Diastereo- and enantioselective synthesis of (E)-2-methyl-1,2- syn- and (E)-2-methyl-1,2-anti-3-pentenediols via allenylboronate kinetic resolution with (dIpc)2BH and aldehyde allylboration

Article abstract of DOI:10.1021/ol3010968

Enantioselective hydroboration of racemic allenylboronate (±)-1 with 0.48 equiv of (^dIpc)₂BH at -25 °C proceeds with efficient kinetic resolution and provides allylborane (R)-Z-4. When heated to 95 °C, allylborane (R)-Z-4 isomerizes

Full text of DOI:10.1021/ol3010968

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3028–3031
Diastereo- and Enantioselective Synthesis
of (E)-2-Methyl-1,2-syn- and (E)-2-Methyl-
1,2-anti-3-pentenediols via
Allenylboronate Kinetic Resolution with
(dIpc)2BH and Aldehyde Allylboration
Jeng-Liang Han, Ming Chen, and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received April 24, 2012
ABSTRACT
Enantioselective hydroboration of racemic allenylboronate (()-1 with 0.48 equiv of (dIpc)2BH at À25 °C proceeds with efficient kinetic resolution
and provides allylborane (R)-Z-4. When heated to 95 °C, allylborane (R)-Z-4 isomerizes to the thermodynamically more stable allylborane isomer
(S)-E-7. Subsequent allylboration of aldehydes with (R)-Z-4 or (S)-E-7 at À78 °C followed by oxidative workup provides 1,2-syn- or 1,2-anti-diols, 2
or 3, respectively, in 87À94% ee.
Asymmetric synthesis of chiral, nonracemic molecules is
a major objective of current researchin organic chemistry.1
Because it is generally easier and more cost-effective to
synthesize racemic compounds rather than to perform an
enantioselective synthesis, resolution of racemates remains
a valuable tool to access highly enantiomerically enriched
compounds, especially for the synthesis of ligands or
reagents needed for enantioselective synthetic methods.
Among many available resolution strategies, kinetic reso-
lution of a racemic starting material is a well-established
approach.2 By taking advantage of the different rates of
reaction of each enantiomer of a racemate with a chiral,
nonracemic reagent or catalyst, kinetic resolution enables
partial or complete separation of the racemate and allows
access to a variety of highly enantiomerically enriched
molecules. As part of ongoing studies to expand the scope
of the double allylboration chemistry developed in our
laboratory,3 we describe here the diastereo- and enantio-
selective synthesis of (E)-2-methyl-1,2-syn- and (E)-2-
methyl-1,2-anti-3-pentenediols via the efficient kinetic res-
olution of racemic allenylboronate (()-14 with (dIpc)2BH.
(3) (a) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
13644. (b) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am.
Chem. Soc. 2009, 131, 14174. (c) Kister, J.; Nuhant, P.; Lira, R.; Sorg, A.;
Roush, W. R. Org. Lett. 2011, 13, 1868. (d) Nuhant, P.; Kister, J.; Lira,
R.; Sorg, A.; Roush, W. R. Tetrahedron 2011, 67, 6497. Corrigendum:
Tetrahedron 2012, 68, 774.
(4) Allenylboronates (()-1, (P)-1, and (M)-1 were prepared accord-
ing to the procedure reported by Sawamura and co-workers: (a) Ito, H.;
Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774. (b) Chen,
M.; Roush, W. R. Manuscript submitted.
(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.
r
10.1021/ol3010968
Published on Web 05/30/2012
2012 American Chemical Society

The enantioselective hydroboration of allenes has re-
ceived remarkably little attention until recently.5,6 Caserio
and Moore documented low levels of enantioselectivity
in attempts to accomplish the kinetic resolution of 2,3-
pentadiene via hydroboration with diisopinocampheyl-
borane [(Ipc)2BH].5 More recently, we demonstrated the
remarkable, highly enantioselective and enantioconver-
gent hydroboration of racemic 1-stannyl-1,2-butadiene
by using (dIpc)2BH.6 The latter study prompted us to
explore more broadly the enantioselective hydroboration
of racemic allenes.
In an initial experiment (Scheme 1a), the enantiomeri-
cally enriched allenylboronate (M)-14 (1 equiv, 95% ee)
was treated with (dIpc)2BH (1 equiv) atÀ25 °C followedby
addition of hydrocinnamaldehyde at À78 °C and subse-
quent oxidative workup. This reaction provided the 1,2-
a kinetic resolution manifold to access enantioenriched
1,2-syn-diols 2. Gratifyingly, treatment of allene (()-1 (2.1
equiv) with (dIpc)2BH (1 equiv) at À25 °C for 5 h followed
by the addition of hydrocinnamaldehyde (0.8 equiv) at
À78 °C provided the 1,2-syn-diol 2a in 75% yield with >
20:1 diastereoselectivity and 90% ee after oxidation (entry
1, Table 1). Compared to the results in Scheme 1a, the
erosion of the enantioselectivity (90% vs >95% ee) is
likely due to involvement of minor amounts of allylbor-
anes deriving from the mismatched hydroboration of
allene (P)-1 with (dIpc)2BH. The conditions developed
for the synthesis of 2a were then applied to a variety of
aldehydes; 1,2-syn-diols 2bÀe were obtained in 63À75%
yield with g10:1 diastereoselectivity and 90À94% ee
(entries 3À6, Table 1). The absolute stereochemistry of the
secondary hydroxyl groups of 2aÀe was assigned by using
the modified Mosher ester analysis.8 The syn stereochem-
istry of 2a was assigned by the 1H NOE studies of a derived
acetonide derivative (see Supporting Information (SI)).
Scheme 1. Initial HydroborationÀAllylboration Studies
Table 1. Synthesis of 2-Methyl-1,2-syn-diols 2 via Kinetically
Controlled Hydroboration of (()-1a
entry
RCHO
product
yield
ds
% eeb
1
2
3
4
5
6
Ph(CH2)2CHO
Ph(CH2)2CHOc
BnO(CH2)2CHO
PhCHO
2a
75%
82%
72%
63%
73%
74%
>20:1
>20:1
>20:1
>20:1
>20:1
10:1
90
90
90
93
94
92
ent-2a
2b
2c
CyCHO
2d
PhCHdCHCHO
2e
syn-diol 2a in 88% yield with >20:1 diastereoselectivity
and >95% ee. In contrast, when (M)-1 was treated with
(lIpc)2BH (1 equiv) at À25 °C under otherwise identical
conditions, a 1:1 mixture of 1,2-syn-diol 2a (49% ee) and
1,2-anti-diol 3a (81% ee) was obtained in 12% combined
yield (Scheme 1b).
a Reactions were performed by treating (()-1 (0.87 mmol, 2.1 equiv)
with (dIpc)2BH (1.0 equiv) in toluene at À25 °C for 5 h, followed by
addition of RCHO (0.8 equiv) at À78 °C. The mixture was then allowed
to stir at À78 °C for 4 h. The reactions were subjected to a standard
workup (NaOH, H2O2) at 0 °C prior to product isolation. b Determined
by Mosher ester analysis.8 c (lIpc)2BH was used.
It is apparent from the data in Scheme 1 that the hydro-
boration of enantioenriched allene (M)-1 with (dIpc)2BH is
most probably a matched double asymmetric reaction,
while the hydroboration of (M)-1 with (lIpc)2BH is likely a
mismatched case.7 It is also apparent that the rates of the
hydroboration reactions of allenylboronate (M)-1 with
(dIpc)2BH and (lIpc)2BH are quite different. These data
suggested that it might be possible to effect the enantiose-
lective hydroboration of racemic allenylboronate (()-1 in
Consistent with our previous studies of allene hydro-
boration,6,11 the results in Table 1 suggest that hydrobora-
tion of allenylboronate (M)-1 with (dIpc)2BH at À25 °C
proceeds via TS-1 to produce the γ-boryl-(Z)-allylborane
(R)-Z-4 (Scheme 2). Allylboration of aldehydes with (R)-
Z-4 at À78 °C then provides boronate intermediate 5 via
the chairlike transition state TS-2.9 Compared to dialkyl-
allylborane (R)-Z-4, the remaining allenylboronate (P)-1
(5) (a) Waters, W. L.; Caserio, M. C. Tetrahedron Lett. 1968, 5233.
(b) Moore, W. R.; Anderson, H. W.; Clark, S. D. J. Am. Chem. Soc.
1973, 95, 835.
(8) (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.
(6) (a) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2011, 133, 5744.
For recent synthetic applications 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.
(7) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(9) (a) Roush, W. R. In Comprehensive Organic Synthesis; Trost,
B. M., Ed. Pergamon Press: Oxford, 1991; Vol. 2, p 1. (b) Yamamoto,
Y.; Asao, N. Chem. Rev. 1993, 93, 2207. (c) Denmark, S. E.; Almstead,
N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; p 299. (d) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763. (e) Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1. (f) Yus,
ꢀ
ꢀ
M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
Org. Lett., Vol. 14, No. 12, 2012
3029

and boronate intermediate 5 are much less reactive toward
aldehyde addition. Therefore, products deriving from
reactions of these intermediates with aldehydes were not
observed. Subsequent oxidation of 5 under standard con-
ditions gives the isolated 1,2-syn-diols 2.
Table 2. Synthesis of 2-Methyl-1,2-anti-diols 3 via Thermody-
namically Controlled Hydroboration of (()-1a
Scheme 2. Proposed Kinetic Hydroboration of (M)-1 and
Allylboration of (R)-Z-4 with Aldehydes
entry
RCHO
product
yieldb
ds
% eec
1
2
3
4
5
6
Ph(CH2)2CHO
BnOCH2CHO
BnO(CH2)2CHO
PhCHO
3a
3b
3c
3d
3e
3f
89%
52%
84%
80%
87%
86%
1:7
87
90
92
88
90
87
1:7
1:10
1:10
1:6
CyCHO
PhCHdCHCHO
1:15
a Reactions were performed by treating (()-1 (0.44 mmol, 2.1 equiv)
with (dIpc)2BH (1.0 equiv) in toluene at À25 °C for 5 h and heating at 95 °C
for 1.5 h, followed by the addition of RCHO (0.8 equiv) at À78 °C.
The mixture was then allowed to stir at À78 °C for 4 h. The reactions
were subjected to a standard workup (NaOH, H2O2) at 0 °C prior to
product isolation. b Combined yield of 2 and 3. c Determined by Mosher
ester analysis.8
It has been demonstrated11a that the kinetically gener-
ated γ-boryl-(Z)-allylboranes isomerize to the thermody-
namically more stable γ-boryl-(E)-allylboranes via re-
versible 1,3-boratropic shifts.10,11 Accordingly, we antici-
pated that allylborane (S)-E-7 could be obtained from
(R)-Z-4 under thermodynamically controlled isomeriza-
tion conditions, which would permit access to 1,2-anti-
diols 3. Indeed, when the hydroboration of allenylboro-
nate (()-1 with (dIpc)2BH was performed at À25 °C for 5 h
followed by heating the solution of (R)-Z-4 at 95 °C for
1.5 h and treatmentofthe resulting allylborane with hydro-
cinnamaldehyde atÀ78 °C, a 1:7 mixture of 1,2-syn-diol 2a
and 1,2-anti-diol 3a (87% ee) was obtained in 89% com-
bined yield after oxidative workup. Similar results were
obtained when the isomerization was carried out at
higher temperatures. The hydroborationÀisomerizationÀ
allylboration reaction sequence was applied to a variety of
aldehydes (Table 2); 1,2-anti-diols 3bÀf were obtained in
52À87% yield with synthetically useful diastereoselectivity
(dsg 6:1) and 87À92%ee. The absolutestereochemistry of
the secondary hydroxyl group of 3aÀf was assigned by
using the modified Mosher ester analysis.8 The anti stereo-
Scheme 3. Proposed Thermodynamically Controlled Isomeri-
zation and Allylboration of (S)-E-7 with Aldehydes
1
chemistry of 3a was assigned by H NOE studies of the
derived acetonide derivative (see SI).
As illustrated in Scheme 3, we postulate that kinetic
hydroboration of allenylboronate (M)-1 with (dIpc)2BH
at À25 °C initially generates allylborane (R)-Z-4, which
isomerizes at 95 °C to the thermodynamically more stable
allylborane (S)-E-7 via the intermediacy of the 1,1-diboryl
species 6. Allylboration of aldehydes with (S)-E-7 at
À78 °C proceeds via the chairlike transition state TS-3 to
give the boronate 8. Subsequent oxidation of 8 gives 1,2-
anti-diols 3. Based on these considerations, it is readily
apparent that the absolute configuration of the secondary
alcohol of 3 is controlled by the R-boryl stereocenter of (S)-
E-7, since the re-face addition to the aldehyde in TS-3 is
opposite to that expected based on the known enantio-
selectivity of the (dIpc)2B- unit.12 By comparison, the
relative disposition of the aldehyde and the crotyl unit of
(10) (a) Hancock, K. G.; Kramer, J. D. J. Am. Chem. Soc. 1973, 95,
6463. (b) Kramer, G. W.; Brown, H. C. J. Organomet. Chem. 1977, 132,
9. (c) Henriksen, U.; Snyder, J. P.; Halgren, T. A. J. Org. Chem. 1981, 46,
3767. (d) Fang, G. Y.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2007, 46,
ꢀ
359. (e) Canales, E.; Gonzalez, A. Z.; Soderquist, J. A. Angew. Chem.,
Int. Ed. 2007, 46, 397. (f) Gonzalez, A. Z.; Roman, J. G.; Alicea, E.;
Canales, E.; Soderquist, J. A. J. Am. Chem. Soc. 2009, 131, 1269.
(11) For recent studies from our group, see ref 6 and: (a) Chen, M.;
Handa, M.; Roush, W. R. J. Am. Chem. Soc. 2009, 131, 14602. (b) Ess,
D. H.; Kister, J.; Chen, M.; Roush, W. R. Org. Lett. 2009, 11, 5538. (c)
Chen, M.; Ess, D. H.; Roush, W. R. J. Am. Chem. Soc. 2010, 132, 7881.
(d) Stewart, P.; Chen, M.; Roush, W. R.; Ess, D. Org. Lett. 2011, 13,
1478. (e) Chen, M.; Roush, W. R. Org. Lett. 2011, 13, 1992.
(12) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
2092. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
3030
Org. Lett., Vol. 14, No. 12, 2012

(S)-E-7 in the competing transition state TS-4 is consistent
with asymmetric induction derived from the (dIpc)2B-
unit;12 however, significant A1,3 interactions13 develop
between the two methyl groups of the crotyl unit (shown
in red in TS-4). We conclude that the unfavorable A1,3
interaction in TS-4 is sufficiently large to override the
enantioselectivity of the (dIpc)2B- auxiliary.
Scheme 5. Evidence in Support of a Kinetic Resolution of (()-1
with (dIpc)2BHa
The mismatched hydroboration reaction of allenylboro-
nate (M)-1 with (lIpc)2BH (Scheme 1b) must generate
two diastereomeric allylboranes (R)-Z-9 and (S)-E-10, in
order to explain the formation of a mixture of alcohols 2
and 3 in 12% yield (Scheme 4). The low efficiency is
presumably due to the fact that the hydroboration path-
Scheme 4. Mismatched Hydroboration of (M)-1 with (lIpc)2BH
a The enantiomeric purity and absolute configuration (P)-1 was
determined following its reaction with hydrocinnamaldehyde, as de-
scribed in the SI.
(Scheme 5b). The enantiomeric purity of the remaining
allene (P)-1 in these experiments was determined by the
reaction of this species with hydrocinnamldehyde, as
described in the SI. The results presented in Scheme 5,
together with the data presented in Tables 1 and 2, support
our conclusion that an efficient kinetic resolution indeed
occurs when racemic allenylboronate 1 is treated with
0.45À0.55 equiv of (dIpc)2BH.
ways involved in these reactions are either mismatched
with the known enantioselectivity of (lIpc)2BH (as inferred
from the hydroboration of (Z)-olefins)14 or mismatched
with respect to the preference of allene hydroboration to
occur anti to bulky substituents at the distal position.10f,11
These stereochemical mismatches provide the basis to
rationalize that the rate of mismatched hydroboration of
(M)-1 with (lIpc)2BH at À25 °C is slow. This then enables
kinetic resolution to occur in the enantioselective hydro-
boration of the racemic allenylboronate (()-1 using
(dIpc)2BH at this temperature.
To obtain further evidence that a kinetic resolution
process is indeed involved in this reaction sequence, addi-
tional studies to determine the enantiomeric excess of the
remaining allenylboronate (P)-1 were carried out as sum-
marized in Scheme 5. Under kinetic hydroboration con-
ditions using 1.8 equiv of racemic 1 under conditions
described in Table 1, the enantiomeric excess of the
remaining allenylboronate (P)-1 was determined to be
79% ee (Scheme 5a). When the hydroboration was per-
formed with 2.0 equiv of racemic 1 under the thermody-
namically controlled isomerization conditions as described
in Table 2 using 2.0 equiv of racemic 1, the enantiomeric
excess of the remaining allenylboronate (P)-1 was 55% ee
In summary, we demonstrate that efficient kinetic reso-
lution of racemic allenylboronate (()-1 with 0.48 equiv of
(dIpc)2BH at À25 °C provides the allylborane (R)-Z-4.
Subsequent allylboration of aldehydes with (R)-Z-4
at À78 °C followed by oxidation gives 1,2-syn-diols 2
in 63À82% yield with g10:1 diastereoselectivity and
90À94% ee. Allylborane (R)-Z-4 isomerizes to the ther-
modynamically more stable allylborane (S)-E-7 when
heated to 95 °C. Allylboration of aldehydes with (S)-E-7
provides 1,2-anti-diols 3 in 52À89% yield with syntheti-
cally useful diastereoselectivity (ds g6:1) and 87À92% ee.
Synthetic applications of this methodology will be re-
ported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) is gratefully
acknowledged. Wethank Eli Lilly for a predoctoral fellow-
ship to M.C. and the National Science Council, Taiwan for
providing a postdoctoral fellowship to J.L.H. (NSC98-
2917-I-564-141).
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.
(13) Hoffman, R. W. Chem. Rev. 1989, 89, 1841.
(14) (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.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
3031