Enantioselective Allylation of β-Haloacrylaldehydes: Formal Total Syntheses of Pteroenone and Antillatoxin

Article abstract of DOI:10.1002/ejoc.201600286

A comparative study of the catalytic allylations and crotylations of (E)- and (Z)-haloacrylaldehydes by Lewis bases (chiral N,N′-dioxides) and Br?nsted acids (chiral phosphoric acids) was undertaken. The reactions proceeded with high enantio- and diastereoselectivities with slightly better asymmetric induction observed in the case of N,N′-dioxide catalysis. The formed enantioenriched chiral unsaturated haloalcohols could be considered general building blocks, as they could be used in the syntheses of more complex natural products possessing substituted 1,3-diene fragments. This was exemplified by the formal total syntheses of pteronenone and antillatoxin. A comparative study of allylations and crotylations of (E)- and (Z)-haloacrylaldehydes is undertaken under Lewis base and Br?nsted acid catalysis. The reactions proceed in both cases with high enantio- and diastereoselectivities. The formed chiral unsaturated haloalcohols can be considered as general building blocks, as exemplified by the formal total syntheses of pteronenone and antillatoxin; HBPin = pinacolborane.

Full text of DOI:10.1002/ejoc.201600286

DOI: 10.1002/ejoc.201600286
Communication
Allylation
Enantioselective Allylation of ꢀ-Haloacrylaldehydes: Formal
Total Syntheses of Pteroenone and Antillatoxin
Petr Koukal,[a] Jan Ulč,[a] David Nečas,[a] and Martin Kotora*[a]
Abstract: A comparative study of the catalytic allylations and formed enantioenriched chiral unsaturated haloalcohols could
crotylations of (E)- and (Z)-haloacrylaldehydes by Lewis bases
(chiral N,N′-dioxides) and Brønsted acids (chiral phosphoric
acids) was undertaken. The reactions proceeded with high en-
antio- and diastereoselectivities with slightly better asymmetric
induction observed in the case of N,N′-dioxide catalysis. The
be considered general building blocks, as they could be used
in the syntheses of more complex natural products possessing
substituted 1,3-diene fragments. This was exemplified by the
formal total syntheses of pteronenone and antillatoxin.
Introduction
In principle, intermediate A and its congeners can be used
for the syntheses of various natural compounds such as pter-
oenone (a defensive metabolite from the Antarctic pteropod
Clione Antarctica),[3] antillatoxin (isolated from a marine cyano-
bacterium Lyngbya majuscule),[4] papulacandin D (isolated from
the deuteromycetous fungus Papularia sphaerosperma),[5] and
tiacumicin A (an antibiotic isolated from Dactylosporangium au-
rantiacum)[6] (Figure 1). The syntheses of these compounds can
also be based on enantioselective crotylations of the corre-
sponding dienals,[7] as exemplified in the syntheses of papula-
candin D,[7a,7b] macrolactin A,[7e,8] a natural 5,6-dihydro-2H-
pyran-2-one,[9] and pteroenone.[10] Nonetheless, allylation of
haloacrylaldehydes could allow preparation of these com-
pounds starting from a common intermediate. Furthermore, it
could also enable the synthesis of their hitherto unknown ana-
logues, which could be especially attractive in the design of
compounds with better biological selectivities and activities.
The chiral 1,5-hexadien-3-ol moiety is a frequent motif in a
plethora of natural compounds. In principle, the preparation of
this moiety can be accomplished by enantioselective vinylation
of ꢀ,γ-unsaturated aldehydes[1] or by enantioselective 1,2-addi-
tion of carbon nucleophiles to α,ꢀ-unsaturated aldehydes. In
both cases, chiral intermediates are formed that are applicable
as building blocks for the synthesis of more structurally com-
plex compounds. In general, enantioselective allylation, crotyl-
ation, and so on of various aldehydes (aryl, heteroaryl, alkenyl,
and alkyl) has been intensively studied under catalytic and stoi-
chiometric conditions.[2]
In principle, chiral 1-halohexa-1,5-dien-3-ols A, prepared by
reaction of 1-haloacrylaldehydes B with allylic nucleophiles C,
can also serve as useful building blocks (Scheme 1), because
the C–halogen bond can be used in further functionalization
reactions, for example, cross-coupling reactions. Moreover, the
presence of the halogen atom on the double bond results in
reduced electron density, which makes it less vulnerable to oxi-
dative attack; this allows selective oxidative transformations of
the terminal double bond originating from reagent C to be per-
formed.
Scheme 1. Retrosynthetic analysis of the preparation of chiral 1-halohexa-1,5-
dien-3-ol building blocks A.
[a] Department of Organic Chemistry, Faculty of Science,
Charles University in Prague,
Hlavova 8, 12343 Praha 2, Czech Republic
E-mail: kotora@natur.cuni.cz
https://www.natur.cuni.cz/chemistry/orgchem/kotora
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600286.
Figure 1. A list of potential candidates that could be prepared by enantiose-
lective allylation (in red) of ꢀ-haloacrylaldehydes (in blue) followed by cross-
coupling reactions (in violet).
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Considering this, it is rather surprising that allylation of ꢀ- high enantioselectivities [the best results were usually obtained
haloacrylaldehydes has been neglected. As far as the enantiose- with (R,Sa)-IIa].[17] As the allylation reagents, allylboronic acid
lective allylation and crotylation of ꢀ-haloacrylaldehydes is con- ester 1a, (E)-crotylboronic acid ester 2a, allyltrichlorosilane 1b,
cerned, only a handful of examples have so far been reported. and (E)-crotyltrichlorosilane 2b were used.
To the best of our knowledge, only one example of the enantio-
selective allylation of ꢀ-haloacrylaldehydes with allyltrimethyl-
silane catalyzed by TiF4/(R)-BINOL (10 mol-%) with mediocre
asymmetric induction (48 % ee) has been reported.[11] As for the
enantioselective allylations by using stoichiometric amounts of
chiral reagents, procedures based on chiral boron,[11,12] sili-
con,[11] and titanium[11,13] reagents have been reported. Given
that knowledge in this area is rather limited, we undertook an
effort to explore the scope of the allylation and crotylation of
ꢀ-haloacrylaldehydes under Lewis base and Brønsted acid catal-
ysis. By transformation of the obtained haloalcohols into ad-
vanced intermediates, the formal total syntheses of two natural
products were achieved, and this approach was compared with
allylation of the corresponding dienals.
At the outset, we decided to explore the allylation and crot-
ylation of (E)-iodoacrylaldehyde [(E)-3]. Notably, its preparation
and handling, owing to its low boiling point, were to a certain
extent problematic. Hence, the allylation and crotylation reac-
tions were screened under a limited number of reaction condi-
tions (Table 1). Reactions with the pinacol ester of allylboronic
acid (1a) and (E)-crotylboronic acid (2a) catalyzed by (Sa)-Ia pro-
vided corresponding products (E)-4 and (E)-5 in high yields (91
and 93 %) with good enantioselectivities of 74 and 94 % ee
(Table 1, entries 1 and 2). In a similar manner, reactions with
allyltrichlorosilane (1b) and (E)-crotyltrichlorosilane (2b) also
proceeded to give rise to the corresponding products in yields
of 85 and 84 %, respectively (Table 1, entries 3 and 4). The
former proceeded with a good enantioselectivity of 75 % ee.
Surprisingly, the crotylation reaction proceeded with low asym-
metric induction of only 68 % ee.
Results and Discussion
Our attention then focused on the allylation (crotylation)
of isomeric (E)- and (Z)-3-iodometacrylaldehydes 6a[18]
(Table 2).[19] Allylations catalyzed by chiral phosphoric acids Ia–
Id were conducted at –40 °C to slow down the undesirable
noncatalytic reaction. Allylation catalyzed by (Sa)-Ia gave rise to
(E)-7a with a high asymmetric induction of 96 % ee in a good
yield of 70 % (Table 2, entry 1). Reactions catalyzed by the re-
maining three chiral phosphoric acids Ib–Id proceeded with
high conversions but with low asymmetric inductions (2–
48 % ee). Then, we proceeded with crotylation reactions. Given
that the abovementioned natural products have anti arrange-
ment of the hydroxy and methyl groups, catalytic crotylations
with 2a providing the anti diastereoisomers were performed.
As in the previous cases, the use of (Sa)-Ia gave desired product
(E)-8a with high asymmetric induction (94 % ee) and perfect
diastereoselectivity (anti/syn ≥99:1; Table 2, entry 2). Chiral
phosphoric acids Ib, Ic, and Id yielded products with 1, 84, and
80 % ee, respectively.
To obtain detailed insight into the catalytic allylation (crotyl-
ation) process, we decided to compare several Brønsted acids
and Lewis bases as catalysts (Figure 2). The former were repre-
sented by chiral phosphoric acids I.[14] It was previously demon-
strated that acid Ia[15] efficiently catalyzed the enantioselective
allylation and crotylation with good asymmetric induction, but
no study regarding the catalytic activities of acids Ib–Id (struc-
tures are given in the Supporting Information) has so far been
published.[16] The latter were represented by N,N′-dioxides II,
developed in our laboratory, which catalyzed allylations with
Then, allylations with allyltrichlorosilane (1b) catalyzed by
diastereomeric N,N′-dioxides IIa were screened. The catalysis by
(R,Ra)-IIa provided (E)-7a with mediocre asymmetric induction
(57 % ee); however, catalysis by (R,Sa)-IIa yielded (E)-7a with an
excellent asymmetric induction of 98 % ee and 65 % yield
Figure 2. Used chiral phosphoric acids, N,N′-dioxides, and allylation reagents;
BPin = (pinacolato)boryl.
Table 1. Allylation of (E)-3 with 1 or 2 under catalytic conditions.
Entry
Catalyst
Reagent
Product
Yield[a] [%]
ee[b] [%]
anti/syn
1
2
3
4
(S)-Ia
(S)-Ia
(R,Sa)-IIa
(R,Sa)-IIa
1a
2a
1b
2b
(E)-4
(E)-5
(E)-4
(E)-5
91
93
85
84
74
94
75
68
–
45:1
–
11:1
[a] Yield of isolated product. [b] Determined by HPLC on a column with a chiral stationary phase.
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Table 2. Allylation of (E)-6 with 1 or 2 under catalytic conditions.
Entry
Catalyst
Reagent
Substrate
Product
Yield[a] [%]
ee[b] [%]
anti/syn
1
2
3
4
5
6
7
8
9
(Sa)-Ia
(S)-Ia
1a
2a
1b
1b
2b
2b
1a
2a
1b
2b
(E)-6a
(E)-6a
(E)-6a
(E)-6a
(E)-6a
(E)-6a
(E)-6b
(E)-6b
(E)-6b
(E)-6b
(E)-7a
(E)-8a
(E)-7a
(E)-7a
(E)-8a
(E)-8a
(E)-7b
(E)-8b
(E)-7b
(E)-8b
70
95
71
65
79
60
50
68
44
48
96
94
57
98
69
98
91
96
97
95
–
>99:1
–
(R,Ra)-IIa
(R,Sa)-IIa
(R,Ra)-IIa
(R,Sa)-IIa
(S)-Ia
(S)-Ia
(R,Sa)-IIa
(R,Sa)-IIa
–
>99:1
>99:1
–
>30:1
–
10
>30:1
[a] Yield of isolated product. [b] Determined by HPLC on a column with a chiral stationary phase.
(Table 2, entries 3 and 4). In an analogous manner, reactions properties of 1b (or 2b) and, thus, it cannot be avoided during
with crotyltrichlorosilane (E)-2b catalyzed by N,N′-dioxides IIa the allylation reaction.
also proceeded. The reaction catalyzed by (R,Ra)-IIa provided
(E)-8a with acceptable asymmetric induction (69 % ee), whereas
catalysis by (R,Sa)-IIa yielded (E)-8a with excellent asymmetric
induction of 98 % ee and 60 % yield (Table 2, entries 5 and 6).
In both cases, only the anti isomer was detected. The above-
mentioned results clearly indicate that allylation or crotylation
catalyzed by (R,Sa)-IIa gave superior results in terms of asym-
metric induction. To assess the effect of the halogen atom,
chloroaldehyde 6b was prepared. Both allylation and crotyl-
ation copied the previously described pattern and furnished
corresponding homoallylic alcohols (E)-7b and (E)-8b with
asymmetric inductions in the range of 91–97 % ee (Table 2, en-
tries 7–10). The almost identical asymmetric inductions indicate
that the nature of the halogen atom does not play any signifi-
cant role.
In the next stage, we focused on the allylation and crotyl-
ation of (Z)-6a under the abovementioned conditions (Table S3,
Supporting Information). Although the reactions catalyzed by
chiral phosphoric acids Ia–Id proceeded to give the isolated
products in high yields, asymmetric induction was surprisingly
low (23 % ee was the highest). A similar trend was also ob-
served in the N,N′-dioxide IIa catalyzed reactions, for which,
in addition to low asymmetric induction, partial isomerization
providing (E)-7a was also observed. To determine the origin of
the isomerization, (Z)-6a was treated individually or in combina-
tion with coreactants, catalysts, and so on present during allyl-
ation with allyltrichlorosilane (for details see the Supporting In-
formation). The screening indicated that the isomerization was
induced by allyltrichlorosilane 1b, whereas neither catalyst rac-
IIc nor the base had any significant effect. The isomerization
could thus be induced by the Lewis acid character of 1b or by
HCl as a Brønsted acid formed from 1b and trace amounts of
water. Pure HCl (a dioxane solution) induced the isomerization
very powerfully; however, in the presence of base, formation of
To demonstrate the possibility of converting the enantioen-
riched crotylation products into more advanced intermedi-
ates,[20] the crotylation of (E)-6a was performed with 2a cata-
lyzed by (Sa)-Ia (2.5 mol-%) on a larger scale to acquire a larger
amount of enantioenriched (S,S,E)-8a for further experiments
(81 % yield, 94 % ee).
With (S,S,E)-8a in hand, it was subjected to a cross-coupling
reaction with vinylborane 9a, (prepared by hydroboration of
tert-butylmethylethyne) under Suzuki–Miyaura conditions to
furnish (S,S)-10 in a good yield of 62 % without loss of optical
purity (97 % ee)[21,22] (Scheme 2). Compound (S,S)-10 is an inter-
mediate in the synthesis of antillatoxin (see below). In an analo-
gous manner, the cross-coupling reaction with vinylborane 9b
(prepared by hydroboration of 2-butyne) was executed that
gave rise to (S,S)-11 in 88 % yield. It is the known intermediate
in the synthesis of pteroenone.[10]
Scheme 2. Synthesis of antillatoxin and pteroenone intermediates 10 and 11.
Reagents and conditions: Pd(PPh3)4, aq. NaOH, THF, 65 °C, 2 h; Py = 3-pyridyl.
Given that we recently showed that crotylation of α,ꢀ,γ,δ-
free HCl by decomposition of 1b was suppressed. This suggests unsaturated aldehydes proceeds with a high degree of asym-
that the isomerization was caused solely by the Lewis acidic metric induction and that this method could be applied in the
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Communication
total synthesis of (+)-pteroenone, comparison of efficacy of the gave rise to corresponding acrylate (S,S)-13 in a good 93 %
crotylation of iodoacrylates with the crotylation of α,ꢀ,γ,δ-un- yield. This compound, in turn, was subjected to ring-closing
saturated aldehydes 12 was the next obvious task.
metathesis[23] in the presence of Hoveyda–Grubbs second-gen-
eration catalyst and titanium tetraisopropoxide to promote the
formation of the unsaturated lactone moiety.[24] The metathesis
gave rise to lactone (S,S)-14 (93 % ee), which was isolated in a
very nice 94 % yield. Given that lactone (S,S)-14 is the known
intermediate in the synthesis of antillatoxin,[25] its formal total
synthesis was accomplished.
The crotylation with (E)-2a catalyzed by (Sa)-Ia gave desired
product 10 with high asymmetric induction (94 % ee) and very
good diastereoselectivity (anti/syn ≥30:1; Table 3, entry 1). Chi-
ral phosphoric acids Ib–Id catalyzed the crotylation with excel-
lent diastereoselectivity as well; however, their ability to induce
asymmetric induction was considerably different: (Sa)-Ib proved
to be a rather poor catalyst, as it provided almost racemic 10
(9 % ee; Table 3, entry 2), whereas the use of (Sa)-Ic and (Sa)-Id
gave 10 with 83 and 75 % ee, respectively (Table 3, entries 3
and 4). In an analogous manner, the crotylation with (E)-2b
catalyzed by N,N′-dioxides IIa also proceeded. The crotylation
catalyzed by (R,Ra)-IIa provided 10 with very low asymmetric
induction (7 % ee), whereas catalysis by (R,Sa)-IIa yielded 10
with an excellent enantiomeric excess value of 99 % (61 % yield;
Table 3, entries 5 and 6). In both cases, only the anti isomer
was detected.
Conclusion
In conclusion, we showed that (1) allylation (crotylation) of 3-
haloaldehydes proceeds under Lewis base and Brønsted acid
catalysis and provides the corresponding enantioenriched alco-
hols with high asymmetric induction, (2) the reactions catalyzed
by (R,Sa)-IIa give products with slightly higher asymmetric in-
duction than reactions catalyzed by chiral phosphoric acids,
(3) the crotylation of iodoaldehydes and dienals proceeds with
similar enantioselectivities, which shows the complementarity
of both approaches. However, the presence of a vinyl halide
moiety offers higher synthetic flexibility: compound (E)-8a
served as the common intermediate for the formal total synthe-
ses of antillatoxin and pteroenone.
Table 3. Crotylation of dienal 12 with (E)-1b under different conditions.
Experimental Section
Entry
Catalyst
Reagent
Yield[a] [%]
ee[b] [%]
anti/syn
Supporting Information (see footnote on the first page of this
article): Experimental details such as synthetic procedures, com-
pound characterization data, asymmetric induction determination,
and copies of the spectra.
1
2
3
4
5
6
(Sa)-Ia
(Sa)-Ib
(Sa)-Ic
(Sa)-Id
(R,Ra)-IIa
(R,Sa)-IIa
2a
2a
2a
2a
2b
2b
80
49
73
70
45
61
94
9
83
75
7
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
99
Acknowledgments
[a] Yield of isolated product. [b] Determined from the corresponding Mosher
esters.
This work was supported by a grant from the Czech Science
Foundation (P207/11/0587) and the Grant Agency of the
Charles University, Prague (GAUK 794216).
With enantioenriched (S,S)-10 (93 % ee) in hand, we decided
to explore its application as a chiral building block for the for-
mal synthesis of antillatoxin (Scheme 3). Esterification of alcohol
(S,S)-10 with acryloyl chloride under the standard conditions
Keywords: Asymmetric synthesis · Allylation · Aldehydes ·
Brønsted acids · Lewis bases
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(2 equiv.), iPrNEt2 (3 equiv.), CH2Cl2, 23 °C, 15 h; (c) Hoveyda–Grubbs 2nd
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Received: March 10, 2016
Published Online: April 6, 2016
Eur. J. Org. Chem. 2016, 2110–2114
www.eurjoc.org
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