Enantioselective homocrotylboration of aliphatic aldehydes

Article abstract of DOI:10.1021/ja311061n

A practical route to optically pure syn-homocrotylation reagents is described, including highly diastereo- and enantioselective preparation of numerous syn-homocrotyl products, as well as several matched mismatched pairs. NMR experiments suggest that the active homocrotylating species is a cyclopropylcarbinyldichloroborane generated by chloride exchange from the PhBCl₂ activator. Computational studies support the intermediacy of chloroboranes and suggest that homoallyl/homocrotyl transfers occur through Zimmerman-Traxler transition states.

Full text of DOI:10.1021/ja311061n

Communication
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Enantioselective Homocrotylboration of Aliphatic Aldehydes
Hongkun Lin,† Wenbo Pei,† Hao Wang,‡ Kendall N. Houk,*,‡ and Isaac J. Krauss*,†
†Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
Scheme 2. Prediction of Highly Enantioselective
Homocrotylation
ABSTRACT: A practical route to optically pure syn-
homocrotylation reagents is described, including highly
diastereo- and enantioselective preparation of numerous
syn-homocrotyl products, as well as several matched
mismatched pairs. NMR experiments suggest that the
active homocrotylating species is a cyclopropylcarbinyldi-
chloroborane generated by chloride exchange from the
PhBCl2 activator. Computational studies support the
intermediacy of chloroboranes and suggest that homo-
allyl/homocrotyl transfers occur through Zimmerman−
Traxler transition states.
regioisomer 5 rather than ent-3, and axial placement of the
aldehyde R in transition state 6 would lead to diastereomer 7.
Thus, we predicted that optically pure 1 would be useful for
enantioselective homocrotylations, and the primary challenge
was to develop a nonracemic reagent synthesis (Scheme 3).
ighly enantio- and diastereoselective methods have been
H
developed for allylation and crotylation of aldehydes.1
The success of these methods is in part due to the fact that six-
membered Zimmerman−Traxler transition states2 are possible
for allylation. Not only does this result in high selectivity, but
the stereochemical outcome of these reactions is readily
predictable from the chairlike transition state model. We
recently showed that this logic can be extended to
homoallylation reactions (Scheme 1), in which the alkene
Scheme 3. Synthesis of Homocrotylation Reagent
Scheme 1. Homoallylation Using Allylation Logic
Whereas we previously obtained homocrotylation reagents by
cyclopropanation of crotylboronates, we suspected that
enantioselective cyclopropanation could more easily be
achieved on vinylboronates. Known auxiliary-directed vinyl-
boronate cyclopropanations required diazomethane and/or did
not consistently afford the desired level of selectivity.4 Due to
its easy removal, we opted to reexamine the N,N-tartaramides
utilized by Deng,4f,g substituting Et2Zn/CH2I2 for his published
conditions with diazomethane/Pd(OAc)2. At −78 °C, the
cyclopropanation of 8 gave promising but variable results (70−
86% ee after pinacol addition to displace the auxiliary). We
suspected that impurities present in the boronate could account
for the variation in ee, and we were pleased to see that addition
of 0.5 equiv of excess tartaramide diol 9 to the reaction resulted
in a consistently excellent ee of 97% for 10 on multigram scale.
One-carbon homologation5 and conversion of the pinacol
boronate to the more reactive propanediol boronate3 afforded
the desired homocrotylation reagent 1 in multigram quantities.
component of the allylation reagent is replaced with a
cyclopropane.3 Not only does this enable access to homocrotyl
products which are difficult to obtain stereoselectively by other
methods, but either syn or anti homocrotylation can be selected
through the choice of trans or cis cyclopropane reagents,
respectively. Herein we report further advances enabling
enantioselective homocrotylation, as well as NMR spectro-
scopic and computational insight into the mechanism of the
reaction.
A difference between crotylation and homocrotylation
reagents is that the latter contain chiral centers in the B−C
carbon fragment being transferred (Scheme 2); thus, no chiral
diol auxiliary is necessary for an asymmetric reaction. According
to the Zimmerman−Traxler model, homocrotylation of RCHO
with optically pure 1 can lead to only one enantiomer of 3. The
pseudoenantiomeric transition state 4 would lead to disfavored
Received: November 9, 2012
Published: December 20, 2012
© 2012 American Chemical Society
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As predicted by the Zimmerman−Traxler model, 1
homocrotylated a wide range of aliphatic aldehydes6 11x with
high diastereo- and enantioselectivity (Table 1). Enantiose-
Homocrotylation with 1 proceeded with virtually complete
(>20:1) selectivity for the matched Felkin product. By contrast,
ent-1 homocrotylated 11h with virtually complete anti-Felkin
selectivity, demonstrating essentially complete reagent control
of stereochemistry. Similar homocrotylations of optically pure
aldehyde 11i with 1 and ent-1 each resulted in a single
homocrotylated product.
a
Table 1. Enantioselective Homocrotylation Scope
To help delineate the nature of activation by PhBCl2, we
initiated spectroscopic studies. Unsubstituted cyclopropyl
reagent 13 was treated with 0.5 equiv of PhBCl2 in CDCl3,
1
and the reaction was monitored by H NMR (Figure 1A). In
Figure 1. 1H NMR of (A) addition of 0.5 equiv of PhBCl2 to boronate
13 in CDCl3, followed by addition of 0.5 of equiv of tBuCHO and (B)
the final mixture from 30 min until completion of the reaction.
a
addition to the original cyclopropylcarbinyl peaks, two
additional sets of peaks were now observed downfield; due to
the deshielding effect of chlorides, we interpret the most
downfield peaks as cyclopropylcarbinylborondichloride 15 and
the remaining peaks as a mixture of monochloride species 14.
After addition of pivaldehyde, no CHO resonance was
observed. Instead, two singlets (Figure 1B) appeared at 6.17
and 5.96 ppm δ, concurrent with the disappearance of the
resonances for dichloride 15. We interpret the two singlets
3.0 equiv of 1 and 1.5 equiv of PhBCl2. Yields are isolated except
b
where parentheses indicate NMR yields. Ee’s measured by chiral
HPLC of alcohol or its benzoate derivative and are probably equal
within error of measurement. Entries 1−7: No anti diastereomer was
detected. Ent-1 was used. Dr’s measured by RP HPLC or GC.
c
d
lectivities (entries 1−7) were uniformly high, and in these cases
only the syn products were observed by NMR. These results are
significant in that no other type of aldehyde addition is capable of
affording these syn adducts, either racemic or optically active.
Previous nonracemic syntheses of this motif have required
sequences of 4−9 steps.7
We were also interested in the ability of 1 to overcome
aldehyde facial bias (Table 1, entries 8−11). 11h is known to
undergo Grignard additions with significant Felkin control.8
t
around 6 ppm, together with Bu resonances at 1.14 and 1.06
ppm, as belonging to RBCl2 adducts of the aldehyde, 16 and
17. Similar adducts with BCl3 have been proposed by Lappert,9
and more recently SiCl4 adducts were observed by Denmark.10
As homoallylation progresses, adducts 16/17 gradually
disappear as product alkene peaks grow in (Figure 1B).
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Journal of the American Chemical Society
Communication
Although only 16 can proceed to form product 20, it is
consumed more slowly than 16 and 17 interconvert: thus 16
and 17 disappear at roughly the same rates. Although 16/17 are
the only aldehyde-derived species observed during the course of
the reaction, the homoallylation likely proceeds through a
short-lived intermediate 19.
To explore the origins of regio- and stereoselectivity, we
performed theoretical calculations for the TSs of the
dichloroborane derived from 1 (Scheme 2). TS-2 (Figure 3)
We then investigated the possible intermediacy of 19 and
compared various transition state energies by DFT computa-
tional methods. The calculated enthalpy of complexation to
form 19 from aldehyde and 13 is favorable, but the free energy
of 19 is 5.9 kcal/mol above that of 16, consistent with the fact
that only 16 is observed (see Supporting Information). We next
looked at possible homoallylation transition states (Figure 2),
Figure 3. Optimized isomeric transition state structures proposed in
Scheme 2.
is the most stable, 7.0 and 5.5 kcal/mol more stable than TS-4
and TS-6, respectively. TS-6 has an axial methyl and is
destabilized in the normal Zimmerman−Traxler sense. TS-4 is
even higher in energy than TS-2, and the breaking cyclo-
propane bond is longer. This indicates steric hindrance to
formation of the new bond at the substituted carbon of the
cyclopropane, due to a gauche interaction.
In summary, we have developed the first enantioselective syn
homocrotylation of aldehydes by applying the allylation logic to
the homoallylation problem. NMR studies show that cyclo-
propylcarbinyldichloroboranes are generated by ligand ex-
change of cyclopropylcarbinylboronates with the PhBCl2
activator. Theoretical calculations further support the theory
that the active homoallylating species is a dichloroborane,
which transfers the homoallyl group through a Zimmerman−
Traxler transition state. We expect that this method will be
amenable to enantioselective construction of other stereo-
chemical patterns, and we will report those advances in due
course.
Figure 2. Zimmerman−Traxler transition states for homoallylations.
beginning with the proposed active species, dichlorocyclopro-
pylcarbinylborane 15. A six-membered chairlike homoallylation
transition state, TS-Cl, was located with an activation barrier of
27.7 kcal/mol. We then compared this to the potential direct
reaction of boronate 13 with acetaldehyde. This transition state,
TS-O, is a normal chairlike TS, but the activation energy of
49.7 kcal/mol is very high; no reaction is expected, consistent
with experiment. By analogy to allylation precedent, we next
considered Lewis acid catalysis of homoallylation,11 with
PhBCl2 complexation on the boronate oxygen. We located a
transition state, TS-LA, with an activation energy of 43.0 kcal/
mol, which was also very high. The remarkable energy
difference between TS-Cl and TS-O is due to the stronger
B−O coordination and higher electrophilicity of the dichlor-
oborane. In TS-Cl, the forming bond distance between the
carbonyl oxygen and the boron atom is 1.47 Å, which is shorter
than that of TS-LA (1.50 Å) or TS-O (1.53 Å). The
cyclopropane bond is stretched substantially in the concerted
homoallylations. The fact that the energy of TS-LA is much
closer to TS-O than to TS-Cl is partly due to the entropic cost
of bringing together three rather than two molecules, which
adds a −TΔS term of 6 kcal/mol.12
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure for preparation of 1, general procedure
for homocrotylation. and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
kraussi@brandeis.edu; houk@chem.ucla.edu
Notes
The authors declare no competing financial interest.
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Communication
ACKNOWLEDGMENTS
■
I.J.K. gratefully acknowledges the generous support of Brandeis
University and the Donors of the American Chemical Society
Petroleum Research Fund (51975-DNI). K.N.H. acknowledges
support from the NIH (R01 GM-036700).
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