Cross-metathesis/iridium(I)-catalyzed allylic etherification strategy: (Iterative) catalytic asymmetric synthesis of syn- and anti-1,2-diols

Article abstract of DOI:10.1002/anie.201209112

Protection optional: The title reaction strategy is used to prepare 1,2-diols with complete control of their absolute and relative stereochemistry. The method tolerates free and Me-/Bn-/TBS-protected alcohol functionalities, and its diastereoselectivity i

Full text of DOI:10.1002/anie.201209112

Angewandte
Chemie
DOI: 10.1002/anie.201209112
Asymmetric Catalysis
Cross-Metathesis/Iridium(I)-catalyzed Allylic Etherification Strategy:
Iterative) Catalytic Asymmetric Synthesis of syn- and anti-1,2-Diols**
(
Dongeun Kim, Jae Seung Lee, Suk Bin Kong, and Hyunsoo Han*
1
,2-Diol functional groups are common structures in many
strates, which complements the more traditional palladium-
catalyzed allylic substitution reactions which typically give
rise to linear allylation products. Iridium-catalyzed allylic
[1]
biologically active natural products and “privileged” chiral
[2]
[11]
catalysts/ligands. Furthermore, 1,2-diols can serve as val-
uable synthetic precursors for the construction of a wide
variety of other useful structures. 1,2-Diols can appear in
many different forms depending on their protection state (di-
protected, monoprotected, or free diol), as well as their
absolute and relative stereochemistry (syn or anti). Thus, an
ideal synthetic method/strategy for 1,2-diols would be one
that can a) furnish any of the aforementioned 1,2-diol forms
and b) control their absolute and relative stereochemistry by
using a pair of enantiomeric ligands/catalysts, but such
methodology is not currently available.
etherification reactions have been shown to generate a wide
range of protected and free chiral allylic alcohols in high
yields at synthetically useful levels of stereoselectivity
[
12]
[Eq. (1); PG = protecting group].
Despite tremendous methodological advancements, liter-
ature inspection surprisingly revealed that almost all prior
asymmetric methods for the synthesis of 1,2-diols focused on
controlling relative stereochemistry of 1,2-diols, thus giving
either syn- or anti-1,2-diols, and employed chiral reagents and
We recently demonstrated that iridium(I)-catalyzed
decarboxylative allylic etherification exhibited much broader
substrate scope and higher reaction yield than the corre-
sponding intermolecular version, and that stereoselection in
iridium(I)-catalyzed
diastereoselective
decarboxylative
[
3–8]
auxiliaries for stereochemical control.
In addition, they
allylic etherification was controlled by the ligands/catalysts
[13]
often suffered from a narrow substrate scope, low yields, and
low stereoselectivities. To our knowledge, the only catalytic
asymmetric method that met the above two criteria was
recently reported by the McQuade group, who employed the
copper-catalyzed asymmetric allylic boronation/cross-meta-
used [Eq. (2); PMP = p-methoxyphenyl]. Based on these
[9]
thesis (AAB/CM) strategy. Although highly selective for-
mation of differentiated syn- and anti-1,2-diols could be
achieved by using a pair of enantiomeric ligands, the strategy
required two extra steps for the in situ oxidation of the
boronate product of the AAB reaction and the subsequent
alcohol protection, and the AAB reaction did not occur with
a TBS protecting group, thus considerably limiting the
generality and practicality of the strategy.
results, we envisioned that iridium(I)-catalyzed decarboxyla-
tive allylic etherification, coupled with olefin cross-meta-
[
14]
thesis, could be used to synthesize any form of 1,2-diols with
complete stereochemical control [Eq. (3)]. Also envisaged
was that this strategy could be used in an iterative fashion to
give poly-1,2-diols [Eq. (4)]. Herein we describe our success
in developing these methodologies.
In recent years, iridium(I)-catalyzed allylic substitution
reactions have emerged as a powerful tool for the enantio-
selective introduction of carbon–carbon and carbon–heter-
[
10]
oatom bonds.
A distinct feature of iridium(I)-catalyzed
allylic substitution reactions is the formation of chiral
branched allylation products from achiral linear allyl sub-
[*] Dr. D. Kim, Dr. J. S. Lee, Prof. Dr. H. Han
Department of Chemistry, University of Texas at San Antonio
1
UTSA Circle, San Antonio, TX 78249 (USA)
E-mail: Hyunsoo.Han@utsa.edu
The PMP-protected allylic alcohols 1 were selected to
represent a variety of allylic alcohols with simple linear alkyl,
functionalized linear alkyl, branched/cyclic alkyl, and aro-
matic side chains, and prepared by iridium(I)-catalyzed
enantioselective decarboxylative allylic etherification of
Prof. Dr. S. B. Kong
Department of Chemistry, University of the Incarnate Word
4301 Broadway, San Antonio, TX 78209 (USA)
[
**] Research reported in this publication was supported by the US
National Science Foundation (CHE 0911134).
[13]
PMP allyl carbonates.
As shown in Table 1, CM was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209112.
explored by using 1a, the Hoveyda–Grubbs second-genera-
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Table 1: Ruthenium-catalyzed cross-metathesis of the PMP-protected
allylic alcohols 1 with (Z)-but-2-ene-1,4-diyl bis(4-methoxybenzoate) (B).
Table 2: Asymmetric synthesis of di-protected syn- and anti-1,2-diols by
iridium(I)-catalyzed diastereoselective decarboxylative allylic etherifica-
tion of 2.
[
c]
Entry
R
2
Ligand Product Yield d.r.
[
a]
[b]
[a]
[b]
Entry
1
R
Product
Yield [%]
84
E/Z
ee [%]
[%]
2a
>25:1
>25:1
1
2
L*
ent-L*
3 a
4 a
92
90
>25:1
1:20
9
9
5
0
2
3
2b
2c
78
81
3
4
L*
ent-L*
3 b
4 b
91
94
20:1
1:18
>25:1
>25:1
5
6
L*
ent-L*
3 c
4 c
91
93
>25:1
1:>25
4
2d
76
95
[
a] Yield of the isolated product. [b] E/Z selectivities determined by the
H NMR spectroscopy of the reaction mixtures.
1
7
8
L*
ent-L*
3 d
4 d
84
86
20:1
1:19
93
[
15]
[a] Determined using precursors 1. [b] Yield of the isolated product.
[c] Determined by the H NMR spectroscopy of the reaction mixtures.
tion catalyst A, and (Z)-but-2-ene-1,4-diyl bis(4-methoxy-
1
[
16]
benzoate) (B) in methylene chloride. An initial attempt
employing 3 mol% of A and 2 equivalents of B at room
temperature gave rise to the desired CM product 2a in 40%
yield and with a greater than 25:1 trans/cis selectivity, and
increasing the loadings of the catalyst did not improve the
yields. During the course of further studies, it was observed
that CM reactions did not proceed after the initial burst of
product formation and B isomerized to the corresponding
trans isomer at room temperature. Based on the reasoning
that the trans isomer is the slower CM substrate and a higher
temperature could make it participate more effectively in the
CM reaction, the temperature was raised to 40–458C.
Reaction yields improved to 60% with 3 mol% of A and
dbcot=dibenzocyclooctatetraene.
corresponding diastereomeric product 4a in 90% yield and
with 20:1 diastereoselectivity (entry 2), thereby indicating
that diastereoselectivity of the reactions was predominantly
governed by the catalysts used, and the substrate stereo-
chemistry had little effect on reaction stereochemistry
[17]
(catalyst-controlled versus substrate-controlled). To probe
the generality of the reaction, other structurally diverse
substrates with functionalized linear alkyl (entries 3 and 4),
branched/cyclic alkyl (entries 5 and 6), and phenyl (entries 7
and 8) groups were studied, and uniformly good yields and
high diastereoselectivities were obtained. In all cases studied,
diastereoselectivities were dictated by the stereochemistry of
the catalysts used, albeit the mismatched cases (entries 2, 4, 6,
and 8) showed slightly lower diastereoselectivities than the
matched ones. The results in Table 2 show that di-protected
syn- and anti-1,2-diols can be prepared by CM of 1 with B
followed by iridium(I)-catalyzed diastereoselective allylic
etherification.
1 equivalent of B. When an additional 2 mol% of A and
0.5 equivalent of B were added, reaction yields increased to
84% (Table 1). Adding more A and B did not improve yields
additionally. Under the optimized reaction conditions involv-
ing 5 mol% of A and 1.5 equivalents of B in methylene
chloride at 40–458C, 2b–d (entries 2–4) were obtained in
good yields (ꢀ 76%) and with excellent trans/cis selectivities
(> 25:1).
Now the stage was set for the critical iridium(I)-catalyzed
diastereoselective decarboxylative allylic etherification.
When 2a was subjected to the catalytic conditions employing
To study the functional group compatability of iridium(I)-
catalyzed decarboxylative allylic etherification, the free
alcohols 5 were prepared by CM of the corresponding allylic
[
(
{Ir(dbcot)Cl} ] (2 mol%), the phosphoramidite ligand L*
alcohol precursors with B in the presence of A (see the
2
[
13]
[18]
4 mol%), and DBU (1 equiv) in THF,
the desired
Supporting Information) and tested in the reaction.
If
decarboxylative allylic etherification reaction did not occur
even after prolonged reaction times at room temperature.
However, upon raising the temperature to 758C, the reaction
took place cleanly to give the desired product 3a with 92%
yield and a greater than 25:1 diastereoselectivity (Table 2,
entry 1). The use of the enantiomeric ligand ent-L* reversed
the reaction stereochemistry to favor the formation of the
enabled, these reactions should provide monoprotected syn-
and anti-1,2-diols with complete stereochemical control by
the chiral ligands (L* and ent-L*) used. As shown in Table 3,
excellent reaction yields (ꢀ 84%) and diastereoselectivities
(> 25:1) were obtained in all examples, and the allylic
hydroxy group was well tolerated in the reactions. Because
of their tolerance of the hydroxy group, the use of CM and
2
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Table 3: Asymmetric synthesis of monoprotected syn- and anti-1,2-diols
by the iridium(I)-catalyzed diastereoselective decarboxylative allylic
etherification of 5.
prove that the developed CM/iridium(I)-catalyzed decarbox-
ylative allylic etherification strategy is a very efficient
stereoselective synthetic route toward various 1,2-diol forms.
Finally, to highlight the powerful iteration of the CM/
iridium(I)-catalyzed decarboxylative allylic etherification
strategy, protected 1,2,3,4-tetraols were synthesized
(Scheme 1). CM of the PMP-protected triol 3b (entry 3 of
[
b]
[c]
Entry
R
Ligand Product Yield d.r.
ee [%]
[
a]
[%]
1
2
L*
ent-L*
6 a
7 a
90 >25:1
>99
>99
93
1:>25
[
[
d]
d]
[c]
3
4
L*
ent-7b
90 >25:1
91
>99
>99
[c]
ent-L* ent-6b
1:>25
5
6
L*
ent-L*
6 c
7 c
90 >25:1
–
–
92
1:>25
[
[
d]
d]
[c]
7
8
L*
ent-7d
87 >25:1
84
99
99
[c]
ent-L* ent-6d
1:16
1
[
a] Yield of the isolated product. [b] Determined by the H NMR
spectroscopy of the reaction mixtures. [c] Determined by HPLC. [d] Used
ent-5.
Scheme 1. Iteration of the iridium(I)-catalyzed decarboxylative allylic
etherification and CM to synthesize PMP-protected 1,2,3,4-tetraols.
iridium(I)-catalyzed allylic etherification enabled the asym-
metric synthesis of differentiated syn- and anti-1,2-diols
without using protecting groups.
Table 2) with B generated 11 in 86% yield. Iridium(I)-
catalyzed decarboxylative allylic etherification of 11 in the
presence of L* at 758C gave the PMP-protected tetraol 12 in
82% yield and with a 20:1 diastereoselectivity. In contrast, the
use of ent-L* generated the corresponding diastereomeric
protected tetraol 13 in 94% yield and with 13:1 diastereo-
selectivity. Once again, diastereoselectivity was determined
by the catalysts used.
Next, the scope with respect to the alcohol protecting
groups in the iridium(I)-catalyzed decarboxylative allylic
[
19]
[19]
etherification was studied with Me, Bn, and TBS groups,
and the results are shown in Table 4. Both Me and Bn groups
Table 4: Asymmetric synthesis of orthogonally protected syn- and anti-
In summary, we have developed a very efficient CM/
iridium(I)-catalyzed decarboxylative allylic etherification
strategy for preparing 1,2-diols with complete control of
absolute and relative stereochemistry, as well as the protect-
ing group scheme. Iridium(I)-catalyzed diastereoselective
decarboxylative allylic etherification is tolerable to free and
Me-/Bn-/TBS-protected alcohol functionalities, and its dia-
stereoselectivity is controlled by the stereochemistry of the
ligands/catalysts used. Protected 1,2,3,4-tetraols have been
synthesized by iterative applications of the strategy. Consid-
ering the ubiquitous presence of 1,2-diol functionalities in
organic compounds, the strategy should find a wide range of
applications in organic synthesis.
1
of 8.
,2-diols by the iridium(I)-catalyzed decarboxylative allylic etherification
[
b]
Entry
PG
Ligand
Product
Yield
d.r.
[
a]
[%]
1
2
3
4
L*
ent-L*
L*
ent-L*
L*
9 a
10a
9 b
10b
9 c
93
95
91
92
82
86
>25:1
1:>25
>25:1
1:>25
12:1
1:19
Me
Bn
[
c]
c]
5
6
TBS
[
ent-L*
10c
1
[
a] Yield of the isolated product. [b] Determined by the H NMR
Experimental Section
General procedure for the ruthenium-catalyzed cross-metathesis of 1:
spectroscopy of the reaction mixtures. [c] Reaction ran at 758C.
The Hoveyda–Grubbs second-generation catalyst
.020 mmol, 3 mol%) was added to a solution of 1 (0.640 mmol)
and (Z)-but-2-ene-1,4-diyl bis(4-methoxyphenyl) dicarbonate
250 mg, 0.640 mmol, 1 equiv) in CH Cl (2.5 mL) at room temper-
A (12.5 mg,
0
B
worked well at 608C and proceeded with excellent yields and
diastereoselectivities (entries 1–4). The TBS group required
(
2
2
ature. After stirring for 6 h at 458C, an additional portion each of A
8.00 mg, 0.013 mmol, 2 mol%) and (125 mg, 0.320 mmol,
.5 equiv) in CH Cl (2.0 mL) was added. The reaction mixture was
7
58C, and exhibited a slightly reduced, but still synthetically
(
B
useful yield and diastereoselectivity (entries 5 and 6). These
results, taken together with those in Table 2 and Table 3,
0
2
2
stirred for 6 h at 458C. The reaction mixture was concentrated in
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vacuo, and the residue was purified by flash chromatography using
n-hexane/ethyl acetate as an eluent to give the desired product.
General procedure for the iridium(I)-catalyzed decarboxylative
allylic etherification: A flame-dried 5 mL spherical flask was cooled
under vacuum and flushed with N2. [{Ir(dbcot)Cl}2] (3.5 mg,
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0
.004 mmol, 2 mol%), phosphoramidite ligand L* (5.0 mg,
0
.008 mmol, 4 mol%), and THF (1.0 mL) were added to this flask
under N . The reaction mixture was stirred to obtain a homogenous
2
orange solution. Upon addition of DBU (30.0 mL, 0.200 mmol,
1
equiv), the color of the solution was changed from orange to light
yellow. A PMP allyl carbonate (2, 5, or 8; 0.200 mmol) in THF
2.0 mL) was added to this yellow solution, and then the resulting
(
homogenous solution was stirred at 608C until the starting PMP
carbonate disappeared on TLC. The reaction mixture was concen-
trated in vacuo, and the residue was purified by silica gel column
chromatography using n-hexane/ethyl acetate as an eluent to give the
desired product.
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Received: November 14, 2012
Published online: && &&, &&&&
Keywords: alcohols · allylation · asymmetric catalysis ·
.
metathesis · iridium
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687; h) T. Luanphaisarnnont, C. O. Ndubaku, T. F. Jamison,
[
19] The TBS- and Bn-protected 8 can in principle be more efficiently
prepared by iridium(I)-catalyzed allylic etherification
Org. Lett. 2005, 7, 2937 – 2940; i) K. Sa-ei, J. Montgomery, Org.
Lett. 2006, 8, 4441 – 4443; j) B. M. Savall, N. A. Powell, W. R.
Roush, Org. Lett. 2001, 3, 3057 – 3060; k) L. Albrecht, H. Jiang,
G. Dickmeiss, B. Gschwend, S. G. Hansen, K. A. Jørgensen, J.
(Ref. [12a] for the TBS-protected 8 and Ref. [12b] for the Bn-
protected 8) followed by CM with B.
4
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Catalysis
D. Kim, J. S. Lee, S. B. Kong,
H. Han*
&&& — &&&
Cross-Metathesis/Iridium(I)-catalyzed
Allylic Etherification Strategy: (Iterative)
Catalytic Asymmetric Synthesis of syn-
and anti-1,2-Diols
Protection optional: The title reaction
strategy is used to prepare 1,2-diols with
complete control of their absolute and
relative stereochemistry. The method tol-
erates free and Me-/Bn-/TBS-protected
alcohol functionalities, and its diastereo-
selectivity is controlled by the stereo-
chemistry of the ligands/catalysts used.
Protected 1,2,3,4-tetraols are synthesized
by iterative applications of the strategy.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!