was used as
the substrate (entry 5).
To verify that the reductive coupling is indeed directed
by the propargylic hydroxy group, the PMB-protected
propargylic alcohol 1d′ and cyclohexanecarboxaldehyde were
subjected to the same titanium-mediated reductive coupling
conditions (Scheme 2).12 Although the coupling reaction did
In summary, a titanium-mediated, hydroxy-directed reduc-
tive coupling of propargylic alcohols and aldehydes/ketones
has been developed. Excellent diastereoselectivity and
synthetically useful yields were obtained with a range of
substrates. This reaction enabled a highly convergent three-
component approach to syn-1,3-diols using (trimethylsilyl)-
acetylene as a C1 linchpin and with other reagents of low
costs.14 These diols could be conveniently transformed into
valuable building blocks for target-oriented synthesis. Ap-
plications of this approach in target-oriented synthesis are
in progress and the results will be reported in due course.
Scheme 2. Reductive Coupling of 1d′
Acknowledgment. Support was provided by Texas A&M
University and The Welch Foundation (A-1700). We thank
the Laboratory for Biological Mass Spectrometry (TAMU)
for mass spectral analysis and the X-ray Diffraction Labora-
tory (TAMU) for X-ray analysis.
occur in 62% yield, the diastereoselectivity (dr ) 2:1) of
the reaction was mostly lost, indicating the pivotal role of
the hydroxy group in the stereoselectivity of the reaction.
However, a better understanding of the directing effect of
the hydroxy group in the titanium-mediated reductive
coupling still awaits further mechanistic studies.
The synthetic utility of these syn-1,3-diols was deomon-
strated by the stereoselective conversion of 2f to both the
anti,anti- and syn,syn-stereotriads 6 and 7 (Scheme 3). First,
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902609K
(13) (a) Taguchi, H.; Ghoroku, K.; Tadaki, M.; Tsubouchi, A.; Takeda,
T. Org. Lett. 2001, 3, 3811–3814. (b) Taguchi, H.; Ghoroku, K.; Tadaki,
M.; Tsubouchi, A.; Takeda, T. J. Org. Chem. 2002, 67, 8450–8456.
(14) For an interesting comparison of the true costs of the reductive
coupling by the stoichiometric Ti(Oi-Pr)4/i-PrMgCl system and the sub-
stoichiometric Ni-, Rh-, Ir-, and Ru-based systems, see ref 11 of Chen,
M. Z.; Micalizio, G. C. Org. Lett. 2009, 11, 4982–4985.
(12) A single example of titanium-mediated reductive coupling of a THP-
protected secondary propargylic alcohol and propionaldehyde had been
reported, but with no indication of diastereoselectivity of the reaction:
Yamashita, K.; Sato, F. Tetrahedron Lett. 1996, 37, 7275–7278.
290
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