A new and more powerfully activating diamine for practical and scalable enantioselective aldehyde crotylsilylation reactions

Article abstract of DOI:10.1039/c3sc50714a

A new diaminophenol ligand for crotylsilylation reactions with cis- and trans-crotyltrichlorosilane has been developed. The conformational constraints that result from the tethering of the phenol to one of the amino groups attenuate the stereoelectronic effects that reduce activity in the corresponding untethered diaminosilanes, and the resulting crotylsilane reagents are as active as our previously reported EZ-CrotylMix reagents, but without requiring the use of the Sc(OTf)₃ catalyst. In turn, this has allowed the development of an experimentally straightforward, sustainable, efficient, and scalable one-pot procedure which may be carried out in ≤8 hours, and in which the diaminophenol activator ligand may be easily recovered in ≥90% yield by recrystallization.

Full text of DOI:10.1039/c3sc50714a

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A new and more powerfully activating diamine for
practical and scalable enantioselective aldehyde
crotylsilylation reactions†
Cite this: Chem. Sci., 2013, 4, 2413
*
Linda M. Suen, Michael L. Steigerwald and James L. Leighton
A new diaminophenol ligand for crotylsilylation reactions with cis- and trans-crotyltrichlorosilane has been
developed. The conformational constraints that result from the tethering of the phenol to one of the
amino groups attenuate the stereoelectronic effects that reduce activity in the corresponding
untethered diaminosilanes, and the resulting crotylsilane reagents are as active as our previously
reported EZ-CrotylMix reagents, but without requiring the use of the Sc(OTf)3 catalyst. In turn, this has
allowed the development of an experimentally straightforward, sustainable, efficient, and scalable one-
pot procedure which may be carried out in #8 hours, and in which the diaminophenol activator ligand
may be easily recovered in $90% yield by recrystallization.
Received 14th March 2013
Accepted 9th April 2013
DOI: 10.1039/c3sc50714a
www.rsc.org/chemicalscience
otherwise meet every single condition listed above save one:
their preparation is involved enough that they cannot be offered
Introduction
Asymmetric aldehyde crotylation reactions rank among the
most important and widely used methods for non-aromatic
polyketide natural product synthesis.1,2 Despite several impor-
tant conceptual and/or practical advances3–10 since the devel-
at a low enough price for use on larger scales ($tens of mmols),
a problem which is exacerbated by the fact that the crotylsilane
reagents are heavy (569 g molꢀ1) due in large part to the
bromine atoms which are necessary for crystallinity. Thus,
while the EZ-CrotylMixes remain a highly attractive option for
smaller scale reactions and in particular for complex aldehydes,
the important goal of devising an equally user-friendly and
scalable yet also inexpensive crotylation method remains
unmet.
The preparation of the EZ-CrotylMixes involves the reaction
of the requisite enantiomer of the diamine ligand with either
cis- or trans-crotyltrichlorosilane and DBU, followed by
concentration, trituration, and ltration of the DBU$HCl salts
with pentane, recrystallization of the crotylsilane reagent, and
admixture with the Sc(OTf)3 catalyst, all under strictly
opment
of
Brown's
crotylboranes11
and
Roush's
crotylboronates,12 it remains an unmet but eminently worthy
goal to devise an asymmetric aldehyde crotylation method that
is characterized by (1) wide scope and generality with respect to
the aldehyde substrate, (2) access to either product diaste-
reomer with uniformly very high levels of both diaster-
eoselectivity and enantioselectivity, and (3) sustainable, safe,
inexpensive, and otherwise practical and scalable procedures
such that the crotylation of a low MW aldehyde on a tens-of-
grams or larger scale is a simple undertaking that may be
carried out in less than a day by a single chemist. There are only
two methods that meet most of these conditions, the Brown
protocol11 and our recently reported EZ-CrotylMix method-
ology.13 The former suffers from being quite labor intensive,
requiring the metallation of butene under cryogenic conditions,
and quite oen from difficulties in product isolation, and it is
no accident that this has historically been the method of choice
in academic settings where labor is relatively inexpensive. By
contrast, the commercially available EZ-CrotylMixes are espe-
cially attractive in terms of extraordinary ease of use and
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York,
10027, USA. E-mail: leighton@chem.columbia.edu; Fax: +1 212-932-1289; Tel: +1
212-854-4262
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data; computational procedures and optimized geometries for
3 and 8. See DOI: 10.1039/c3sc50714a
Scheme 1 (A) The procedure for the synthesis and isolation of the EZ-Cro-
tylMixes. (B) Attempts to form and employ the EZ-CrotylMixes in situ are
unsuccessful.
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anhydrous conditions (Scheme 1A). While this procedure their performance in the allylation reactions of several alde-
facilitated commercialization of the EZ-CrotylMixes, it seems hydes was evaluated. Both 2 and 3 were characterized by reac-
clear that the ideal approach for larger scale applications would tivity that is similar to that of silane 1 (generally poor reactivity
involve skipping all of these technically challenging operations in the absence of Sc(OTf)3 e.g.), but with reduced levels of
and instead simply adding the Sc(OTf)3 catalyst and the alde- enantioselectivity (Scheme 2A). In addition, silanes 2 and 3 did
hyde to the crotylsilane reagent in situ. Unfortunately, under not appear to be signicantly more hydrolytically stable than
these conditions no catalysis is observed, a failure which may be silane 1, and could not be exposed to air for long periods of time
attributed to deactivation of the Sc(OTf)3 by the large quantities without signicant decomposition. The breakthrough came
of chloride ion present in the mixture (Scheme 1B). There thus unexpectedly when we decided to explore further the phenoxy-
appeared to be no obvious simple technical solution, and it silane motif, except with the phenol ring tethered to one of the
seemed that the only way to solve this problem would be to amino groups. Diaminophenols 5 and 6 were synthesized and
devise a new crotylsilane reagent that is as active as the EZ- used to prepare allylsilanes 7 and 8,14 which for the purposes of
CrotylMix system, but without requiring the use of a catalyst.
initial evaluation were isolated from the DBU salts (Scheme 2B).
Noting surprisingly fast reactions with simple aldehydes in the
absence of the Sc(OTf)3 catalyst, we interrogated the ability of
silanes 7 and 8 to allylate a-methylcinnamaldehyde in the
absence of the catalyst. Remarkably, both silanes 7 and 8
reacted smoothly and rapidly with the reactions proceeding to
Results and discussion
Having few good ideas about how to induce signicantly higher
levels of reactivity in these crotylsilane reagents without using
Lewis acid catalysis, we began instead by focusing on devel-
oping derivatives that would display greater hydrolytic stability.
The notion was that we might be able to render the isolation of
the silane reagent a much simpler and less sensitive process,
and in turn that we might then be able to obviate the need for
the bromine atoms and arrive at a signicantly more air stable
and lower MW reagent. Displacement of the chloride of silane 1
with alcohols proved straightforward as outlined in Scheme 2A.
Both methoxy and phenoxysilanes 2 and 3 were prepared and
ꢁ
completion in less than 1 h at 0 C, a level of reactivity that is
both dramatically higher than that of silanes 1–3 and at least as
high as the combination of silane 1 and 5 mol% Sc(OTf)3. In
addition, silane 8 proved highly enantioselective, delivering
alcohol 4 in 97% ee. Ligand 6 was selected for further evaluation
and much to our delight was found to be quite effective in a one-
pot procedure (Scheme 2C). Thus, 6 was treated with allyltri-
chlorosilane and DBU and aer 1 h, a-methylcinnamaldehyde
was simply added directly to the mixture. The reaction was
ꢁ
complete in less than 1 h at 0 C, and aer isolation alcohol 4
was obtained in 94% yield and 96% ee.
With an effective one-pot procedure established, an explo-
ration of the reaction scope was initiated with an emphasis on
the types of aldehydes that are commonly employed in the early
stages of polyketide natural product syntheses, including the
o-used aldehydes that are derived from the Roche ester12b
(Table 1). Allyltrichlorosilane 9, cis-crotyltrichlorosilane 10,15
and trans-crotyltrichlorosilane 1116 were all employed to great
effect, and the reactions were generally highly efficient and
diastereoselective and/or enantioselective. The reaction
described in entry 12 is especially noteworthy because the
alternate procedure using (R,R)-1 and 5 mol% Sc(OTf)3 causes
signicant decomposition of this sensitive aldehyde.
We turned next to a demonstration of the practicality and
utility of the process with respect particularly to scalability. We
selected the crotylation of benzyloxyacetaldehyde with cis-cro-
tyltrichlorosilane 10 as the test reaction, and began with a
reaction conducted with 30 mmol (8.71 g) of (R,R)-6 (Scheme 3).
The one-pot procedure was employed, and 1 h aer the addition
of the aldehyde the reaction was quenched by the addition of
n-Bu4NF, and aer 2 h this was followed by an aqueous workup
that effectively separates the diamine 6 from the product. The
product 12 was puried by ltration through a small pad of
silica, and the diamine 6 was recovered by recrystallization. The
recovered 6 was then employed in another run, and then the
process was repeated a third time. In total, 14.1 g (68.3 mmol) of
12 was produced starting with 8.71 g (30.0 mmol) of 6, and at
the end of this sequence, we still had on hand 6.44 g
(22.2 mmol) of 6. Each run may be carried out in #8 hours, and
Scheme 2 (A) Synthesis and allylation reactions of methoxy- and phenox-
ysilanes 2 and 3. (B) Synthesis and allylation reactions of tethered phenoxysilanes
7 and 8. (C) Optimized one-pot procedure for enantioselective aldehyde allylation
reactions with diamine 6 and allyltrichlorosilane.
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Table 1 Highly diastereo- and enantioselective one-pot aldehyde allylation and crotylation reactions with diaminophenol 6
Entry
Silane
RCHO
Product
Yield (%)a
Dr
ee (%)
1
2
9
9
83
—
—
>99
98
81b
3
10c
11e
10c
9
94b
88
92
82
82
80
80
80
80
98 : 2d
94 : 6d
>98 : 2d
98 : 2f
92 : 8g
93 : 7g
98 : 2f
94 : 6g
95 : 5g
96
97
93
4
5
6
—
7
10c
11e
9
—
—
—
—
—
8
9
10
11
10c
11e
12
9
87b
96 : 4f
—
a
b
c
Isolated yield of puried products. A modied workup and isolation procedure was employed. The geometric purity of the cis-
crotyltrichlorosilane employed was measured to be >99 : 1 by 1H NMR spectroscopic analysis. Syn:anti diastereoselectivity as measured by 1H
d
NMR spectroscopic analysis. The geometric purity of the trans-crotyltrichlorosilane employed was measured to be 95 : 5 by 1H NMR
e
spectroscopic analysis. Aldehyde diastereoface selectivity as measured by 1H NMR spectroscopic analysis. Ratio of the major diastereomer to
f
g
1
the sum of the minor diastereomers as measured by HPLC and H NMR spectroscopic analysis. See the ESI for details.
we noted no other obvious impediments to this chemistry being products over 3 cycles, with ꢂ15 g of 6 still in hand at the end.
scaled up further. Because of the experimentally straightfor- Especially for crotylation reactions, we believe this method has
ward and efficient recovery of the ligand 6, we believe this the potential to be economically competitive with the relatively
methodology has signicant potential for commercialization: inexpensive Brown protocol,11 while being substantially less
an initial stock of 20 grams of 6, for example, would be enough laborious and less time-consuming to carry out. As for the tri-
to produce $150 mmol of aldehyde allylation or crotylation chlorosilanes, 9 is commercially available, and we will also be
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of p-type donation from oxygen to the Si–N1 antibonding
orbital, which reduces the Lewis acidity of the silicon. Whereas
the oxygen in 3 is free to rotate and dynamically interact with
both Si–N antibonding orbitals, however, the oxygen in 8 is not,
and though the differences are small, the shorter O–Si bond
distance and larger C3–O–Si bond angle in 3 are consistent with
greater O to Si p-type donation and therefore reduced silane
acidity. Transition state effects are almost certainly relevant as
well,18 and as the geometry around Si changes along the reac-
tion coordinate for the allylsilylation reaction, the phenoxy
group in 3 is more free to rotate than is the phenoxy group in 8.
This freer rotation insures that the O to Si p-type donation – and
therefore the minimization of the acidity of the silicon center –
can be maintained throughout the allylsilylation reaction more
fully in 3 than in 8. The substantial planarization of N1 in both 3
and 8 (C1–N1–C2–Si improper torsion angle ¼ 144ꢁ) implies
that p-type donation from nitrogen to silicon may also be
important. In that regard, it is noteworthy that the small but
signicant planarization observed for N2 in 3 (C4–N2–C5–Si
improper torsion angle ¼ 135ꢁ) is precluded for N2 in 8 as it
occupies a bridgehead position and is forced to remain almost
completely pyramidalized (C4–N2–C5–Si improper torsion
angle ¼ 123ꢁ).
Scheme 3 Practical and scalable one-pot enantioselective aldehyde crotylation
with recovery and recycling of the activating ligand 6.
pursuing the commercialization of both 10 and 11. In the
meantime, we note that 10, especially, is quite straightforward
to prepare on scales as large as 50 g or more, using a modi-
cation of the original Tsuji protocol15 (see the ESI†). In terms of
signicant limitations, we have thus far noted only one: the
workup procedure we developed to facilitate the recovery of
diamine 6 is not compatible with acid-sensitive protecting
groups (see, for example, entries 2 and 12 in Table 1). In these
cases an effective (and simpler) alternate workup procedure is
used, but as a result the diamine 6 may not easily be recovered.
The remarkable and dramatic difference in reactivity/Lewis
acidity between silanes 3 and 8 is all the more interesting
because of their structural similarity. We suggest that it is
attributable to stereoelectronic effects that render 8 more acidic
than 3, and note that the 29Si NMR chemical shis of 3 (ꢀ25.2
ppm) and 8 (ꢀ15.4 ppm) are consistent with this hypothesis. We
performed DFT calculations17 on silanes 3 and 8 to gain insight
into the nature of these stereoelectronic effects (Fig. 1). In both
silanes, the C3–O–Si–N1 torsion angle is close to 90ꢁ suggestive
Based on this analysis, a model for the reactivity of our
family of allylsilane reagents may be advanced. In the chlor-
osilane series (1, e.g.), donation from nitrogen to the Si–Cl
antibonding orbital is the dominant ground state effect that
reduces the acidity of the silane, and the only effective way to
neutralize this deactivating interaction is the binding of a Lewis
acid (i.e. Sc(OTf)3) to the offending nitrogen. In the aryloxysilane
series (3, e.g.), donation from nitrogen and oxygen to silicon is
similarly responsible for reduced silane acidity, but in addition
to the use of Lewis acids, these deactivating interactions may
alternatively be counteracted by the imposition of conforma-
tional constraints as in silane 8. We note as well that this
analysis may facilitate a richer understanding of the origin of
activity in our previously reported chiral silane Lewis acid
catalyst for Diels–Alder reactions.19
Conclusions
Many non-aromatic polyketide natural products are possessed
of truly important and interesting biological activities, while
also being both structurally complex and not available in
meaningful quantities from natural sources. Having any chance
of advancing these compounds or analogs thereof into the clinic
will require ever more efficient synthetic methods that are
sustainable, safe, inexpensive, technically simple to perform,
and readily scalable, all while being possessed of a broad scope.
Enantioselective aldehyde crotylation reactions are among the
most important methods in this regard, but despite many
beautiful conceptual advances over the years, a method that
truly satises all of these criteria has proved elusive. We believe
the method reported here represents a signicant advance
towards that ultimate aim, and together with the EZ-Cro-
tylMixes, comprises a powerful suite of silane-based reagents
for the crotylation of almost any aldehyde, whether simple or
Fig. 1 Calculated lowest energy structures for (S,S)-3 and (S,S)-8 with selected
torsion angles, bond lengths, and bond angles.
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complex and whether in the beginning, middle or late stages of
a synthesis. Mechanistically, we believe the effect reported here
promises to guide the development of a new generation of more
powerful silicon based Lewis acidic reagents and catalysts.
7 H. Lachance, X. Lu, M. Gravel and D. G. Hall, J. Am. Chem.
Soc., 2003, 125, 10160–10161.
8 B. M. Hackman, P. J. Lombardi and J. L. Leighton, Org. Lett.,
2004, 6, 4375–4377.
9 C. H. Burgos, E. Canales, K. Matos and J. A. Soderquist, J. Am.
Chem. Soc., 2005, 127, 8044–8049.
Acknowledgements
10 (a) I. S. Kim, S. B. Han and M. J. Krische, J. Am. Chem. Soc.,
2009, 131, 2514–2520; (b) X. Gao, I. A. Townsend and
M. J. Krische, J. Org. Chem., 2011, 76, 2350–2354.
11 (a) H. C. Brown and K. S. Bhat, J. Am. Chem. Soc., 1986, 108,
293–294; (b) H. C. Brown and K. S. Bhat, J. Am. Chem. Soc.,
1986, 108, 5919–5923.
12 (a) W. R. Roush, K. Ando, D. B. Powers, A. D. Palkowitz and
R. L. Halterman, J. Am. Chem. Soc., 1990, 112, 6339–6348; (b)
W. R. Roush, A. D. Palkowitz and K. Ando, J. Am. Chem. Soc.,
1990, 112, 6348–6359; (c) W. R. Roush and P. T. Grover, J.
Org. Chem., 1995, 60, 3806–3813.
This work was supported by a grant form the National Institute
of General Medical Sciences (GM58133). L. M. S. is the recipient
of a National Science Foundation Graduate Research Fellow-
ship. M. L. S. is supported by the Center for Re-Dening
Photovoltaic Efficiency Through Molecular Scale Control, an
Energy Frontier Research Center (EFRC) funded by the
Department of Energy (DOE), Office of Science, Office of Basic
Energy Sciences, under Award Number DE-SC0001085.
Notes and references
13 H. Kim, S. Ho and J. L. Leighton, J. Am. Chem. Soc., 2011, 133,
6517–6520.
1 (a) S. E. Denmark and N. G. Almstead, in Modern Carbonyl
Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 10;
(b) S. R. Chemler and W. R. Roush, in Modern Carbonyl
Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 11.
2 (a) Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207–
2293; (b) C. E. Masse and J. S. Panek, Chem. Rev., 1995, 95,
1293–1316; (c) S. E. Denmark and J. Fu, Chem. Rev., 2003,
103, 2763–2793; (d) J. W. J. Kennedy and D. G. Hall, Angew.
Chem., Int. Ed., 2003, 42, 4732–4739; (e) D. G. Hall, Synlett,
2007, 1644–1655.
3 J. Garcia, B. M. Kim and S. Masamune, J. Org. Chem., 1987,
52, 4831–4832.
4 A. Hafner, R. O. Duthlaer, R. Marti, G. Rihs, P. Rothe-Streit and
F. Schwarzenbach, J. Am. Chem. Soc., 1992, 114, 2321–2336.
5 N. F. Jain, N. Takenaka and J. S. Panek, J. Am. Chem. Soc.,
1996, 118, 12475–12476.
14 Silanes 7 and 8 were formed as single diastereomers, and the
conguration at silicon was unambiguously established by
1H NMR spectroscopy. See the ESI for details.†
15 J. Tsuji, M. Hara and K. Ohno, Tetrahedron, 1974, 30, 2143–
2146.
16 (a) N. Furuya and T. Sukawa, J. Organomet. Chem., 1975, 96,
C1–C3; (b) M. Kira, T. Hino and H. Sakurai, Tetrahedron Lett.,
1989, 30, 1099–1102; (c) K. Iseki, Y. Kuroki, M. Takahashi,
S. Kishimoto and Y. Kobayashi, Tetrahedron, 1997, 53,
3513–3526.
17 Calculations were performed with Jaguar, version 7.8,
Schrodinger, LLC, New York, NY, 2010, using the B3LYP
functional and the 6–31G**/LACVP basis sets.
18 X. Zhang, K. N. Houk and J. L. Leighton, Angew. Chem., Int.
Ed., 2005, 44, 938–941.
6 S. E. Denmark and J. Fu, J. Am. Chem. Soc., 2001, 123, 9488–
9489.
19 K. Kubota, C. L. Hamblett, X. Wang and J. L. Leighton,
Tetrahedron, 2006, 62, 11397–11401.
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