Enantioselective synthesis of (E)-δ-Stannyl homoallylic alcohols via aldehyde allylboration using α-Stannylallylboranes generated by allene hydroboration followed by a highly diastereoselective 1,3-boratropic shift

Article abstract of DOI:10.1021/ja103041u

A highly enantioselective synthesis of (E)-δ-stannyl homoallylic alcohols 4 via aldehyde allylboration reactions of the double-chiral allylborane reagent 2a is reported. Allylborane 2a was generated from the hydroboration of commercially available allenylstannane 1 with (^dIpc)₂BH at -40 to -20 C followed by a kinetically controlled and highly diastereoselective 1,3-boratropic shift in intermediate 3a.

Full text of DOI:10.1021/ja103041u

Published on Web 05/24/2010
Enantioselective Synthesis of (E)-δ-Stannyl Homoallylic Alcohols via
Aldehyde Allylboration Using r-Stannylallylboranes Generated by Allene
Hydroboration Followed by a Highly Diastereoselective 1,3-Boratropic Shift
Ming Chen, Daniel H. Ess, and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458
Received January 23, 2010; E-mail: roush@scripps.edu
The asymmetric carbonyl allylation reaction is an important
transformation in organic synthesis.1 Although extensive efforts over
the past three decades have provided many useful allylmetal
reagents, new developments in this area continue to emerge.2–6 One
disadvantage of the vast majority of prior allylation methods,
however, is that homoallylic alcohols with terminal vinyl groups
are generated. Several-step manipulations are often required for
further carbon-carbon bond formation at this position.7 Several
procedures exist for synthesis of nonracemic R-substituted allyl-
Figure 1
boron reagents, which undergo aldehyde allylboration reactions to
give products with substituted olefins,1 but such reagents typically
Table 1. Synthesis of δ-Stannyl Homoallylic Alcohols 4 via
require multistep syntheses (e.g., involving the Matteson homolo-
Hydroboration of 1 at -40 to -20 °C (via Kinetically Controlled
gation,8 as in Hall’s recent work5e) and have not been widely
adopted in the literature. An important advance in this area involving
the lithiation-borylation of allylic carbamates has recently been
achieved by Aggarwal.9 Olefin cross-metathesis is one method that
permits a terminal olefin to be modified directly. However, the
efficiency as well as the E/Z selectivity of cross-metathesis depends
on the properties of the olefin metathesis partners.10 Consequently,
olefin metathesis does not provide a general solution to the problem
of synthesis of homoallylic alcohols with substituted alkenes.
Therefore, a simple method that provides direct access to homoal-
lylic alcohols with functionalized olefins is highly desirable. Toward
this end, we have discovered and report herein a direct, one-step,
highly enantioselective synthesis of (E)-δ-stannyl homoallylic
alcohols via an allene hydroboration-aldehyde allylboration sequence.
Allylborane Isomerization)a
entry
RCHO
product
yield
% eeb
1
2
3
4
5
Ph(CH2)2CHO
PhCH2CHO
PhCHO
BnO(CH2)2CHO
BnOCH2CHO
PhCHdCHCHO
CyCHO
t-BuCHO
Ph(CH2)2CHO
Ph(CH2)2CHO
4a
4b
4c
4d
4e
4f
4g
4h
64%
67%
78%
68%
71%
73%
55%
51%
71%
73%
>95
>95
93
>95
>95
>95
92
94
94
30
6
7
8
9c
10d
ent-4a
ent-4a
In connection with an ongoing problem in natural products
synthesis, we explored the hydroboration of allenylstannane 1 with
diisopinocampheylborane [(dIpc)2BH]. In principle, hydroboration
of 1 could provide allylboranes 2 or 3, depending on the hydrobo-
ration regioselectivity and the rate and equilibrium constant for 1,3-
boratropic isomerization in this system.11 On the basis of the ability
of -SnR3 groups to stabilize a ꢀ-carbocation,12 we anticipated that
the formation of allylborane intermediate 2 might be thermody-
namically favored.13 If so, (E)-δ-stannyl homoallylic alcohols 4
would be available following the reaction of 2 with an aldehyde
(Figure 1).
Treatment of allenylstannane 1 at -40 °C with (dIpc)2BH in
diethyl ether, with warming of the solution to -20 °C over 5 h to
complete the hydroboration, followed by treatment of the resulting
allylborane with hydrocinnamaldehyde at -78 °C provided (E)-δ-
stannyl homoallylic alcohol 4a in 64% yield and, remarkably, with
>95% ee (Table 1, entry 1). Application of this procedure to a
variety of other representative aldehydes (Table 1, entries 2-9)
provided homoallylic alcohols 4b-h in 51-78% yield and 92 to
>95% ee (absolute configurations were assigned by Mosher ester
analysis14). The olefin geometry of homoallylic alcohols 4a-h was
E (JE ) 18.8-19.2 Hz); the corresponding Z-olefin isomers as well
as the regioisomeric homoallylic alcohols 5 (or dienes accessible
a Reactions were performed by treatment of 1 with (dIpc)2BH (0.7
equiv) in Et2O at -40 °C and warming to -20 °C over 5 h followed by
the addition of RCHO (0.5 equiv) at -78 °C. The mixture was then
allowed to stir at -78 °C for 8 h. The reactions were subjected to a
standard workup (NaHCO3, H2O2) at 0 °C prior to product isolation.
b Determined by Mosher ester analysis. c (lIpc)2BH was used. d This
reaction was performed by treatment of 1 with (dIpc)2BH (0.7 equiv) in
Et2O at 0 °C followed by addition of RCHO (0.5 equiv) at -78 °C.
by elimination of 5) were not detected in any of the experiments
performed under these conditions.
The enantioselectivity of this sequence proved to be highly
dependent on the experimental conditions. As shown in entry 10
of Table 1, when the hydroboration of 1 was performed at 0 °C
with subsequent addition of hydrocinnamaldehyde at -78 °C, the
enantiomeric homoallylic alcohol ent-4a was obtained in 73% yield
and 30% ee (as measured by Mosher ester analysis14). Similarly,
when the hydroboration step was carried out at -40 °C and the
solution was then allowed to warm to 0 °C, addition of hydrocin-
namaldehyde at -78 °C provided ent-4a in 30% ee and 77% yield.
Here again, products with a (Z)-vinylstannane unit (e.g., 6 in
Scheme 1a) were not detected.
On the basis of recent work on allenylboronate hydroboration,15
the reaction of allenylstannane 1 with (dIpc)2BH would be expected
9
10.1021/ja103041u  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 7881–7883 7881

C O M M U N I C A T I O N S
Scheme 1. Hydroboration of 1 and Allylborane Isomerization Pathways
following three theses: (i) the kinetic mode of hydroboration of 1
is that depicted in Scheme 1a, leading to (Z)-γ-stannylallylborane
3a (the precursor to 5); (ii) the 1,3-boratropic shift of 3a at
temperatures below -20 °C is highly diastereoselective for 2a; and
(iii) the equilibrium constant for the 1,3-boratropic shift is highly
displaced in favor of 2a [and/or 2b, depending on the reaction
temperature (see above)].
The data for the experiment summarized in entry 10 of Table 1
indicate that when the hydroboration of 1 was performed at 0 °C
(or when the product of the hydroboration at -40 to -20 °C was
allowed to warm to 0 °C), a rapid and reversible 1,3-boratropic
shift occurred that gave a thermodynamic mixture of allylboranes
2a and 2b, slightly favoring 2b. Indeed, when the hydroboration
reaction of 1 was monitored at 0 °C, a ∼1:2 mixture of two
1
R-stannyl allylborane species (2a and 2b) was observed via H
NMR spectroscopy (see the SI). Allylborane 2a reacts with
aldehydes via TS-2 to give 4, and 2b reacts via TS-3 to give ent-
4. These data indicate that pseudoequatorial placement of the
R-stannyl unit in TS-3 overrides the enantiofacial selectivity of the
(dIpc)2B- group, which, if dominant, would have dictated the
formation of (Z)-δ-stannyl homoallylic alcohols 6 via TS-4. That
is, the stereodirecting influences of the R-stannylboryl stereocenter
and that of the (dIpc)2B- group are mismatched in 2b, with the
R-stannylboryl stereocenter being the more dominant of the two.
We utilized B3LYP density functional theory (DFT) to explore
the transition states (TSs) of the hydroboration, 1,3-boratropic
rearrangement, and aldehyde allylation steps leading to 4 and ent-4
(with SnBu3 groups modeled as SnMe3).17 As shown in Scheme
1a, the lowest energy pathway17 for hydroboration of 1 proceeds
through TS-1 (∆Hq ) 9.4 kcal/mol) and gives (Z)-δ-stannylal-
lylborane 3a (∆H ) -24.0 kcal/mol) as the kinetic product. These
DFT calculations indicate that hydroboration transition states that
lead directly to 2a and 2b are substantially higher in energy because
of severe congestion between the Bu3Sn and Ipc groups.18 Two
possible concerted diastereomeric 1,3-boratropic shift transition
states lead from 3a to either 2a or 2b. TS-5 (∆Hq ) -5.8 kcal/
mol) is favored over TS-6 (∆Hq ) -3.6 kcal/mol) by 2.2 kcal/
mol because the right-hand isopinocampheyl group is oriented to
place the hydrogen and methylene positions closest to the Bu3Sn
group, while in TS-6 the Bu3Sn group is next to the hydrogen and
large tertiary carbon center (Scheme 1b). The repulsion between
the isopinocampheyl and Bu3Sn groups in TS-6 results in an
asynchronous TS with partial bond lengths of 1.76 and 2.01 Å, in
contrast to the nearly synchronous partial bond lengths in TS-5
(1.88 and 1.82 Å). Finally, allylborations of 2a with aldehyde
substrates provide homoallylic alcohols 4 via TS-2 with pseu-
doequatorial placement of the R-Bu3Sn group.
Double asymmetric allylboration reactions of 2a with chiral alde-
hydes 7 and 8 are shown in Table 2. Hydroboration of allenylstannane
1 with either (dIpc)2BH and (lIpc)2BH at -40 °C (with warming to
-20 °C) followed by addition of aldehyde 7 at -78 °C provided 4i
and 4j, respectively, in 70-75% yield with >50:1 diastereoselectivity,
as determined by 1H NMR analysis (the alternative minor diastereomers
could not be detected in either experiment). Similarly, use of the more
elaborated aldehyde 8 as the substrate provided 4k and 4l, respectively,
in 71-78% yield, again with >50:1 diastereoselectivity (Table 2). The
very high diastereoselectivities of these pairs of double asymmetric
reactions attest to the enantioselectivity of reagent 2a and the remark-
able, highly diastereoselective 1,3-boratropic shift that is involved in
the generation of 2a.
to provide (Z)-γ-stannylallylborane 3a as the kinetic product
(Scheme 1a). If this is the case, the results in Table 1 (entries 1-9)
indicate that 3a undergoes a kinetically controlled and highly
diastereoselective 1,3-boratropic shift at temperatures below -20
°C to give R-stannylallylborane 2a, which then reacts with the
aldehyde at -78 °C to give 4 via the usual chairlike transition state,
TS-2. The E olefin geometry of 4 dictates that the R-stannyl unit
occupies a pseudoequatorial position in TS-2. The absolute con-
figuration of the hydroxyl group of 4 [which we assigned by
conversion of 4 to known compounds or by application of the
modified Mosher method,14 as described in the Supporting Informa-
tion (SI)] is fully consistent with the normal sense of asymmetric
induction by the -B(Ipc)2 unit.16
Support for this analysis was provided by the results of a low-
temperature 1H NMR study of the hydroboration of 1 (see the SI),
which showed that (Z)-3a was present at short reaction times, as
well as by data from an experiment in which the hydroboration of
allenylstannane 1 with (dIpc)2BH was performed at -40 °C for
2 h before addition of hydrocinnamaldehyde at -78 °C. Small
amounts (<5%) of syn-ꢀ-hydroxyallylstannane 5a were isolated
along with recovered allenylstannane 1 and homoallylic alcohol
4a as the major product (the allene hydroboration was not complete
under these conditions). Because neither ꢀ-hydroxyallylstannanes
5 nor the corresponding dienes were observed in any experiments
in which the hydroboration solution was allowed to warm to -20
°C prior to addition of the aldehyde, the results of the -40 °C
hydroboration experiment and the low temperature 1H NMR study
of the hydroboration reaction (see the SI) are consistent with the
In conclusion, we have developed a highly enantioselective
synthesis of (E)-δ-stannyl homoallylic alcohols via aldehyde
allylboration reactions of the double-chiral allylborane reagent 2a.
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C O M M U N I C A T I O N S
Table 2. Double Asymmetric Stannyl Allylboration Reactions with
Aldehydes 7 and 8
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Allylborane 2a is easily generated from the hydroboration of
commercially available allenylstannane 1 with (dIpc)2BH at -40
to -20 °C followed by a kinetically controlled and highly
diastereoselective 1,3-boratropic shift of intermediate 3a. While 1,3-
boratropic shifts, including examples that occur with 1,3-stereo-
chemical transfer, are well-known,3a,11 the discovery of the highly
diastereoselective 1,3-boratropic shift of 3a to 2a was totally
unexpected. To the best of our knowledge, the asymmetric induction
due to the asymmetry of the -B(Ipc)2 group (or any other chiral
dialkylboryl unit) in the conversion of 3a to 2a has not been
previously documented in the literature.3a,11 Subsequent allylbo-
ration reactions of reagent 2a with aldehydes provide homoallylic
alcohols 4 in good yields and with excellent enantioselectivities.
In comparison with conventional allylmetal chemistry, which
typically provides homoallylic alcohols with a terminal olefin unit,
this stannylallylboration reaction is exceptionally valuable in that
it provides homoallylic alcohols with a functionalized olefin unit
that is suitable for use in subsequent C-C bond formations
(numerous examples of which are documented in the literature).19
Applications of this methodology in the synthesis of natural products
will be reported in due course.
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Acknowledgment. Financial support provided by the National
Institutes of Health (GM038436 and GM026782) is gratefully
acknowledged. We thank Professor William A. Goddard III of Cal
Tech for use of his computational facilities and software for some
of these calculations.
(16) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092. (b)
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(17) (a) Jaguar, version 7.5; Schro¨dinger, LLC: New York, 2008. (b) All of
the B3LYP/LACVP** stationary points were confirmed to be minima or
first-order saddle points by full calculation of the Hessian. Standard enthalpy
corrections were applied at 298 K.
(18) TS-1 is 3.3 kcal/mol lower than the TS that gives the corresponding (E)-
δ-stannylallylborane (∆Hq ) 12.7 kcal/mol). Hydroboration TSs that
directly give 2a or 2b are 6-10 kcal/mol higher in energy because of severe
congestion between the Bu3Sn and Ipc groups. See the SI for details.
(19) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina, V.;
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Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds; xyz coordinates and absolute
energies of transition structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
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JA103041U
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