Nonracemic homopropargylic alcohols via asymmetric allenylboration with the robust and versatile 10-TMS-9-borabicyclo[3.3.2]decanes

Article abstract of DOI:10.1021/ol0476164

(Chemical Equation Presented) The asymmetric allenylboration of representative aldehydes with the stable, storable 1 is reported. Easily and efficiently prepared in either enantiomeric form from the air-stable crystalline 4 through simple Grignard procedures, 1 gives 6 cleanly. The latter is easily isolated in high yield and ee with predictable stereochemistry. The procedure also regenerates 4 for its direct conversion back to 1 and facilitates the efficient recovery of the pseudoephedrine. The net process is the synthetic equivalent of the asymmetric addition of allenylmagnesium bromide to aldehydes.

Full text of DOI:10.1021/ol0476164

ORGANIC
LETTERS
2005
Vol. 7, No. 5
799-802
Nonracemic Homopropargylic Alcohols
via Asymmetric Allenylboration with the
Robust and Versatile
10-TMS-9-borabicyclo[3.3.2]decanes†
Chunqiu Lai and John A. Soderquist*
Department of Chemistry, UniVersity of Puerto Rico,
Rio Piedras, Puerto Rico 00931-3346
jas@janice.uprr.pr
Received November 19, 2004
ABSTRACT
The asymmetric allenylboration of representative aldehydes with the stable, storable 1 is reported. Easily and efficiently prepared in either
enantiomeric form from the air-stable crystalline 4 through simple Grignard procedures, 1 gives 6 cleanly. The latter is easily isolated in high
yield and ee with predictable stereochemistry. The procedure also regenerates 4 for its direct conversion back to 1 and facilitates the efficient
recovery of the pseudoephedrine. The net process is the synthetic equivalent of the asymmetric addition of allenylmagnesium bromide to
aldehydes.
Asymmetric allenylboration provides a highly useful route
to nonracemic homopropargylic alcohols. Although less
common than its allylboration counterpart,1 this mechanisti-
cally related SE2′ addition was first reported by H. Yama-
moto, who employed chiral 1,3,2-dioxaborolanes derived
from modified tartrates.2 Corey later introduced vicinal
diamine-based 1,3,2-diazaborolanes from which either B-
allenyl or B-propargyl systems could be prepared from
appropriate organotin precursors. These reagents proved to
be highly effective for both asymmetric allenyl- and prop-
argylboration.3 The Grignard reagent derived from propargyl
bromide is effectively used for the synthesis of these systems,
in the first, to prepare alleneboronic acid and, in the second,
to prepare either the propargyl- or allenyltin precursors to
the B-allenyl- or propargyl-1,3,2-diazaborolanes, respectively.
As illustrated with this second process, the clean formation
of allenylmetallic reagents and their additions to carbonyl
compounds can be quite challenging.4 Both organotin and
silicon derivatives provide useful stoichiometric sources of
† This work is dedicated to the memory of my mentor, the late, great
Professor Herbert C. Brown, whose love of chemistry, standards of
excellence, and levels of accomplishment have been profoundly influential
and inspirational to me and to many others. His passing marks the end of
an era.
(1) (a) Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23-35 and
references therein. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-
2793. (c) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412-
4428 and references therein. (d) Ishiyama, T.; Ahiko, T.; Miyaura, N. J.
Am. Chem. Soc. 2002, 124, 12414-12415. (e) Wada, R.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910-8911. (f) Wu, T.
R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701-2704. (g) Flamme, E.
M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644-13645. (h) Yakelis,
N. A.; Roush, W. R. J. Org. Chem. 2003, 68, 3838-3843. (i) Gung, B.
W.; Xue, X.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 10692-10697.
(j) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 9308-9309. (k)
Morgan, J. B.; Morken, J. P. Org. Lett. 2003, 5, 2573-2575. (l) Barrett, A.
G. M.; Braddock, D. C.; de Koning, P. D.; White, A. J. P.; Williams, D. J.
J. Org. Chem. 2000, 65, 375-380. (m) Barrett, A. G. M.; Beall, J. C.;
Braddock, D. C.; Flack, K.; Gibson, V. C.; Salter, M. M. J. Org. Chem.
2000, 65, 6508-6514.
(2) (a) Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc. 1986, 108,
483-486. (b) Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am.
Chem. Soc. 1982, 104, 7667-7669.
(3) Corey, E. J.; Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112,
878-879.
10.1021/ol0476164 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/01/2005

the allenylmetallic for catalytic asymmetric allenylations.4m,n,s
For organoboranes, Zweifel observed that R-substituted
allenyldialkylboranes undergo a 1,3-boratropic rearrangement
to the propargyl system if the allenylboranes were allowed
to thermally equilibrate at 25 °C.5 However, this rearrange-
ment is not observed for unsubstituted B-allenyl systems,
and isomerically pure B-allenyl-9-BBN is readily prepared,
free of propargylic impurities, from C3H3MgBr and B-Cl-
9-BBN.6 This reagent adds rapidly at -78 °C to both
aldehydes and ketones to give racemic homopropargylic
alcohols exclusively.
Scheme 1
We felt that if more direct access to effective reagents for
asymmetric allenylboration were available, new applications
for the versatile homopargylic alcohols would follow.2,7 The
ideal reagent should be readily available in either enantio-
meric form directly from a simple Grignard procedure. It
should also be easy to isolate in pure form and be a stable
reagent that can be stored indefinitely. The reagent should
also be highly enantioselective, adding rapidly to aldehydes
in a highly predictable manner. Moreover, the allenylboration
procedures with the reagent should also be designed to
recycle the chiral borane moiety by producing the precursor
to this reagent. If this intermediate was also an air-stable
crystalline compound, the difficulties associated with the
handling of air-sensitive organoboranes could be eliminated.
In a general sense, we felt that the reagent should provide
the equivalent of the asymmetric addition of allenylmagne-
sium bromide to aldehydes. Mindful of these goals, we wish
to report the synthesis of the enantiomeric B-allenyl-10-TMS-
9-borabicyclo[3.3.2]-decanes (1) and their use in the asym-
metric allenylboration process.
(4) See, for Mg: (a) Moreau, J.-L.; Gaudemar, M. Bull. Soc. Chim. Fr.
1970, 2171-2174. (b) Moreau, J.-L.; Gaudemar, M. Bull. Soc. Chim. Fr.
1970, 2175. For Li: (c) Corey, E. J.; Rucker, C. Tetrahedron Lett. 1982,
23, 719-722. (d) Wang, K. K.; Nikam, S. S.; Ho, C. D. J. Org. Chem.
1983, 48, 5376-5377. (e) Reich, H. J.; Holladay, J. E.; Walker, T. G.;
Thompson, J. L J. Am. Chem. Soc. 1999, 121, 9769-9780. For Ti: (f)
Furata, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto, H. Bull. Chem.
Soc. Jpn. 1984, 57, 2768. (g) Ishiguro, M.; Ikeda, N.; Yamamoto, H. J.
Org. Chem. 1982, 47, 2225-2227. (h) Keck, G. E.; Krishnamurthy, D.;
Chen, X. Tetrahedron Lett. 1994, 35, 8323-8324. (i) Konishi, S.; Hanawa,
H.; Maruoka, K. Tetrahedron: Asymmetry 2003, 14, 1603-1605. For Zn,
Al: (j) Daniels, R. G.; Paquette, L. A. Tetrahedron Lett. 1981, 22, 1579-
1582. For Zn: (k) Zweifel, G.; Hahn, G. J. Org. Chem. 1984, 49, 4565-
4569. (l) Pearson, N. R.; Hahn, G.; Zweifel, G. J. Org. Chem. 1982, 47,
3364-3366. For Sn: (m) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991,
56, 3211-3213. (n) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55,
6246-6248. (o) Marshall, J. A.; Adams, M. D. J. Org. Chem. 1997, 62,
8976-8977. (p) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199-6200. (q) Roy, S.; Banerjee, M. Org. Lett. 2004, 6, 2137-2140. (r)
Yu, C.-M.; Yoon, S. K.; Back, K.; Lee, J.-Y. Angew. Chem., Int. Ed. 1998.
37, 2392-2395. For Si: (s) Danheiser, R. L.; Carini, D. J. J. Org. Chem.
1980, 45, 3925-3927. (t) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C.
A. J. Org. Chem. 1986, 51, 3870-3878. (u) Nakajima, M.; Saito, M.;
Hashimoto, S. Tetrahedron: Asymmetry 2002, 13, 2449. (v) Kobayashi,
S.; Nishio, K. J. Am. Chem. Soc. 1995, 117, 6392-6393. For B: (w) Farve,
E.; Gaudemar, M. J. Organomet. Chem. 1974, 76, 297-304. (x) Farve, E.;
Gaudemar, M. J. Organomet. Chem. 1974, 76, 305-313. (y) Brown, H.
C.; Khire, U. R.; Narla, G. J. Org. Chem. 1995, 60, 8130-8131. (z) Wang,
K. K.; Nikam, S. S.; Ho, C. D. J. Org. Chem. 1983, 48, 5376-5377. (aa)
Kulkarni, S. V.; Brown, H. C. Tetrahedron Lett. 1996, 37, 4125-4128.
For In: (ab) Loh, T.-P.; Lin, M.-J.; Tan, K.-L. Tetrahedron Lett. 2003, 44,
507-509.
Recently, we described the clean insertion of CHTMS into
a ring B-C bond in 2 by TMSCHN2 (10 h, C6H14, 70 °C)
to afford the very stable B-MeO-10-TMS-9-BBD (3) in 97%
yield after distillation (bp 80 °C, 0.10 mmHg) (Scheme 1).8
Not only is 3 thermally stable, but also it is unusually stable,
for a borinate ester, to the open atmosphere for brief periods
of time (17 h, 3% oxidation). Moreover, 3 is cleanly
converted to (()-1 with allenylmagnesium bromide in ether.
The isolation of (()-1 in pure form is quite simple, involving
only filtration, concentration, and distillation (90%, bp 88-
91 °C, 0.10 mmHg) (Scheme 1).9 To our knowledge, this is
the first time that a chiral allenylborane has been isolated in
pure form.2,3
Compound (()-3 is easily resolved through a modified
version of the Masamune amino alcohol protocol10 employing
0.5 equiv of (1S,2S)-pseudoephedrine (PE) in acetonitrile to
give (+)-4R (38%) as a pure crystalline compound, leaving
(+)-3S in solution. After concentration of the supernatant
to remove the liberated methanol, 0.5 equiv of (1R,2R)-PE
(8) (a) Soderquist, J. A.; Matos, K.; Burgos, C. H.; Lai, C.; Vaquer, J.;
Medina, J. R.; Huang, S. D. In ACS Symposium Series 783; Ramachandran,
P. V., Brown, H. C., Eds.; American Chemical Society: Washington, DC,
2000; Chapter 13, pp 176-194. (b) Burgos, C. H.; Matos, K.; Canales, E.;
Soderquist, J. A. J. Am. Chem. Soc., submitted for publication, Supporting
Information. (c) The upfield 11B NMR signal for 4 exhibits variability with
the concentration of 4.
(5) Zweifel, G.; Backlund, S. J.; Leung, T. J. Am. Chem. Soc. 1978,
100, 5561-5562.
(6) (a) Brown, H. C.; Khire, U. R.; Racherla, U. S. Tetrahedron Lett.
1993, 34, 15. (b) Brown, H. C.; Khire, U. R.; Narla, G.; Racherla, U. S. J.
Org. Chem. 1995, 60, 544-549.
(7) (a) Fryhle, C. B.; Williard, P. G.; Rybak, C. M. Tetrahedron Lett.
1992, 33, 2327-2330. (b) Rao, A. V. Rama; Reddy, S. P. Synth. Commun.
1986, 16, 1149. (c) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999,
121, 11680-11683. (d) See also, for example: Corey, E. J.; Cheng, X.-M.
The Logic of Chemical Synthesis; Wiley: New York, 1989.
(9) We initially investigated several alternative routes to (()-1 including
the B-X-10-TMS-9-BBD (X ) Cl, Br)/allenyltributyltin exchange process
for which the B-Br derivative is successful (CH2Cl2, 25 °C, 28 h).
(10) Short, R. P.; Masamune, S. J. Am. Chem. Soc. 1989, 111, 1892-
1894.
800
Org. Lett., Vol. 7, No. 5, 2005

Scheme 2
Table 1. Allenylboration of RCHO with 1R
6
[R]2D8
(c, MeOH)
(+)-4R
(%)
R
entrya (%)
% eeb (abs conf)
n-Pr
i-Pr
t-Bu
Ph
a
b
c
d
e
f
82 -28.18(2.2)
81 -3.45(1.2)
75 +45.37(1.1)
78 +11.18(1.7)
74 -36.79(2.1)
94 (S)
93 (R)
94 (R)
93 (R)
94 (R)
95 (R)
84
85
80
81
82
80
Vic
2-furyl
80
-6.61(2.4)
a All runs were made in duplicate (at least) and the a series was performed
with both (-)-1R and (+)-1S. (6a′, 80%, 93% ee (R) [R]2D8 ) +28.10 (c
2.2, MeOH)). b Product ee determined by conversion to the Mosher esters
and analysis by 13C and 1H NMR. Absolute configurations were determined
from literature values and by analogy to closely related compounds. c Vi
) vinyl.
1H and 13C NMR analysis of their Mosher esters, 6 was found
to be formed with consistently high enantioselectivity (93-
95% ee).12
was added to a fresh solution of the residue in acetonitrile,
ultimately giving (-)-4S (28%), also as a pure crystalline
compound. The order of addition of the enantiomeric PEs
can be reversed to give, first, (-)-4S and, second, (+)-4R.
In this way, (()-3 is converted into separated enantiomeri-
cally pure components whose combined yield total 66%!
These complexes are air-stable and can be stored indefinitely.
In the solid state, the complex (+)-4R exists as the chelated
form exhibiting both the open and closed forms in solution
(11B NMR (C6D6) δ 55.4, 17.4).7
To demonstrate further the versatility of 1 in the asym-
metric allenylboration process, the enantiomeric reagent 1S
was examined in its addition to n-butyraldehyde to afford
the enantiomeric (+)-6a′ (80%, 93% ee) together with
recovered (-)-4S (84%). This result is consistent with those
obtained from the 1R reagent and demonstrates the versatility
of 1 for the preparation of both enantiomeric forms of 6.
The chemoselectivity of 1 was examined with a 1:1:1
mixture of (()-1, PhCHO, and PhCOCH3 in ether at -78
°C (3 h). Only (()-5d and unreacted PhCOMe were observed
by 1H and 13C NMR. In fact, in a separate experiment, (()-1
failed to react with PhCOMe even at 25 °C for 1 week. Thus,
the bulky 1 is even more aldehyde-selective than is its 9-BBN
counterpart.
In the absence of high-level computational data, simple
MM calculations13 provide useful models for the prediction
of the product stereochemistry through the relative stabilities
of their diastereomeric pre-transition-state complexes. These
calculations reveal that the B-chiral anti-aldehyde complex
that forms cis to the 10-TMS group in the boat-chair form
of 1R (i.e., 7) is consistently favored over any conformation
Clearly, the enantiomerically pure forms of 1 could be
prepared from the optically pure forms of 3. However, a more
direct route to these allenylboranes was found through the
reaction of allenylmagnesium bromide with either (+)-4R
or (-)-4S, which cleanly produces either pure 1R (93%) or
1S (91%), respectively. Thus, despite the presence of the
secondary amine functionality in 4, this Masamune metath-
esis9 is very clean. Moreover, the pseudoephedrine is easily
recovered from the precipitated magnesium salts in 90% yield
(Scheme 2). The reagents 1 can be stored in bulk indefinitely
at -20 °C under a N2 atmosphere for subsequent use in the
asymmetric allenylboration process. The allenylboration of
representative aldehydes with 1R was examined at -78 °C
(3 h) to provide both the corresponding homopropargylic
alcohols 6 (74-82%) and the crystalline (+)-4R (80-85%)
efficiently. The 1R is easily directly regenerated from (+)-
4R through a simple Grignard procedure (>90%) (Scheme
2, Table 1). The six representative substrates examined
include aliphatic (primary, secondary, and tertiary), aromatic,
R,â-unsaturated and heterocyclic aldehydes. The stable
intermediate borinates 5R, which are formed quantitatively
and are easily characterized by NMR, were treated with
(1S,2S)-PE to precipitate crystalline (+)-4R.11 The product
alcohols 6 were obtained through simple distillation. Their
absolute configuration was assigned by comparing the sign
of their optical rotations to reported values.2,4p Through the
of its syn and/or trans counterparts. This leads to the selective
allenylation of the re face of the aldehyde with the 1R
reagent. For 7, the γ-allenylic carbon is within 3.4 Å of the
(12) The C-3 (propargylic) position in the (R)-Mosher chloride-derived
esters of 6 is consistently shifted upfield (∆δ 0.1-0.3) when compared to
those from the enantiomeric alcohols. Other NMR signals were also used
(see Supporting Information).
(11) Attempts to substitute other amino alcohols, such as 2-amino ethanol,
for PE failed to produce a crystalline precipitate.
(13) Performed using the Spartan 4.0.4a GL MM program.
Org. Lett., Vol. 7, No. 5, 2005
801

aldehydic carbon, well positioned for reaching the expected
chairlike transition state. Any attempt to reach an alternative
transition state through rotation about the B-O and B-allenyl
bonds is thwarted by the TMS group, which completely
blocks this pathway. Through an extensive examination of
alternative complexes, the data suggests that the anti-
aldehyde complex that forms trans to the 10-TMS group in
the chair-chair form of 1R (1.3 kcal/mol higher in energy
than 7 (R ) Ph)) is responsible for the formation of the minor
enantiomer of 6 (∼3%).
high ee’s. The allenylation procedure developed for 1
incorporates the regeneration of 4 for its direct conversion
back to 1 through a simple, highly efficient Grignard
procedure that also permits the efficient recovery of the
pseudoephedrine. Through these procedures, the 10-TMS-
9-BBD system orchestrates the equivalent of the asymmetric
addition of allenylmagnesium bromide to aldehydes.
Acknowledgment. The support of the NSF (CHE0217550)
and the NIH SCORE Program (S06GM8102) is gratefully
acknowledged.
In summary, the reagents 1 are easily prepared as stable,
storable chiral allenylboranes in either enantiomeric form in
high yield through simple Grignard procedures that employ
the air-stable crystalline borane complexes 4. In their
allenylborations of aldehydes, the homopropargylic alcohol
products 6 are produced cleanly and are easily isolated in
high yield with predictable stereochemistry and consistently
Supporting Information Available: Full experimental
procedures, characterization data, and selected spectra for
1-6 and derivatives This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0476164
802
Org. Lett., Vol. 7, No. 5, 2005