Asymmetric Propargylboration of Aldimines and Ketimines with the Borabicyclo[3.3.2]decanes: Novel Entries to Allenyl Carbinamines, Amino Acids, and Their α-Methyl Counterparts

Article abstract of DOI:10.1021/acs.orglett.6b03506

Available in either enantiomerically pure form through quantitative Grignard procedures from air-stable crystalline complexes (1, 3), the B-γ-TMS propargylic derivatives of the 10-TMS- (2) and 10-phenyl-9-borabicyclo[3.3.2]decanes (4) provide highly selec

Full text of DOI:10.1021/acs.orglett.6b03506

Letter
pubs.acs.org/OrgLett
Asymmetric Propargylboration of Aldimines and Ketimines with the
Borabicyclo[3.3.2]decanes: Novel Entries to Allenyl Carbinamines,
Amino Acids, and Their α‑Methyl Counterparts
Eyleen Alicea-Matías and John A. Soderquist*
Department of Chemistry, University of Puerto Rico, Rio Piedras 00931-3346, Puerto Rico
S
* Supporting Information
ABSTRACT: Available in either enantiomerically pure form
through quantitative Grignard procedures from air-stable
crystalline complexes (1, 3), the B-γ-TMS propargylic
derivatives of the 10-TMS- (2) and 10-phenyl-9-borabi-
cyclo[3.3.2]decanes (4) provide highly selective entries to
2°-allenyl carbinamines (8, 60−85%, 78−99% ee) and their 3°
counterparts (13, 62−82%, 95−99% ee) through their
additions to aldimines and ketimines, respectively. The
absolute configurations of these amines were obtained from
the known amino acid derivatives 16eR and 19dR through the
ozonolysis of 8eR and 13dR and from the single-crystal X-ray
structure of 14fR.
Scheme 1. Preparation of Propargylboranes 2 and 4
or over a decade, we have employed the robust 10-R-9-
F
borabicyclo[3.3.2]decanes (BBDs) in highly effective
chiral ligation for a wide variety of asymmetric organoborane
conversions. In this regard, we have demonstrated that the 10-
trimethylsilyl (TMS) derivatives are extremely effective in
their additions to aldehydes and aldimines,1 while their 10-
phenyl counterparts are particularly selective in the corre-
sponding additions to ketones and ketimines.2 One
application that has been relatively unexplored is in the
potential of the propargylboration of aldimines to provide a
very useful entry to nonracemic allenyl carbinamines, products
which can undergo a variety of further useful conversions.3,4
The selectivities of these reported processes can vary as can
the regiochemistry of the additions. Moreover, the asymmetric
propargylation of ketimines has not been reported.
Previous studies in our laboratories have revealed that the
enantiomerically pure air-stable crystalline complexes 1 and 3
can provide, through simple Grignard procedures, either
enantiomer of the reagents 2 and 4 both quantitatively and in
optically pure form (Scheme 1).1c,2c The use of the TMS
group to provide the propargylic rather than the allenylic form
to methyl ketones to give the corresponding 3°-carbinols
(62−82%, 78−98% ee). Moreover, we had also found that N-
H aldimines and Z-TMS ketimines (from their enamine
precursors) were excellent substrates for allylboration and
related processes with the appropriate BBD reagents.1d,2b This
led us to examine the novel asymmetric propargylboration of
imines with 2 and 4 with the goal of providing allenyl
carbinamines in a highly selective manner.
The generation of N-DIBAL aldimines (5) was easily
accomplished through Itsuno’s partial reduction of represen-
tative nitriles with DIBAL-H.7,8 In each case, the imine was
added to 2 at −78 °C followed by the addition of 1 molar
equiv of MeOH8a to provide the corresponding syn N-H
of the boranes was first demonstrated by Wang et al.,5a
a
process which was adapted and developed by Brown et al.5b
for the asymmetric synthesis of homoallenic alcohols. Wang
also applied this methodology to the racemic synthesis of
homoallenyl amines.6 Our use of the Grignard vs the
corresponding lithium reagent previously employed was
based upon the insolubility of the magnesium byproduct
which, greatly facilitates the procedure.
The 10-TMS BBD reagent 2 was found to add smoothly to
aldehydes at −78 °C to provide allenyl carbinols (60−87%,
94−98% ee), whereas the less hindered 10-Ph reagent 4 adds
Received: November 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03506
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Organic Letters
Letter
aldimines.1d,9 After 3 h, the aminoborane intermediate 7 was
observed by 11B NMR δ 50. An oxidative workup (3 equiv of
H2O2 and 3 M NaOH, reflux 3 h) was employed to provide
the allenyl carbinamines 8 (60−85%) in 78−99% ee (Table
1). As can be seen from these data, the observed selectivities
place. Since these Z-ketimines are minor components of even
the equilibrated mixtures, their generation through the
borane-mediated process greatly facilitates the addition
process.2b Thus, methyllithium was added to representative
nitriles, the intermediates were silylated, and the mixtures
were allowed to equilibrate to provide greater amounts of the
N-silylenamines (9).2b,10 The addition of 2 equiv of 9 to 4
was conducted at −78 °C, and after 16 h, the aminoborane
intermediate 12 was observed by 11B NMR δ 55. We view the
borane-mediated enamine to Z-ketimine tautomerism (i.e., 10
→ 11) to be facilitated by 9.11 The mixture was allowed to
reach room temperature, after which an oxidative workup (3
equiv of H2O2 and 3 M NaOH, reflux 3 h) gave the desired
amines 13 with remarkable selectivity (95−99% ee) (Table
2).
Table 1. Propargylboration of N-H Aldimines with 2
Table 2. Propargylboration of Z-TMS Ketimines with 4
a
b
c
series
R
2
yield of 8 (%)
ee (%)
config
a
b
b
c
d
e
f
4-MeOC6H4
R
R
S
85
70
70
60
69
70
80
78
90
90
92
95
99
S
Ph
Ph
S
R
R
R
R
R
d
2-Th
R
S
i-Pr
t-Bu
c-Pr
S
S
90
a
b
Isolated yield employing a 1:1:1 ratio of 2/5/MeOH. Enantiomeric
excess determined by the NMR of the Mosher amide derivatives.
c
Absolute configuration was determined by comparison of the
literature published optical rotations of the desilylated allene 8b′
and of the known amino acid 16e.7,8 2-Thienyl.
d
a
b
c
series
R
4
yield of 13 (%)
ee (%)
config
a
b
c
d
e
f
c-Hx
S
S
S
S
R
S
62
75
62
82
80
78
97
95
99
99
99
99
R
R
R
R
S
generally exceed 90% ee. Simple molecular mechanics
calculations (Spartan 08) suggest that the somewhat lower
selectivity (i.e., 78% ee) observed for the 4-methoxyphenyl
example (8a) may be due to adverse steric interactions
between the γ-TMS and 4-methoxy groups in the transition
state (see pretransition state 6).
We were very pleased that compounds such as 8 could be
constructed with ease in such a highly selective manner. Built
into these products are the very useful chiral amine and
allenylsilane functional groups. It is no wonder that this
process has been identified as an important new conversion in
organoborane chemistry.3,4
4-MeOC6H4
Ph
i-Pr
c-Pr
4-BrC6H4
R
a
b
Isolated yield based upon 4 (1:2 ratio of 4/9). Enantiomeric excess
determined by NMR analysis of the Mosher amide derivatives.
Absolute configuration was determined by single-crystal X-ray
structure analysis of N-Boc-protected amine 14fR and through the
ozonolysis of 17dR to provide the known 19dR.
c
The success of the above process led us to address the
greater challenge of the construction of the tert-alkylamines
(13) in optically pure form. Previous studies in our
laboratories had revealed that the 10-Ph-9-BBDs were
extremely well-suited to the allylation, allenylation, and
propargylation of methyl ketones.2,7 We had also discovered
that the allylation of N-TMS ketimines could also be
accomplished to achieve higher selectivities than with the
corresponding N-H ketimines.2b Whereas no allylboration was
observed with 5 and 2, the corresponding process between 9
and 4 is an excellent pairing that exhibits nearly perfect
selectivity. The stereochemical aspects of the imine proved to
be critical to the success of this process. This issue was
resolved when we found that their enamine isomers provide a
simple entry through tautomerization to the Z-ketimine
geometries which are required for the addition to take
To establish the absolute stereochemistry of 13, the single-
crystal X-ray structure of 14fR (N-Boc derivative of 13fR) was
obtained from the 4S BBD reagent (Figure 1). This is
consistent with the stepwise process depicted above in Table
2. The “upside down” orientation of the ketimine (i.e., 11) is
in complete accord with the observed selectivity of γ-
alkoxyallylboration2d but is opposite to the product stereo-
chemistry obtained from the simple allylboration of ketimines
with the BBD reagents.2b While the attack of 4 by 9 from the
10-Ph side of the molecule is possible, MM calculations
suggest that this is energetically unfavorable (ca. 20 kJ/mol)
compared to 10. However, the preference for 11 over other
orientations for the addition is less clear and may even be due
to steric factors present during its formation through
protonation.11
B
DOI: 10.1021/acs.orglett.6b03506
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Organic Letters
Letter
in 83% yield as the R enantiomer consistent with the process
depicted in Table 2 ([α]20 +4.5 (c 1.0 MeOH), lit.13 (for S
D
enantiomer); [α]20 −1.4 (c 1.0 EtOH).
D
In summary, the γ-TMS propargylboranes 2 and 4, which
are easily prepared in either enantiomeric forms, provide a
very selective entry to allenyl carbinamines 8 and 13 through
their additions to N-H aldimines and N-TMS enamines,
respectively. High selectivity (≥90% ee) is generally observed
for the aldimines in all but a para-substituted phenyl example
(8a, 78% ee). The generation of Z-TMS ketimines though a
borane-mediated tautomerism of the corresponding enamines
results in the smooth formation of the 3°-alkyl carbinamines
being formed from 4 as essentially single enantiomers (95−
99% ee). The ozonolysis of these allenyl carbinamines
provides a simple and novel entry to amino acids (16) and
their α-methyl counterparts (19) in high optical purity.
Figure 1. Single-crystal X-ray structure of 14fR.
ASSOCIATED CONTENT
* Supporting Information
■
S
As potential applications for the present new chemistry, we
chose to demonstrate the role of these new allenyl
carbinamines, 8 and 13, as useful precursors to amino acids
through simple ozonolysis procedures. For these purposes, we
chose to prepare the known N-Boc amino acid 16eR and the
N-Ac α-methyl amino acid 19dR. After the installation of the
appropriate N-protection, the allenes in MeOH were treated
with excess ozone to obtain the desired acids. For 16eR,
treatment of 15eR with ozone for 2 h at −78 °C followed by
warming to room temperature and addition of water gave the
desired amino acid in 61% yield as a known mixture of
carbamate rotamers (Scheme 2).12 Their negative rotation
agreed with the reported R configuration of 8dR that was
obtained from 2S, consistent with our interpretation of the
process as presented in Table 1.
The ozonolysis of 17dR was carried out in a manner similar
to that used for 15eR except that the process was interrupted
after 15 min and examined by 13C NMR. This revealed the
intermediacy of the acylsilane 18dR whose downfield carbonyl
carbon (δ 242) was clearly evident.1c After the oxidation and
hydrolysis processes were completed, pure 19dR was isolated
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03506.
X-ray data for compound 14fR (CIF)
Full experimental procedures and spectroscopic data for
8, 13, 14fR, 16eR, 17dR, and 19dR (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jasoderquist@yahoo.com.
ORCID
John A. Soderquist: 0000-0002-5599-3949
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The support of the NSF (CHE-0967814) and Merck, Puerto
Rico, is gratefully acknowledged. We thank Professor Arnold
Rheingold and Mr. Michael Heberlein (Department of
Chemistry and Biochemistry, University of California, San
Diego) for the X-ray structure for 14fR.
Scheme 2. Amino Acids from the Ozonolysis of 15eR and
17dR
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D
DOI: 10.1021/acs.orglett.6b03506
Org. Lett. XXXX, XXX, XXX−XXX