A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a Z-Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole

Article abstract of DOI:10.1021/jacs.9b11178

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, Z-chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F₃C-substituted alkene can also be prepared with similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, generating mycothiazole in 14.5% overall yield.

Full text of DOI:10.1021/jacs.9b11178

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
A Catalytic Approach for Enantioselective Synthesis of Homoallylic
Alcohols Bearing a Z‑Alkenyl Chloride or Trifluoromethyl Group. A
Concise and Protecting Group-Free Synthesis of Mycothiazole
Ryan J. Morrison,†,§ Farid W. van der Mei,†,§ Filippo Romiti,*,†,‡ and Amir H. Hoveyda*,†,‡
†Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
‡Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, Strasbourg 67000, France
S
* Supporting Information
ABSTRACT: A protecting group-free strategy is presented
for diastereo- and enantioselective routes that can be used to
prepare a wide variety of Z-homoallylic alcohols with
significantly higher efficiency than is otherwise feasible. The
approach entails the merger of several catalytic processes and
is expected to facilitate the preparation of bioactive organic
molecules. More specifically, Z-chloro-substituted allylic
pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato)
and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central
transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral
aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric
purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The
aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive
starting materials. A significant assortment of homoallylic alcohols bearing a Z-F3C-substituted alkene can also be prepared with
similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can
be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the
approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally
occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of
which are catalytic, generating mycothiazole in 14.5% overall yield.
oxidation of the primary alcohol to an aldehyde, and reaction
with a halogen-substituted phosphonium salt (Scheme 2a).2c,8
The Z-alkenyl halide may then be transformed to a protected
form of a Z-homoallylic alcohol by catalytic cross-coupling
(stereoretentive). Alternative strategies include enzymatic
kinetic resolution of an allylic alcohol and subsequent
transformation to a homoallylic alcohol.9
Z-Homoallylic alcohols that are without an allylic substituent
and contain an alkenyl halide moiety may be prepared via
enantiomerically enriched allyl boronates,10 but such strategies
require extremely low temperatures, several days of reaction
time, and/or do not furnish products in high enantiomeric ratio
(er; Scheme 2b). There are a limited number of protocols that
directly furnish Z-homoallylic alcohols.11 Again, one involves
the use of a chiral auxiliary,11a and the other is a catalytic kinetic
resolution for which a racemic secondary allyl−B(pin)
compound is needed (Scheme 2b).11b Notably, the applicability
of these approaches is confined to products that contain a
simple n-alkyl-substituted olefin (mostly Me).
1. INTRODUCTION
Homoallylic alcohols are used widely in chemical synthesis, and
many past studies have led to the development of catalytic
methods that generate these entities efficiently and in high
enantiomeric purity.1 However, several key shortcomings
remain unaddressed, one of which is the efficiency and
enantioselectivity with which a Z-homoallylic alcohol, especially
those lacking an allylic substituent, can be accessed. These
fragments can be found in numerous bioactive molecules, such
as antitumor agent macrolactin A,2 anticancer and antifungal
agent disorazole C1,3 antitumor mycothiazole,4 and cytotoxic
and antimalarial bipinnatin J (Scheme 1).5
A common strategy for preparation of enantiomerically
enriched Z-homoallylic alcohols entails initial synthesis of the
derivative that contains a monosubstituted alkene, either by
diastereoselective addition of an unfunctionalized allyl unit to
an enantiomerically enriched aldehyde6 or by an enantiose-
lective process that involves an achiral aldehyde.7 Typically,
after alcohol protection, the monosubstituted alkene is
converted to a Z-alkenyl iodide by oxidative alkene cleavage
and a Wittig reaction (Scheme 2a).8 Another approach entails
catalytic enantioselective aldol addition followed by secondary
alcohol protection, reduction of the ester (to alcohol),
Received: October 17, 2019
© XXXX American Chemical Society
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Scheme 1. Representative Biologically Active Natural Products with One or More Z-Homoallylic Alcohol-Derived Fragments
Despite the above advances, significantly more efficient
routes and more broadly applicable strategies are needed, as is
evident from two representative cases (Scheme 2c), performed
in the context of natural product total synthesis. One relates to
the preparation of a fragment of disorazole C1 (Scheme 2c).3d
To access products in high stereochemical purity, stoichio-
metric amounts of an enantiomerically pure allylic silane
reagent were required, and it was necessary to mask the hydroxy
group prior to a cross-metathesis reaction that generated the
derived Z-alkenyl boronate. Five steps, only one of which is
catalytic, were therefore needed to convert the aldehyde to the
desired Z-homoallylic alcohol.12 In the second instance, relating
to the only reported enantioselective synthesis of mycothiazole
(2015; Scheme 2c),4e preparation of the requisite β-siloxy
aldehyde demanded 13 steps; this was followed by a Wittig
reaction that had to be carried out with 10 equiv of
hexamethylphosphoramide (HMPA) for it to be highly Z-
selective.
To design a more general and efficient catalytic strategy, we
envisioned a route that would entail synthesis of an
enantiomerically enriched homoallylic alcohol containing a
terminal alkene followed by catalytic stereoretentive cross-
metathesis to form a Z-alkenyl halide. This would provide a
convenient diversification point for generating a range of Z-
homoallylic alcohols through catalytic cross-coupling. We had
two major concerns, however: protection of the alcohol would
be necessary (Mo-based catalysts used as Ru complexes are
ineffective12), and cross-metathesis is typically inefficient with
alkenes that carry a β substituent, especially a sterically
demanding one. To probe, we prepared homoallylic silyl
ether 2 from aldehyde 1a4i,j (Scheme 2d), based on a reported
catalytic enantioselective protocol (99:1 er).7a,f,h Subsequent
studies revealed that, under the best of circumstances, with
monoaryloxide pyrrolide (MAP) complex Mo-1a, cross-meta-
thesis between 2 and Z-1,2-dichloroethene12,13 does not
proceed beyond ∼50% conversion (5.0 mol % loading; Scheme
2d). We could isolate Z-homoallylic alcohol 3a in only 34%
yield and 98:2 Z:E ratio after silyl group removal. If the silyl
ether form of 3a were desired, separating it from unreacted 2
would be difficult.
latter step could be promoted by a chiral, proton-activated
aminophenol-boryl catalyst,14 generating 3a directly. Ensuing
catalytic cross-coupling reactions could then be used to
establish a concise and protecting group-free total synthesis of
mycothiazole, a natural product recently prepared in 26 total
steps (longest linear sequence = 20 steps; 1.8% overall yield).4e
2. RESULTS AND DISCUSSION
2.1. α-Selective Additions of a Z-Cl-Substituted
Allylboronate to Aldehydes. 2.1.1. Mechanistic Consid-
erations. Since the discovery of chiral aminophenol-boryl
catalysts,14 we have been focused on additions to various
aldimines14,15 and ketones.16 Initial studies with aldehydes had
shown that such transformations, although efficient, are
minimally enantioselective. Considering that stereodifferentia-
tion in additions to ketones is typically more challenging
(smaller size difference between substituents), and because
aldehydes are sterically less encumbered and more reactive (vs
imines or ketones), we presumed that low er was due to fast and
competitive noncatalytic addition of allylic boronates. To check
the validity of this assumption, we examined a process with a
deuterium-labeled allyl−B(pin) (Scheme 3a). If the reason for
low er is fast and competitive uncatalyzed addition, a γ-selective
process that proceeds via a six-membered transition structure,
then the D atoms will be found attached to the terminal alkenyl
carbon; if the catalytic process, which is α-selective, is the major
pathway, then the D atoms will be at the sp3-hybridized
methylene site. In the event, we established that our hypothesis
was incorrect (Scheme 3a): the catalytic process is faster (vs
noncatalytic) and is minimally enantioselective.
The above findings were somewhat surprising because,
typically, it is easier to achieve high enantiofacial selectivity with
an aldehyde, where the difference between the size of the two
carbonyl substituents is more substantial (vs a ketone). Why
would additions to aldehydes afford products with low er but
not when aldimines (phosphinoyl- or Boc-protected)15a,c or
ketones,16 including trifluoromethyl ketones,16a,c,d are in-
volved? Examination of stereochemical models, which are
based on former investigations, suggested that this is likely
because a small hydrogen atom substituent renders reaction via
II (Scheme 3a) too competitive when I is involved. We
therefore wondered whether reactions with Z-allylic boronate
4a might prove to be more enantioselective. We considered this
possibility on the basis of the initial formation of chiral allylic
We reasoned that a more attractive option would be to
combine catalytic enantioselective allyl addition to an aldehyde
and catalytic cross-metathesis in a different way: Z-allylic
boronate 4a might be synthesized first and then used in an α-
and enantioselective addition to aldehyde 1a (Scheme 2e). The
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a
Scheme 2. Synthesis of Enantiomerically Enriched Z-Homoallylic Alcohols: State-of-the-Art and the Aim of This Study
a
Reactions (1a → 3a) were carried out under N2 atm. Conversion was determined by analysis of 1H NMR spectra of unpurified mixtures ( 2%).
Yields are for purified products ( 5%). Enantiomeric ratios were determined by HPLC analysis ( 1%). Experiments were run at least in triplicate.
See the Supporting Information for details.
boronate V, which would be generated by the reaction of III
with 4a via IV (Scheme 3b).15b,c,16c The main issue therefore
was: Could it be that transformation via VI, which would afford
an E-homoallylic alcohol, suffers from sufficient steric repulsion
as compared to VII to generate a Z-homoallylic alcohol more
enantioselectively?
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a
Scheme 3. Synthesis of Enantiomerically Enriched Homoallylic Alcohols: The Initial Studies
a
Reactions were carried out under N2 atm. Conversion was determined by analysis of 1H NMR spectra of unpurified mixtures ( 2%).
Enantiomeric ratios were determined by HPLC analysis ( 1%). Experiments were run at least in triplicate. See the Supporting Information for
details.
2.1.2. Identification of an Optimal Catalyst. Homoallylic
alcohol 3b (Scheme 4) was indeed generated with considerably
higher enantioselectivity when 4a was used in the presence of
2.0 mol % ap-1 (87:13 er) or related derivatives ap-2 and ap-3
(91:9 and 92:8 er, respectively). The transformations afforded
the Z-alkenyl chloride isomer preferentially (97:3−98:2 Z:E)
and were uniformly and exceptionally α-selective, particularly
when the latter two aminophenols were involved (98:2 α:γ
selectivity). We obtained higher er when we utilized
hydroxyadamantyl-substituted ap-4 and ap-5, with the latter
delivering 3b in 95% yield, complete α selectivity, 98:2 Z:E
ratio, and 95:5 er (Scheme 4). The necessary enantiomerically
pure amino alcohol, which is used in the commercial synthesis
of saxagliptin,17 is readily available and less expensive than the
parent adamantyl-containing variant (no hydroxy group).
Control experiments indicate that the free hydroxy unit is not
required, as it does not impact the outcome (e.g., reaction with
the derived methyl ether aminophenol was similarly efficient
and selective).
2.1.3. Scope. The method has considerable scope (Scheme
5). Aryl aldehydes, including those that contain a sterically
demanding ortho substituent, undergo reaction readily; for
example, 3c and 3d were isolated with complete α selectivity,
83% and 86% yield, 98:2 and >98:2 Z:E ratio, and 95:5 and
94:6 er, respectively. The same applied to m- and p-substituted
aryl aldehydes (3e−j) and those containing a heterocyclic
moiety (3k,l). Notably, the reaction leading to 3g proceeded
with complete chemoselectivity (<2% addition to ketone).
D
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a
Scheme 4. Identification of an Effective Catalyst for α-Selective Addition with Cl-Substituted Allylic Boronate 4a
a
Reactions were carried out under N2 atm. Conversion (>98% in all cases) and α:γ selectivity were determined by analysis of 1H NMR spectra of
unpurified mixtures ( 2%). Yields correspond to purified products ( 5%). Enantiomeric ratios were determined by HPLC analysis ( 1%).
Experiments were run at least in triplicate. See the Supporting Information for details.
a
Scheme 5. Catalytic Synthesis of Enantiomerically Enriched Z-Cl-Substituted Homoallylic Alcohols
a
(a) Reactions were carried out under N2 atm. Conversion (>98% in all cases) and α:γ selectivity were determined by analysis of 1H NMR spectra
of unpurified mixtures ( 2%). Yields correspond to purified α isomer products ( 5%). Enantiomeric ratios were determined by HPLC analysis
( 1%). (b) Performed at 40 °C for optimal efficiency; 40−50% conversion was observed at 22 °C. Experiments were run at least in triplicate. See
the Supporting Information for details.
Enals, as represented by homoallylic alcohols 3m and 3n, and
alkyl-substituted aldehydes were suitable substrates (3o,p).
Whereas 3o, derived from addition to an n-alkyl-substituted
aldehyde, was less enantioselective (79:21 er), reaction with
cyclohexyl aldehyde afforded 3p in 93:7 er.
The α selectivities and Z:E ratios were uniformly high, and
purified homoallylic alcohols were isolated in 82−96% yield
(pure α-addition isomers in all cases). However, there were
some variations. Reactions involving p-keto-, p-methoxy-, and
p-thiomethyl-substituted aryl aldehydes afforded the corre-
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sponding products with lower enantioselectivity (3g−i; Scheme
5). The precise reason for this selectivity profile, which control
experiments show is not due to adventitious uncatalyzed
reaction, is unclear at the present time. The lower α selectivity
in the case of cyclohexyl-substituted 3p is probably because
adventitious borotropic shift15b is more competitive with
addition to the relatively hindered and somewhat less
electrophilic aldehyde. Still, the γ-addition isomer was easily
removed, and the desired product was obtained in 80% yield.
Two additional points are worthy of note:
Scheme 6. Reactions with Enantiomerically Pure Chiral
Aldehydes
a
(1) The reaction with an n-alkyl substrate, leading to 3o, was
less stereodifferentiating, a trend that is consistent with the
proposed stereochemical model, as represented by complex
VIII.
a
Reactions were carried out under N2 atm; α:γ selectivity was
(2) Use of excess aldehyde (1.5 equiv) is needed for
maximum efficiency and α selectivity. For example, with 1.0
equiv of the aldehyde, under otherwise identical conditions, we
obtained 3b and 3o in 67% and 56% yield (pure α isomer) and
78:22 and 73:27 α:γ ratio, respectively (vs 95% and 88% yield,
and >98:2 and 95:5 α:γ ratio, respectively). This likely arises
from a less competitive borotropic shift prior to C−C bond
formation, which would generate the corresponding γ-isomer.
[As shown below (Scheme 8b), >95% of the unreacted
aldehyde can be recovered.]
Transformations with chiral (enantiomerically pure) alde-
hydes, an important but particularly challenging set of
substrates,18 were carried out to enhance the scope of the
approach as well as reveal additional mechanistic attributes
(Scheme 6). Homoallylic alcohol 3q was isolated in 81% yield,
98:2 Z:E ratio, and 83:17 dr. Product 3r was obtained in 85%
yield, 97:3 α:γ ratio, 98:2 Z:E selectivity, and 97:3 dr. In
contrast, when the alternative aldehyde enantiomer was used,
while 3s was obtained with virtually the same regio- and
stereoselectivity, the reaction was significantly less efficient
(>98% vs 49% conv and 85% vs 32% yield for 3r and 3s,
respectively). These findings show that, despite more severe
steric pressure in the mismatched mode of addition represented
by X (vs IX, based on the Felkin−Anh model), the process
remains catalyst-controlled.
An unusual feature of the additions to sterically demanding
and less reactive chiral aldehydes (Scheme 6) is that
significantly higher α:γ ratios were observed in the absence of
MeOH. For example, 3r and 3s were generated with 53:47 and
32:68 α:γ selectivity with MeOH present (1.3 equiv), which led
to considerably lower yields (51% and 14% of α-addition
product, respectively; Z:E ratios and dr remained the same).19
While, as described previously,14 a proton source ensures rapid
generation of the requisite aminophenol-boryl catalyst, we often
find that residual moisture can serve as a suitable proton source.
The present data indicate that in cases involving less reactive
substrates, excess alcohol can cause a borotropic shift of the
initially generated chiral allylic boronates to occur faster than
1
determined by analysis of H NMR spectra of unpurified mixtures
( 2%). Yields correspond to purified products ( 5%). Enantiomeric
ratios were determined by HPLC analysis ( 1%). Experiments were
run at least in triplicate. See the Supporting Information for details.
C−C bond formation (see Scheme 7b), resulting in lower α:γ
ratios. Precisely how an alcohol can facilitate borotropic shifts
requires more detailed investigations. Nonetheless, it is
plausible that an increase in medium polarity and/or H-
bonding with one of the Lewis basic sites within the chiral allylic
boronate, as attributed formerly to the Lewis acidic Zn(II)
cation,15b can lower the barrier to the formation of the less
sterically hindered isomer.
Trisubstituted alkenyl chlorides may be used with similarly
high efficiency and stereochemical control to afford valuable Z-
trisubstituted homoallylic alcohols (e.g., see bipinnatin J,
Scheme 1). For instance, allylic boronate 4c (Scheme 7a) was
prepared (98:2 Z:E) from a commercially available alkenyl
bromide and a boronic acid by a fully catalytic sequence of
cross-coupling, hydroboration, and stereoretentive cross-meta-
thesis with MAP complex Mo-1b and via allylic boronate 4b.20
Homoallylic alcohols 5a−c, containing a trisubstituted alkenyl
halide, were obtained in 54−77% yield, 97:3−98:2 Z:E ratio,
and 86:14−95:5 er. A variety of other trisubstituted homoallylic
alcohols may be synthesized through catalytic cross-coupling
with 5a−c. Furthermore, the majority of the reagents,
substrates, transition metal complexes, and ligands are
commercially available (i.e., many alkenyl boronic acids,
pinacolatoborane, 1,2-E-dichloroethene, and the Pd- and Ni-
based complexes).
The lower α:γ selectivity in the reactions with a trisubstituted
allylic boronate may be rationalized on the basis of the relative
rate of reaction of the initially formed branched/more hindered
XI (Scheme 7b) as compared to its isomerization to the lower
energy XII (less hindered and more substituted alkene).
Transformation via XII would generate the γ-addition isomer.
Moreover, on the basis of stereochemical models, the presence
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a
Scheme 7. Additions with Trisubstituted Allylic Boronates
a
Reactions were carried out under N2 atm. Conversion (>98% in all cases) and α:γ selectivity were determined by analysis of 1H NMR spectra of
unpurified mixtures ( 2%). Yields correspond to purified products ( 5%). Enantiomeric ratios were determined by HPLC analysis ( 1%).
Experiments were run at least in triplicate. See the Supporting Information for details.
of a C2-methyl group within the allylic boronate leads to more
steric pressure in XIII (Scheme 7c), allowing alternative modes
of addition to become more competitive, resulting in lower er.
While the precise identity of the latter minor pathways is
unclear at the present time, it is noteworthy that, despite the
increased steric repulsion in these latter reactions, products are
formed in high Z:E ratios; this indicates that pathways leading
to the E-alkenyl chlorides (XIV, Scheme 7c) remain less
favored.
2.2. α-Selective Additions of a Z-F3C-Substituted
Allylboronate to Aldehydes. The present approach is not
limited to the formation of Z-alkenyl chlorides. Another
important class of homoallylic alcohols that can be readily
accessed consists of those that contain a Z-F3C-substituted
alkene (Scheme 8), a functional unit that has recently been used
to generate, with high stereoselectivity, desirable and versatile
allyl boronates21 and allyl silanes21c that contain a 1,1-
difluoroalkene moiety. These transformations, involving the
use of just 1.0 mol % ap-222 as the optimal ligand and allylic
boronate 4d,23 which may also be accessed through catalytic
stereoretentive cross-metathesis, are broadly applicable as well,
affording the desired aryl- (6a−g), heteroaryl- (6h−j), alkynyl-
(6k), alkenyl- (6l−m), or alkyl-substituted (6n) products in
65−98% yield (often of the pure α isomer), 70:30 to >98:2 α:γ
selectivity, 81:19−98:2 Z:E selectivity, and 88:12−98:2 er.
2.3. A Concise, Protecting Group-Free, and Enantio-
selective Synthesis of Mycothiazole. We began by
synthesizing multigram quantities of aldehyde 1a and Z-
chloro-substituted allylic boronate 4a (Scheme 9a). The former
(1a) was synthesized (1.76 g) starting from commercially
available 7 via 8 based on a procedure by Cossy4i,j in three steps
and 77% overall yield.24 To prepare 4a, with 10 mol %
pinacolatoborane (HB(pin), to remove residual moisture13)
and with commercially available MAP complex Mo-1c, cross-
metathesis was efficient, affording 4a in 81% yield and 98:2 Z:E.
It is worth emphasizing that allylic boronate 4d and Z-1,2-
dichloroethene are commercially available and did not require
any purification before use. When monoaryloxide chloride
(MAC) species Mo-223 was used (Scheme 9a), under otherwise
identical conditions, 1.6 mol % loading was sufficient for
accessing 4.3 g of 4a in higher yield (purified by distillation)
and similar stereochemical purity (96% yield, >98:2 Z:E).
We then turned our attention to another key fragment, α-
alkenyl boronate 11 (Scheme 9a). We first prepared allenyl
carbamate 10 from propargyl carbamate 9 (obtained in one step
from the commercially available propargyl amine).25 Organo-
boronate intermediate 11 was generated directly through
regioselective proto-boryl addition to the allene site of 10
catalyzed by the Cu−B(pin) complex derived from imid-1; use
of i-PrOH (vs MeOH, as reported originally)26 allowed us to
obtain the desired product with higher α selectivity (92:8 vs
96:4 α:β selectivity and 61% vs 76% yield of 11 with MeOH
and i-PrOH, respectively). We were thus able to secure 1.5 g of
11 (76% yield, 96:4 α:β selectivity). With substantial amounts
of Z-allylic boronate 4a available, we carried out the critical
catalytic addition to aldehyde 1a under the same conditions as
described above (Scheme 5): 1.76 g of the aldehyde was
transformed to 1.30 g of 3a in 86% yield, >98:2 α:γ ratio, >98:2
Z:E ratio, and 94:6 er (Scheme 9b). As was noted, reactions
with 1.5 equiv of 1a were optimal (53% yield, 80:20 α:γ with 1.0
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a
Scheme 8. Catalytic Synthesis of Enantiomerically Enriched Z-F3C-Substituted Homoallylic Alcohols
a
Reactions were carried out under N2 atm. Conversion (>98% in all cases) and α:γ selectivity were determined by analysis of 19F NMR spectra of
unpurified mixtures ( 2%). Yields correspond to purified products ( 5%). Enantiomeric ratios were determined by HPLC analysis ( 1%).
Experiments were run at least in triplicate. See the Supporting Information for details.
equiv of 1a, under otherwise identical conditions), and the
unreacted aldehyde was recovered as part of product
purification in high yield (i.e., 0.57 g, 97% recovery).
retentive cross-metathesis of 13 and commercially available 14
with Ru catechothiolate complex Ru-130 (9.0 mol %) delivered
primary alcohol 15 in 77% yield (>98:2 Z/Z:Z/E). The ensuing
conversion to the primary bromide and elimination of HBr
were catalyzed by a phosphine−Pd complex, as reported by
Fu,31 affording mycothiazole in 56% overall yield (Scheme 9b).
The above route allowed us to obtain 0.25 g of the natural
product. The above route contains a total of 12 steps and a
longest linear sequence of nine transformations, seven of which
are catalytic. The antitumor natural product was isolated in
14.5% overall yield.
Next, two catalytic cross-coupling reactions were performed.
The first was to accomplish the chemoselective merger of allyl−
B(pin) at the C−Br site, catalyzed by 2.5 mol % of a catalyst
derived from Pd(dppf)Cl2, according to a recent procedure by
Aggarwal,27 to generate 12 in 72% yield. Next, we needed to
establish whether the alkenyl chloride moiety would undergo
efficient catalytic cross-coupling. We expected that conversion
of 12 to 13 would be a particularly challenging process for two
reasons. First, the diene moiety is sensitive and prone to
isomerization/decomposition; accordingly, the reaction had to
be performed in the dark and at 55 °C. Second, strongly basic
conditions led to cleavage of the carbamate moiety, leading us
to use the milder K3PO4 along with a minimal amount of H2O
instead. After optimization studies, we were able to establish
that alkenyl−B(pin) 11 and Z-alkenyl-chloride 12 react readily
in the presence of 10 mol % ruphos-Pd-G3 and 10 mol %
ruphos (both are commercially available), as outlined by
Buchwald and co-workers,28 affording 13 in 71% yield (>98:2
Z:E). Various other cross-partners, including alkylzinc halide
compounds (Negishi-type coupling), can be used efficiently
with a Z-di- or trisubstituted alkenyl chloride.29 Synthesis of the
1,4-diene side chain was then carried out. Catalytic stereo-
3. CONCLUSIONS
We introduce a catalytic strategy that may be used to access a
wide variety of Z-homoallylic alcohols efficiently and with high
levels of diastereo- and enantioselectivity. The effectiveness of
the approach is largely due to the involvement of three C−C
bond forming transformations: catalytic stereoretentive cross-
metathesis to generate Z-chloro-substituted allylic boronates,
aminophenol-boryl-catalyzed addition of the aforementioned
organoboron compound to deliver a Z-chloroalkenyl-substi-
tuted homoallylic alcohol, and catalytic stereoretentive cross-
coupling that can afford enantiomerically enriched Z-homo-
allylic alcohols bearing a C-based substituent. Furthermore, we
show that the same approach may be used to generate
H
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Journal of the American Chemical Society
Article
a
Scheme 9. Application to a Concise Total Synthesis of Mycothiazole
a
Reactions were carried out under N2 atm. Conversion, regioselectivity, and diastereoselectivity were determined by analysis of 1H NMR spectra of
unpurified mixtures ( 2%). Yields are for purified products ( 5%). Enantiomeric ratios were determined by HPLC analysis ( 1%). Experiments
were run at least in triplicate. See the Supporting Information for details.
homoallylic alcohols that contain a Z-F3C-substituted alkene
efficiently and with high regio- and stereochemical control. A
strategically significant point is that catalytic cross-metathesis
and catalytic allyl addition are utilized in a convergent manner:
the organoboronate is prepared first and then used to generate a
chloroalkene-substituted homoallylic alcohol enantioselec-
tively. This is in contrast to performing cross-metathesis on a
homoallylic alcohol or a related derivative. The need for a priori
masking of the secondary alcohol was thus obviated. Because
late transition metal complexes typically used in cross-coupling
are not sensitive to hydroxy groups, the three-stage all-catalytic
sequence may be performed without resorting to protection/
deprotection strategies.
I
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Article
Tucci, F. C. Stereocontrolled synthesis of (−)-macrolactin A. J. Am.
Chem. Soc. 2002, 124, 1664−1668.
There are other factors that render the present advance
noteworthy. Other than the synthetically useful yields, the
transformations are scalable, the γ-addition isomer, if formed,
can be easily removed in most cases, and diastereo- (up to 97:3
dr) or enantioselectivities are typically high (up to 98:2 er). The
requisite aminophenol ligands can be prepared easily and are
indefinitely stable, and a commercially available Mo complex
can be used to synthesize the requisite allylic boronates.
Perhaps the most convincing indicator of the utility of the
approach is the 12-step and protecting group-free total
synthesis of mycothiazole, a sequence that is considerably
shorter than the one reported previously.4e
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J. Am. Chem. Soc. 2014, 136, 16136−16139.
The development of additional multicatalytic strategies that
allow access to otherwise difficult-to-prepare and valuable
fragments for use in chemical synthesis is in progress.
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̀
̃
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b11178.
■
S
Experimental details for all reactions and analytic details
for all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
*romiti@unistra.fr
*amir.hoveyda@bc.edu, ahoveyda@unistra.fr
■
ORCID
Filippo Romiti: 0000-0003-1903-9901
Amir H. Hoveyda: 0000-0002-1470-6456
Author Contributions
§R.J.M. and F.W.v.d.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by grants from the National
Institutes of Health (GM-57212), the CNRS (Make Our Planet
Great Again program, PRACTACAL project), and the
Frontiers in Chemistry Research Fondation (University of
Strasbourg).
́
9037. (k) Rega, M.; Candal, P.; Jimenez, C.; Rodríguez, J.
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