Strict reagent control in the asymmetric allylboration of N-TIPS-α-amino aldehydes with the B-allyl-10-TMS-9-borabicyclo[3.3.2] decanes

Article abstract of DOI:10.1021/ol802685e

(Chemical Equation Presented) The allylboration of enantiomerically pure N-triisopropylsilyl-α-amino aldehydes (2) with B-allyl-10-trimethylsilyl- 9-borabicyclo[3.3.2]decanes (1) proceeds cleanly at -78 °C, exhibiting essentially complete reagent control. After an oxidative workup, an HOAc-mediated N→O TIPS rearrangement facilitates the clean formation of stable O-TIPS protected β-amino alcohol derivatives 3 which are isolated in 60-83% yields in >96% de and >99% ee. For the leucinal series (R = i-Bu), an efficient entry to either statine (8aSS) or epi-statine (8aRS) is reported illustrating the versatility of this potent 1/2 combination.

Full text of DOI:10.1021/ol802685e

ORGANIC
LETTERS
2009
Vol. 11, No. 2
401-404
Strict Reagent Control in the
Asymmetric Allylboration of
N-TIPS-r-Amino Aldehydes with the
B-Allyl-10-TMS-9-borabicyclo[3.3.2]decanes‡
Buddy Soto-Cairoli and John A. Soderquist*
UniVersity of Puerto Rico, Department of Chemistry, Rio Piedras, Puerto Rico
00931-3346
jas@janice.uprr.pr
Received November 20, 2008
ABSTRACT
The allylboration of enantiomerically pure N-triisopropylsilyl-r-amino aldehydes (2) with B-allyl-10-trimethylsilyl-9-borabicyclo[3.3.2]decanes
(1) proceeds cleanly at -78 °C, exhibiting essentially complete reagent control. After an oxidative workup, an HOAc-mediated NfO TIPS
rearrangement facilitates the clean formation of stable O-TIPS protected ꢀ-amino alcohol derivatives 3 which are isolated in 60-83% yields
in g96% de and >99% ee. For the leucinal series (R ) i-Bu), an efficient entry to either statine (8aSS) or epi-statine (8aRS) is reported
illustrating the versatility of this potent 1/2 combination.
Recently, we reported the simple preparation of the
B-allyl-10-trimethylsilyl-9-borabicyclo[3.3.2]decanes (1)
from the reaction of allylmagnesium bromide in ether
with air-stable crystalline pseudoephedrine borinic ester
complexes.1 These robust reagents exhibit remarkable
selectivities in their additions to aldehydes at -78 °C
(96-99% ee). While only a very limited number of chiral
aldehydes have been examined with 1, a high level of
reagent control has been observed in these examples.1,2
The present study was designed to address the allylation of
chiral R-amino aldehydes to provide a simple entry to
functionalized ꢀ-amino alcohols which have a variety of
useful applications.
The substrate-controlled allylation of N-protected-R-
amino aldehydes with achiral reagents can involve either
nonchelation or chelation-controlled additions which
selectively produce anti (erythro) and syn (threo) diaster-
eomeric products, respectively.3 A more versatile strategy
for the stereoselective synthesis of ꢀ-amino alcohols
employs the addition of chiral reagents to chiral N-
protected R-amino aldehydes. Allyltitanium complexes and
especially organoboranes such as diisopinocampheylbo-
rane and tartrate-based boronic ester reagents have been
used with variable levels of diastereoselectivity for these
substrates.4 This phenomenon can often be attributed to
(3) (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149. (b) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. (c) Reetz, M. T. Chem.
ReV. 1999, 99, 1121.
‡ This work is dedicated to Professor Donald S. Matteson, an outstanding
chemist and good friend, in the year of his 77th birthday.
(1) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am. Chem.
Soc. 2005, 127, 8044.
(4) (a) Shi, Y.; Peng, L. F.; Kishi, Y. J. Org. Chem. 1997, 62, 5666. (b)
Roush, W. R.; Hunt, J. A. J. Org. Chem. 1995, 60, 798. (c) Hafner, A.;
Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F.
J. Am. Chem. Soc. 1992, 114, 2321.
(2) Alexander, M. D.; Fontaine, S. D.; La Clair, J. J.; DiPasquale, A. G.;
Rheingold, A. L.; Burkart, M. D. Chem. Commun. 2006, 4602
.
10.1021/ol802685e CCC: $40.75
Published on Web 12/22/2008
2009 American Chemical Society

partially racemized amino aldehydes (e.g., Garner’s N-Boc
serine-based aldehyde).
Table 1. Asymmetric Allylboration of Representative Amino
Aldehydes 2 with 1
To address these issues, we recently reported the
synthesis of the chemically and configurationally stable
N-triisopropylsilyl (TIPS) R-amino aldehydes (2) as enan-
tiomerically pure compounds.5 These new N-protected
R-amino aldehydes were strategically designed to exhibit
a complete absence of chelation control unlike many
N-protected R-amino aldehydes. This behavior was ex-
pected to result from the well-known ability of the TIPS
group to retard reactions at adjacent centers.6 Moreover,
in contrast to the doubly substituted N,N-dibenzyl deriva-
tives, which can exert a strong stereochemical bias on the
additions to the aldehydic moiety, use of a single bulky
group (e.g., N-9-phenylfluoren-9-yl) results in essentially
stereorandom additions.3c,7 This is precisely what is needed
for a strictly reagent-controlled process and 2 meets these
requirements. We also envisaged the NfO TIPS migration
of the initially formed adducts 4 through a mild acid-
catalyzed process to the more stable and versatile O-protected
free amines 3. Thus, we viewed the allylboration of 2 with
1 as a potentially ideal combination for the reagent-controlled
allylation of R-amino aldehydes. Representative systems were
chosen to establish the generality of the approach to the
asymmetric synthesis of O-TIPS protected ꢀ-amino alcohols
3 (Scheme 1). These results are presented in Table 1.
dra syn/anti eeb yield (%)c abs. config.d e
,
1
2
3, R
S
S
R
R
S
S
R
R
S
R
S
R
S
R
S
R
S
R
R
S
S
R
R
S
S
S
S
S
S
S
S
S
a, i-Bu
<99:1
<1:99
<99:1
<1:99
99:1
1:99
99:1
1:99
<99:1
<1:99
<99:1
<1:99
98:2
2:98
98:2
2:98
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
83
73
83
66
71
62
70
64
70
60
68
60
80
60
76
70
4S,5S
4S,5R
4R,5R
4R,5S
4S,5S
4S,5R
4R,5R
4R,5S
4S,5S
4R,5S
4S,5S
4R,5S
4S,5S
4R,5S
4S,5S
4R,5S
a, i-Bu
a, i-Bu
a, i-Bu
b, Pr
b, Pr
b, Pr
b, Pr
c, Me
c, Me
d, Bn
d, Bn
e, (CH2)2SMe
e, (CH2)2SMe
f, CH2OBn
f, CH2OBn
a Determined by 13C NMR of the crude before TIPS NfO migration.
b Calculated by examination of the Mosher’s amide derivatives of 3. c Yields
of pure and isolated materials. d Absolute configuration of the isomers of
3a were determined by 1-D and 2-D NMR examination of pyrrolidinones
7aSS and 7aRS and confirmed by the synthesis of statine 8aSS and
epi-statine 8aRS. e Absolute configuration of 3b-f were determined by NMR
reagents 1 add to 2 to provide essentially a single isomeric
amino alcohol with the new stereogenic center being
determined solely by the enantiomer of 1 chosen for the
process. Thus, 1S gives 3 with the (4S) configuration in
g99% ee and 1R produces 3 with the (4R) configuration
with the same high level of selectivity. Any enantiomeric
impurities in 2 are faithfully reflected as diastereomeric
products, a phenomenon only observed for methional (2e)
and O-benzylserinal (2f) (e2%).8
Scheme 1
Previously, we had employed both oxidative (H2O2, base)
and nonoxidative (pseudoephedrine) workup procedures for
the allylboration of aldehydes with 1.1 However, since both
pseudoephedrine and 3 are ꢀ-amino alcohol derivatives, we
chose to employ an oxidative workup procedure to avoid
potential separation and isolation problems.
In the case of leucinal 2a, the initially formed N-TIPS
product 4a (R ) i-Bu) proved to be unstable with respect to
chromatography or distillation. Based upon the apparent
sensitivity of these systems to an acid medium, we developed
an efficient protocol to effect the smooth NfO TIPS
migration with dry HOAc (25% mol) in EtOAc (Scheme
2). As expected, the transposition is faster for the threo
Initially, the allylations of alaninal (2cS) and O-benzylseri-
nal (2fS) were examined with allylmagnesiun bromide in
ether producing, after TIPS rearrangement, 3c and 3f in 56:
44 and 52:48 syn/anti ratios, respectively. Essentially no
substrate control is observed with 2 in this process. Thus,
the remarkable selectivity of 1 in the allylboration reaction
can completely dominate the process as is observed from
the results illustrated in Table 1. In each case, the BBD
Scheme 2
(5) Soto-Cairoli, B.; Justo de Pomar, J.; Soderquist, J. A. Org. Lett. 2008,
10, 333.
(6) (a) Soderquist, J. A.; Colberg, J. C.; Del Valle, L. J. Am. Chem.
Soc. 1989, 111, 4873. (b) Soderquist, J. A.; Miranda, E. I. J. Am. Chem.
Soc. 1992, 114, 10078. (c) See also citations in ref 5.
(7) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236.
(8) No diastereomeric amplification is observed in any step of the process
as revealed from the 1:1 reaction of 1R with (()-2a which gives the borinate
adducts, 4, crude 3, pure 3, and their Mosher amides, all in a 1:1
diastereomeric ratio (see Supporting Information).
402
Org. Lett., Vol. 11, No. 2, 2009

isomers (e.g., 4aSS) than for their erythro (e.g., 4aSR)
counterparts. Hence, in general, a reaction time of 72 h at
25 °C was employed for this isomerization to ensure its
completion in all cases. After neutralization with TEA, the
ꢀ-amino alcohol derivatives 3 are completely stable to
standard silica gel chromatography and can be isolated as
analytically pure compounds in 60-83% yields. NMR
analysis of the well resolved signals from the corresponding
Mosher amides revealed a consistently high level of enan-
tiomeric purity in 3 (major isomer g99% ee in every case).
The existence of the free 1°-amine in 3a was observed in
the FTIR spectrum by the presence of the N-H asymmetric
stretch at 3389 cm-1 and the N-H symmetric stretch at 3321
cm-1 as well as by the absence of the O-H stretch. This
process selectively transfers the protection from NfO
thereby further utilizing the TIPS group protection for
subsequent conversions.
Moreover, epi-statine is of interest because it is a member
of the anti series of statine analogues present in depsipeptides
with biological activitiy.10
Preparation of the Boc carbamates 5aSS and 5aRS initially
proved difficult, a problem overcome with 1-N-(tert-butoxy-
carbonyl)-1H-benzotriazol-3-N-oxide11 in dioxane which
provides 5 in excellent yields as mixtures of E/Z rotamers
(Scheme 3). Catalytic oxidation12 of these 5a isomers with
RuO4 through the Sharpless protocol produces the corre-
sponding cis- or trans-4-O-TIPS-5-isobutylpyrrolidinones as
single isomers (6aSS and 6aRS). Treatment of 6a with 1.1
equiv of TBAF in THF at room temperature for 2 h afforded
the corresponding desilylated pyrrolidinones 7a in good
yields. For these, 2D-NMR experiments were conducted
(COSY 45, HMQC and NOESY) to establish the cis
relationship of the groups on C-4 and C-5. All these data
are in agreement with reported values as is the optical
rotation.13 NOESY experiments also revealed no cross-peaks
between H-4 and H-5 in 7aRS.
We chose to prepare the known N-Boc derivatives of
statine (8aSS) and epi-statine (8aRS) to demonstrate the
versatility of the present method and to confirm the absolute
stereochemistry of 3 (Scheme 3). The leucine-based com-
The hydrolysis of the appropriate lactams 7 in THF under
basic conditions furnished the known N-Boc-statine 8aSS
Scheme 3
pounds have been studied extensively. Statine has been found
in the backbone of pepstatin, a microbial inhibitor of aspartic
proteolytic enzymes such as pepsin, cathepsin D and rennin.9
(9) Marciniszyn, J.; Hartsuck, J. A.; Tang, J. J. Biol. Chem. 1976, 251,
7088.
(10) (a) Rinehart, K. L.; Gloer, J. B.; Cook, J. C.; Mizsak, S. A.; Scahill,
T. A. J. Am. Chem. Soc. 1981, 103, 1857. (b) Stratmann, K.; Burgoyne,
D. L.; Moore, R. E.; Patterson, G. M. L.; Smith, C. D. J. Org. Chem. 1994,
59, 7219. (c) Vervoort, H.; Fenical, W.; Epifanio, R. A. J. Org. Chem.
2000, 65, 782.
(11) Singh, J.; Fox, R.; Wong, M.; Kissick, T. P.; Moniot, J. L.;
Gougoutas, J. Z.; Malley, M. F.; Kocy, O. J. Org. Chem. 1988, 53, 205.
(12) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, B. J. Org.
Chem. 1981, 46, 3936.
Figure 1. Space-filling MM Models of 2aS paired with 1S and
1R. Energy-minimized pretransition state complexes which repre-
sent a model for the observed selectivities (color code for atoms:
C, black, H, yellow, O, red; B, green, N, purple, Si, gray).
(13) Jouin, P.; Castro, B. J. Chem. Soc., Perkin Trans. I 1987, 1177.
(14) Rich, D. H.; Sun, E. T.; Boparai, A. S. J. Org. Chem. 1978, 43,
3624.
(15) Calculations were conducted using Spartan 06 programs.
Org. Lett., Vol. 11, No. 2, 2009
403

and epi-N-Boc-statine 8aRS in good yields. These com-
By utilizing configurationally stable N-TIPS R-amino alde-
hydes 2 with near perfect optical purities, obtaining diaster-
eomeric products from enantiomeric impurities in the amino
aldehydes employed is no longer problematic.4b,c With 2,
substrate control is also eliminated in this process. Thus, with
the remarkable level of reagent control exhibited by 1, match/
mismatch considerations are moot and lowered selectivities
and even unexpected products are avoided in traditionally
mismatched cases.2,16 Completely predictable stereochem-
istry can be incorporated into 3 through the appropriate
choice of a 1/2 combination. This chemistry reflects the
powerful utility of silicon in the orchestration of organobo-
rane conversions.1,6,17
pounds were obtained as mixtures of amide rotamers. The
1
optical rotations, in addition to the H- and the 13C NMR
spectra of the major rotamers in CDCl3 are in full agreement
with the reported data.14
In the above study, we have demonstrated that the 1/2
combination represents a powerful new approach to stere-
ochemically pure 1,2-amino alcohols 3. Strict reagent control
is observed because, not only is 1 an incredibly selective
reagent, but also, the N-TIPS substitution essentially removes
any stereochemical bias associated with amino aldehyde
substrates in these additions. We were interested in identify-
ing possible features of these compounds that could explain
this reactivity. Toward this end, we examined simple MM-
generated models for these reagent/substrate combinations.15
It was found that the formyl groups in 2 dramatically protrude
from the molecule’s remaining bulk, permitting O-coordina-
tion and nucleophilic addition to the carbonyl from either
face (Figure 1). The well defined chiral pockets in 1 highly
favor attack of the aldehyde cis to the 10-TMS to provide
less severe steric repulsions for the O/TMS vs allyl/TMS
interactions. Thus, the fact that 2 is accessible from either
diastereotopic face leads to reagent control with allylborations
employing the highly selective B-allyl-10-TMS-9-BBDs 1.
As previously noted, both pinene- and tartrate-derived
allylboranes have been used for the asymmetric allylation
of N-protected R-amino aldehydes.4 The new chemistry
described herein provides major advances in this process.
Acknowledgment. The support of the NSF (CHE0517194)
is gratefully acknowledged.
Supporting Information Available: Full experimental
procedures, characterization data, selected spectra for 3, 5-8,
and derivatives. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL802685E
(16) Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2003, 68, 3838
.
(17) (a) Herna´ndez, E.; Soderquist, J. A. Org. Lett. 2005, 7, 5397. (b)
Herna´ndez, E.; Canales, E.; Gonza´lez, E.; Soderquist, J. A. Pure Appl. Chem.
2006, 78, 1389. (c) Hernandez, E.; Burgos, C. H.; Alicea, E.; Soderquist,
J. A. Org. Lett. 2006, 8, 4089. (d) Gonza´lez, A. Z.; Roma`ın, J. G.; Gonza´lez,
E.; Mart´ınez, J.; Medina, J. R.; Matos, K.; Soderquist, J. A. J. Am. Chem.
Soc. 2008, 130, 9218
.
404
Org. Lett., Vol. 11, No. 2, 2009