Enantioselective synthesis of anti - And syn -homopropargyl alcohols via chiral Br?nsted acid catalyzed asymmetric allenylboration reactions

Article abstract of DOI:10.1021/ja3031467

Chiral Br?nsted acid catalyzed asymmetric allenylboration reactions are described. Under optimized conditions, anti-homopropargyl alcohols 2 are obtained in high yields with excellent diastereo- and enantioselectivities from stereochemically matched aldeh

Full text of DOI:10.1021/ja3031467

Article
pubs.acs.org/JACS
Enantioselective Synthesis of anti- and syn-Homopropargyl Alcohols
via Chiral Brønsted Acid Catalyzed Asymmetric Allenylboration
Reactions
Ming Chen and William R. Roush*
Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
S
* Supporting Information
ABSTRACT: Chiral Brønsted acid catalyzed asymmetric
allenylboration reactions are described. Under optimized
conditions, anti-homopropargyl alcohols 2 are obtained in
high yields with excellent diastereo- and enantioselectivities
from stereochemically matched aldehyde allenylboration
reactions with (M)-1 catalyzed by the chiral phosphoric acid
(S)-4. The syn-isomers 3 can also be obtained in good diastereoselectivities and excellent enantioselectivities from the
mismatched allenylboration reactions of aromatic aldehydes using (M)-1 in the presence of the enantiomeric phosphoric acid
(R)-4. The stereochemistry of the methyl group introduced into 2 and 3 is controlled by the chirality of the allenylboronate (M)-
1, whereas the configuration of the new hydroxyl stereocenter is controlled by the enantioselectivity of the chiral phosphoric acid
catalyst used in these reactions. The synthetic utility of this methodology was further demonstrated in highly diastereoselective
syntheses of a variety of anti, anti-stereotriads, the direct synthesis of which has constituted a significant challenge using previous
generations of aldol and crotylmetal reagents.
and enantioselective carbonyl propargylation reaction remains
an important objective.
INTRODUCTION
■
Asymmetric carbonyl allylation is an important transformation
in organic synthesis.1 These reactions, together with the
asymmetric aldol reaction, represent some of the most widely
adopted methods for the synthesis of acyclic molecules with
contiguous stereocenters. As a useful extension of allylation
chemistry, the asymmetric carbonyl propargylation reaction has
attracted the attention of the community, and substantial
advances have been achieved recently using several allenylmetal
reagents.2−8 However, compared to the exceptionally well-
developed asymmetric crotylation reactions, the analogous
propargylation reactions of carbonyl compounds using
allenylmetal reagents remain largely underdeveloped. One
significant advance in this area is the asymmetric carbonyl
propargylation reactions developed by Marshall and co-workers
using enantioenriched allenylstannanes, allenylsilanes or chiral
allenyl zinc, and indium reagents generated in situ from
propargyl mesylate intermediates.5a−c Depending on the
transition states involved in these transformations, either syn-
or anti-homopropargyl alcohols can be synthesized.9 The
synthetic utility of these methods has been demonstrated in
the context of several polyketide natural product syntheses.10,11
However, the diastereoselectivity of aldehyde propargylation
reactions, in many occasions, is only moderate, in particular, in
reactions with aldehydes lacking α-branches or advanced
aldehyde intermediates.11 Furthermore, the requirement of
strong Lewis acids to attain syn-selectivity is often incompatible
with ornately functionalized aldehyde substrates. Moreover,
highly diastereoselective syntheses of the anti-homopropargyl
alcohol stereoisomers via these procedures are generally
lacking. Therefore, the development of a mild, highly diastereo-
In connection with an ongoing problem in natural product
synthesis, we became interested in asymmetric propargylation
of aldehydes with allenylboronate reagents. Accordingly, we
have developed and report herein highly diastereo- and
enantioselective syntheses of anti- and syn-homopropargyl
alcohols via chiral, nonracemic Brønsted acid catalyzed
propargylation reactions of aldehydes with allenylboronates 1
(Scheme 1). Key to the success of this procedure is the use of a
chiral phosphoric acid catalyst, (R)- or (S)-4, to control the
stereochemistry of the hydroxyl groups in 2 and 3 and to
achieve levels of diastereomeric control not possible by using
the chiral allenylboronate (M)-1 alone.
It is well documented that the reactions of 3-substituted
allenylboronates (c.f., 1) with aldehydes often give mixtures of
the anti- and syn-homopropargylic product diastereomers
(analogous to 2 and 3).3d,e,i,12 Significantly, in view of the
well-established cyclic transition states involved in carbonyl
addition reactions using allenylboron reagents,2−4,8 the
reactions of a single enantiomer allenylboronate such as (M)-
112 proceed with essentially perfect chirality transfer of the axial
chirality of the allene into the propargyl center of the products
(e.g., the methyl-bearing carbons of 2 and 3). However, the
reactions suffer from lack of diastereochemical control. The
anti-isomer 2 is typically favored from reactions of
allenylboronates with aliphatic aldehydes, while the syn-isomer
3 generally is predominate in the allenylboration reactions of
Received: April 1, 2012
Published: June 25, 2012
© 2012 American Chemical Society
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Article
assigned by 1H NMR studies of the acetonide derivatives
obtained following oxidative cleavage of the alkyne unit (see
Supporting Information). Gratifyingly, when this reaction was
performed in toluene in the presence of 20 mol % of (S)-416 at
−30 °C for 48 h, the anti-homopropargyl alcohol 2a was
obtained in 94% yield with >50:1 diastereoselectivity and >98%
ee (Table 1, entry 2). Similar results were obtained when the
reaction was carried out at −20 °C for 48 h (Table 1, entry 3).
When 10 mol % of catalyst (S)-4 was used at either −20 or 0
°C, alcohol 2a was obtained in 95−98% yield, again with
outstanding diastereo- and enantioselectivity (Table 1, entries 4
and 5). Finally, when the reaction was performed at 0 °C in the
presence of 5 mol % of acid (S)-4 followed by stirring the
reaction mixture to ambient temperature for 24 h, alcohol 2a
was again obtained in 98% yield with >50:1 diastereoselectivity
and >98% ee (Table 1, entry 6).
Scheme 1
aromatic aldehyde substrates.3i We envisioned that a potential
solution to this problem would be to decouple the elements of
stereochemical control for the propargyl vs homopropargyl
centers via the use of complementary sources of asymmetric
induction. By proper selection of a second, external source of
chirality for control of the configuration of the hydroxyl group,
enantioselective addition of (M)-1 to aldehydes would, in
principle, allow independent stereoselective access to either of
the anti- or syn-homopropargyl alcohol isomers, 2 and 3.
Inspired by the recent work of Antilla and Reddy8 and related
work on Brønsted acid-catalyzed allylboration reactions,13l−o
we anticipated that this plan could be reduced to practice by
using the appropriate enantiomer of the chiral, nonracemic
Brønsted acid catalyst13 (R)-4 or (S)-4 to control the
enantiotopic face of the aldehyde that participates in the
reaction with the allenylboronate (M)-1.14
The optimized conditions developed for the synthesis of 2a
were then applied to the allenylboration of a variety of
aldehydes (Scheme 2). In all cases, anti-homopropargyl
Scheme 2. Matched Double Asymmetric Allenylboration
a
Reactions of Aldehydes with Allenylboronate (M)-1.
RESULTS AND DISCUSSION
■
In initial experiments, treatment of benzaldehyde with
allenylboronate (M)-112 (1.2 equiv) in toluene at −20 °C for
48 h provided a 1:1.2 mixture of the anti-homopropargyl
alcohols 2a and the syn-isomer 3a in 55% combined yield; both
2a and 3a were obtained with 95% ee (Table 1, entry 1). The
absolute stereochemistry of the secondary hydroxyl groups of
2a and 3a was assigned by using the modified Mosher ester
analysis.15 The anti vs syn stereochemistry of 2a and 3a was
Table 1. Optimization of Matched Allenylboration Reactions
Using Allenylboronate (M)-1 and Chiral Acid (S)-4
a
a
All reactions were run on 0.2 mmol scale. Diastereoselectivities of
1
these reactions were determined by H NMR analysis of the crude
reaction mixtures. Enantioselectivities for the anti-isomer 2 were
determined by Mosher ester analysis.15 Control experiments
performed in the absence of any catalyst demonstrated that the
reaction of hydrocinnamaldehyde with (M)-1 in toluene provided a
3.5:1 mixture of 2h and 3h, while the diastereoselectivity of the
allenylboration of cyclohexanecarboxaldehyde favored formation of 2i
(over 3i) with 6.5:1 selectivity.
ds
(2a:3a)
yield
(2a + 3a)
b
c
d
entry
conditions
ee
e
1
2
3
4
5
6
no acid catalyst, −20 °C, 48 h
(S)-4, 20 mol %, −30 °C, 48 h
(S)-4, 20 mol %, −20 °C, 48 h
(S)-4, 10 mol %, −20 °C, 48 h
(S)-4, 10 mol %, 0 °C, 24 h
1:1.2
>50:1
>50:1
>50:1
>50:1
>50:1
55%
94%
96%
95%
98%
98%
95%
>98%
>98%
>98%
>98%
>98%
alcohols 2b−i were obtained in 83−98% yield with >50:1
diastereoselectivity and >98% ee. The absolute stereochemistry
of the secondary hydroxyl groups of 2b−i was assigned by
using the modified Mosher ester analysis.15
(S)-4, 5 mol %, 0 °C to rt,
24 h
As indicated in the Introduction Section, we were interested
in determining if the diastereomeric syn-homopropargyl
alcohols 3 could be accessed from allenylboration reactions of
aldehydes with (M)-1 by using the enantiomeric chiral acid
catalyst (R)-4.16 Because these transformations are double
a
b
All reactions were performed using 0.2 mmol of (M)-1. Based on 1H
c
NMR analysis of the crude reaction mixture. Yield of isolated mixture
of products. Determined by Mosher ester analysis.15 Both 2a and 3a
d
e
were obtained with 95% ee.15
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asymmetric reactions,17 the interplay between the chiral reagent
and the chiral phosphoric acid catalyst will determine the
diastereoselectivity of these reactions. As shown in Table 2,
Scheme 3. Mismatched Double Asymmetric Allenylboration
Reactions of Aldehydes with Allenylboronate (M)-1
d
Table 2. Optimization of Mismatched Allenylboration
Reactions Using Allenylboronate (M)-1 and acid (R)-4
a
ds
(3a:2a)
yield
(3a + 2a)
b
c
d
entry
conditions
ee
e
1
2
3
4
no acid catalyst, −20 °C, 48 h
(R)-4, 20 mol %, 0 °C, 48 h
(R)-4, 20 mol %, −20 °C, 48 h
1.2:1
5:1
55%
94%
96%
95%
95%
>98%
>98%
>98%
8:1
(R)-4, 10 mol %, −20 °C,
8:1
48 h
5
6
7
(R)-4, 20 mol %, −30 °C, 48 h
(R)-4, 10 mol %, −30 °C, 48 h
(R)-4, 5 mol %, −30 °C, 48 h
10:1
10:1
10:1
98%
98%
>98%
>98%
>98%
98%
a
b
All reactions were performed using 0.2 mmol of (M)-1. Based on 1H
c
NMR analysis of the crude reaction mixture. Combined yield of 2a
and 3a. Determined by Mosher ester analysis for alcohol 3a.15 Both
d
e
2a and 3a were obtained with 95% ee.15
a
b
Combined yield of 2 and 3. ee % of the syn-isomers 3g−i were
determined by Mosher ester analysis.15 Reaction diastereoselectivities
c
treatment of benzaldehyde with (M)-1 (1.2 equiv) at 0 °C for
48 h in the presence of 20 mol % of catalyst (R)-4 provided a
5:1 mixture of the syn-homopropargyl alcohol 3a and the anti-
isomer 2a in 94% combined yield and >98% ee (for 3a) (Table
2, entry 2). When the reaction was performed at −20 °C with
the same catalyst loading, an 8:1 mixture of 3a and 2a was
obtained (Table 2, entry 3). Similar results were obtained when
the reaction was performed by using 10 mol % of catalyst (R)-4
at −20 °C (Table 2, entry 4). When the reaction was carried
out at −30 °C in the presence of as little as 5 mol % of catalyst
(R)-4, a 10:1 mixture of 3a (>98% ee) and 2a, was obtained in
excellent yield (Table 2, entries 5−7).
1
were determined by H NMR analysis of the crude reaction mixtures.
d
All reactions were run on 0.2 mmol scale.
phosphoric acid catalyst (R)-4 is incapable of overriding the
intrinsic 3.5−6.5:1 anti preference of aliphatic aldehydes in the
attempted mismatched double asymmetric reactions summar-
ized in Scheme 3 for the allenylboration of hydrocinnamalde-
hyde (leading to 3h) and cyclohexanecarboxaldehyde (leading
to 3i).
Based on the transition-state model presented by Antilla and
Houk8a (see also refs 3i and 9h and especially ref 13p for an
alternative transition-state proposal), we propose that the
stereochemically matched allenylboration reactions of alde-
hydes with allenylboronate (M)-1 and catalyst (S)-4 provides
anti-homopropargyl alcohol 2 through the boat-like transition
state TS-1. The mismatched reactions of allenylboronate (M)-1
with the enantiomeric catalyst (R)-4 presumably proceed
through transition state TS-2 to give the syn-isomer 3. As
depicted in Scheme 4, it is readily apparent that the terminal
methyl group of allenylboronate (M)-1 and the R group of the
aldehyde are eclipsed in TS-2. When the aldehyde R group is
less demanding sterically (i.e., a flat aromatic ring), the
enantioselectivity of the chiral catalyst is capable of overriding
this interaction, such that the mismatched double asymmetric
reactions provide the syn-isomer 3 with synthetically useful
diastereoselectivity (≥9:1). However, when the aldehyde R
group is bulky (e.g., a cyclohexyl group), the eclipsing
interaction between the terminal methyl group of the allene
(M)-1 and the R group of the aldehyde is sufficiently large that
the chiral acid (R)-4 is unable to overcome this interaction. By
comparison, in transition state TS-1 that leads to the formation
of the anti-isomer 2, the terminal methyl group of allene (M)-1,
and the aldehyde R group are aligned in such a way that serious
steric repulsion is not apparent in the transition state.
Therefore, the stereochemically matched double asymmetric
The conditions developed for the synthesis of 3a (Table 2,
entry 7) were then applied to a variety of other aldehydes
(Scheme 3). Syn-homopropargyl alcohols 3b−f were obtained
from aromatic aldehyde precursors in 90−98% yield with ≥9:1
diastereoselectivity and >98% ee (Scheme 3). The absolute
stereochemistry of the secondary hydroxyl groups of 3a−f was
assigned by using the modified Mosher ester analysis.15 The syn
1
stereochemistry of 3a was assigned by H NMR studies of an
acetonide derivative synthesized after oxidative manipulation of
the alkyne unit (see Supporting Information). However, a
limitation to the syn-selective aldehyde allenylboration reaction
is that only aromatic aldehydes are good substrates. As the data
for 3g−i indicate, unsaturated or aliphatic aldehydes, such as
cinnamaldehyde or hydrocinnamaldehyde, only gave a 2:1 or
1:2 mixtures of the syn- and anti-isomers. When cyclo-
hexanecarboxaldehyde was used as the substrate, a 1:4.5
mixture was obtained, favoring the anti-isomer 2i.
The results summarized above suggest that propargylation
reactions of aldehydes with allenylboronate (M)-1 and catalyst
(S)-4 (Scheme 2) are matched double asymmetric reactions,
whereas the reactions with (M)-1 and catalyst (R)-4 (Scheme
3) are likely stereochemically mismatched.17 These conclusions
follow from the fact that the anti-homopropargyl alcohols 2 are
favored in reactions of allenylboronate 1 with achiral aldehydes
(e.g., see footnote a in Scheme 2).3i,12 Evidently, the chiral
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Scheme 4. Transition-State Analysis of the Double
Asymmetric Allenylboration Reactions
Table 3. Diastereoselective Syntheses of anti, anti-
Stereotriads 6 via Triple Asymmetric Allenylboration
Reactions
reactions provide anti-adducts with exceptional diastereo- and
enantioselectivity.
The synthesis of the anti, anti-stereotriad unit present in
homopropargyl alcohol 6 by using aldol or crotylmetal
chemistry represents a notoriously challenging problem in
organic synthesis.18 Because, unlike crotylmetal reagents, only
one face of allenylboronate (M)-1 is accessible to the aldehyde
substrate and because the transition-state analysis presented in
Scheme 4 suggests that the interactions between the aldehyde R
group and the terminal methyl group of allenylboronate (M)-1
are negligible in TS-1, we anticipated that the anti-
propargylation reaction of chiral aldehydes 5 using (M)-1 in
combination with the chiral phosphoric acid catalyst (S)-4 (see
Scheme 5) might constitute an exceedingly simple and direct
a
Scheme 5. Transition-State Analysis
with ≥50:1 diastereoselectivity. The absolute stereochemistry
of the secondary hydroxyl groups of 6a−f was assigned by using
the modified Mosher ester analysis.15 The anti stereochemistry
of the newly formed stereocenters in 6a and 6e was assigned by
1H NMR studies of acetonide derivatives synthesized following
manipulation of the alkyne unit (see Supporting Information).
This methodology can also be utilized to synthesize the anti,
syn-stereotriads 8. As shown in Scheme 6, treatment of
aldehyde 5a with the enantiomeric allenylboronate (P)-1 in
the presence of 5 mol % of chiral acid catalyst (R)-4 provided
the anti, syn-stereotriad 8a in 93% yield and with >50:1
diastereoselectivity. When the same conditions were applied to
the allenylboration of aldehyde 5b, the anti, syn-adduct 8b was
obtained in 91% yield, also with >50:1 diastereoselectivity.
These reactions proceed with the favored boat-like transition
state TS-5.
a
The chiral phosphoric acid counter ion is omitted for clarity.
CONCLUSIONS
■
In summary, we developed highly diastereo- and enantiose-
lective syntheses of anti- and syn-homopropargyl alcohols 2 and
3 via allenylboration reactions of achiral aldehydes using the
chiral, nonracemic allenylboronate (M)-1 in combination with
the appropriate enantiomer of the chiral phosphoric acid
catalyst 4. Under optimized conditions, the anti-homopropargyl
alcohols 2 are obtained in excellent yield and with >50:1
diastereoselectivity via double asymmetric allenylboration
solution to this problem. Toward this end, a variety of chiral
aldehydes 5a−f (most of which are exceptionally challenging
substrates for mismatched crotylboration reactions)18f−h were
subjected to propargylation reactions with the appropriate
enantiomers of allenylboronate 1 and chiral acid 4. The results
of these experiments are summarized in Table 3. In all cases,
the anti, anti-stereotriads 6a−f were obtained in 86−95% yield
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of α-methyl branched aldehydes.18,20 In addition, it has been
amply documented that the alkyne unit in homopropargyl
alcohols, like 2 or 6, can be transformed into many other
functional groups, such as (Z)- or (E)-olefins,21a−c vinyl
iodides,10e,11d−f,21d and many other units that can be derived
therefrom. The homopropargyl unit can also be engaged in
many C−C forming reactions, such as alkyne ring-closing
metathesis21f and cross coupling reactions.11g,h,21g,h,22 Synthetic
applications of this method will be reported in due course.
Scheme 6. Diastereoselective Syntheses of anti, syn-
Stereotriads 8 via Allenylboration Reactions using (P)-1 and
Acid Catalyst (R)-4
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
roush@scripps.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank professor Glenn C. Micalizio for insightful
discussions and suggestions. We also thank Dr. Jeng-Liang
Han for assisting with initial syntheses of allenylboronates (P)-
and (M)-1, and Dr. Andy S. Tsai for scale-up of the
allenylboration reaction. Financial support provided by the
National Institutes of Health (GM038436) and Eli Lilly (for a
predoctoral fellowship to M.C.) is gratefully acknowledged.
reactions in which the stereochemical preferences of
allenylboronate (M)-1 and chiral acid catalyst (S)-4 are
matched (Scheme 2). The syn-isomers 3 can also be
synthesized with good diastereoselectivity (≥9:1) with aromatic
aldehydes in reactions in which the stereochemical preferences
of (M)-1 and the enantiomeric chiral acid catalyst (R)-4 are
mismatched (Scheme 3).
REFERENCES
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Key to the success of these reactions is the use of the chiral
phosphoric acid catalysts, (S)- and (R)-4, to control the
stereochemistry of the hydroxyl groups in 2 and 3, respectively.
The stereochemistry of the methyl group introduced into 2 and
3 is controlled by the chirality of the allenylboronate (M)-1, but
use of the appropriate enantiomer of the chiral phosphoric acid
catalyst is required in order to achieve synthetically useful
diastereochemical control of these reactions. This study
represents a striking case of a growing number of
examples4d,13l,14 in which the diastereoselectivity of an
inherently nondiastereoselective but highly enantioselective
transformation (e.g., Table 1, entry 1) is rectified by using a
chiral catalyst to alter the relative energetics of the competing
transition states in order to control the stereochemistry of the
center (e.g., the hydroxyl group in 2 and 3) that is not
controlled by using the primary chiral reagent alone (the
allenylboronate (M)-1, for the work described here). The
reactions we describe here differ fundamentally from traditional
examples of double asymmetric synthesis, which involve the use
of a chiral substrate in combination with the appropriate
enantiomer of a chiral reagent.17 In contrast, we use a chiral
reagent in combination with the appropriate enantiomer of a
chiral catalyst in order to achieve high diastereochemical
control in an inherently highly enantioselective transformation.
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syntheses of a variety of compounds 6 containing the
historically challenging anti, anti-stereotriad configuration, the
synthesis of which has proven to be difficult to accomplish via
mismatched double asymmetric aldol and crotylmetal reactions
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(12) Allenylboronates (M)- and (P)-1 were prepared according to
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benzaldehyde..
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̌
́
(g) Coric, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536.
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10952
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