Synthesis of enantioenriched α-(hydroxyalkyl)-tri-n-butylstannanes

Article abstract of DOI:10.1002/anie.200802313

(Chemical Equation Presented) Li and Mg are pesky: A catalytic asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes (1) in good to excellent yields and enantioselectivities was achieved (see scheme; PG=protecting group; L=chiral ligand). Compound 1 was isolated as an ester or thiocarbamate, and the reagent was prepared from equimolar amounts of nBu₃SnH and Et₂Zn in dimethoxyethane. Conditions employing lithium or magnesium ions suppress enantioselectivity.

Full text of DOI:10.1002/anie.200802313

Communications
DOI: 10.1002/anie.200802313
Synthetic Methods
Synthesis of Enantioenriched a-(Hydroxyalkyl)-tri-n-butylstannanes**
Anyu He and John R. Falck*
Dedicated to Professor E. J. Corey on the occasion of his 80th birthday
a-(Hydroxyalkyl)triorganostannanes are versatile synthetic
intermediates that have found wide applicability in natural
products total synthesis.[1] Most notably, they offer a higher
level of structural and stereochemical complexity compared
with their tetraorganotin congeners, yet still participate in a
variety of stereospecific transformations including transition-
metal-catalyzed cross-coupling reactions,[2] generation of
configurationally stable anions,[3] Wittig rearrangements,[4]
SE’ additions to carbonyl groups,[5] nucleophilic displace-
ments,[6] and other reactions.[7] Numerous synthetic strategies
to enantioenriched a-(hydroxyalkyl)triorganostannanes have
been devised, inter alia, i) asymmetric reduction of acyl
stannanes,[8] ii) classical resolution,[9] iii) enzymatic resolu-
tion,[10] iv) cleavage of C2-symmetric stannyl acetals,[11]
v) electrophilic stannylation,[12] and vi) nucleophilic stannyla-
tion,[13] however, the goal of a widely applicable, economical,
and operationally simple synthesis from readily available
starting materials remains elusive. Herein, we report the
catalytic, asymmetric synthesis of a-(hydroxyalkyl)-tri-n-
butylstannanes (1) in good to excellent yields and enantiose-
lectivities by the addition of ethyl(tri-n-butylstannyl)zinc to
various aldehydes [Eq. (1)]. In practice, the adduct was
isolated after protection as its more stable ester or thiocarba-
mate (1; PG = protecting group).
to be straightforward. Despite extensive attempts to use tri-n-
butylstannyllithium or Grignard reagents[16] in combination
with various ratios of zinc halides and chiral ligands, 1 (PG =
Ac) was generated with little, if any, useful enantioselectivity,
albeit in good yield. Reasoning that the Li or Mg ions might
have detrimental effects, alternative approaches to stannyl-
zinc generation were systematically investigated. Finally, we
were gratified to discover that the addition of ethyl(tri-n-
butylstannyl)zinc,[17] generated in situ by transmetalation of
tri-n-butyltin hydride with diethylzinc,[18] to benzaldehyde (2)
in the presence of (S)-a,a-diphenyl-2-pyrrolidinemethanol
(3, 10 mol%) at À408C in dimethoxyethane (DME) afforded
adduct 4 in poor yield, but undeniably good stereoselectivity
(i.e. 95% ee), after in situ acetylation (Table 1, entry 1).[19] In
the absence of catalyst 3, the uncomplexed organozinc
reagent was lifeless under the same conditions (Table 1,
Table 1: Reaction parameters.[a]
Entry nBu3SnH
Et2Zn
3 [mol%] T [8C] Yield [%] ee[b] [%]
(equiv)
(equiv)
1
2
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
1.5
4
4
4
4
4
1.5
1.5
1.5
1.5
1.5
4
4
4
4
4
10
0
0
10
10
10
20
50
20
20
À40
À40
4
15
0
95
n.a.[c]
n.a.[c]
95
90
95
96
96
96
94
20
23
29
58
65
67
57
54
À20
4
À20
À20
À20
À20[d]
À20[e]
10
Bolstered by the precedent of catalytic, asymmetric
organozinc additions to carbonyl groups[14] and the equally
well documented preparation of racemic a-(hydroxyalkyl)-
triorganostannanes from aldehydes and ketones by using
triorganostannyl nucleophiles,[15] we were attracted to the
possibility of comparable asymmetric additions of tri-n-
butylstannylzinc reagents to aldehydes. Yet, this proved not
[a] Conducted on a 0.3 mmol scale in DME unless otherwise indicated.
[b] Measured by chiral HPLC analysis. [c] n.a.=not applicable. [d] THF
used as the solvent. [e] Et2O used as the solvent.
entry 2); aldehyde addition did not proceed at an appreciable
rate until 48C was attained (Table 1, entry 3). Higher temper-
atures (Table 1, entry 4) improved the yield modestly, but
eventually started a downward trend in the ee values (Table 1,
entry 5). The most significant improvement was achieved with
a four-fold excess of ethyl(tri-n-butylstannyl)zinc (Table 1,
entry 6) which, when combined with a doubling of the catalyst
loading to 20 mol%, additionally increased the yield (Table 1,
entry 7); additional increases in the mol% of the catalyst had
no effect (Table 1, entry 8). Solvents such as THF (Table 1,
entry 9) and Et2O (Table 1, entry 10) were less effective
compared with DME; toluene, CH2Cl2, acetonitrile, and
hexane were also not suitable.
[*] Dr. A. He, Prof. J. R. Falck
Departments of Biochemistry and Pharmacology
University of Texas, Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, TX 75390-9038 (USA)
Fax: (+1)214-648-6455
E-mail: j.falck@UTSouthwestern.edu
[**] We thank the NIH (GM31278, DK38226) and the Robert A. Welch
Foundation for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802313.
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Evaluation of a series of commercial, chiral diphosphine,
diamine, and amino alcohol catalysts under the reaction
conditions described in Table 1, entry 7, revealed that the
latter were the most efficacious (see the Supporting Informa-
tion). In concert with the proposed structure for other chiral
zinc intermediates,[20] the amine can be either secondary (e.g.
3) or tertiary (e.g. 5 and 7 in Figure 1), but the alcohol should
be unsubstituted for maximum asymmetric induction (e.g. 3
versus 6).
Experimental Section
General procedure: nBu3SnH (1.06 mL, 4 mmol) was added dropwise
to a stirred solution of Et2Zn (4 mL, 1m in hexanes) in anhydrous
DME (10 mL) under an argon atmosphere at À788C . After 5 min,
the reaction mixture was warmed to 48C and kept at this temperature
for 1 day. Upon dilution with more DME (27 mL), the reaction
mixture was recooled to À788C and then the catalyst (0.2 mmol) in
DME (2 mL) and aldehyde (1 mmol) in DME (1 mL) were added
sequentially. After 5 min, the temperature was raised to that indicated
in the table and maintained by using a cryogenic cooler. After
complete reaction, typically 3–6 h, AcCl (0.2 mL) was added and the
reaction mixture was then warmed to RT over 0.5 h. After an
additional 2 h, the reaction mixture was subjected to extractive
isolation by using CH2Cl2 and the crude product was purified by SiO2
column chromatography.
Thiocarbamate product: The reaction mixture was quenched with
saturated aq. NH4Cl, extracted with CH2Cl2 (3 ” 50 mL), and the
combined organic extracts were then washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude a-hydroxyalkylstan-
nane was redissolved in CH2Cl2 (10 mL), to which was added Im2C(S)
(2 mmol) and DMAP (10 mol%) at RT. After ca. 2 h, the reaction
mixture was filtered through a short pad of silica gel. The silica gel pad
was rinsed with hexanes (40 mL) first to remove the nonpolar tin
byproduct, then with hexanes/EtOAc (1:1, 100 mL). The combined
hexanes/EtOAc filtrates were concentrated in vacuo. The residue was
immediately dissolved in neat, anhydrous pyrrolidine (2 mL) at RT
and after 1 h the pyrrolidine was removed and the residue was
purified by SiO2 column chromatography to afford a-thiocarbamoyl
protected stannane.
The 4-nitrobenzoate (29): The reaction mixture was quenched
with saturated aq. NH4Cl and then extracted with CH2Cl2 (3 ” 15 mL).
The combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude a-hydroxyalkylstan-
nane was protected by directly adding 4-nitrobenzoyl chloride
(0.5 mmol) and pyridine (0.2 mL) in CH2Cl2 (10 mL) at RT. After
stirring for ca. 4 h, the reaction was quenched with water and then
extracted with CH2Cl2. The combined organic extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The crude
mixture was purified by SiO2 column chromatography.
Figure 1. Select chiral catalysts used in the preparation of 4. The yields
and ee values of 4 are given.
To help define the scope of the reaction, a panel of
representative aldehydes was subjected to asymmetric stan-
nylation (Table 2). In the case of propionaldehyde (8), the
absolute configuration of adduct 9 (Table 2, entry 1) was
established by comparisons (optical rotation and chiral HPLC
analysis) with a standard compound of known stereochemis-
try.[11b,21] Dihydrocinnamaldehyde (10) was also well-behaved
and gave rise to acetate 11 (Table 2, entry 2) and thiocarba-
mate 12 (Table 2, entry 3) with equal ease, although catalyst 7
furnished a somewhat better enantioselectivity than 3. As
expected, the antipode of 12, that is, 13 (Table 2, entry 4), was
formed in virtually the same yield and optical purity when 3
was replaced by (R)-a,a-diphenyl-2-pyrrolidinemethanol
((R)-3). The trend of obtaining superior enantioselectivity
with 7, and slightly better yields with 3 was also observed with
cyclohexanecarboxaldehyde (14; Table 2, entry 5), but less
evident for the related benzaldehyde (2; Table 2, entry 6).
The ortho substituent of 2-tolualdehyde (16; Table 2, entry 7)
did not significantly influence the reaction, but the presence
of an electron-donating para-methoxy group (Table 2,
entry 8) and even a para-bromo group (Table 2, entry 9)
were well tolerated. In contrast, moderately strong electron-
withdrawing substituents, such as methoxycarbonyl (Table 2,
entry 10), cyano (Table 2, entry 11), and trifluoromethyl
(Table 2, entry 12) groups, seemed to lower the enantioselec-
tivities. Gratifyingly, despite the reputation of the stannyl
anion as a good Michael nucleophile,[22] its addition to
(E,E)-farnesal (28) under our standard conditions produced
allylic adduct 29 in useful yield with a high ee value (Table 2,
entry 13).
Received: May 17, 2008
Published online: July 21, 2008
Keywords: aldehydes · asymmetric synthesis ·
.
organometallic compounds · tin · zinc
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In summary, this report describes a convenient, widely
applicable, and highly enantioselective preparation of pro-
tected a-hydroxyalkylstannanes, which should expedite ap-
plications of this intriguing, but comparatively inaccessible
class of tin reagents. We hope, in the future, to extend these
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Angew. Chem. Int. Ed. 2008, 47, 6586 –6589
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Communications
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Entry RCHO
Ligand T [8C] Adduct
Yield [%] ee[b] [%]
1
3
3
À25
À30
58
97
96
2
66[c]
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3
7
À30
À30
71
69
93
98
3
4
10
10
(R)-3
À30
68
93
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3
7
À15
À25
73
70
90
98
5
3
7
À50
À40
60
58
96
95
6
7
7
À40
54
95
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3
7
À30
À40
72
83
92
97
8
9
7
7
7
À40
À50
À40
60
96
90
83
10
40[d]
86
11
12
13
7
3
À40
À30
72
86
95
56[e]
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[a] Reaction conditions: ethyl(tri-n-butylstannyl)zinc (4 equiv) and catalyst (20 mol%) in DME.
Entries 1–6 and 8 were performed on a 1 mmol scale and all others on a 0.3 mmol scale. The reaction
temperature was varied to give the optimum ee values. Derivatizations are described in the General
Procedure. [b] Measured by chiral HPLC analysis. [c] 3-Phenylpropan-1-ol was the main product in THF
and 11 was obtained in only 20% yield. [d] 40% recovered starting material. The yield of 23 improved
when reaction was run at higher temperatures, but the ee values decreased. [e] PNB=p-nitrobenzoate.
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thesis, Vol. 7 (Ed.: L. A. Paquette), Wiley, Chichester, 1995,
pp. 5026 – 5029; b) T. Sato, Synthesis 1990, 259 – 270.
[16] J. Podlech, Sci. Synth.2003, 5, 285 – 297.
[17] Whereas ethyl(tri-n-butylstannyl)zinc (I) is generated by using
equimolar amounts of reagents, other species, such as II, may be
present.
presence of LiBr (2 equiv) at À788C and À208C furnished 4 in
53% and 76% yields, respectively, but with 0% ee. Presumably,
Lewis acids such as Li+ (and likely Mg2+) are capable of
catalyzing the addition of uncomplexed stannylzinc to aldehydes.
This assertion would explain why reagents generated from
stannyllithium and stannylmagnesium halides were not useful
for asymmetric additions.
[20] E. Erdik, Organozinc Reagents in Organic Synthesis, CRC, Boca
Raton, FL, 1996, chap. 4, pp. 108 – 206.
[21] The absolute configurations of all other adducts were assigned in
analogy. Catalysts 3 and 7 furnished the same major stereoiso-
mer in Table 2, entries 3, 5, 6, and 8.
[22] For example, see: A. Kirschning, J. Harders, Synlett 1996, 772 –
774.
[18] In contrast with our experience, at least one laboratory has
reported transmetalation of trialkylstannyl hydrides with dia-
lkylzinc leads to decomposed products: F. J. A. Des Tombe,
G. J. M. Van Der Kerk, J. Organomet. Chem. 1972, 34, 247 – 252.
[19] It is instructive that similar additions [2, ethyl(tri-n-butylstan-
nyl)zinc (4 equiv), 3 (20 mol%) in DME] when conducted in the
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