Enantioselective synthesis of (Z)- and (E)-2-methyl-1,5- anti-pentenediols via an allene hydroboration-double-allylboration reaction sequence

Article abstract of DOI:10.1021/ja4033633

Kinetically controlled hydroboration of allenylboronate 5 followed by double allylboration with the resulting allylborane (Z)-7 gave (Z)-2-methyl-1,5-anti-pentenediols 6 in good yield and high enantioselectivity in the presence of 10% BF₃·OEt

Full text of DOI:10.1021/ja4033633

Article
pubs.acs.org/JACS
Enantioselective Synthesis of (Z)- and (E)‑2-Methyl-1,5-anti-
Pentenediols via an Allene Hydroboration−Double-Allylboration
Reaction Sequence
Ming Chen and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
S
* Supporting Information
ABSTRACT: Kinetically controlled hydroboration of allenyl-
boronate 5 followed by double allylboration with the resulting
allylborane (Z)-7 gave (Z)-2-methyl-1,5-anti-pentenediols 6 in
good yield and high enantioselectivity in the presence of 10%
BF3·OEt2 as the catalyst in the second allylboration step.
Under thermodynamically controlled isomerization conditions,
(Z)-7 can readily isomerize to (E)-7. Double allylboration of
representative aldehydes with allylborane (E)-7 gave (E)-2-
methyl-1,5-anti-pentenediols 4 in good yield and high
enantioselectivity without requiring use of the BF3·OEt2
catalyst. Thus, 2-methyl-1,5-anti-pentenediols with either
olefin geometry can be synthesized from the same allenylboronate precursor 5. Furthermore, 1,5-pentenediols 4 and 6 can
be easily converted to 1,3,5-triols with excellent diastereoselectivity in one step.
such reagents has been challenging and largely remains
underdeveloped.2−4
INTRODUCTION
■
Enantioselective carbonyl addition using allylmetal reagents is
an important transformation in organic synthesis.1 In
comparison to the vast majority of conventional carbonyl
allylation methods that produce homoallylic alcohols with a
terminal olefin unit, allylation with enantioenriched, bifunc-
tional allylboron reagents represents an important advance in
allylmetal chemistry.2−4 Specifically, not only does addition of
bifunctional allylboron reagents to aldehydes provide stereo-
chemically defined, enantioenriched homoallylic alcohols but
also, more importantly, the olefin unit in the alcohol products is
properly functionalized to enable a variety of subsequent
transformations (Figure 1).5,6 Given the mild conditions
typically involved in allylboration reactions, these reagents are
particularly attractive for use in late-stage convergent fragment
assemblies.6,7 However, the enantioselective preparation of
Recently, enantioselective allene hydroboration2n has
emerged as an efficient method to access enantioenriched
bifunctional allylboranes. By appropriate selection of the metal
species used in the allene precursors, a variety of chiral
bifunctional allylboranes have been prepared via hydroboration
with diisopinocampheylborane or Soderquist’s borane2c (10-
TMS-9-borabicyclo[3.3.2]decane).4 Several of these bifunc-
tional allylboranes have been applied in synthetic studies
targeting natural products.7 In connection with an ongoing
problem in natural product synthesis, we have developed and
report herein new bifunctional allylboranes which enable
enantioselective convergent aldehyde fragment assembly to
give 2-methyl-1,5-anti-pentenediols with intervening (Z)- or
(E)-olefin units with high selectivity from the same
allenylboronate precursor.
In 2002 we reported a diastereo- and enantioselective
synthesis of 1,5-pentenediols using a bifunctional allylborane
reagent derived from allenylboronate hydroboration.4a By
analogy, we envisioned that allylborane reagents such as (Z)-
2 and (E)-2 might be suitable reagents to prepare methyl-
substituted 1,5-pentenediols 3 and 4 (Figure 2), respectively. In
previous studies of the hydroboration−allylboration reactions
of allenylboronate 1a (wherein the boronate ester is a
tetraphenylethane-1,2-diol unit) we demonstrated that (Z)-2
and (E)-2 can be obtained with high efficiency via kinetic
hydroboration (for (Z)-2) or by thermal allylborane equilibra-
Figure 1. Representative allylboration reactions with bifunctional
allylboron reagents.
Received: April 8, 2013
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of (Z)-1,5-anti-Diols 6 via Kinetically
Controlled Hydroboration of 5 and the Lewis Acid BF3·OEt2
Catalyzed Double-Allylboration Reactions of Allylborane
a
(Z)-7
Figure 2. Proposed hydroboration−double-allylboration strategy for
the synthesis of 1,5-pentenediols 3 and 4.
tion of the allylborane intermediates (for (E)-2).4b However,
the tetraphenylethane-1,2-diol unit proved to be too bulky, and
double-allylboration reactions using these first-generation
bifunctional allylboranes could not be achieved. After a brief
screening of additional boronate ester units, allenylboronate 5
with a 2,2-dimethylpropanediol ester was identified for
subsequent double-allylboration studies. As described herein,
use of allenylboronate 5 indeed proved highly useful in the
development of a highly diastereo- and enantioselective
synthesis of (E)-2-methyl-1,5-pentenediols 4 and 6.
a
Reactions were performed by treating 5 with (dIpc)2BH (1 equiv) in
toluene at −30 °C and warming to −10 °C over 5 h followed by the
addition of R1CHO (0.7 equiv) at −78 °C. The mixture was stirred at
−78 °C for 8 h, and then BF3·OEt2 (10%) followed by R2CHO (1.5
equiv) were added slowly to the reaction mixture, which was kept at
−78 °C for 36 h. The reaction mixture was warmed slowly to 0 °C and
subjected to a standard workup (NaOH, H2O2) at 0 °C prior to
RESULTS AND DISCUSSION
■
In initial experiments, kinetically controlled hydroboration of
allenylboronate 5 with (dIpc)2BH (diisopinocampheylborane)
was carried out at −30 °C with the solution being warmed
slowly to −10 °C to complete the hydroboration. Sequential
treatment of the resulting allylborane intermediate (not
isolated) with hydrocinnamaldehyde (0.7 equiv) at −78 °C
for 8 h and then with benzaldehyde (1.5 equiv) provided a 1:1
mixture of (E)-syn- and (Z)-anti-1,5-pentenediols 3a and 6a in
36% and 39% yields with 93% and 95% ee, respectively
(Scheme 1).
product isolation. Determined by Mosher ester analysis.10 (lIpc)2BH
b
c
was used.
conditions to double-allylboration reactions of a variety of
aldehydes using the allylborane generated from kinetic
hydroboration of 5 with (dIpc)2BH gave (Z)-anti-1,5-
pentenediols 6b−e in 71−89% yield (based on R1CHO as
the limiting reagent) with >20:1 diastereoselectivity and 95−
96% ee (Scheme 2). The only example that did not proceed
with ≥20:1 diastereoselectivity is the double-allylboration
reaction leading to 6f. In this case, a 4:1 mixture was obtained
with 6f (66% yield, 90% ee) as the major product. (When this
reaction was performed without BF3·OEt2 in the second step, a
1:4 mixture was obtained favoring the (E)-syn-1,5-diol 3 as the
major component.) The absolute stereochemistry of the
secondary hydroxyl groups of 6 was assigned by using a
modified Mosher ester analysis.10 The Z olefin geometry of 6
was assigned by 1H NOE studies (see the Supporting
Information for details).
Scheme 1. Initial Attempts at Hydroboration−Double
Allylboration with 5
Because all previous literature examples of Lewis acid
catalyzed allylboration of aldehydes with α-substituted
allylboronates are E-selective,2f,9 the formation of (Z)-anti-
1,5-pentenediols 6 presented in Scheme 2 (with BF3·OEt2 as
the catalyst for the second step) was unexpected and, to the
best of our knowledge, unprecedented. As shown in Figure 3a,
on the basis of our prior studies,4b kinetically controlled
hydroboration of allenylboronate 5 provides the bifunctional
allylborane intermediate (Z)-γ-boryl-allylborane (Z)-7, which
reacts with the first aldehyde to give syn-β-alkoxy-allylboronate
8 (the absolute and relative configuration of 8 was derived from
the corresponding 1,2-diol obtained from oxidative workup of 8
with NaOH/H2O2).4b Assuming that the second allylboration
proceeds through a chairlike transition state, the results in
Scheme 2 indicate that transition state TS-2 with pseudo-
That two products 3a and 6a were obtained in a 1:1 ratio
indicates that the two competing transition states for the second
allylboration step (which lead to the formation of 3a and 6a) are
very close in energy. In order to improve the diastereose-
lectivity of the second allylboration step, a number of options,
in particular the use of Lewis acid catalyzed allylboration,8,9
were considered. Because several highly E-selective, Lewis acid
catalyzed allylboration reactions have been reported,2f,9 we
anticipated that application of this strategy to the double
allylboration presented in Scheme 1 would give the E isomer
3a. Intriguingly, however, when the second allylboration step
was carried out in the presence of 10% BF3·OEt2, (Z)-anti-1,5-
pentenediol 6a was obtained as the only product (ds > 20:1) in
89% yield and with 96% ee (Scheme 2). Application of these
B
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were intrigued by the possible stereochemical outcome of
double allylboration of aldehydes with bifunctional allylboranes
such as (E)-2. For this purpose, the hydroboration of
allenylboronate 5 with (dIpc)2BH was carried out at 0 °C for
2 h followed by heating at 65 °C for 1 h. Treatment of the
resulting (thermodynamic) allylborane with hydrocinnamalde-
hyde (0.7 equiv) at −78 °C and then benzaldehyde (1.5 equiv)
provided (E)-anti-1,5-pentenediols 4a in 87% yield and with
>20:1 diastereoselectivity and 90% ee without the assistance of
BF3·OEt2. It is worth noting that the addition of a Lewis acid
(BF3·OEt2) to the second allylboration reaction did not change
the stereochemical outcome of this reaction. This reaction
protocol was then applied to double-allylboration reactions
with a variety of aldehydes (Scheme 3). In all cases, (E)-anti-
Scheme 3. Synthesis of (E)-1,5-anti-Diols 4 under
Thermodynamically Controlled Allylborane Isomerization
a
Conditions
Figure 3. (a) Analysis of transition states for Lewis acid catalyzed
second allylboration with allylboronate 8. (b) Analyses of the potential
interaction of BF3 with an oxygen atom in the dioxaborinane unit.
equatorial placement of the methyl group is favored (Figure
3a). We speculate that a six-membered chelate may be
responsible for the unexpected Z-selective allylboration. It has
been demonstrated that the addition of a Lewis acid such as
BF3·OEt2 can accelerate the rate of allylation of aldehydes with
allylboronates, owing to the coordination between BF3 and one
of the oxygen atoms in the dioxaborinane unit.8 As shown in
Figure 3b, among the four nonbonded pairs of electrons on the
oxygen atoms in the dioxaborinane unit that BF3 could
coordinate to, the two pairs that occupy pseudo-axial positions
(shown in red in A) are likely not accessible, owing to the
unfavorable 1,3-diaxial steric interactions. Likewise, coordina-
tion to the lone pair of electrons which project toward the top
of the boron−aldehyde six-membered chelate (shown in black
in B) is also disfavored. Coordination of BF3 to the last lone
pair of electrons (shown in blue in C) apparently suffers from
steric interactions with the substituent in the pseudo-axial
position. However, if disproportionation of BF3 and inter-
mediate alkoxyborane 8 occurs, a difluoroalkoxyborane
substituent would be generated, as indicated in the
allylboronate species in TS-2.12 Indeed, NMR studies
demonstrated that treatment of Ipc2BOMe with 1 equiv of
BF3·OEt2 led to rapid conversion to Ipc2BF(OEt2) (11B NMR,
16 ppm)13a and MeOBF2 (11B NMR, 0 ppm).13b Owing to the
Lewis acidity of the difluoroalkoxyborane unit, the boron atom
could coordinate to one of the oxygen atoms of the boronate
ester (as shown in blue in TS-2) to form a six-membered
chelate. If so, the second allylboration could proceed via TS-2
with minimal nonbonding steric interactions to give (Z)-anti-
1,5-pentenediols 6 preferentially. The competing transition
state TS-1 involves an unfavorable 1,3-syn-pentane interaction
(shown in red)9e,14 and is therefore disfavored. Moreover, all
possible internally coordinated complexes corresponding to
TS-1 (en route to 3), by analogy to that depicted in TS-2 for
the pathway leading to 6, suffer from severe nonbonded
interactions involving the −OBF2 and an axial methyl group of
the 5,5-dimethyl-1,3-dioxa-2-borinane unit in the transition
state and therefore are considered to be disfavored.15
a
Reactions were performed by treating 5 with (dIpc)2BH (1 equiv) in
toluene at 0 °C for 2 h followed by heating at 65 °C for 1 h to effect
allylborane equilibration via reversible 1,3-boratropic shifts. The
solution was cooled to −78 °C, and R1CHO (0.7 equiv) was added
at −78 °C. The mixture was stirred at −78 °C for 8 h, and then
R2CHO (1.5 equiv) was added to the reaction mixture at −78 °C. The
reaction mixture was warmed slowly to ambient temperature and
stirred for 36 h. The reaction mixtures were then subjected to a
standard workup (NaOH, H2O2, 0 °C) prior to product isolation.
b
c
Determined by Mosher ester analysis.10 (lIpc)2BH was used.
1,5-pentenediols 4b−f were obtained in 71−92% yields with
>20:1 diastereoselectivity and 88−92% ee. The absolute
stereochemistry of the secondary hydroxyl groups of 4 was
assigned by using a modified Mosher ester analysis.10 The E
olefin geometry of 4 was assigned by 1H NOE studies (see the
Supporting Information for details).
The results in Scheme 3 may be rationalized as follows
(Figure 4). Under thermodynamically controlled hydrobora-
tion−isomerization conditions, (E)-γ-boryl-allylborane (E)-7
was generated from allenylboronate 5, via the intermediacy of
(Z)-7 (see Figure 3, not shown here).4b Allylboration of the
first aldehyde with (E)-7 gave the anti-β-alkoxy-allylboronate 9.
(The absolute and relative configuration of 9 was determined
from the derived 1,2-diol obtained from oxidation of 9 with
NaOH/H2O2).4b The second allylborationin the absence of
a Lewis acidproceeds via TS-3 with pseudo-axial placement
of the small methyl group to give (E)-anti-1,5-pentenediols 4
(Figure 4a). The competing transition state TS-4 with pseudo-
axial placement of the larger group (shown in red in Figure 4a)
As anticipated in Figure 2, the kinetic hydroboration adduct
(Z)-2 can undergo reversible 1,3-borotropic shifts11 at elevated
temperatures to give the (E)-γ-boryl-allylborane (E)-2.4b We
C
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Scheme 4. (a) Transformation of 1,5-Diols 4e and 6a to
1,3,5-Triols 12 and 14 via a Hydroboration−Oxidation
Reaction Sequence and (b) Potential Natural Product
Targets for this Methodology
Figure 4. (a) Transition state analyses of second allylboration with
allylboronate 9. (b) Transition state analyses of the Lewis acid
BF3·OEt2 catalyzed second allylboration with allylboronate 9.
is disfavored. If the Lewis acid BF3·OEt2 was used, the
alkoxydifluoroborane 10 could be generated via a disproportio-
nation pathway (Figure 4b). Evidently, however, the second
allylation does not proceed via TS-5 with a six-membered
chelate to give 1,5-diol 11, as the R1 group is oriented in TS-5
such that significant nonbonding steric interactions between the
R1 group and the six-membered boronate−aldehyde (R2CHO)
chelate are inevitable (shown in red in Figure 4b). Therefore,
TS-5 is disfavored and the addition of BF3·OEt2 does not
change the stereochemical outcome of the second allylboration
reaction.
While 1,5-diols 4 and 6 are common structural motifs in
many natural products,16 the olefin unit can also be further
functionalized. For example, hydroboration reactions of 4e and
6a were carried out as summarized in Scheme 4. Hydroboration
of diol 6a with thexylborane17 followed by oxidative workup
provided the 1,3,5-triol 12 in 71% yield and >20:1
diastereoselectivity. The 3,5-syn-diol relationship was estab-
pentenediols from allenylboronate 5. Kinetically controlled
hydroboration of 5 followed by double allylboration of the
(kinetic) allylborane (Z)-7 gave (Z)-2-methyl-1,5-anti-pente-
nediols 6 when 10% of BF3·OEt2 was used as the catalyst in the
second allylboration step. Key to both transformations is the
ability to control the relative placement of two substituents α to
boron in axial or equatorial positions in the second allylboration
transition state. To the best of our knowledge, the results
presented here for the double-allylboration reactions of (Z)-7
and (E)-7 are the first examples where such control has been
achieved.
A six-membered chelate model was proposed to rationalize
the unexpected (Z)-selective allylboration reaction of 8, the
intermediate produced for the first allylboration reaction of
(Z)-7. When allylborane (Z)-7 was allowed to isomerize at 65
°C, the resulting allylborane (E)-7 underwent double-
allylboration reactions with two aldehydes to give (E)-2-
methyl-1,5-anti-pentenediols 4 with excellent diastereoselectiv-
1
lished by H NMR analysis of the acetonide derivative 13
(Scheme 4).18 Alternatively, hydroboration of diol 4e with
thexylborane followed by oxidative workup provided the 1,3,5-
triol 14 in 75% yield and >20:1 diastereoselectivity. Here again,
the 1,3-syn-diol relationship was established by 1H NMR
analysis of the acetonide derivative 15 (Scheme 4). Thus, 1,5-
diols 4 and 6 can be transformed into 1,3,5-triols with four
stereocenters without any protecting group manipulations. We
anticipate that this methodology will be applicable to the
synthesis of many polyketide natural products that contain such
structural motifs, as illustrated by the highlighted substructures
of several natural products in Scheme 4.19
CONCLUSIONS
In summary, we have developed highly diastereo- and
enantioselective syntheses of (Z)- and (E)-2-methyl-anti-1,5-
■
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achieve diastereoselective allylboration reactions of the derived
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text and figures giving experimental procedures and spectro-
scopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for W.R.R.: roush@scripps.edu.
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Professor Larry E. Overman on the occasion of
his 70th birthday. Financial support provided by the National
Institutes of Health (GM038436) is gratefully acknowledged.
We thank Eli Lilly for a Graduate Fellowship to M.C.
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E
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