Highly functionalized tertiary- carbinols and carbinamines from the asymmetric γ-alkoxyallylboration of ketones and ketimines with the borabicyclodecanes

Article abstract of DOI:10.1021/ol5019486

The first asymmetric γ-alkoxyallylboration of representative ketones provides β-alkoxy tert-homoallylic alcohols 10 whose diastereoselectivities range from 99% syn (acetophenone) to 99% anti (pinacolone) both with high ee (>95%). This distribution is attributable to the c/t isomerization of the BBD reagents and the greater reactivity of 7 vs 1 and of aromatic vs alkyl ketones. A ketone-based direct synthesis of a fostriecin intermediate and the tert-amine 26 are reported, each with high selectivities.

Full text of DOI:10.1021/ol5019486

Letter
pubs.acs.org/OrgLett
Highly Functionalized tertiary-Carbinols and Carbinamines from the
Asymmetric γ‑Alkoxyallylboration of Ketones and Ketimines with the
Borabicyclodecanes
Lorell Munoz-Hernandez,† Luis A. Seda,† Bo Wang,‡ and John A. Soderquist*,†
́
̃
†Department of Chemistry, University of Puerto Rico, Rio Piedras, Puerto Rico 00931-3346, United States
‡BioTools, Inc., 17546 Bee Line Hwy, Jupiter, Florida 33478, United States
S
* Supporting Information
ABSTRACT: The first asymmetric γ-alkoxyallylboration of
representative ketones provides β-alkoxy tert-homoallylic
alcohols 10 whose diastereoselectivities range from 99% syn
(acetophenone) to 99% anti (pinacolone) both with high ee
(>95%). This distribution is attributable to the c/t isomer-
ization of the BBD reagents and the greater reactivity of 7 vs 1
and of aromatic vs alkyl ketones. A ketone-based direct
synthesis of a fostriecin intermediate and the tert-amine 26 are
reported, each with high selectivities.
Scheme 1. Hoffmann Approach to 1
n the hierarchy of chemical conversions, allylboration meets
Iall of the criteria for a “top-10” reaction, because it is
enantio-, diastereo-, and regioselective in its construction of
new C−C bonds and incorporates useful functional groups for
further structural elaboration.1 The utility of γ-alkoxyallylbor-
anes in this regard, first demonstrated to be both diastereo- and
regioselective by Hoffmann in 1981,2 was upgraded to a highly
asymmetric conversion by Brown in 1988 with his diisopino-
campheylborane [B(Ipc)2] reagents.3 Many notable applica-
tions of this method have been forthcoming, including the
cytotoxic agents, peloruside A by De Brabander4 and
palmerolide A by Nicolaou5 to mention only two.6 Aldimines
are also useful substrates for these reagents.7 Early on, it was
recognized that the B(Ipc)2-based reagents were ineffective for
the allylboration of ketones or ketimines.8 This has led to the
use of aldehydes in the allyboration process followed by an
oxidation/nucleophilic alkylation sequence which can give
undesired diastereomeric products.9a While our 10-TMS-9-
BBD reagents have proven to be highly competitive with the
B(Ipc)2 systems for both aldehydes and aldimines, we knew
that they were ineffective for more hindered substrates.10
Fortunately, the corresponding 10-Ph-9-BBD ligation has been
found to be ideally suited to more hindered substrates such as
ketones and ketimines.11 As a new approach to highly
functionalized tertiary-carbinols and carbinamines, we chose
to examine the γ-alkoxyallylboration of these substrates with 1.
The preparation of 1 was accomplished by the initial
metalation of allyl methyl ether with s-BuLi in THF at −78 °C.
The resulting cis-lithium reagent 3 is treated with B-methoxy-
10-phenyl-9-BBD (4) at −78 °C, producing the organoborate
complex 5, which is demethoxylated with TMSCl to generate 1
in 87% yield (Scheme 1).
The Z-10-TMS counterpart of 1 (i.e., 11) has remarkable
configurational stability.10b,i,k The stereochemical integrity of
the B-crotyl-9-BBD system is also remarkable, the behavior of
which has been studied computationally.12 However, this is not
the case for 1, which isomerizes much more rapidly [i.e., 1/7
(Z/E) = 84:16 (1 h); 74/26 (2 h); 54/46 (24 h)] at 25 °C.
While this process was not allowed to reach equilibrium, MM
calculations (Spartan 06) suggest that 7 is ca. 1 kcal/mol more
stable than 1. However, since 1 is generated at −78 °C, and it
adds to 8a at this temperature without significant Z → E
Received: July 4, 2014
Published: July 11, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
isomerization, we carried out the allylborations at −78 °C for 8
h. This was followed by a slow warm-up to 25 °C to result
ultimately in the formation of 10, employing overall reaction
times of 16−36 h (Table 1).
because Hoffmann had found that his E-γ-methoxyallylboro-
nates were more reactive than their Z-counterparts,14 we
allowed ( )-1 to isomerize to an ∼50:50 E/Z mixture (7/1) in
THF (24 h at 25 °C), followed by the addition of 0.5 equiv of
either 8e or 8f, which gives the product 10e or 10f, respectively,
as ca. 9:1 anti/syn mixtures consistent with the greater reactivity
of 7 vs 1. However, the addition of 1 equiv of 8b to a 54:46 1/7
mixture faithfully produces 10b as a 55:45 syn/anti product
mixture. Fourth, we conducted independent syntheses of the
carbinols 10a and 10g to establish their syn- and anti-
configurations, respectively, from the allylation process
(Scheme 2).
Table 1. Asymmetric γ-Methoxyallylboration of
a
Representative Ketones with 1
Scheme 2. Independent Syntheses of 10
b
c
d
e
1
8, R1, R2
a, Me, Ph
10
dr
ee
config
S
S
S
S
R
R
S
78
88
65
68
60
54
45
99:1
97
98
84
84
70
68
98
R,R
R,R
R,R
R,R
S,S
b, Me, p-BrC6H4
c, Me, CHCHPh
d, Et, Ph
99:1
97:3
85:15
73:26
56:44
1:99
e, Me, Et
f, Me, i-Pr
S,S
g, Me, t-Bu
R,S
a
Reactions were maintained at −78 °C for 8 h and then, with the
indicated reaction times, were allowed to slowly warm to 25 °C and
b
stirred at rt a,b,c (8 h); d (12 h); e,f,g (28 h). Isolated yield.
To this end, the allylboration of PhCHO was carried out
with the 10-TMS reagent 11R10i to provide the known 13aSS,
which was oxidized with the Dess-Martin periodane to afford
the nonracemic ketone 14aS. Addition of LiMe to the chelate
15 produces only a minor amount (8%) of the syn-isomeric
alcohol 10aSS, the major product (92%) being the anti-isomer,
10aRS.9,15 Conversion of these alcohols to their Alexakis
esters13 and 31P NMR analysis of this mixture, compared to that
from the allylboration of acetophenone, establishes the (R,R)
absolute configuration of 10aRR from the 1S reagent.
Repeating the sequence for 12g (R2 = t-Bu) employing
( )-11 provides the anti-alcohol 10gR*S* as the major
isomeric product (93%), which matched the diastereomer
obtained from the γ-methoxyallylboration of 8g. We were now
confident that 7, but not 1, is reacting with pinacolone.
c
1
Determined by H NMR analysis of the reaction mixture prior to
purification. Analysis of the purified 10a−g revealed dr values (syn/
anti) of 99:1, 99:1, 98:2, 93:7, 78:22, 61:39, and 1:99, respectively.
d
Calculated from the 31P NMR peak areas using the Alexakis
method.13 The absolute stereochemistry of 10a was assigned on the
e
basis of the oxidation/nucleophilic addition protocol to the known
secondary threo-β-methoxyhomoallylic alcohol (13SS).10i Others were
assigned based on this determination for the stereochemistry of 10a.
Knowing the susceptibility of 1 to Z/E isomerization to 7, we
were pleased with the high syn selectivity exhibited for the
additions to aromatic and vinylic ketones 8a−c which was
understandably lower (i.e., 70% de) for the slower reacting
ethyl ketone 8d. This suggested that allylboration is faster than
isomerization for the aromatic and unsaturated methyl ketones.
This contrasts with the slower addition to aliphatic ketones,
which shows a regular increase in the amount of anti-alcohol 10
with increasing R2 bulk [i.e., 26, 44, 99 for 10e−g (R2 = Et, i-Pr,
t-Bu), respectively]. The pinacolone example (8g) was
particularly interesting because even after 36 h, the addition
had reached only ca. 50% completion (monitored by 11B
NMR). It was the 98% product de which alerted us to the fact
that 10g may have had the anti, rather than syn, stereo-
chemistry. Clearly, the formation of 10e,f as diastereomeric
mixtures would be otherwise enigmatic.
To explain the crossover from syn → anti stereochemistry in
10 with the lowering of ketone reactivity, it is helpful to
examine the pretransition state model 16 vs 18 (Scheme 3).
With increased O-basicity, flat aromatic (and vinylic) ketones
Scheme 3. Models to Explain the syn vs anti
Diastereoselectivities
We chose to conduct several experiments to be certain of the
absolute and relative stereochemical features of 10 since these
systems were unknown. First, a competitive experiment
employing 8a, 8g, and ( )-1 in a 1:1:1 ratio revealed that
only 8a reacts, showing that pinacolone is particularly
unreactive toward the Z-allylborane. Second, a trend was
identified in the 13C NMR of 10 for the signal of the methoxy
carbon at ca. 56 ppm. The signals for the syn isomers are
consistently upfield relative to their anti-counterparts. Third,
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Letter
reach 17 and, with a lack of severe (PhOMeax) repulsions,
proceed smoothly through 9, ultimately producing the syn-
alcohol 10aSS from 1R. However, with pinacolone, more
significant (t-BuOMeax) repulsions would exist in a transition
state analogous to 17 (see Supporting Information). Thus, this
ketone reacts exclusively with 7 after it forms from 1,
proceeding through 18/19, ultimately giving the anti-product,
10gSR from 7R. The stereochemistry of only C-3 changes with
this phenomenon. The approach of 8 to the boranes is anti B-
complexation, down with respect to the BBD ring and cis to the
10-Ph group in each case with 10R-boranes producing (2S)-
alcohols.
Scheme 5. γ-Alkoxyallylboration of 24/25 with 22S and 1S
An interesting application for this new method was suggested
by the work of Boger who prepared the cytoxic compound,
fostriecin, a natural product containing the syn-3° homoallylic
1,2-diol moiety (20, Scheme 4). It is isolated from Streptomyces
of 22 (46%, 90% de, 20% ee).8b,17 We conducted the Z-γ-
methoxyallylboration of 24/25 with a diluted 1S in an attempt
to slow the allylboration to produce more of the anti-27, which
would permit a comparison of the NMR signals for both
diastereomers of the carbinamine. We lacked confidence that
the low ee and rotation of 27 would permit its reliable absolute
stereochemical assignment based upon the B(Ipc)2 data alone
(cf., 20% ee, [α]20D −2.7 (c 1.0 CHCl3) vs 80% ee, [α]20D −18.4
(c 1.1 CHCl3)). However, we were confident in the reported
syn-stereochemistry of this amine.8b
Scheme 4. Synthesis of the C5−C11 Fragment of Fostriecin
(20)
A solution to this issue was found through the use of VCD
(vibrational circular dichroism, see Supporting Information) for
the determination of the absolute configuration of 26RR. VCD
couples optical activity to infrared vibrational spectroscopy
wherein a differential response of a chiral molecule to left and
right circularly polarized light is observed. The analysis was
performed by a numerical comparison describing the similarity
in the range 1000−1600 cm−1 between the calculated IR and
the VCD spectra for the enantiomer at the B3LYP/6-31G(d)
level and the observed IR and VCD spectra for the sample.
These data are wholly consistent with the R,R (syn)
configuration of 26 and, by analogy, 27.
However, the (R,R) stereochemistry from the S−borane
reagents was entirely unexpected. Bulky enamines such as 25
would be expected to attack 1 or 22 trans to the 10−Ph group
rather than the cis−positioning of the carbonyl oxygen in 8 as is
illustrated for 16 and 18 in Scheme 3. Therefore, we had
expected the opposite (S,S) stereochemistry. Our observations
together with the syn product stereochemistry also indicated
that this was a relatively rapid addition process occurring with
little Z → E isomerization of the boranes. Our previous studies
had suggested that added congestion could lead to increasing
amounts of an “upside down” orientation for 10−Ph-9-BBD
reacting with N-silyl ketimines.11b We illustrate this geometry
(29) together with the “down” orientation (28), which we view
as the dominant process for the simple, unsubstituted allyl
analogue of 1 (Figure 1). This orientation removes the
repulsive interactions between the TMS group and the
OMEM and Ph groups in the chair-like TS that would be
pulveraceus and selectively inhibits protein phosphatase 2A
(PP2A).16 As can be seen from Scheme 2, the typical Z-
alkoxyallylboration of aldehydes followed by an oxidation/
reductive methylation gives the anti-carbinol, not the desired
syn-stereochemistry which is found in 20. This is precisely what
Ramachandran found in his reported synthesis of a precursor to
the unnatural 8-epi-fostriecin employing B(Ipc)2 reagents for
the allylation.9a With the added versatility of the BBDs, we were
able to γ-alkoxyallylborate the known ketone 219b with 22S to
obtain directly the desired syn-3°-carbinol precursor to
fostriecin 23RR in 81% yield, 94% de, and 82% ee! Careful
comparison of our NMR data to those reported for the anti-
isomer confirmed our syn-stereochemistry, and the (R,R)
absolute configuration follows from 10a and the related 10c
(Scheme 4).
We identified another important application for the BBDs to
distinguish them from more limited B(Ipc)2 systems. The
allylation of ketimines through their borane-facilitated enamine
→ Z-ketimine isomerization is a process which we discovered
some time ago (Scheme 5).11b
Employing 22S, which was available from a modified
Ramachandran protocol,7 we carried out the Z-γ-alkoxyallyl-
boration of an enamine−ketimine mixture (i.e., 24/25) to
obtain the desired syn-β-OMEM 3°-carbinamine 26RR (57%,
98% de, 94% ee)! This result was particularly gratifying
especially when one compares this to the only reported
example employing B(Ipc)2 systems in related processes,
namely Jager’s Z-γ-methoxyallylboration of a methanolized
mixture of 24/25. This was reported to give the MeO analogue
̈
Figure 1. γ-Alkoxyallylation of N-TMS Ketimines with 1.
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Organic Letters
Letter
Z.; Soderquist, J. A. Angew. Chem., Int. Ed. 2007, 46, 397. (f) Gonzal
A. Z.; Soderquist, J. A. Org. Lett. 2007, 9, 1081. (g) Roman, J. G.;
Soderquist, J. A. J. Org. Chem. 2007, 72, 9772. (h) Soto-Cairoli, B.;
Soderquist, J. A. Org. Lett. 2009, 11, 401. (i) Munoz-Hernandez, L.;
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Gonzalez, A. Z.; Soderquist, J. A. J. Am. Chem. Soc. 2009, 131, 9924.
́
ez,
expected from 28. Therefore, 29 would appear to be a better
alternative, and it predicts the correct stereochemistry for 26RR.
In summary, the 10-Ph-9-BBDs have proven to be effective
reagents for the γ-alkoxyallylboration of ketones and ketimines.
We observed a wide range of diasteroselectivities which reflect
the stereochemistry of the actual reacting borane. The initial
Z−stereochemistry of 1 is reflected in the high product syn−
diasteroselectivity of aromatic and vinylic ketones. Aliphatic
ketones are slower to undergo allylboration and Z → E (1 →
7) isomerization permits the greater reactivity of the latter to
dominate the allylboration process for these ketones, especially
for pinacolone (8g), but even with less bulky ketones when
they are used in substoichiometric quantitites (i.e., 9:1 dr). The
use of the 10-Ph-9-BBD reagents permits the direct synthesis of
3°-carbinols such as was demonstrated for a fostriecin precursor
23 and carbinamines 26 and 27 with excellent diastereo− and
enantioselectivities in contrast to the low selectivities exhibited
by B(Ipc)2 for these applications.
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Aluminum in Stoichiometric Asymmetric Synthesis, 3.22. In
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ASSOCIATED CONTENT
* Supporting Information
Full experimental procedures and spectroscopic data for 1−7,
10, 11, 13−14, 26, 27, and VCD analysis data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jasoderquist@yahoo.com.
Notes
(16) (a) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc.
2001, 123, 4161. (b) Boger, D. L.; Hirota, M.; Lewis, B. M. J. Org.
Chem. 1997, 62, 1748. (c) McCluskey, A.; Sim, A. T. R.; Sakoff, J. A. J.
Med. Chem. 2002, 45, 1151. (d) Lewy, D. S.; Gauss, C. M.; Soenen, D.
R.; Boger, D. L. Curr. Med. Chem. 2002, 9, 2005 and references cited
therein.
(17) While we observed both a diminution of the product ee and
also, a reversal of the absolute stereochemistry with the simple
allylboration of ketimines with added MeOH,11b no differences were
observed for 1S, which gave the same efficiency and stereochemical
outcome for the addition to 24/25 with or without the MeOH. This
strongly suggests that no N-H ketimine is forming with the present
system. This hydrolysis process18 has been examined in greater detail,
and the failure of 1 to catalyze the methanolysis of 24/25 is consistent
with this picture.10c,11b
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The support of the NSF (CHE-0967814) is gratefully
acknowledged as is the help of Dr. Joseph M. Barendt (Chiral
Technologies, Inc.), Dr. Rina K. Dukor and Diane M. Errigo
(BioTools, Inc.) and Professor Gary Molander (U. Penn) with
materials.
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