Enantioselective synthesis of (E)-δ-silyl-anti-homoallylic alcohols via an enantiodivergent hydroboration-crotylboration reaction of a racemic allenylsilane

Article abstract of DOI:10.1021/ol4004405

The enantioselective hydroboration of racemic allenylsilane (±)-4 with (^dIpc)₂BH proceeds via enantiodivergent pathways to give vinylborane 11 and crotylborane intermediate (S)-E-5. Subsequent crotylboration of aldehyde substrates with (S)-E-5 at -78 C provides (E)-δ-silyl-anti-homoallylic alcohols in 71-89% yield and with 93-96% ee.

Full text of DOI:10.1021/ol4004405

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1662–1665
Enantioselective Synthesis
of (E)‑δ-Silyl-anti-homoallylic Alcohols
via an Enantiodivergent
Hydroboration-Crotylboration Reaction
of a Racemic Allenylsilane
Ming Chen and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received February 15, 2013
ABSTRACT
The enantioselective hydroboration of racemic allenylsilane (()-4 with (dIpc)2BH proceeds via enantiodivergent pathways to give vinylborane 11
and crotylborane intermediate (S)-E-5. Subsequent crotylboration of aldehyde substrates with (S)-E-5 at À78 °C provides (E)-δ-silyl-anti-
homoallylic alcohols in 71À89% yield and with 93À96% ee.
A prevailing approach to the synthesis of chiral, non-
racemic molecules focuses on introducing chirality in
reactions of prochiral substrates using chiral reagents or
chiral catalysts.1 Resolution of racemates, however, re-
mains a valuable tool to access highly enantioenriched
molecules. Amongresolutionstrategies, kinetic resolution2
and dynamic kinetic resolution3 have received consider-
able attention. The enantiodivergent transformation of a
racemate, introduced by Kagan,4 represents another at-
tractive approach to prepare chiral, nonracemic molecules
from racemic starting materials. In contrast to kinetic
resolution and dynamic kinetic resolution, the enantiodi-
vergent transformation of a racemate involves distinct
reactions of each enantiomer of a racemic mixture with a
single enantiomer of a chiral reagent or catalyst that
proceed at comparable reaction rates (KR ≈ KS) to gen-
erate two products that are not enantiomers (Scheme 1).
Several elegant transformations utilizing this strategy have
been reported.5 In our continuing efforts to expand the
scopeof allenehydroboration for thesynthesis offunction-
alized allylboranes,6 we describe here an enantiodivergent
hydroboration of a racemic allenylsilane with the chiral,
nonracemic borane reagent, diisopinocampheylborane
[(dIpc)2BH], by which the two enantiomers of the racemic
allene react efficiently to give two different, nonequilibrat-
ing intermediates. Subsequent reaction of one of the two
(5) For selected examples: (a) Chen, Y.; Deng, L. J. Am. Chem. Soc.
2001, 123, 11302. (b) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.;
Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 930. (c) Davies, H. M. L.;
Walji, A. M. Angew. Chem., Int. Ed. 2005, 44, 1733. (d) Tanaka, K.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 11492. (e) Wu, B.; Parquette, J. R.;
RajanBabu, T. V. Science 2009, 326, 1662.
(6) (a) Chen, M.; Handa, M.; Roush, W. R. J. Am. Chem. Soc. 2009,
131, 14602. (b) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am.
Chem. Soc. 2009, 131, 14174. (c) Ess, D. H.; Kister, J.; Chen, M.; Roush,
W. R. Org. Lett. 2009, 11, 5538. (d) Chen, M.; Ess, D. H.; Roush, W. R.
J. Am. Chem. Soc. 2010, 132, 7881. (e) Stewart, P.; Chen, M.; Roush,
W. R.; Ess, D. Org. Lett. 2011, 13, 1478. (f) Chen, M.; Roush, W. R. Org.
Lett. 2011, 13, 1992. (g) Chen, M.; Roush, W. R. Org. Lett. 2012, 14,
1556. (h) Kister, J.; Nuhant, P.; Lira, R.; Sorg, A.; Roush, W. R. Org.
Lett. 2011, 13, 1868. (i) Han, J.-L.; Chen, M.; Roush, W. R. Org. Lett.
2012, 14, 3028.
(1) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis I-III, Springer: Berlin, 1999. (b) Ojima, I. Catalytic
Asymmetric Synthesis, 2nd ed.; Wiley/VCH: New York, 2000.
(2) For selected reviews on kinetic resolution: (a) Kagan, H. B.;
Fiaud, J. C. In Topics in Stereochemistry; Allinger, A. L., Eliel, E., Eds.;
Wiley: New York, 1988; Vol. 18, p 249. (b) Vedejs, E.; Jure, M. Angew.
Chem., Int. Ed. 2005, 44, 3974.
(3) (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc.
Jpn. 1995, 68, 36. (b) Huerta, F. F.; Minidis, A. B. E.; Backvall, J.-E.
Chem. Soc. Rev. 2001, 321. (c) Trost, B. M.; Fandrick, D. R. Aldrichim.
Acta 2007, 40, 59. (d) Pellissier, H. Tetrahedron 2008, 64, 1563.
(4) Kagan, H. B. Tetrahedron 2001, 57, 2449.
r
10.1021/ol4004405
Published on Web 03/27/2013
2013 American Chemical Society

intermediates with aldehydes provides homoallylic alcohols
in high yields and with excellent enantioselectivity.
58% ee, respectively (entry 1, Table 1). When the hydro-
boration was carried out at 40 °C for 2 h and the resulting
crotylborane was treated with benzaldehyde at À78 °C, a
2:1 mixture of 6a (60% ee) and 7a (50% ee) was obtained in
54% combined yield (entry 2, Table 1). Hydroboration of
(()-4 at higher temperatures (e.g., 60 °C) followed by
crotylboration of benzaldehyde at À78 °C also provided
a 2:1 mixture of 6a and 7a, but the alcohol products were
obtained with much lower enantioselectivity (entry 3,
Table 1). When the hydroboration step was performed at
À20 °C for 8 h followed by crotylboration of benzaldehyde
at À78 °C, a 16:1 mixture of the anti-homoallylic alcohol
6a and syn isomer 7a was obtained in 42% yield and 90%
ee (for 6a, entry 4, Table 1). When the hydroboration of
(()-4 was carried out at À40 °C for 10 h followed by
additionof benzaldehyde atÀ78°C, 6awasobtainedasthe
only product with >95% ee, albeit in diminished yield
(31%), owing to incomplete allene hydroboration under
these conditions (entry 5, Table 1). Interestingly, a ketone
byproduct 8 (ca. 40%) was identified from all of these
reactions. Additionally, treatment of racemic allenylsilane
(()-4 with 0.5 equiv of (dIpc)2BH in toluene at À20 °C for
8 h followed by addition of benzaldehyde (0.45 equiv) at
À78 °C provided alcohol 6a with 92% ee in 58% yield
(based on 0.45 equiv aldehyde) (entry 6, Table 1). Once
again, ketone 8 was detected. The recovered allene 4 was
nearly racemic (<10% ee).
Scheme 1. Enantiodivergent Transformation of a Racemate
We recently reported an enantioselective synthesis of
(E)-δ-stannyl-anti-homoallylic alcohols from racemic alle-
nylstannane (()-1 via an enantioconvergent hydrobora-
tion-crotylboration reaction sequence.7 As illustrated in
Scheme 2, hydroboration of racemic allene (()-1 with
(dIpc)2BH converted both enantiomers of allenylstannane
(()-1 into the same crotylborane intermediate, (S)-E-2.
Subsequent crotylboration of aldehydes with (S)-E-2 gave
homoallylic alcohols 3 in good yields and with excellent
enantioselectivities. We envisioned that an analogous en-
antioconvergent reaction sequence might be applicable to
an environmentally benign alternative, racemic allenylsi-
lane (()-4,8 which would then allow the access to highly
enantioenriched (E)-δ-silyl-anti-homoallylic alcohols 6.
The vinylsilane motif of 6 is as useful for many subsequent
transformations as is the vinylstannane unit of 3.
Table 1. Initial Studies of the Hydroboration-Crotylboration of
Racemic Allenylsilane (()-4a
Scheme 2. Proposed Enantioconvergent Reaction of Racemic
Allenylsilane (()-4
entry t(°C) time (h)
ds
5:1
yield (6a) % eeb yield (7a) % eeb
1
2
3
4
5
6c
0
40
4
2
41%
38%
36%
42%
31%
58%
76
60
7%
16%
16%
2%
58
2:1
2:1
50
60
2
28
24
À20
À40
À20
8
16:1
>20:1
16:1
90
ND
ND
ND
In initial experiments, treatment of racemic allenylsilane
(()-4 with (dIpc)2BH (1 equiv) in toluene at 0 °C for 4 h
followed by addition of benzaldehyde (1 equiv) at À78 °C
provided a 5:1 mixture of anti-homoallylic alcohol 6a and
syn isomer 7a in 41% yield with 76% ee, and 7% yield with
10
8
>95
92
<1%
<1%
a Reactions were performed by treating (()-4 with (dIpc)2BH
(1 equiv, except for entry 6) in toluene followed by the addition of PhCHO
(1 equiv) at À78 °C. The mixture was then allowed to stir at À78 °C for
12 h. The reactions were subjected to a standard workup (NaHCO3,
H2O2) at 0 °C prior to product isolation. b Determined by Mosher ester
analysis.9 c 0.5 equiv of (dIpc)2BH was used for the hydroboration and
0.45 equiv of PhCHO was used for the crotylboration. The enantiomeric
purity of recovered allene (()-4 is less than 10% ee.
(7) (a) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2011, 133, 5744.
For recent synthetic applications of reagent (S)-E-2, see: (b) Sun, H.;
Abbott, J. R.; Roush, W. R. Org. Lett. 2011, 13, 2734. (c) Yin, M.;
Roush, W. R. Tetrahedron 2011, 67, 10274. (d) Chen, M.; Roush, W. R.
Org. Lett. 2012, 14, 426. (e) Chen, M.; Roush, W. R. Org. Lett. 2012, 14,
1880. (f) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 3925. (g)
Chen, M.; Roush, W. R. J. Org. Chem. 2013, 78, 3.
(8) (a) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000, 65, 630. (b)
Fleming, I.; Waterson, D. J. Chem. Soc., Perkin Trans. 1 1984, 1809. (c)
Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc., Perkin Trans. 1
1981, 2527.
Gratifyingly, when the hydroboration of racemic allene
(()-4 was performed using (dIpc)2BH (1 equiv) in toluene
atÀ25°C withwarmingofthe solutiontoÀ15°C, followed
by treatment of the resulting crotylborane (not isolated) with
Org. Lett., Vol. 15, No. 7, 2013
1663

benzaldehyde (0.45 equiv) at À78 °C, homoallylic alcohol
6a was obtained in 85% yield and 95% ee (entry 1, Table 2).
Application of this procedure to a variety of other repre-
sentative achiral aldehydes (entries 3À7, Table 2) provided
homoallylic alcohols 6bÀf in 71À89% yields (based on the
amounts of the aldehydes used in the crotylboration
reactions) and with 93À96% ee. The absolute stereochem-
istry of the secondary hydroxyl groups of alcohols 6aÀf
was assigned by using the modified Mosher ester analysis.9
The olefin geometry of homoallylic alcohols 6aÀf was as-
signed as Ebased on 1H NMR analysis (JE = 18.8À19.2 Hz).
hydroboration of the (P)-enantiomer of allenylsilane 4
with (dIpc)2BH is presumed to be a matched case. Hydro-
boration of (P)-4 with (dIpc)2BH should occur on the re-
face (bottom face, as drawn in the first equation of
Scheme 3) of the methyl substituted allene carbon of (P)-4,
anti to the PhMe2SiÀ group to give intermediate (R)-Z-9,
which can isomerize to crotylborane (S)-E-5 via a reversible
boratropic shift. The face selectivity of this hydroboration
step is consistent with the known enantioselectivity of
hydroboration of (Z)-olefins by (dIpc)2BH.7a,10 Hydro-
boration of (P)-4on the allenyl unit adjacent to the PhMe2Si-
group leads to the diastereomeric reagent (S)-Z-10 (bottom
face hydroboration, as drawn in the second equation of
Scheme 3). Crotylboration of benzaldehyde with (S)-Z-10
would give syn-homoallylic alcohol 7a. However, (S)-Z-10
can undergo a sequence of reversible 1,3-boratropic shifts
to give the diastereomeric reagent (R)-E-5. Crotylboration
of benzaldehyde with (R)-E-5 would give the enantiomeric
alcohol product, ent-6a. The hydroboration pathway illu-
strated in the second equation of Scheme 3 is suppressed
when the hydroboration is performed at low temperature
(e.g., < À20 °C). However, it becomes much more opera-
tional at higher hydroboration temperatures, which corre-
sponds to the reduced diastereoselectivity and reduced
enantioselectivity of the reactions summarized in entries
1À3 of Table 1.
Table 2. Syntheses of (E)-δ-Silyl-anti-homoallylic Alcohols 6a
entry
RCHO
PhCHO
product
yieldb
% eec
1
6a
85%
82%
78%
89%
71%
72%
75%
95
94
95
93
94
95
96
2d
3
PhCHO
ent-6a
6b
PhCHdCHCHO
Ph(CH2)2CHO
CyCHO
4
6c
5
6d
6
TBSO(CH2)2CHO
BnOCH2CHO
6e
On the other hand, hydroboration of the other allene
enantiomer, (M)-4, with (dIpc)2BH is likely stereochemi-
cally mismatched.7a The three hydroboration pathways
illustrated in the fifth line of Scheme 3 are either mis-
matched with respect to the enantiofacial selectivity of
(dIpc)2BH [as determined by the hydroboration of (Z)-
olefins7a,10] or mismatched in that hydroboration occurs
on the sterically disfavored face of the allene, syn to the
PhMe2SiÀ group. Alternatively, the hydroboration could
proceed with opposite regioselectivity, with boron adding
to the central allenyl carbon atom of (M)-4, anti to the
PhMe2Si group to give vinylborane 11, the precursor of
ketone 8 (as drawn in the fourth line of Scheme 3). The
sense of hydroboration in the conversion of (M)-4 to 11 is
consistent withthe knownenantioselectivityofhydrobora-
tion of (Z)-olefins by (dIpc)2BH,7a,10 and is also favored
in that the hydroboration occurs on the less hindered side
of the allene, anti to the distal PhMe2SiÀ group. It appears
that the rates of hydroboration of the two enantiomers of
the racemic allenylsilane (()-4 with (dIpc)2BH are compar-
able (1st and fourth lines of Scheme 3), but also that the
hydroboration proceeds with different modes of addition
to produce two structurally distinct intermediates, (S)-E-5
and 11, respectively.
7
6f
a Reactions were performed by treating (()-4 with (dIpc)2BH
(1 equiv) in toluene at À25 °C and warming to À15 °C over 8 h followed
by the addition of RCHO (0.45 equiv) at À78 °C. The mixture was then
allowed to stir at À78 °C for 12 h. The reactions were subjected to a
standard workup (NaHCO3, H2O2) at 0 °C prior to product isolation.
b Based on the amount of the aldehydes used in the crotylboration
reaction. c Determined by Mosher ester analysis.9 d (lIpc)2BH was used
for the hydroboration reaction.
These results indicate that the hydroboration of the two
enantiomers of racemic allenylsilane (()-4 with (dIpc)2BH
follows different pathways compared to those for the
racemic allenylstannane (()-1. Based on the efficiency of
the reactions of (()-4 and the observed formation of
ketone 8 (Table 1), we speculated that hydroboration of
racemic allenylsilane (()-4 with (dIpc)2BH proceeds in an
enantiodivergent manner. As illustrated in Scheme 3, by
analogy to the hydroboration of allenylstannane (()-1,7a
(9) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(10) (a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 486. (b)
Zweifel, G.; Brown, H. C. J. Am. Chem. Soc. 1964, 86, 397.
(11) For early reports on the syntheses of racemic δ-silyl-homoallylic
alcohols: (a) Yamamoto, Y.; Yatagai, H.; Maruyama, K. J. Am. Chem.
Soc. 1981, 103, 3229. (b) Sato, F.; Uchiyama, H.; Iida, K.; Kobayashi,
Y.; Sato, M. J. Chem. Soc., Chem. Commun. 1983, 921. (c) Tsai, D. J.;
Matteson, D. S. Organometallics 1983, 2, 236. (d) Fugami, K.; Nakat-
sukasa, S.; Oshima, K.; Utimoto, K.; Nozaki, H. Chem. Lett. 1986, 869.
(e) Hodgson, D. M.; Wells, C. Tetrahedron Lett. 1992, 33, 4761. (f)
Shimizu, M.; Kitagawa, H.; Kurahashi, T.; Hiyama, T. Angew. Chem.,
Int. Ed. 2001, 40, 4283. (g) Takeda, T.; Wasa, H.; Tsubouchi, A.
Tetrahedron Lett. 2011, 52, 4575.
To gain support for this analysis, enantiomerically en-
riched (g95% ee) allenylsilanes (P)-4 and (M)-4 were
prepared for use in hydroboration-crotylboration studies.8
(13) For select reviews of Hiyama coupling: (a) Denmark, S. E.; Liu,
J. H.-C. Angew. Chem., Int. Ed. 2010, 49, 2978. (b) Denmark, S. E.;
Sweis, R. F. In Metal Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Chapter 4. (c)
Hiyama, T. In Metal Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 10 and references
cited therein.
(12) (a) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857.
(b) Fleming, I. Org. React. 1989, 37, 57. (c) Fleming, I.; Barbero, A.;
Walter, D. Chem. Rev. 1997, 97, 2063.
1664
Org. Lett., Vol. 15, No. 7, 2013

Scheme 3. Proposed Enantioselective and Enantiodivergent
Hydroboration-isomerization of the Two Enantiomers of the
Racemic Allenylsilane (()-4 with (dIpc)2BH
Scheme 4. Hydroboration-Crotylboration Studies of Single
Enantiomeric Allenylsilanes (P)-4 and (M)-4
signals (<10%) at 5.83 and 5.20 ppm were also observed.
1
In both experiments, H NMR signals corresponding to
(R)-Z-9 or (S)-Z-10 (Scheme 3) were not observed. These
data clearly indicate that the enantioselective hydrobora-
tion of the two enantiomers of the racemic allenylsilane
(()-4 proceed with distinct regioselectivities to give differ-
ent intermediates from each allene enantiomer (P)-4 and
(M)-4. These results are fully consistent with the proposed
enantiodivergent hydroboration pathways for racemic alle-
nylsilane (()-4 depicted in Scheme 3. Additionally, the
efficiency of the reaction as summarized in Table 1 and the
enantiomeric purity (<10% ee) of the recovered allene
(entry 6, Table 1) suggest that the rates of the two hydro-
boration pathways (eqs 1 and 4, Scheme 3) are comparable.
In summary, we have developed an enantioselective
synthesis of (E)-δ-silyl-anti-homoallylic alcohols 6 via an
enantiodivergent hydroboration-crotylboration reaction
sequencethatoriginateswiththehydroborationof racemic
allenylsilane (()-4 with (dIpc)2BH. Under optimized con-
ditions, homoallylic alcohols 611 were obtained in high
yields and with excellent enantioselectivities from racemic
allenylsilane (()-4. Thus, the preparation of enantioen-
riched allenylsilane is not required to produce highly
enantioenriched homoallylic alcohols. In addition, the silyl
substituted olefin unit embedded in the homoallylic alco-
hol products is suitable for use in a variety of subsequent
transformations.12,13Synthetic applications of this metho-
dology will be reported in due course.
As illustrated in Scheme 4, hydroboration of (P)-4 with
(dIpc)2BH at À20 °C for 8 h followed by addition of
benzaldehyde at À78 °C provided homoallylic alcohol 6a
in 80% yield and 95% ee (eq 1). In contrast, when the
identical reaction conditions were used for the hydrobora-
tion of the enantiomeric allene (M)-4 with (dIpc)2BH,
ketone 8 was obtained in 75% yield along with 6% of
alcohol 6a, obtained with 72% ee (eq 2). Thus, the
enantioconvergent hydroboration process that is domi-
nant in the enantioselective hydroboration of racemic
allenylstannane (()-1 is only a minor pathway for the
enantioselective hydroboration of allenylsilane (M)-4 with
(dIpc)2BH that produces crotylborane (S)-E-5 (as drawn in
the third line of Scheme 3); the latter reaction is dominated
by the enantiodivergent hydroboration pathway that leads
to vinylborane 11 (the fourth line of Scheme 3).
Other evidence in support of this analysis was obtained
from 1H NMR studies of the hydroboration reactions of
(P)-4 or (M)-4 with (dIpc)2BH. Hydroboration of (P)-4
with (dIpc)2BH in d8-toluene produced a major product
with two sets of olefinic signals (δ 5.83 ppm, ddq, J = 14.8,
11.2, 1.6 Hz; δ 5.20 ppm, dq, J = 15.2, 6.4 Hz), corre-
sponding to the two (E)-olefinic protons of (S)-E-5. Hy-
droboration of (M)-4 with (dIpc)2BH, however, produced
a major product with a singlet at 5.68 ppm, corresponding
to the olefinic proton of vinylborane 11. Weak olefinic
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) is gratefully
acknowledged. Wethank Eli Lilly for a predoctoral fellow-
ship to M. Chen.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
1665