Application of the lithiation-bborylation reaction to the preparation of enantioenriched allylic boron reagents and subsequent in situ conversion into 1,2,4-trisubstituted homoallylic alcohols with complete control over all elements of stereochemistry

Article abstract of DOI:10.1021/ja910593w

The reactions of Hoppe's lithiated carbamates with vinylboranes and boronic esters give allylic boranes/boronic esters, and subsequent addition of aldehydes provides a new route to enantioenriched homoallylic alcohols with high enantiomeric ratios and diastereomeric ratios. Specifically, reactions of sparteine-complexed lithiated carbamates with frans-alkenyl-9-BBN derivatives followed by addition of aldehydes gave (Z)-anti-homoallylic alcohols in greater than 95:5 er and 99:1 dr. However, in the special case of the methyl-substituted lithiated carbamate, diamine-free conditions were required to achieve high selectivity. Reactions of sparteine-complexed lithiated carbamates with (2)-alkenyl pinacol boronic esters and (E)-alkenyl neopentyl boronic esters gave (E)-syn- and (E)-anti-homoallylic alcohols, respectively, in greater than 96:4 er and 98:2 dr. In these reactions, a Lewis acid (MgBr₂ or BF ₃·OEt₂) was required to promote both the 1,2-metalate rearrangement and the addition of the intermediate allylic boronic ester to the aldehyde. This methodology provides a general route to each of the three classes of homoallylic alcohols with high selectivity.

Full text of DOI:10.1021/ja910593w

Published on Web 03/01/2010
Application of the Lithiation-Borylation Reaction to the
Preparation of Enantioenriched Allylic Boron Reagents and
Subsequent In Situ Conversion into 1,2,4-Trisubstituted
Homoallylic Alcohols with Complete Control over All
Elements of Stereochemistry
Martin Althaus, Adeem Mahmood, Jose´ Ramo´n Sua´rez, Stephen P. Thomas, and
Varinder K. Aggarwal*
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
Received December 16, 2009; E-mail: v.aggarwal@bristol.ac.uk
Abstract: The reactions of Hoppe’s lithiated carbamates with vinylboranes and boronic esters give allylic
boranes/boronic esters, and subsequent addition of aldehydes provides a new route to enantioenriched
homoallylic alcohols with high enantiomeric ratios and diastereomeric ratios. Specifically, reactions of
sparteine-complexed lithiated carbamates with trans-alkenyl-9-BBN derivatives followed by addition of
aldehydes gave (Z)-anti-homoallylic alcohols in greater than 95:5 er and 99:1 dr. However, in the special
case of the methyl-substituted lithiated carbamate, diamine-free conditions were required to achieve high
selectivity. Reactions of sparteine-complexed lithiated carbamates with (Z)-alkenyl pinacol boronic esters
and (E)-alkenyl neopentyl boronic esters gave (E)-syn- and (E)-anti-homoallylic alcohols, respectively, in
greater than 96:4 er and 98:2 dr. In these reactions, a Lewis acid (MgBr2 or BF3 ·OEt2) was required to
promote both the 1,2-metalate rearrangement and the addition of the intermediate allylic boronic ester to
the aldehyde. This methodology provides a general route to each of the three classes of homoallylic alcohols
with high selectivity.
the stereocontrolled synthesis of 1,5-diols,4c,d,6 and the develop-
ment of a new chiral allylborane by Soderquist which gives
Introduction
high enantioselectivity even with ketones.7
The asymmetric allylboration of aldehydes is one of the most
reliable and useful methods for making carbon-carbon bonds
with control over relative and absolute stereochemistry.1 In
particular, Hoffmann’s realization that relative stereochemistry
could be controlled by the double bond geometry of crotylbo-
ronates2 and Brown’s discovery of highly enantioselective
allylborations using pinane-derived reagents3 provided the
foundations to this important reaction which continues to evolve
to this date.4 The most notable recent developments include
Hall’s discovery that Lewis acids promote reactions of allylic
boronic esters,4a,b,5 Roush’s use of bisallylboron reagents for
However, generally, these powerful transformations are
limited to simple allyl or crotylboron reagents, which ultimately
lead to terminal alkenes; substitution in the R-position is
considerably less common.8 We recognized that if we could
prepare such reagents with control over enantioselectivity, then,
by judicious choice of the achiral groups on boron and the initial
double bond geometry we had the potential to control all of the
(4) For selected examples published in 2009, see: (a) Rauniyar, V.; Hall,
D. G. J. Org. Chem. 2009, 74, 4236. (b) Penner, M.; Rauniyar, V.;
Kaspar, L. T.; Hall, D. G. J. Am. Chem. Soc. 2009, 131, 14216. (c)
Chen, M.; Handa, M.; Roush, W. R. J. Am. Chem. Soc. 2009, 131,
14602. (d) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am.
Chem. Soc. 2009, 131, 14174.
(1) (a) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 10,
p 299. (b) Chemler, S. R.; Roush, W. R. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000;
Chapter 11, p 403. (c) Lachance, H.; Hall, D. G. In Organic Reactions;
Denmark, S. E., Ed.; John Wiley & Sons: New York, 2008, Vol. 73.
(d) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (e) Roush,
W. R. In StereoselectiVe Synthesis, 4th ed.; Helmchen, G., Hoffman,
R. W., Muler, J., Schaumann, E., Eds.; Thieme Verlag: Stuttgart, 1996;
Vol. 3, p 1410.
(5) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586.
(b) Gravel, M.; Lachance, H.; Lu, X.; Hall, D. G. Synthesis 2004, 8,
1290. (c) Carosi, L.; Lachance, H.; Hall, D. G. Tetrahedron Lett. 2005,
46, 8981. (d) Carosi, L.; Hall, D. G. Angew. Chem., Int. Ed. 2007,
46, 5913. For reviews, see: (e) Hall, D. G. Synlett 2007, 11, 1644. (f)
Kennedy, J. W. J.; Hall, D. G. In Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, Germany, 2005; Chapter 6, p 241.
(6) Flamme, E. F.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
(7) (a) Gonza´lez, A. Z.; Roma´n, J. G.; Alicea, E.; Canales, E.; Soderquist,
J. A. J. Am. Chem. Soc. 2009, 131, 1269. (b) Burgos, C. H.; Canales,
E.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 8044.
(c) Canales, E.; Prasad, G.; Soderquist, J. A. J. Am. Chem. Soc. 2005,
127, 11572. (d) Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799.
(8) The 2008 comprehensive review of allylation reaction using allylboron
reagents by Hall1c cites 49 pages of tabulated individual reactions using
an R-substituted allylboron reagent compared to 419 pages of reactions
using allylboron reagents without R-substitution.
(2) (a) Hoffmann, R. W.; Zeiss, H.-J. Angew. Chem., Int. Ed. Engl. 1979,
18, 306. (b) Hoffmann, R. W.; Zeiss, H.-J. J. Org. Chem. 1981, 46,
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(b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293. (c)
Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23.
9
10.1021/ja910593w  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 4025–4028 4025

A R T I C L E S
Althaus et al.
Scheme 1. Stereoselective Aldehyde Allylation Using Allylic Boron
Reagents
the boronic ester is moderately hindered (e.g., pinacol, dicy-
clohexyl-1,2-ethanediol).2 In contrast, trans-allylic boronic esters
only give good selectivity if the boronic ester is unencumbered
(e.g., 1,3-propanediol4c,d,6), enabling the reaction to occur via
the less hindered TS5 (TS6 suffers a degree of A1,3 strain).
Moderately hindered boronic esters, such as pinacol boronic
esters, give low diastereoselectivity and usually in favor of the
Z-isomer.12a
Thus, each class of reagents has the potential to deliver high
levels of relative stereocontrol, but absolute control is not equally
facile. The best known and utilized reagents are Hoffmann’s
(Z)-crotylboronic esters (class II),12 which have been prepared
in high enantiomeric ratios using Matteson homologation.13 For
class I9,10a,b and class III4c,10c reagents, only sporadic examples
for their generation in enantioenriched form exist.
In this paper, we describe a common general strategy to each
class of these reagents, which in the subsequent reactions with
aldehydes leads to each class of homoallylic alcohols in >95:5 er
and >98:2 dr in all cases. Our common, general strategy involves
the reactions of Hoppe’s lithiated carbamates14 with appropriately
substituted vinylboranes or boronic ester (Scheme 2).
Scheme 2. Synthesis of R-Substituted Allylic Boron Reagents and
In Situ Aldehyde Allylation
A conceptually related reaction had been reported by Hoppe
(Scheme 3), in which an enantioenriched carbamoyl-substituted
boronic ester was first reacted with a Grignard reagent and
subsequent reaction with an aldehyde gave the homoallylic
alcohol.15 However, the diastereomeric ratios were only ∼80:
20, presumably because pinacol esters had been used, which
only leads to low diastereoselectivity in the subsequent allylbo-
ration reaction, and the enantiomeric ratio was only 93:7 due
to the source of the starting boronic ester.
elements of stereochemistry of the homoallylic alcohol products
at will (enantioselectivity, E/Z-stereochemistry and syn/anti-
stereochemistry) without the need for additional stereodirecting
reagents (Scheme 1).
Results and Discussion
The high selectivity in such reactions originates from the
closed chair transition-state structures involved and the basic
need to minimize nonbonded steric interactions.2d,9 For example,
a hindered borane (e.g., 9-BBN10 as illustrated) or hindered
boronic ester (e.g., tetraphenyl-1,2-ethanediol6,11) reacts via TS1
because TS2 suffers severe steric interactions between the
equatorial substituent and the borane moiety (Scheme 1, class
I). A cis-Allylic boronic esters, which constitute the most
commonly used crotylboronic ester derivatives, reacts via TS3
as TS4 suffers severe A1,3 strain (Scheme 1, class II).2,4d,11a,12
As this is the dominant interaction, steric hindrance between
the equatorial substituent and boronic ester is tolerated, even if
We began our investigations with the class I reactions. The
key intermediate allylboron reagents could potentially be
(11) (a) Pietruszka, J.; Scho¨ne, N. Angew. Chem., Int. Ed. 2003, 42, 5638.
(b) Pietruszka, J.; Scho¨ne, N. Eur. J. Org. Chem. 2004, 5011. (c) Stru¨rmer,
R.; Hoffmann, R. W. Synlett 1990, 759. (d) Hoffmann, R. W.; Landmann,
B. Tetrahedron Lett. 1983, 24, 3209. (e) Hoffmann, R. W.; Landmann,
B. Angew. Chem., Int. Ed. Engl. 1984, 23, 437. (f) Hoffmann, R. W.;
Landmann, B. Chem. Ber. 1986, 119, 2013. (g) Hoffmann, R. W.;
Landmann, B. Chem. Ber. 1986, 119, 1039. (h) Hoffmann, R.
W.; Wiedmann, U. J. Organomet. Chem. 1980, 195, 137.
(12) (a) Andersen, M. W.; Hildebrndt, B.; Kosher, G.; Hoffmann, R. W.
Chem. Ber. 1989, 122, 1777. (b) Hoffmann, R. W.; Dirich, K.; Kosher,
G.; Stru¨rmer, R. Chem. Ber. 1989, 122, 1783.
(13) (a) Matteson, D. S.; Sadhu, K. M. J. Am. Chem. Soc. 1983, 105, 2077.
(b) Tsai, D. J. S.; Matteson, D. S. Organometallics 1983, 2, 236.
(14) (a) Zschage, O.; Hoppe, D. Angew. Chem., Int. Ed. 1989, 28, 69. (b)
Hoppe, D.; Carstens, A.; Kra´mer, T. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422.
(9) Corey, E. J.; Rhodes, J. J. Tetrahedron Lett. 1997, 38, 37.
(10) (a) Yamamoto, Y.; Fjikawa, R.; Yamada, A.; Miyaura, N. Chem. Lett.
1999, 1069. (b) Andemichael, Y. W.; Wang, K. K. J. Org. Chem.
1992, 57, 796. (c) Wang, K. K.; Gu, Y. G.; Liu, C. J. Am. Chem. Soc.
1990, 112, 4431.
(15) (a) Beckmann, E.; Desai, V.; Hoppe, D. Synlett 2004, 2275. (b)
Beckmann, E.; Hoppe, D. Synthesis 2005, 217.
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4026 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010

Application of the Lithiation-Borylation Reaction
A R T I C L E S
Scheme 3. Hoppe’s Synthesis of R-Substituted Allylic Boronic
Esters and Reaction with Aldehydes
Table 2. Diamine-Free Aldehyde Allylation Using R-Stannylated
O-Ethyl Carbamate
prepared by the reaction of lithiated carbamates with vinylbo-
ranes or boronic esters.16 We had previously shown that R-aryl
allylboranes bearing the 9-BBN group (Scheme 1, R1 ) aryl)
could be easily obtained through reaction of an aryl-stabilized
sulfur ylide with a vinylborane and that the allylic borane
generated reacted with aldehydes with high enantio- and
diastereoselectivity.17 This reaction was limited to aryl-stabilized
ylides; simple alkyl-substituted ylides reacted with boranes with
low enantioselectivity.18 However, more recently, we have
shown that lithiated alkyl carbamates could react with boranes
with high enantioselectivity.16b,c
entry
R1
R2
yield 4 (%)
er (4)
dr (4/5)
1
2
3
Me
Me
Bu
Ph
Cy
Ph
84
78
64
95:5
94:6
93:7
>99:1
>99:1
>99:1
1).5a,9,21 Severe hindrance between the 9-BBN ring and R1 would
force the R-carbon substituent into a pseudoaxial position,
resulting in the anti-diastereoisomer and (Z)-alkene geometry.
In extending this transformation to vinylboranes, it was important
that the conditions required for 1,2-metalate rearrangement did not
result in isomerization of the labile allylic borane that was
generated. We believed that this could be achieved by adding the
aldehyde to the ate complex at low temperature. Upon warming,
the ate complex would undergo a 1,2-metalate rearrangement,
giving the allyl borane which would be immediately trapped by
the aldehyde before isomerization could occur. This protocol was
found to be successful with a range of representative trans-
vinylboranes 11, carbamates, and aldehydes (Table 1, entries 1-9).
In all cases, high enantiomeric ratios and perfect diastereomeric
ratios were observed except for the simplest carbamates (R1 ) Me,
entries 10 and 11), which gave much lower enantiomeric ratio.
This was surprising as we had previously found that the same
carbamate reacted with B-Ph-(9-BBN) with high enantiomeric
ratio.16 After some experimentation, we discovered that the
diamine-free lithiated carbamate generated from the corresponding
stannane19 12 rescued this important substrate, giving the homoal-
lylic alcohol with excellent enantiomeric ratios and perfect dia-
stereomeric ratios for a range of aldehydes and alkenyl 9-BBN
derivatives (Table 2).20
Figure 1. Competing transition-state structures in the addition of R-sub-
stituted allyl-(9-BBN) reagents to aldehydes.
In order to target class II reactions, we chose cis-vinyl pinacol
boronic esters 13, which were easily prepared by esterification of
commercially available vinylboronic acids. In this case, the presence
of the boronic ester in place of the borane presents additional
challenges: (i) the 1,2-metalate rearrangement is now much slower;
and (ii) the allylic boronic ester is much slower at allylboration.
Fortunately, both processes can be accelerated with Lewis acid
catalysis.5a,22 After optimization of the reaction conditions, a
protocol was developed which showed broad generality for a
representative range of boronic esters, aldehydes, and carbamates
leading to the (E)-syn-homoallylic alcohol with high diastereomeric
ratio and enantiomeric ratio in all cases (Table 3).
The stereochemical outcome can be rationalized by consider-
ing the Lewis acid activated closed TS for the reaction. In this
case, the cis R2 substituent imposes severe A1,3 strain and forces
R1 into a pseudoequatorial position, TS8, thus leading to the
E-syn-isomer (Figure 2).
The high diastereoselectivity observed in the allylation
reaction can be rationalized by the increased steric encumbrance
in transition-state structure TS2 compared to that in TS1 (Figure
In order to obtain the E-anti-isomer, we would “simply”
require the (E)-allylic boronic ester. However, this is one of
the most challenging diastereoisomers to prepare selectively
Table 1. Aldehyde Allylation Using R-Substituted Allyl-(9-BBN)
Reagents
Table 3. Aldehyde Allylation Using (Z)-Allylic Boronic Esters
entry
R1
R2
R3
yield 4 (%)
er (4)
dr (4/5)
1
2
3
4
5
6
7
8
9
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
i-Pr
i-Pr
i-Pr
Me
Me
Me
Me
Bu
Bu
Cy
Ph
Ph
Cy
Ph
Bu
Ph
Cy
Ph
Ph
Cy
84
82
91
78
73
80
58
54
60
88
65
96:4
97:3
98:2
98:2
98:2
98:2
98:2
96:4
95:5
60:40
88:12
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98:2
entry
R1
R2
R3
yield 6 (%)
er (6)
dr (6/7)
CH2OSiMe3
Me
Me
Me
Bu
Me
Me
1
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Me
Bu
Ph
Ph
Cy
Ph
Cy
54
46
59
56
46
99:1
99:1
99:1
99:1
99:1
>99:1
>99:1
>99:1
>99:1
>99:1
2
Me
Me
Me
Me
3a
4
5a
Me
10
11
>99:1
>99:1
a Four equivalents of MgBr2 ·OEt2 used.
9
J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010 4027

A R T I C L E S
Althaus et al.
Table 4. Allylation of Aldehydes Using (E)-Allylic Boronic Esters
Figure 2. Stereoselectivity of (Z)-allylic-boronic esters.
since the two competing closed transition-state structures both
suffer from different forms of steric interactions (Figure 3): TS9
suffers from A1,3 interactions between R1 and the vinyl proton,
while TS10 suffers from steric hindrance between R1 and the
boronic ester diol group.
entry
R1
R2
R3
yield 8 (%)
er (8)
dr (8/9)
1
2
3
4
5
6
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Me
Me
Me
Bu
Bu
Me
Me
Ph
Cy
Ph
Cy
Ph
Cy
67
60
58
67
51
58
98:2
98:2
99:1
99:1
95:5
99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
Me
Figure 3. Stereoselectivity within the allylation reaction using (E)-allylic
boronic esters.
esters, and aldehydes to give 1,2,4-substituted homoallylic alcohols
with control over relative and absolute stereochemistry. The
absolute stereochemistry is controlled through sparteine-mediated
lithiation of the carbamate, a reaction where the other enantiomer
is also easily accessible through the use of the (+)-sparteine
surrogate.25 The relative stereochemistry is controlled by the nature
of the boron substituent and the geometry of the initial vinylboron
reagent: (i) the hindered 9-BBN combined with (E)-vinylborane
leads to the Z-anti-isomer (class I); (ii) the relatively hindered
pinacol boronic ester combined with the (Z)-vinylboronic ester leads
to the E-syn-isomer (class II); and (iii) the unhindered neopentyl
boronic ester combined with the (E)-vinylboronic ester gives the
E-anti-isomer (class III). The new processes described significantly
expand the scope of allylboron reactions as it not only introduces
substitution in the alkene of the homoallylic alcohol product with
control of double bond geometry but also achieves exquisite levels
of stereocontrol. The predictable stereochemical outcome and ease
of access to the reagents are features that readily lend this protocol
to use in complex natural product synthesis. Studies in this area
are ongoing.
In order to favor TS10, we required an unhindered boronic ester
and chose the neopentyl boronic ester for the class III reactions.
These boronic esters have similar steric hindrance to propane-1,3-
diol boronic esters but are more robust and can even be purified
by silica gel chromatography in many cases. These were easily
prepared by hydroboration of an alkyne with HBBr2 followed by
addition of neopentyl glycol.23 After some experimentation, a
general protocol was again found that gave moderate to high yields,
high enantiomeric ratios, and very high diastereomeric ratios in
this most challenging of cases. The optimum conditions involved
addition of the boronic ester 14 to the lithiated carbamates followed
by solvent exchange (Et2O f CH2Cl2), addition of BF3 ·OEt2 (4
equiv) at room temperature, cooling to -78 °C, addition of the
aldehyde, and quenching at -78 °C, after completion of the
reaction. We believe the excess Lewis acid is required as some is
sequestered by the diamine and LiOCb which are present in the
reaction mixture. Without the solvent exchange, the reaction times
are considerably longer.24 Under the optimized conditions, a
representative range of carbamates, trans-vinylboronic esters, and
aldehydes all gave excellent results (Table 4).
Acknowledgment. V.K.A. thanks the EPSRC for a Senior
Research Fellowship, research support and the Royal Society for a
Wolfson Research Award. We also thank Frontier Scientific for the
generous donation of boronic acids and boronic esters. M.A. thanks
the Swiss National Science Foundation for a postdoctoral scholarship.
A.M. thanks the Higher Education Commission of Pakistan for a
studentship. J.R.S. thanks the Spanish Ministerio de Educacio´n y
Ciencia for a postdoctoral fellowship.
Conclusion
In conclusion, we have developed a general and convergent
protocol for combining lithiated carbamates, vinylboranes/boronic
(16) (a) Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal, V. K. Chem.
Rec. 2009, 9, 24. (b) Stymiest, J. L.; Dutheuil, G.; Mahmood, A.;
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J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008,
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Supporting Information Available: Full experimental and
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) This observation was also seen in the reactions with B-ꢀ-trimethyl-
silylvinyl-9-BBN substrates but to an even greater extent. Full details
will be published shortly.
JA910593W
(21) Yamamoto, Y. J. Org. Chem. 1986, 51, 886.
(22) (a) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc.
2003, 125, 10160. (b) Kennedy, J. W. J.; Hall, D. G. Angew. Chem.,
Int. Ed. 2003, 42, 4732. (c) Rauniyar, V.; Hall, D. G. J. Am. Chem.
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(24) In CH2Cl2, full conversion of the intermediate allylic boronic ester
was observed within 2 h for PhCHO and within 15 h for CyCHO.
However, in the same reaction times in Et2O, reactions with PhCHO
only reached ∼80% conversion, and CyCHO only reached ∼60%
1
conversion (by H NMR spectroscopy).
(23) Lombardo, M.; Morganti, S.; Trombini, C. J. Org. Chem. 2000, 65,
8767.
(25) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870.
9
4028 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010