Asymmetric allyl- and crotylboration with the robust, versatile, and recyclable 10-TMS-9-borabicyclo[3.3.2]decanes

Article abstract of DOI:10.1021/ja043612i

The remarkable versatility and selectivity of the 10-(trimethylsilyl)-9- borabicyclo[3.3.2]decanes (10-TMS-9-BBDs) in the allyl- and crotylboration of representative aldehydes are reported. The new reagents are prepared through air-stable crystalline pseudoephedrine borinic ester complexes of the 10-TMS-9-BBDs (4), which are available in 63% overall yield from B-MeO-9-BBN through a simple two-step procedure. These complexes 4 are directly converted to the corresponding B-allyl-10-TMS-9-BBDs (1) with allylmagnesium bromide, which either can be isolated (98%) or used in situ for the allylations. The remarkable enantioselectivity (96 to ≥99% ee) of these reagents in the rapid (<3 h), asymmetric allylboration process at -78 °C is only slightly diminished when it is conducted at 25 °C, a phenomenon attributable to its rigid bicyclic structure. In addition to providing the homoallylic alcohols 6 efficiently (68-80%), the procedure also permits the efficient recovery of 4 (68-84%) for the direct regeneration of 1. Alternatively, an oxidative workup procedure can be used for the preparation of 6. The reagent gives predictable stereochemistry and exhibits an extremely high level of reagent control in the allylboration of D-glyceraldehyde acetonide. A simple and efficient procedure has been developed for the preparation of all four geometric and enantiomeric isomers of the B-crotyl-10-TMS-9-BBDs (10) from optically pure enantiomers of B-MeO-10-TMS-9-BBD (3). These reagents 10 also add rapidly (<3 h) and efficiently to representative aldehydes at -78 °C, providing ready access to all four of the possible stereoisomers of the β-methyl homoallylic alcohols 12-15 (69-92%) in high dr (≥98:2) and ee (94-99%).

Full text of DOI:10.1021/ja043612i

Published on Web 05/10/2005
Asymmetric Allyl- and Crotylboration with the Robust,
Versatile, and Recyclable 10-TMS-9-borabicyclo[3.3.2]decanes
Carlos H. Burgos,† Eda Canales, Karl Matos,‡ and John A. Soderquist*
Contribution from the Department of Chemistry, UniVersity of Puerto Rico,
Rio Piedras, Puerto Rico 00931-3346
Received October 20, 2004; E-mail: jas@janice.uprr.pr
Abstract: The remarkable versatility and selectivity of the 10-(trimethylsilyl)-9-borabicyclo[3.3.2]decanes
(10-TMS-9-BBDs) in the allyl- and crotylboration of representative aldehydes are reported. The new reagents
are prepared through air-stable crystalline pseudoephedrine borinic ester complexes of the 10-TMS-9-
BBDs (4), which are available in 63% overall yield from B-MeO-9-BBN through a simple two-step procedure.
These complexes 4 are directly converted to the corresponding B-allyl-10-TMS-9-BBDs (1) with allylmag-
nesium bromide, which either can be isolated (98%) or used in situ for the allylations. The remarkable
enantioselectivity (96 to g99% ee) of these reagents in the rapid (<3 h), asymmetric allylboration process
at -78 °C is only slightly diminished when it is conducted at 25 °C, a phenomenon attributable to its rigid
bicyclic structure. In addition to providing the homoallylic alcohols 6 efficiently (68-80%), the procedure
also permits the efficient recovery of 4 (68-84%) for the direct regeneration of 1. Alternatively, an oxidative
workup procedure can be used for the preparation of 6. The reagent gives predictable stereochemistry
and exhibits an extremely high level of reagent control in the allylboration of D-glyceraldehyde acetonide.
A simple and efficient procedure has been developed for the preparation of all four geometric and
enantiomeric isomers of the B-crotyl-10-TMS-9-BBDs (10) from optically pure enantiomers of B-MeO-10-
TMS-9-BBD (3). These reagents 10 also add rapidly (<3 h) and efficiently to representative aldehydes at
-78 °C, providing ready access to all four of the possible stereoisomers of the â-methyl homoallylic alcohols
12-15 (69-92%) in high dr (g98:2) and ee (94-99%).
Introduction
reagent that can be prepared and stored in bulk and utilized
through trivial procedures, (3) user and environmentally friendly,
The preparation of nonracemic homoallylic alcohols through
the asymmetric allylboration of aldehydes represents an ex-
tremely important process and one that has undergone continu-
ous evolution since its discovery by Hoffmann over 2 decades
ago.1 Alternatives to allylboration including catalytic processes
have also been reported.2 It has been pointed out that an ideal
reagent for the asymmetric allylation of aldehydes should be
(1) easily prepared in both enantiomeric forms, (2) a stable
and (4) generally effective, exhibiting high efficiency and
enantioselectivity.2a Other attractive features for this ideal system
would be that it is (5) easily recycled, (6) relatively insensitive
to the reaction temperature, (7) highly selective with chiral
substrates, and (8) easily modified to provide ready access to
more complex allylic systems such as the corresponding
crotylboranes. In this paper, we describe the preparation of the
remarkably robust 10-trimethylsilyl-9-borabicyclo[3.3.2]decanes
(10-TMS-9-BBDs) and their use in the asymmetric allyl- and
crotylboration of representative aldehydes, demonstrating that
this new stable chiral ligation for boron largely meets all of
these criteria.
Asymmetric allylboration is generally viewed as occurring
via a chairlike transition state, with allyldialkylboranes being
significantly more reactive than their boronic ester and related
counterparts.1,3 The reactivity of the latter can be increased
through the incorporation of electron-withdrawing groups into
the ligands of these esters or by added Lewis acid catalysts,
and this generally results in enhanced selectivities. Moreover,
the valuable diol precursors to these reagents can also often be
recovered.1d,4 However, the chiral dialkylborane derivatives do
† Current address: Merck, Sharp & Dohme Quimica de Puerto Rico,
Inc., Barceloneta, PR 00617-6060.
‡ Current address: BASF Corp., Inorganics, Evans City, PA 16033.
(1) (a) Herold, T.; Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1978, 17,
768. (b) Herold, T.; Schrott, C.; Hoffmann, R. W. Chem. Ber. 1981, 114,
359. (c) Hoffmann, R. W.; Herold, T. Chem. Ber. 1981, 114, 375. See
also: (d) Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23 and ref.
cited therein. (e) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6,
2701. (f) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
13644. (g) Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2003, 68, 3838.
(h) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 9308. (i) Morgan,
J. B.; Morken, J. P. Org. Lett. 2003, 5, 2573. (j) Barrett, A. G. M.; Braddock,
D. C.; de Koning, P. D.; White, A. J. P.; Williams, D. J. J. Org. Chem.
2000, 65, 375. (k) Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.; Flack,
K.; Gibson, V. C.; Salter, M. M. J. Org. Chem. 2000, 65, 6508.
(2) (a) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946. (b)
Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (c) Waltz, K.;
Gavenonis, J.; Walsh, P. J. L. Angew. Chem., Int. Ed. 2001, 41, 3697. (d)
Kennedy, J. W. J.; Hall, D. G J. Org. Chem. 2004, 69, 4412. (e) Ishiyama,
T.; Ahiko, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 12414. (f) Wada,
R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
8910. (g) Kim, J. G.; Waltz, K. M.; Garcia, I. F.; Kwiatkowski, D.; Walsh,
P. J. J. Am. Chem. Soc. 2004, 126, 12580. (h) Wadamoto, M.; Ozasa, N.;
Yanagisawa, A.; Yamamoto, H. J. Org. Chem. 2003, 68, 5593.
(3) (a) Yamamoto, Y.; Asoa, N. Chem. ReV. 1993, 93, 2207. (b) Gung, B. W.;
Xue, X.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 10692. (c) Li, Y.;
Houk, K. J. Am. Chem. Soc. 1989, 111, 1236.
(4) (a) Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60, 3806.
9
8044
J. AM. CHEM. SOC. 2005, 127, 8044-8049
10.1021/ja043612i CCC: $30.25 © 2005 American Chemical Society

10-TMS-9-BBDs: Asymmetric Allyl- and Crotylboration
A R T I C L E S
Scheme 1
have inherent advantages over their boronate counterparts. The
lack of heteroatom spacers permits the chirality to be placed
closer to the boron center, which also generally results in
increased selectivity. Also, the fact that B-C bonds are
hydrolytically stable has permitted nonoxidative workup pro-
cedures to be devised for the diterpenylboranes processes, which
enable the chiral boron moiety to be recycled. Unfortunately,
these reagents must be freshly prepared from high-purity air-
sensitive precursors prior to their use in the allylboration
process.1d,5a Moreover, with the selectivities of reagents such
as allyldiisopinocampheylborane (Ipc2BAll) exhibiting signifi-
cant temperature dependence, their reactions are best conducted
at -100 °C under salt-free conditions.5b
A powerful extension of the allylboration process, namely,
asymmetric crotylboration,6 represents one of the most useful
organoborane conversions. Providing highly versatile nonrace-
mic stereodefined â-methyl homoallylic alcohols, the process
simultaneously produces two contiguous stereogenic centers in
a controlled and predictable manner. After the pioneering work
of Hoffmann,6 effective tartrate-7 and terpene-based8 reagents
have expanded the scope, versatility, and selectivity of the
process.9 Chiral organoborane catalysts were also introduced
by Yamamoto, which allowed achiral crotylsilanes and stannanes
to provide effective crotyl sources for the process.10 Recently,
Lewis acids have been demonstrated to markedly enhance the
rate of crotylboration.11 While chiral Lewis acids do provide
some enantioselectivity with achiral crotylboranes,2e the en-
hanced reactivity of chiral boronic esters with added Sc(OTf)3
provides highly enantioselective crotylborations.11b Related
silane combinations are also useful for asymmetric crotylation,2b,12
as are chiral crotylsilanes which have been developed for the
uncatalyzed crotylation of aldehydes.13 These advances not-
withstanding, asymmetric crotylboration is particularly versatile,
finding numerous applications for which the syntheses of
superstolide A and B, tetronasin, venturicidines, swinholide A,
and, most recently, (-)-dictyostatin are representative.14
A variety of methods can be used for the synthesis of
stereodefined γ-substituted allylboranes.1d,2d However, the parent
crotyl systems are generally best prepared in a highly stereo-
selective manner through the addition of the appropriate
Schlosser “crotylpotassium” reagents to organoborane sub-
strates.4,7-9 As with allylboration, these reagents add to alde-
hydes in a highly diastereoselective manner, presumably also
through a chairlike transition state, faithfully transmitting the
borane geometry into the product alcohols. Thus, (Z)- and (E)-
boranes produce syn- and anti-â-methyl homoallylic alcohols,
respectively.3 Chiral reagents have been derived from terpenes,8
tartrates,7 tartramides,1g and borolanes,9 which exhibit enantio-
selectivities far exceeding those of asymmetric catalytic pro-
cesses employing stoichiometric quantities of achiral crotyl-
boranes.2e The robust 10-TMS-9-BBD ring system appeared to
us to have the potential to provide very reactive and selective
reagents. Further, we felt that they would be as easy to prepare
and recycle as Brown’s terpene-derived reagents,8 but closer to
Roush’s tartrates and tartramides1f,g,7 in terms of ease of
handling, purification, storage, and use.
Results and Discussion
Synthesis of the Allylboranes 1. Recently, we discovered
that the stable, commercially available TMSCHN2 undergoes
the clean insertion of CHTMS into a ring B-C bond in B-R-
9-BBNs.15 Fortunately, this process (10 h, C6H14, 70 °C) is also
successful for 2, affording the very stable B-MeO-10-TMS-9-
BBD (3) in 97% yield after distillation (bp 80 °C, 0.10 mmHg)
(Scheme 1). Moreover, 3 is stable to the open atmosphere for
brief periods of time (17 h, 3% oxidation), in marked contrast
to 2 and other borinate esters such as MeOB(Ipc)2. Moreover,
3 is readily converted to (()-1 with allylmagnesium bromide
(AllMgBr) in ether (98%).
(5) (a) Brown, H. C.; Racherla, U. S.; Liao Y.; Khanna, V. V. J. Org. Chem.
1992, 57, 6608. (b) Racherla, U.; Liao, Y.; Brown, H. C. J. Org. Chem.
1992, 57, 6614.
(6) See, for example: (a) Hoffmann, R. W.; Ladner, W.; Steinbach, K.; Massa,
W.; Schmidt, R.; Snatzke, G. Chem. Ber. 1981, 114, 2786. (b) Hoffmann,
R. W.; Zeiss, H.-J.; Ladner, W.; Tabche, S. Chem. Ber. 1982, 115, 2357.
(c) Hoffmann, R. W.; Endesfelder, A.; Zeiss, H.-J. Carbohydr. Res. 1983,
320.
(7) (a) Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc. 1986, 108, 294. (b)
Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R.
L. J. Am. Chem. Soc. 1990, 112, 6339. (c) Roush, W. R.; Palkowitz, A.
D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348. (d) Roush, W. R.; Ando,
K.; Powers, D. B.; Halterman, R. L.; Palkowitz, A. D. Tetrahedron Lett.
1988, 44, 5579.
(8) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293. (b) Brown,
H. C.; Racherla, U. S.; Liao, Y.; Khanna, V. V. J. Org. Chem. 1992, 57,
6608. (c) Brown, H. C.; Bhat, K. S.; Randad, R. J. Org. Chem. 1987, 52,
3701.
(9) For chiral borolanes, see: Garcia, J.; Kim, B.; Masamune, S. J. Org. Chem.
1987, 52, 4831.
(10) (a) Furuta, K.; Mouri, M.; Yamamoto, H. Synlett. 1991, 561. (b) Marshall,
J. A.; Tang, Y. Synlett. 1992, 653.
Employing a modified version of the Masamune resolution
protocol,16 (()-3 was added to 0.5 equiv of (1S,2S)-pseudoephe-
(14) (a) Yu, W.; Zhang, Y.; Jin, Z. Org. Lett. 2001, 3, 1447. (b) Ley, S. V.;
Clase, J. A.; Mansfield, D. J.; Osbor, H. M. I. J. Heterocycles Chem. 1996,
33, 1533. (c) Hoffmann, R. W.; Rolle, U.; Gottlich, R. Liebgs Ann. 1996,
1717. (d) Paterson, I.; Yeung, K.-S.; Ward, R. I.; Cumming, J. G.; Smith,
J. D. J. Am. Chem. Soc. 1994, 116, 9391. (e) Patron, A. P.; Richter, P. K.;
Tomaszewski, M. J.; Miller, R. A.; Nicolaou, K. C. J. Chem. Soc., Chem.
Commun. 1994, 1147. (f) Richter, P. K.; Tomaszewski, M. J.; Miller, R.
A.; Patron, A. P.; Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1994,
1151. (g) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K.
G. Angew. Chem., Int. Ed. 2004, 43, 4629.
(11) (a) Kennedy, J. W.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586. (b)
Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003,
125, 10160.
(12) (a) Hu, T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 2002, 122, 12806.
(b) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293. See also: (c)
Schaus, J. V.; Jain, N.; Panek, J. S. Tetrahedron 2000, 56, 10263.
(13) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375.
9
J. AM. CHEM. SOC. VOL. 127, NO. 22, 2005 8045

A R T I C L E S
Scheme 2
Burgos et al.
Table 1. Allylboration of RCHO with 1
% eeb
R in RCHO
1
series
6 (%)a
(abs config)
Me
Pr
i-Pr
t-Bu
CH2dCH
Ph
4-MeOC6H4
4-O2NC6H4
2-furyl
t-PhCHdCH
R
R
S
R
S
a
b
c
d
e
f
g
h
i
71
79
70
79
71
80
90
87
86
92
96 (S)
g99 (S)d
g99 (S)c
g98 (R)c
g99 (S)c,e
g98 (S)c,e
96 (R)c
S
R
R
R
R
97 (R)c
97 (R)c
j
97 (R)c
a All runs were made in duplicate (at least) and those of the a and f
series were performed with both (-)-1R and (+)-1S. For the a-f series,
the intermediate 5 was isolated (87-100%) and converted to 6 and recovered
4 (68-84%) via the PE workup procedure. For the g-j examples, an
oxidative workup procedure was used. b Product ee determined by conver-
sion to the Mosher esters and analysis by 13C NMR, 1H NMR and 13C NMR,
drine (PE) in MeCN, which gave a 38% yield of (+)-4R as a
pure crystalline compound, leaving (-)-3R in solution. After
concentration of the supernatant to remove the liberated MeOH,
0.5 equiv of (1R,2R)-PE was added to a fresh solution of the
residue in acetonitrile, ultimately giving a 28% yield of the pure
crystalline (-)-4S. Reversing this order gives first, (-)-4S and,
second, (+)-4R, also in a 66% combined total yield of
enantiomerically pure forms of 4 from (()-3! These complexes
are air-stable and can be stored indefinitely. The complex (+)-
4R is wholly chelated in the solid state,15 while, in solution, 4
exists in both the open and closed forms (11B NMR (C6D6) δ
56.3, 23.7).
The direct conversion of 4 to 1 was accomplished with
AllMgBr in Et2O, the metathesis proceeding very cleanly at -78
°C. The stable allylboranes 1 can be isolated (98%) in
chemically and optically pure form through simple filtration
through Celite under N2 to remove the Mg2+ salts followed by
concentration in vacuo. Under N2, 1 is stable for weeks at 25
°C. In practice, 1 need not be isolated, but rather merely
quantitatiVely generated with the simple addition of AllMgBr
in Et2O to 4. This admixture is directly used for the allylations,
the Mg2+ salts not interfering with the rate of allylation, in
contrast to the behavior of terpenyl reagents.5b The ease and
efficiency of the preparation of both enantiomers of 1 from 2
in 63% overall yield is greatly enhanced by the air-stability of
its precursor, 4, which largely avoids many of the difficulties
usually associated with dialkylborane reagents.
c
d
or GC as noted. 13C NMR. 1H NMR and 13C NMR. e GC.
the diastereomeric Mosher esters could be observed. Comparing
these results to other known reagents reveals that 1 equals or
exceeds the selectivity observed for any alternative process at
-78 °C.1,2,4,7-10,17
As part of the standard protocol, the borinic ester intermedi-
ates 5 were isolated in excellent yields in essentially pure form
following removal of the solvent (Table 1, series a-f). For the
reactions of (-)-1R, solutions (∼0.5 M) of 5R and (1S,2S)-PE
(1.0 equiv) in MeCN were heated at reflux temperature to effect
the transesterification, giving 6 together with crystalline (+)-
4R, which is easily isolated (70-80%) by simple filtration. An
analogous procedure was used for the (+)-1S reactions employ-
ing (1R,2S)-PE to provide 6 and crystalline (-)-4S. The
homoallylic alcohols 6 were isolated by simple distillation (67-
84%). The byproduct 4 was recycled through its direct conver-
sion back to 1 though a simple Grignard procedure, avoiding
the extra steps needed to recycle other reagents.1,4,5a Alterna-
tively, an oxidative workup procedure can be employed in the
allylation process (Table 1, series g-j).
In the absence of high-level computational data, MM calcula-
tions18 provide useful models for the prediction of the product
stereochemistry through the relative stabilities of their diaster-
eomeric pre-transition state complexes.19 These calculations
reveal that the B-chiral anti-aldehyde complex which forms cis
to the 10-TMS group (i.e., 7) is favored (∼3 kcal/mol, R )
Asymmetric Allylboration with 1. The asymmetric allyl-
boration of representative aldehydes was conducted with either
(-)-1R or (+)-1S in Et2O (3 h, -78 °C), with the homoallylic
alcohols 6 being isolated in high ee (96 to g99% ee) (Scheme
2, Table 1). This process is quite general, being effective for
alkyl, aryl, heteroaryl, and unsaturated aldehydes. The optical
1
yields of 6 were determined by the H and 13C NMR and/or
GC analysis of the known Mosher esters of these alcohols.17 In
each case, the racemic alcohols (()-6 were also prepared
through the addition of AllMgBr or (()-1 to the starting
aldehydes. Using synthetic mixtures, we established our limit
of detection as 1%, except for 6b, 6c, and 6e, where 0.5% of
Ph) over any conformation of its syn and/or trans counterparts
leading to the selective allylation of the re face of RCHO with
the 1R reagent. In 7, the γ-allylic carbon is within 3.0 Å of the
aldehydic carbon, well positioned for collapse to the expected
chairlike transition state. Any attempt to reach an alternative
transition state through rotation about the B-O and B-allyl
bonds is thwarted by the TMS group, which blocks this pathway.
(15) Soderquist, J. A.; Matos, K.; Burgos, C. H.; Lai, C.; Vaquer, J.; Medina,
J. R.; Huang, S. D. In ACS Symposium Series 783; Ramachandran, P. V.,
Brown, H. C., Eds.; American Chemical Society: Washington, DC, 2000;
Chapter 13, p 176.
(16) Short, R. P.; Masamune, S. J. Am. Chem. Soc. 1989, 111, 1892.
(17) (a) Brown, H. C.; Ramachandran, P. V. In AdVances in Asymmetric
Synthesis; Hassner, A., Ed.; JAI Press: Greenwich, CT, 1995; Vol. 1, p
147. (b) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(c) Brown, H. C.; Jadhav, P. K. J. Org. Chem. 1984, 49, 4089. (d)
Wadamoto, M.; Ozasa, N.; Yanagisawa, A.; Yamamoto, H. J. Org. Chem.
1986, 51, 432. (e) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 6536. (f) Soai, K.; Ishizaki, M.;
Yokoyama, S. Chem. Lett. 1987, 341. (g) Wu, T. R.; Shen, L.; Chong, J.
M. Org. Lett. 2004, 6, 2701.
(18) Performed using the Spartan 4.0.4a GL MM program.
(19) Omoto, K.; Fujimoto, H. J. Org. Chem. 1998, 63, 8331.
9
8046 J. AM. CHEM. SOC. VOL. 127, NO. 22, 2005

10-TMS-9-BBDs: Asymmetric Allyl- and Crotylboration
A R T I C L E S
Table 2. Temperature Effects: 1 vs Ipc2BAll
Scheme 3
1R (% ee)a
Ipc2BAll (% ee)b
MeCHO
temp (°C)
PhCHO
MeCHO
25
0
-25
-78
90
94
93
98
96
NA
79
85
93c
94
>98 (94d)
93
a Analysis of Mosher esters by 13C NMR. b Data from ref 20. c For (+)-
1S. d For Ipc2BAll.
The selectivity of 1 exhibits little temperature dependence
in contrast to reagents such as Ipc2BAll (Table 2).20 We attribute
this to the rigid bicyclic ring system in 1, the chiral integrity of
which is largely maintained despite increasingly populated
higher rotational states. As can also be envisaged through 7,
the chiral pocket for 1 is too small to easily accommodate inward
groups larger than H. Thus, the allylboration of ketones is much
slower and less selective than for aldehydes (e.g., PhCOMe, 2
d, 25 °C, 85%, 62% ee).
Scheme 4
The presence of a proximate stereogenic center in RCHO
can markedly influence the diastereoselectivity of the allyl-
boration. For 1, we examined its selectivity for D-glyceraldehyde
acetonide (8, 99% ee), an extensively studied substrate.4 Its
reaction with (-)-1R gave a >99:1 mixture of the (2R,3R)-
threo (a) and (2R,3S)-erythro (b) diastereomers of 9, whereas
(+)-1S gave these products in a 5:95 dr.21 These selectivities
for 1 are comparable to the best tartramide reagents for this
substrate.4
87% yield (Scheme 3). Because no significant manipulation of
1 is required in the procedure and its methanolysis is very clean,
producing only propene as a byproduct, the operation is
exceedingly simple, with 3 being easy to isolate, handle, and
store.
Synthesis of the Crotylboranes 10. With the general
versatility and remarkable selectivities exhibited for 1 in the
asymmetric allylboration process, we chose to extend this
general reaction protocol to crotylboration. Unfortunately, all
attempts to find a clean and effective procedure for the direct
conversion of the complexes 4 to the crotyl reagents 10 were
unsuccessful. Only reagents of the general type RMgBr appear
to be amendable to this method, and Grignard procedures give
crotylborane mixtures.22 On the basis of other dialkyl systems,
3 provides the logical precursor to 10 through the standard
protocol using the Schlosser reagents.23 As noted above, 3 is a
very “user friendly” borinic ester, being distillable, storable, and
unusually resistant toward air oxidation. These characteristics
of 3 were expected to significantly reduce the complexity of
the operations required in generating 10.
By analogy to Brown’s preparation of his terpene-derived
crotylboranes,8 the 3 f 10 conversion was examined with (()-3
employing Schlosser’s “Superbase” to selectively generate the
crotylmetallic species from either cis- or trans-2-butene, fol-
lowed by their addition to 3 giving the borinate complexes 11,
which are demethoxylated with a Lewis acid to give the
crotylborane 10.8 Our modifications include (1) the use of THF
solutions of KO(Bu-t) rather than the solid reagent, which
dramatically reduces the time required for the deprotonation of
cis-2-butene from 12 f 1 h and increases the geometric purity
of E-10 from 94 to 98%; (2) conducting the entire process at
-78 °C, which results in the clean formation of 11 (11B NMR
δ 3.6), avoiding isomerization of the “crotylpotassium” reagents
and the double addition of the crotylmetallic (11B NMR δ -9.6)
to 3; and (3) the use of TMSOTf as the Lewis acid, which avoids
the unwanted decrotylation of 11 to regenerate 3 [e.g., BF3-
Et2O or MgBr2 (40%), TMSCl (20%)] and cleanly produces
10 (95%) in high geometric purity (g98%). With these
modifications in place, both Z and E isomers of 10 in either
enantiomeric form as well as, importantly, also in racemic form,
are readily prepared from 3 (Scheme 4).
We considered several potential routes to the optically pure
forms of 3, finding that the simplest and most efficient method
was through the generation of the allylboranes 1 from either
(+)-4R or (-)-4S and their methanolysis (2 h, reflux) to provide,
after distillation, pure (-)-3R and (+)-3S, respectively, both in
(20) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem.
1996, 51, 432.
(21) The 13C NMR signals for the C-4 position in 9a and 9b were cleanly
resolved, appearing at δ 38.5 and 37.6, respectively (δ 35.1 and 35.6 in
their Mosher esters).
(22) Hoffmann, R. W.; Niels, G.; Schlapback, A. Pure Appl. Chem. 1990, 62,
1993.
(23) Fujita, L.; Schlosser, M. HelV. Chim. Acta 1982, 65, 1258.
With efficient procedures for all of the isomers of 10 in hand,
we chose to examine their configurational stabilities, since
9
J. AM. CHEM. SOC. VOL. 127, NO. 22, 2005 8047

A R T I C L E S
Scheme 5
Burgos et al.
Table 3. Asymmetric Crotylboration of RCHO with 10
R in
yield
(%)b
drc
RCHO
10
product
methoda
syn/anti
eed
Ph
Ph
Me
Me
Me
Pr
Pr
t-Bu
t-Bu
Z-S
E-S
Z-S
Z-R
E-S
Z-R
E-R
Z-S
E-R
12a
14a
12b
13b
14b
13c
15c
12d
15d
A
B
C
C
C
A
A
B
C
72
82
68
68
73
91
94
92
69
g98:2
e2:98
g98:2
g98:2
e2:98
g98:2
e2:98
g98:2
e2:98
98
97
95
95
97
94
96
94
99
a Method A: isolated 10, oxidative workup. Method B: in situ use of
10. Method C: isolated 10, pseudoephedrine workup. b Isolated yield.
c Determined by comparison of peak areas for diastereomeric pairs of the
alcohols through both 1H and 13C NMR. This was also checked through
13C NMR of the corresponding Mosher esters. d Determined by comparison
of the observed peak areas for several sets of signals derived from the
diastereomeric pairs in the corresponding R-Mosher esters through both
1H and 13C NMR. For R ) t-Bu, chiral diazaphospholidine derivatives were
prepared and these were analyzed through 31P NMR.
enantiomeric form of pseudoephedrine. This permits the efficient
recovery of the chiral boron moiety 4 in 70-80% yield for
recycling purposes.25
The syn and anti diastereomers of alcohols 12-15 give
distinctly different 13C NMR spectra, which were in complete
agreement with those reported.7b In each case we determined
the dr to be g98:2 for the major diastereomer produced, a direct
reflection of the high geometric purities of 10 prepared through
the Schlosser reagents. The enantiomeric excess for each
â-methyl homoallylic alcohol 12-15 was normally determined
from the 1H and 13C NMR analysis of the corresponding Mosher
ester derivatives.26 However, for the R ) t-Bu examples (12d,
15d), the product ee’s were determined using chiral diazaphos-
pholidine derivatives and 31P NMR analysis.27 The selectivities
observed for 10 generally equal or exceed those of previously
existing reagents. Data from the analogous asymmetric allyl-
boration (vide ultra) and allenylboration28 processes with our
BBD system, together with the specific rotations for the R )
Me (b) series, were used to assign the absolute stereochemistry
of 12-15.
crotylboranes are prone to isomerization through 1-methallyl-
boranes via 1,3-boratropic rearrangements.8a This process is
normally faster for BR2 vs B(OR′)2 derivatives. Samples of both
Z-10 and E-10 were examined by NMR after 1 week at 25 °C
in CDCl3 solution. The E isomer, which was initially 98:2 E/Z,
was isomerized to 84:16 during this period. The Z isomer (e2:
98 E/Z) was more affected, giving a 53:47 E/Z mixture. As a
consequence, the reagents 10 were not stored but rather
generated as needed for the crotylboration process. The high
reactivity of these trialkylboranes facilitates their clean addition
to even highly hindered aldehydes in <3 h at -78 °C with no
accompanying loss of the reagent’s geometric purity.24
Asymmetric Crotylboration with 10. The crotylboration of
representative aldehydes with Z-10S, E-10S, Z-10R, or E-10R
as well as with the racemic crotylboranes Z-10 and E-10 (for
analytical purposes) was examined in detail (Et2O, 3 h, -78
°C) (Scheme 5). The products â-methyl homoallylic alcohols
12-15 were isolated in good to excellent yields (68-94%) with
high diastereoselectivity (dr >98:2) and enantioselectivity (94-
99% ee) (Table 3). Through the choice of the appropriate
crotylborane 10, any and all of the stereoisomers of the â-methyl
homoallylic alcohols can be prepared.
As in the allylboration process with 1, MM calculations18
provide useful models for the prediction of the product
stereochemistry through the relative stabilities of their diastereo-
meric pre-transition-state complexes. These calculations reveal
that the B-chiral anti-aldehyde complex which forms cis to the
10-TMS group (i.e., Z-16) is favored (∼3 kcal/mol, R ) Ph)
Three procedures were developed for the crotylboration
process, all of which gave similar product yields and selectivi-
ties. Method A was developed to demonstrate that 10 is isolable
and that its solutions can be used for the process. A standard
oxidative workup (3 M NaOH, 30% H2O2) was employed.
Method B uses the same workup but without isolation of the
reagents 10. Method C employs a solution of 10 followed by a
nonoxidative workup through the addition of the appropriate
over any conformation of its syn and/or trans counterparts,
leading to the selective allylation of the re face of RCHO with
the 10R reagent. Calculations with E-16 produce similar results.
(24) The crotylborane geometry is faithfully reflected in the product alcohols
(Table 3). While this is not new, the crotylboration with 10 is much faster
than its isomerization, regardless of the reaction temperature. For example,
early in the present studies we observed that E-10 produced the â-methyl
homoallylic alcohols in a 94:6 anti:syn ratio, both at at 25 and -78 °C.
This led us to isolate E-10 and determine its 94:6 E/Z ratio, ultimately
optimizing this to g98:2 with our modified protocol.
(25) For a similar process with terpene-derived reagents, see ref 8b.
(26) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(27) Alexakis, A.; Mutti, S.; Mangeney, P. J. Org. Chem. 1992, 57, 1224.
(28) Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799.
9
8048 J. AM. CHEM. SOC. VOL. 127, NO. 22, 2005

10-TMS-9-BBDs: Asymmetric Allyl- and Crotylboration
A R T I C L E S
Conclusions
and both oxidative and nonoxidative workups have been
developed for the process. The latter method provides the
recovered chiral borane moiety in the form of the air-stable and
recyclable complex 4 (70-80%). The â-methyl homoallylic
alcohols 12-15 are obtained in good to excellent yields (69-
92%) in high dr (>98:2) and ee (94-99%). Through the
appropriate choice of the enantiomeric and geometric form of
10, any and all of the four possible isomers of the product
alcohols can be prepared in a predictable manner. Efficient with
respect to both the borane and the “allyl” source, asymmetric
allyl- and crotylations with 1 and 10, respectively, provide
attractive alternatives to existing reagents and processes.
In summary, through the insertion of CH(TMS) with tri-
methylsilyldiazomethane into a ring B-C bond in 2, the
remarkably stable chiral borinic ester 3 is prepared in pure form
(97%). Both enantiomeric forms of the air-stable pseudoephe-
drine complexes 4 are isolable as pure crystalline compounds
from 3 in 66% total overall yield. Reaction of AllMgBr and
either enantiomer of 4 produces the allylborane 1, which exhibits
highly reagent controlled and enantioselective additions to
representative aldehydes (<3 h at -78 °C). However, the
allylations with 1 can also be conducted even at room temper-
ature with only a moderate diminution of this exceptional
enantioselectivity. The reagents 1 can either be isolated or used
in situ with no interference from the byproduct magnesium salts
being observed. A nonoxidative workup provides the efficient
recovery of 4 for the regeneration of 1 (68-84%). The product
homoallylic alcohols are isolated (68-80%) in high ee (96 to
>99%). The allylborane 1 also serves as a useful intermediate
for the synthesis of the optically pure forms of 3 (87%), which
are stereospecically converted to the corresponding crotylboranes
10 (94-95%). These reagents undergo the clean addition to even
hindered aldehydes in <3 h at -78 °C. Asymmetric crotyl-
boration with 10 may be conducted with or without its isolation,
Acknowledgment. Dedicated to the memory of Professor
Herbert C. Brown. The support of the NSF (CHE0217550), NIH
(S06GM8102), and the Department of Education GAANN
Program (P200A030197-04) is gratefully acknowledged.
Supporting Information Available: Full experimental pro-
cedures, analytical data, and selected spectra for 1-15 and
derivatives (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA043612I
9
J. AM. CHEM. SOC. VOL. 127, NO. 22, 2005 8049