Iterative stereospecific reagent-controlled homologation of pinacol boronates by enantioenriched α-chloroalkyllithium reagents

Article abstract of DOI:10.1021/ja068808s

Reaction of pinacol boronates with putative enantioenriched α-chloroalkyllithium species, generated in situ from homochiral α-chloroalkylsulfoxides by sulfoxide ligand exchange with t-BuLi in PhMe at -78 °C, gave chain-extended boronic ester products with generally excellent stereochemical fidelity. Iteration of this stereospecific reagent-controlled homologation (StReCH) process enabled the programmed synthesis of all four stereoisomers of a stereodiad-containing model system (4-benzyl-1,6-diphenylhexan-2-ol) with er ≥ 97:3 in all cases. Copyright

Full text of DOI:10.1021/ja068808s

Published on Web 02/28/2007
Iterative Stereospecific Reagent-Controlled Homologation of Pinacol
Boronates by Enantioenriched r-Chloroalkyllithium Reagents
Paul R. Blakemore* and Matthew S. Burge
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
Received December 8, 2006; E-mail: paul.blakemore@science.oregonstate.edu
Scheme 1. Stereospecific Reagent-Controlled Homologation
Generally applicable iterative methods for the programmed
assembly of complex molecules are largely limited to constructs
involving the formation of carbon-heteroatom bonds. Some such
methods, particularly those directed at the synthesis of important
classes of biopolymers, e.g., polypeptides and oligonucleosides, are
highly sophisticated and have been successfully automated.1 By
contrast, similarly versatile technologies for the synthesis of
molecules via carbon-carbon bond formation are limited.2 Implicit
to any general solution of this multifaceted problem must be a
means to arbitrarily control substitution pattern and absolute
stereochemical features during molecular assembly. In an earlier
report,3 we advanced a simple unifying concept for synthesis based
on the stereospecific chain extension of organometallic substrates
1 by enantioenriched main-group chiral carbenoid reagents 2
(Scheme 1). Envisioned to proceed via 1,2-metalate rearrangement
of intermediate ate-complexes (3 f 4),4 iterative application of this
so-called “stereospecific reagent controlled homologation” (StReCH)
process would in principle allow for the programmed assembly of
polysubstituted alkyl moieties with total command over stereo-
chemistry and constitution (e.g., 4 f 5).
Table 1. Synthesis of R-Chlorosulfoxide Carbenoid Precursors
sulfide 6
sulfoxide 7a
chlorosulfoxide 8a
entry
R
R2
% yield
% ee
% yield
% ee
Full realization of the reductionist synthetic paradigm pre-
sented by StReCH would require satisfaction of three basic
conditions,3 while its practical implementation would necessitate
the ready availability of enantioenriched chiral carbenoid reagents
2 and the existence of suitable (isolable) organometallic substrates
1. Seminal guiding contributions from Hoffmann5 and Matteson6
led us to select a StReCH manifold of M1 ) B(OR)2 and M2 )
MgCl for initial consideration. Proof-of-concept experiments
established that an enantioenriched Mg-carbenoid, generated in
>98%ee by sulfoxide ligand exchange,5,7 effected chain extension
of catechol and neopentyl glycol boronic esters with modest
stereochemical fidelity; however, it was later discovered that a
putative Li-carbenoid generated in near identical fashion gave
dramatically improved results.3 Herein, we report a significant
extension of this work to robust pinacol boronate substrates and
describe the first demonstration of iterative StReCH cycles for the
programmed synthesis of molecules containing multiple stereogenic
centers.8
In a departure from earlier work, we employed a Jackson-
Ellman-Bolm catalytic enantioselective sulfoxidation9 in concert
with Yamakawa chlorination10 to efficiently prepare the scalemic
R-chloroalkyl sulfoxides 8 of interest as carbenoid precursors (Table
1). For both steps, the isomeric purity of products was enhanced
by recrystallization wherever possible.
Alkyllithium-effected sulfoxide ligand exchange from R-protio-
R-haloalkyl sulfoxides is complicated by deprotonation.3,7 Prior to
attempting the deployment of putative Li-carbenoids 2 (M2 ) Li,
X ) Cl) generated from precursors 8 via this means in StReCH
reactions, we therefore sought to identify reaction conditions which
might best favor the desired sulfoxide-lithium interchange process
over any competing pathways. Following a survey of reaction
1
2
3
4
5
6
Me
Me
Cl
Me
Me
Me
Bn
Me
Et
i-Pr
i-Bu
CH2Bn
45
83
77
85
52
70
99
99b
99
71
98
99
67
77
72
28
41
53
99
66b
ndc
40
99
99
a Isolated yield and % ee (HPLC, Daicel OD column) data are those
following recrystallization (to give pure syn diastereoisomers in case of 8).
b Not recrystallized. c Enantiomers not resolvable by HPLC method.
variables,11 a combination of t-BuLi in PhMe solvent was revealed
to be optimal for effecting sulfoxide ligand exchange from substrates
of type 8. Initial comparison of the t-BuLi-PhMe carbenoid
generation system (method B) to the n-BuLi-THF system (method
A), used previously for StReCH extension of neopentyl glycol
boronates,3 revealed no advantage (Table 2, entries 1-4). However,
when we next examined the feasibility of essentially identical
StReCH reactions from analogous pinacol boronates, the t-BuLi-
PhMe system was demonstrably superior (entries 5-8). The fact
that StReCH reactions with Li-carbenoids are successful from
pinacol boronates is highly significant. In contrast to neopentyl
glycol-derived boronic esters, pinacol boronates are stable toward
aerial oxidation, resist hydrolysis, and may be subjected to silica
gel chromatography without significant loss. Isolation of product
pinacol boronates from StReCH cycles is therefore potentially
straightforward, enabling ready iteration of the chain extension
process (vide infra).
Up to this point, all of the attempted StReCH reactions had
employed a putative Li-carbenoid (13) related to Hoffmann’s Mg-
carbenoid5 and substituted by a benzyl group (2, R2 ) Bn, X )
Cl). It was then established that the scope of StReCH is not limited
9
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J. AM. CHEM. SOC. 2007, 129, 3068-3069
10.1021/ja068808s CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Stereospecific Reagent-Controlled Homologation
(StReCH) of Neopentyl Glycol (neo) and Pinacol (pin) Boronates
with Putative R-Chloroalkyllithiums Generated by in Situ Sulfoxide
Ligand Exchange
Scheme 2. Programmed Synthesis of a Stereodiad Motif by
Iterative Stereospecific Reagent-Controlled Homologation
boronate 10a
sulfoxide 8b
carbinol 11d
%
T
%
%
entry
R1
B(O
kO)
R2
ee
cond.c
°C
yield
ee
1e
2
BnCH2
BnCH2
c-hex
neo
neo
neo
neo
pin
pin
pin
pin
pin
neo
pin
pin
pin
pin
neo
pin
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Et
Et
i-Pr
i-Bu
BnCH2
BnCH2
BnCH2
99
99
99
99
99
99
99
99
66
ndf
ndf
40
99
99
99
99
A
B
A
B
A
B
A
B
B
B
B
B
B
B
B
B
0
0
0
0
70
79
86
61
35
76
24
67
23
29
31
0
96
90
87
88
84
92
88
82
60
98
76
na
92
na
86
44
second StReCH cycle effectively up-grades the enantiopurity of
the intended ultimate product by preferentially converting the
unwanted minor enantiomer from the first StReCH cycle into a
compound belonging to a different diastereomeric series.15
In summary, it has been demonstrated that pinacol boronates
are chain extended with generally excellent stereochemical fidelity
by enantioenriched Li-carbenoid species generated in situ by
sulfoxide ligand exchange phenomena. Repeated application of this
“StReCH” process enabled the programmed assembly of all
stereoisomers of a simple stereodiad model system. Extension of
the synthetic principle outlined herein to the elaboration of more
complex molecular systems is under active investigation and will
be reported in due course.
3e
4
c-hex
5
6
7
8
BnCH2
BnCH2
c-hex
rt
rt
rt
rt
rt
rt
rt
∆
rt
∆
rt
rt
c-hex
9
BnCH2
BnCH2
BnCH2
BnCH2
BnCH2
BnCH2
c-hex
10
11
12
13
14
15
16
64
46
26
71
c-hex
Acknowledgment. Oregon State University is thanked for
generous financial support of this work. D-L Chiral Chemicals (New
Jersey) are thanked for a gift of (S)- and (R)-tert-leucinol.
a
neo ) B(OCH2CMe2CH2O), pin ) B(OCMe2CMe2O). b Ar ) p-Tol
or p-ClC6H4. c Reaction conditions: A ) n-BuLi in THF, B ) t-BuLi in
PhMe. d Isolated yields, % ee determined by HPLC (Daicel OD column).
e Data previously reported in ref 3 (enantiomeric series was opposite to
that illustrated). f % ee could not be determined by chosen HPLC method.
Supporting Information Available: Experimental procedures,
NMR spectra, and HPLC chromatograms. This material is available
free of charge via the Internet at http://pubs.acs.org
to the original test system (Table 2, entries 9-16). Thus, enantio-
enriched Li-carbenoids bearing R2 groups of varying steric demand
(Me, Et, i-Pr, i-Bu, BnCH2) were generated via method B from
their appropriate precursors 8, and observed to homologate boronic
esters in the desired manner (with the notable exception of R2 )
i-Pr). Stereochemical fidelity was generally excellent; however, the
yield of the chain extension varied widely, and some reactions
required heating prior to oxidative quench to obtain the desired
product 11. It is unlikely that variations in efficacy are due solely
to intrinsic reactivity differences between the various carbenoids.
Significantly, it was discovered that sulfoxide ligand exchange from
8 (R2 ) Bn) is more effective than the comparable reaction from
8 (R2 ) Me) under the conditions of method B.12
The good tolerance of pinacol boronates toward handling and
chromatographic purification allowed for the successful execution
of iterative StReCH cycles from boronic ester 12 (Scheme 2). The
substrate was extended by two treatments with enantioenriched
chiral carbenoid 13 (generated via method B in either (R)- or (S)-
configuration), interspersed by an homologation step with chloro-
methyllithium (generated via I/Li exchange from ICH2Cl),13 to yield
carbinols 14 following oxidation. Intermediate boronates14 were
isolated between successive extension cycles, and all four stereo-
isomers of 14 were separately targeted by deployment of the
appropriate carbenoid presentation sequences (e.g., (R)-13, CH2LiCl,
(R)-13 to target (R,R)-14, etc.). The targeted alcohols 14 were
produced with uniformly excellent enantiopurity and were ac-
companied in each case by a minor diastereomeric coproduct
generated with low enantiomeric excess (typically <20% ee). This
outcome is an expected artifact of stereospecific reagent control; a
References
(1) (a) Fields, G. B. Solid Phase Peptide Synthesis; Academic Press: San
Diego, 1997. (b) Smith, K., Ed. Solid Supports and Catalysts in Organic
Synthesis; Ellis Horwood: New York, 1992.
(2) The Negishi ZACA reaction and Matteson’s asymmetric chain extension
process (an antecedent of the work herein) represent two of the most
versatile iterative C-C bond-forming reactions currently available; see:
(a) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc. 2006,
128, 2770 and refs therein. (b) Matteson, D. S. Tetrahedron 1998, 54,
10555.
(3) Blakemore, P. R.; Marsden, S. P.; Vater, H. D. Org. Lett. 2006, 8, 773.
(4) For illuminating discourse on 1,2-metalate rearrangements from borate
complexes, see: Aggarwal, V. K.; Fang, G. Y.; Ginesta, X.; Howells, D.
M.; Zaja, M. Pure Appl. Chem. 2006, 78, 215.
(5) (a) Hoffmann, R. W.; Nell, P. G.; Leo, R.; Harms, K. Chem. Eur. J. 2000,
6, 3359. (b) Hoffmann, R. W. Chem. Soc. ReV. 2003, 32, 225.
(6) Matteson, D. S.; Mah, R. W. H. J. Am. Chem. Soc. 1963, 85, 2599.
(7) Satoh, T.; Takano, K. Tetrahedron 1996, 52, 2349.
(8) Blakemore, P. R.; Burge, M. S. Presented in part at the 232nd ACS
National Meeting, San Francisco, CA, September 10-14; American
Chemical Society: Washington, D.C., 2006; paper ORGN 353.
(9) (a) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem., Int. Ed.
2005, 44, 7221. (b) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman,
J. A. J. Am. Chem. Soc. 1998, 120, 8011. (c) Bolm, C.; Bienewald, F.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2640.
(10) Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. Tetrahedron Lett. 1988,
29, 313.
(11) Blakemore, P. R.; Burge, M. S. Unpublished results.
(12) Treatment of 8 (R2 ) Bn) with t-BuLi in PhMe at -78 °C followed by
H3O+ after 10 min, returned the expected sulfoxide ligand exchange
product in 85% yield. An identical reaction from 8 (R2 ) Me) gave the
corresponding exchange product in only 50% yield together with 25% of
recovered partially epimerized starting material (syn:anti ) 52:48).
(13) (a) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687. (b)
Soundararajan, R.; Li., G.; Brown, H. C. Tetrahedron Lett. 1994, 35, 8957.
(14) See Supporting Information for details.
(15) For an introduction to this type of “statistical enantiomeric amplification”
phenomenon, see: Negishi, E. Dalton Trans. 2005, 827.
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