Chiral synthesis via organoboranes. 47. Efficient synthesis of unsymmetrical ketones and enantiomerically pure spiroketals using (±)-isopinocampheyldichloroborane

Article abstract of DOI:10.1021/jo980989w

Readily prepared and stable (±)-isopinocampheyldichloroborane [(±)-IpcBCl₂] was conveniently used for the stepwise hydroboration of two different alkenes using the in situ reduction-hydroboration protocol to give mixed trialkylboranes, IpcBR'R2. Convenient elimination of α-pinene from these trialkylboranes by treatment with an aldehyde, RCHO, provided the borinate ester, R¹R²BOCH₂. This intermediate was readily converted into the unsymmetrical ketones, R¹OR₂, in high yields and purity, by an established method. This methodology was successfully applied to the synthesis of enantiomerically pure spiroketals using optically pure TBS ether protected homoallylic alcohols as the alkenes for stepwise hydroboration.

Full text of DOI:10.1021/jo980989w

7030
J . Org. Chem. 1998, 63, 7030-7036
Ch ir a l Syn th esis via Or ga n obor a n es. 47. Efficien t Syn th esis of
Un sym m etr ica l Keton es a n d En a n tiom er ica lly P u r e Sp ir ok eta ls
Usin g (()-Isop in oca m p h eyld ich lor obor a n e
Herbert C. Brown,* Shekhar V. Kulkarni,1a Uday S. Racherla,1b and Ulhas P. Dhokte1c
H. C. Brown and R. B. Wetherill Laboratories of Chemistry, 1393 Brown Building, Purdue University,
West Lafayette, Indiana 47907
Received May 26, 1998
Readily prepared and stable (()-isopinocampheyldichloroborane [(()-IpcBCl2] was conveniently used
for the stepwise hydroboration of two different alkenes using the in situ reduction-hydroboration
protocol to give mixed trialkylboranes, IpcBR1R2. Convenient elimination of R-pinene from these
trialkylboranes by treatment with an aldehyde, RCHO, provided the borinate ester, R1R2BOCH2R.
This intermediate was readily converted into the unsymmetrical ketones, R1COR2, in high yields
and purity, by an established method. This methodology was successfully applied to the synthesis
of enantiomerically pure spiroketals using optically pure TBS ether protected homoallylic alcohols
as the alkenes for stepwise hydroboration.
Ch a r t 1
Spiroketals occur widely as part of naturally occurring
substances from many sources, including insects, mi-
crobes, plants, fungi, and marine organisms.2 The broad
spectrum of biological activities possessed by compounds
containing spiroketal assemblies has generated great
interest in their synthesis and reactivity in recent years.3
One group of compounds which contains the spiroketal
skeleton belongs to the important class of insect phero-
mones. Many of them contain either a spiro[5.5], -[5.4],
or -[4.4] ring system and have unbranched carbon chains
on the carbon atom adjacent to the ring oxygen (1-6,
Chart 1).4
A number of synthetic strategies have been developed
for the synthesis of such enantiomerically pure spiroket-
als. Among the more common ones are the 1,3-dithiane
riveting approach,3a,h,5 addition of optically pure nucleo-
philes to optically pure lactones,6 alkylation of cyclic vinyl
ethers,3g,i,7 and enolate-carbonyl (aldol) condensations.3d,f,8
However, many of these approaches involve a large
number of steps in which the intermediates are often
obtained in low enantiomeric purities leading to a
complicated mixture of products at the end. In this
paper, we report the development of an efficient stepwise
hydroboration methodology based on the use of readily
prepared and stable (()-IpcBCl2 for the synthesis of
unsymmetrical ketones and enantiomerically pure spiro-
ketals.
(1) (a) Present address: Bayer Corp., 8400 Hawthorn Rd., P.O. Box
4913, Kansas City, MO 64120-0013. (b) Present address: Unilever
Research U.S. Inc., 45 River Rd., Edgewater, NJ 07020. (c) Present
address: Bristol-Myers Squibb Co., Pharmaceutical Group, P.O. Box
4755, Syracuse, NY 13221-4755.
Resu lts a n d Discu ssion
(2) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.
During the past decade we have developed several
terpene-derived asymmetric allyl- and crotylborating
reagents [Ter2BAll, Ter2BCrtZ, and Ter2BCrtE, Ter ) dIpc
(3) For example: (a) Khandekar, G.; Robinson, G. C.; Stacey, N. A.;
Thomas, E. J .; Vather, S. J . Chem. Soc., Perkin Trans. 1 1993, 1507.
(b) Rychnovsky, S. D.; Griesgraber, G. J . Chem. Soc., Chem. Commun.
1993, 291. (c) Diez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani,
S.; Menendez, J . C.; Organ, H. M.; White, A. D. Tetrahedron 1992, 48,
7899. (d) Evans, D. A.; Gage, J . R. J . Org. Chem. 1992, 57, 1958. (e)
Evans, D. A.; Rieger, D. L.; J ones, T. K.; Kaldor, S. W. J . Org. Chem.
1990, 55, 6260. (f) Walba, D. M.; Thurmes, W. N.; Haltiwanger, R. C.
J . Org. Chem. 1988, 53, 1046. (g) Boeckman, R. K.; Charette, A. B.;
Asberom, T.; J ohnston, B. H. J . Am. Chem. Soc. 1987, 109, 7553. (h)
Merifield, E.; Steel, P. G.; Thomas, E. J . J . Chem. Soc., Chem. Commun.
1987, 1826. (i) Kocienski, P. J .; Yeates, C.; Street. S. D. A.; Campbell,
S. F. J . Chem. Soc., Perkin Trans. 1 1987, 2183.
(4) (a) Baker, R.; Bacon, A. J . Experentia 1985, 41, 1484. (b)
Bergstrom, G.; Tengo, J .; Reith, W.; Francke, W. Z. Naturforsch. 1982,
37c, 1124. (c) Francke, W.; Reith, W.; Bergstrom, G.; Tengo, J . Z.
Naturforsch. 1981, 36c, 928. (d) Francke, W.; Heeman, V.; Gerken, B.;
Renwick, J . A. A.; Vite, J . P. Natuwissenschaften 1977, 64, 590.
(5) (a) Park, P.-U.; Broka, C. A.; J ohnson, B. F.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 6205. (b) Nakahara, Y.; Fujita, A.; Beppu, K.;
Ogawa, T. Tetrahedron 1986, 42, 6465. (c) Williams, D. R.; Sit, S.-Y.
J . Am. Chem. Soc. 1984, 106, 2949. (d) Mori, K.; Watanabe, H.
Tetrahedron Lett. 1984, 25, 6025. (e) Schreiber, S. L.; Sommer, T. J .
Tetrahedron Lett. 1983, 24, 4781.
(6) (a) Baker, R.; Head, J . C.; Swain, C. J . J . Chem. Soc., Perkin
Trans. 1 1988, 85. (b) Baker, R.; Boyes, R. H. O.; Broom, M. P.;
O’Mahoney, M. J .; Swain, C. J . J . Chem. Soc., Perkin Trans 1 1987,
1613. (c) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.; Richardson,
G.; Walshe, N. G. E. J . Org. Chem. 1986, 51, 4840. (d) Smith, A. B.;
Thompson, A. S. J . Org. Chem. 1984, 49, 1469. (e) J acobson, R.; Taylor,
R. J .; Williams, H. J .; Smith L. R. J . Org. Chem. 1982, 47, 3140. (f)
Smith, L. R.; Williams, H. J .; Silverstein, R. M. Tetrahedron Lett. 1978,
3231.
(7) (a) Chavdarian, C. G.; Chang, L. L.; Onisko, B. C. Heterocycles
1988, 27, 651. (b) Kocienski, P. J .; Yeates, C.; Street, S. D. A.; Campbell,
S. F. J . Chem, Soc., Perkin Trans 1 1987, 2191. (c) Kocienski, P. J .;
Yeates, C. J . Chem. Soc., Chem. Commun. 1984, 151. (d) Kocienski,
P. J .; Yeates, C. Tetrahedron Lett. 1983, 24, 3905.
(8) (a) Evans, D. A.; Gage, J . R. Tetrahedron Lett. 1990, 31, 6129.
(b) Burke, S. D.; Cobb, J . E.; Takeuchi, K. J . Org. Chem. 1985, 50,
3440. (c) Collum, D. B.; McDonald, J . H., III; Still, W. C. J . Am. Chem.
Soc. 1980, 102, 2117. (d) Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi,
Y. J . Am. Chem. Soc. 1979, 101, 259.
S0022-3263(98)00989-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/15/1998

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 63, No. 20, 1998 7031
Sch em e 1
Our next goal was to find a suitable stepwise hydrobo-
rating agent which would permit the clean stepwise
hydroboration of two different TBS-protected homoallylic
alcohols without cleavage of the protecting groups, giving
high yields of the corresponding ketones with minimum
scrambling.13 The dibromoborane reagent BHBr2‚SMe2
has been reported14 as such a stepwise hydroborating
agent for the preparation of unsymmetrical ketones from
two different terminal alkenes. However, the harsh
nature of this reagent made it unsuitable for the present
case. Thexylchloroborane (in which thexyl group serves
as the anchor group) has been used in some cases for
stepwise hydroboration of functionalized alkenes.15 How-
ever, it too suffers from certain disadvantages in the
present application. For example, one of the ways to
convert the B-thexyl group into the carbonyl group
requires carbonylation under high pressures and tempera-
tures.10a Another way to achieve this conversion is to use
the cyanidation reaction,10d which requires rigorously dry
cyanide and fails to proceed in the presence of Li or Mg
salts.10b Similarly, triisopropylphenylborane (TripBH2)16
suffers from the disadvantage that multiple steps are
required for its preparation.
(isopinocampheyl); lIpc, 4-dIcr (derived from (+)-3-carene),
and 2-dIcr (derived from (+)-2-carene)] which can achieve
the synthesis of a wide variety of homoallylic alcohols 7
During the past several years, we have developed
several valuable reagents based on R-pinene as the chiral
auxiliary.17 Some of these reagents include Ipc2BH,
IpcBH2, Ipc2BAll, and Ipc2BCl (Ipc ) isopinocampheyl).
Recently, we have demonstrated the remarkable effect
of an ether solvent in the reduction of IpcBCl2 with Me3-
SiH (1 equiv each).18 For example, the reaction of
equivalent amounts of IpcBCl2 with Me3SiH in the
presence of 2-methyl-2-butene (1 equiv) at 0 °C was
complete in only 15 min in ether to give clean dialkyl-
chloroborane 12 (eq 1), while the same reaction carried
with enantio- and diastereoselectivities approaching
100%.9 Therefore, we envisaged a synthetic plan which
takes advantage of the ready availability of these alcohols
to develop a simple methodology for the synthesis of
spiroketals in high optical purity.
Our basic approach is outlined in Scheme 1. Stepwise
hydroboration of two different protected homoallylic
alcohols using a suitable stepwise hydroborating agent
would give a trialkylborane intermediate 9 which could
be converted into ketone 10 using one of the known
methods.10 Deprotection of the two hydroxyl moieties
would lead to a dihydroxy ketone which cyclizes sponta-
neously into spiroketals 11. Therefore, we expected that
by starting with the correct configurations of the homoal-
lylic alcohols and carrying out the deprotection under
acidic conditions, the spiroketal would be formed under
thermodynamic control with the same configuration at
the spiro carbon as that present in the natural product.
The first objective was to select a protecting group for
the homoallylic alcohols which would not interfere with
the hydroboration, as well as be stable to the reaction
conditions of the subsequent steps. Moreover, it should
be possible to remove it, in the last step, under the mild
acidic conditions necessary for the equilibration of the
spiroketal. We first decided to investigate tert-butyldi-
methylsilyl (TBS) ether as the protecting group since it
can be readily removed quantitatively under mild acidic
conditions (aqueous HF in CH3CN).12
out in pentane required almost 2 days for completion.18
This result contrasts strongly with the hydroboration
characteristics of the thexylchloroborane-dimethyl sul-
fide complex (ThxBHCl‚SMe2), which requires 1 h at 25
°C even with monosubstituted terminal olefins.19
On the basis of these observations, we decided to
investigate the possibility of using (()-IpcBCl2 for the
stepwise hydroboration in this study.20 It was expected
that the second hydroboration would be achieved by
(13) While this work was in progress Pelter et al. reported the use
of mesityleneborane (MesBH2) as a stepwise hydroborating agent.
See: Smith, K.; Pelter, A.; J in, Z. Angew, Chem., Int. Ed. Engl. 1994,
33, 851.
(14) Kulkarni, S. U.; Basavaiah, D.; Zaidlewicz, M.; Brown, H. C.
Organometallics 1982, 1, 212.
(9) Racherla, U. S.; Brown, H. C. J . Org. Chem. 1991, 56, 401 and
references therein.
(10) (a) Brown, H. C.; Rathke, M. W. J . Am. Chem. Soc. 1967, 89,
2738. (b) Brown, H. C.; Negishi, E. J . Am. Chem. Soc. 1967, 89, 5285.
(c) Carlson, B. A.; Brown, H. C. J . Am. Chem. Soc. 1973, 95, 6876. (d)
Pelter, A.; Smith, K.; Hutchings, M. G.; Rowe, K. J . Chem. Soc., Perkin
Trans. 1 1975, 129.
(11) Deslongchamps, P.; Rowan, D. D.; Pothier, N,; Sauve, T.;
Saunders: J . K. Can. J . Chem. 1981, 59, 1105.
(12) (a) Protective Groups in Organic Synthesis, 2nd ed.; Greene, T.
W., Wuts, P. G. M., Eds.; J ohn Wiley and Sons: New York, 1991. (b)
Kocienski, P. J ., Protective Groups; Georg Thieme Verlag: Stuttgart,
New York, 1994.
(15) (a) Brown, H. C.; Racherla, U. S.; Singh, S. M. Synthesis 1984,
923. (b) Zweifel, G.; Pearson, N. R. J . Am. Chem. Soc. 1980, 102, 5920.
(c) Kulkarni, S. U.; Lee, H. D.; Brown, H. C. J . Org. Chem. 1980, 45,
4543.
(16) Smith, K.; Pelter, A. J in, Z. J . Chem. Soc., Perkin Trans. 1 1993,
395.
(17) Brown, H. C.; Ramachandran, P. V. In Advances in Asymmetric
Synthesis; Hassner, A., Ed.; J ai Press: Greenwich, CT, 1995; Vol. 1,
pp 147-210.
(18) Dhokte, U. P.; Kulkarni, S. V.; Brown, H. C. J . Org. Chem. 1996,
61, 5140.
(19) Brown, H. C.; Sikorski, J . A.; Kulkarni, S. U.; Lee, H. D. J .
Org. Chem. 1982, 47, 863.

7032 J . Org. Chem., Vol. 63, No. 20, 1998
Brown et al.
Sch em e 2
hydridation of the dialkylchloroborane (formed in the first
step) in the presence of the second olefin.21 Moreover,
on the basis of our previous studies, it was expected that,
after the stepwise hydroboration of two different alkenes,
the trialkylborane could be readily and quantitatively
converted into a borinate by elimination of R-pinene by
treatment with an aldehyde.22 The dialkylborinates
could then be converted into the corresponding unsym-
metrical ketones via the DCME reaction, which generally
proceeds in high yield and is not very susceptible to
reaction conditions.10c
(()-IpcBCl2 (δ 62, 11B NMR) was conveniently prepared
in essentially quantitative yield in one step from (R-
pinene and BCl3 using Me3SiH.23 It showed no detectable
change in 1H and 13C NMR, even at room temperature
when stored under nitrogen for 4 months.
To test the feasibility of this approach and to standard-
ize the reaction conditions, we decided to try the reactions
first with the simple terminal alkenes 1-octene and
1-hexene. As expected, the in situ reduction-hydrobo-
ration reaction of (()-IpcBCl2 with 1.0 equiv of Me3SiH
in ether in the presence of 1 equiv of 1-octene was quite
fast, complete in less than 2 min at 0 °C. However, the
required dialkylchloroborane 13 (δ 76, 11B NMR) was
contaminated with about 5% each of the trialkylborane
14 (δ 83, 11B NMR) and (()-IpcBCl2 (eq 2).
the presence of the second alkene to minimize the amount
of scrambling, which otherwise ultimately leads to sig-
nificant contamination of the required unsymmetrical
ketone by the symmetrical ketone.21 We investigated this
hydridation step in the presence of a slight excess (1.05
equiv) of 1-hexene at various temperatures (-25 °C, 0
°C, room temperature) and in different solvents (ether,
pentane, ether-pentane) to find conditions which would
provide a minimum of scrambling.25 From this study it
was found that simply adding 1.3 times the theoretical
amount (i.e. 1.3 × 0.25 equiv) of LAH (as a 1.0 M solution
in ether) to the reaction mixture of the first hydroboration
step in the presence of 1.05 equiv of 1-hexene at 0 °C
gave the clean trialkylborane 15.
The reason for adding 1.3 times the theoretical amount
of LAH is the fact that Me3SiCl formed in the first step
also reacts with LAH but at much slower rate than that
of the dialkylchloroborane. Thus, not removing the Me3-
SiCl from the reaction mixture prior to the hydridation
step has two advantages: (i) It simplifies the experimen-
tal procedure since the time required for its evaporation
from the reaction mixture is saved, and (ii) it reacts with
any excess LAH added, preventing the decomposition of
required trialkylborane to dialkylboranes and borohy-
drides. After the hydridation step, the residual Me3SiCl
(bp 57 °C), Me3SiH (bp 7 °C), and solvents were readily
removed to give trialkylborane 15 along with a white
precipitate of AlCl3 and LiCl (Scheme 2).
The elimination of R-pinene from trialkylboranes of the
type 15 to give dialkylborinates 16 has earlier been
studied with various aldehydes.26 For the present study,
we chose isobutyraldehyde since (i) it reacts faster than
other aldehydes such as acetaldehyde, (ii) it would
ultimately lead to isobutanol which could be readily
separated from the products either by distillation or by
washing with water, and (iii) it provided a slightly more
hindered borinate as compared to that with acetaldehyde
or benzaldehyde. It is known that, for a borinate having
less hindered alkyl groups, the yield achieved in the
DCME reaction increases with increase in the steric bulk
of the alkoxy group.10c The elimination of R-pinene with
Gratifyingly, when the same reaction was carried out
in pentane with 2 equiv of ether, the hydroboration was
equally as fast and the 11B NMR showed dialkylchlo-
roborane 13 free from any other boron species (Scheme
2). Remarkably, even when 2 equiv of Me3SiH was used,
equally clean hydroboration was observed.24
Having successfully solved the first hydroboration step,
we next tackled the second hydroboration. Me3SiH was
not successful in achieving the hydridation required for
the second hydroboration even in ethyl ether as the
solvent. Such hydridations are generally carried out
using either LiAlH4 (LAH) or potassium triisopropoxy-
borohydride (KIPBH).21 Considering the ready avail-
ability of LAH, we decided to use it for the hydridation
step. The hydridation is almost always carried out in
(20) The much faster rate of hydroboration using this method as
compared to thexylchloroborane was thought to be advantageous since
the protected homoallylic alcohol would remain in contact with the
chloroborane for a much shorter time and at a lower temperature,
which should minimize side reactions.
(21) Brown, H. C.; Kulkarni, S. U. J . Organomet. Chem. 1981, 218,
299.
(22) Brown, H. C.; Ramachandran, P. V.; Chandrasekharan, S.
Organometallics 1986, 5, 2138.
(23) (a) Soundararajan, R.; Matteson, D. S. J . Org. Chem. 1990, 55,
2274. (b) Soundararajan, R.; Matteson, D. S. Organometallics 1995,
14, 4157.
(24) Since an excess of Me3SiH was not found to have any deleterious
effect on the reaction, a moderate excess (1.5 equiv) of it was used to
avoid having to measure accurately this low-boiling (bp 7 °C) liquid.
(25) To find the amount of scrambling, the trialkylborane 15 in each
case was converted into the unsymmetrical ketone 17, as described in
this paper. The amounts of di-n-hexyl ketone and di-n-octyl ketone
formed along with this unsymmetrical ketone 17 gave a direct measure
of the amount of scrambling.
(26) J oshi, N. N.; Pyun, C.; Mahindroo, V. K.; Singaram, B.; Brown,
H. C. J . Org. Chem. 1992, 57, 504.

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 63, No. 20, 1998 7033
Ta ble 1. Syn th esis of Un sym m etr ica l Keton es by
sponding unsymmetrical ketone 23 in 81% yield without
any incident (Table 1).
Step w ise Hyd r obor a tion Usin g (()-Ip cBCl2
producta % yield
Thus, TBS ethers were good protecting groups for the
homoallylic alcohols. It became clear that this method
can now be used for the synthesis of [5.5] spiroketals as
we had hoped to achieve. It occurred to us that if we
could establish that the TBS ether works well for allylic
alcohols as well, then this method could be extended to
the synthesis of optically pure [4.4] and [4.5] spiroketals,
since a number of methods are also available for the
preparation of allylic alcohols in high optical purity.27
For this purpose, a TBS-protected racemic alcohol 24
was subjected to the same reaction conditions established
alkene 1
1-octene
2-methyl-1-octene 1-hexene
alkene 2
1-hexene
17
18
19
23
27
93b
85b
82b
81c
79c
1-hexene
4-vinyl-1-cyclohexene
20
26
1-hexene
1-hexene
a
e5% symmetrical ketones were also formed in the reaction.
GC yield. c Yield of pure isolated compound.
b
isobutyraldehyde was somewhat slow in pentane, but in
ether it was complete in 1 h at 0 °C, giving cleanly the
required 16. The dialkylborinate 16 (δ 53, 11B NMR) was
then subjected to the DCME reaction after replacing
ether with THF. The intermediate R-chloroboronate
obtained upon alkaline peroxide oxidation provided a 93%
yield (by GC) of the required unsymmetrical ketone 17.
The amount of scrambling represented by the amounts
of symmetrical ketones formed, viz. dihexyl and dioctyl
ketones, was less than 5% (Scheme 2).
Thus we had achieved an efficient and convenient
synthesis of the unsymmetrical ketone 17. The remark-
able features of this synthesis were that both the hy-
droboration steps were complete in less than 30 min, even
at 0 °C, and the whole sequence of reactions was carried
out successfully in one pot for the synthesis of two more
simple ketones 18 and 19 (Table 1).
earlier. To our surprise, although the first hydroboration
took place as readily as before, the product dialkylchlo-
roborane was not stable and had undergone considerable
cleavage of the TBS group, as evidenced by the presence
of a borinate (δ 53) in the 11B NMR taken after 10 min
at 0 °C. The amount of borinate (most likely 25)
gradually increased as the reaction mixture was kept at
0 °C. Fortunately, when the protecting group was
changed to a tert-butyldiphenylsilyl ether (TBDPS, 26),
no trace of cleavage was observed in either of the two
hydroboration steps and the corresponding unsymmetri-
cal ketone 27 was obtained in 79% yield (Table 1).
After establishing proper protecting groups for the
homoallylic and allylic alcohols, we were ready to dem-
onstrate the application of this methodology for the
synthesis of enantiomerically pure spiroketals. We se-
lected first a symmetrical substituted [5.5] spiroketal 28,
The real test now was whether these conditions would
hold true for the stepwise hydroboration of protected
homoallylic alcohols, as needed for the spiroketal syn-
thesis. Since we expected that if there was going to be
any problem in the sequence, it would be in the first step,
we decided to use 1-hexene as the second alkene until
we had established the proper choice of the protecting
group. To test the feasibility of a TBS ether protecting
group, the racemic homoallylic TBS ether 20 was sub-
a major glandular component of the cucumber fly Dacus
cucumis28 as the target molecule. It exists exclusively
in a conformation in which both C-O bonds are axial to
the other ring and the two methyl groups are in a
equatorial arrangement. The synthesis of 28 has been
reported in the literature by various groups.29
jected to the first hydroboration conditions established
earlier. The required dialkylchloroborane 21 was formed
cleanly in less than 10 min at 0 °C and showed a peak at
δ 76 indicating that there was no complexation between
the oxygen and the boron atom of 21. The second
hydroboration in the presence of a slight excess of
1-hexene with LAH under previously described conditions
also proceeded cleanly to give trialkylborane 22. In both
of the hydroboration steps there was no indication of any
decomposition or formation of other boron species. The
trialkylborane 22 was then converted into the corre-
(27) (a) Sugimoto, K.; Aoyagi, S.; Kabayashi, C. J . Org. Chem. 1997,
62, 2322. (b) Dorta, R. L.; Rodriguez, M. S.; Salazar, J . A.; Suarez, E.
Tetrahedron Lett. 1997, 38, 4675. (c) Keck, G. J . Am. Chem. Soc. 1993,
115, 8467 and references therein.
(28) Kitching, W.; Lewis, J . A.; Perkins, R. A.; Drew, R. A.; Moore,
C. J .; Francke, W.; Konig, W. A.; Schurig, V. J . Org. Chem. 1989, 54,
3893.
(29) (a) Solladie, G.; Huser, N. Tetrahedron: Asymmetry 1994, 5,
255. (b) Mori, K.; Tanida, K. Tetrahedron 1981, 37, 3221. (c) Mori, K.;
Watanabe, H. Tetrahedron 1986, 42, 295. (d) Perkins, M. V.; Kitching,
W.; Konig, W. A.; Drew, R. A. I. J . Chem. Soc.. Perkin Trans. 1 1990,
2501. (e) Yadav, J . S.; Gadgil, V. R. Tetrahedron Lett. 1990, 31, 6217.

7034 J . Org. Chem., Vol. 63, No. 20, 1998
Brown et al.
Sch em e 3
arbitrarily decided to synthesize the latter isomer since
this method should be readily applicable to the synthesis
of either isomer with proper choice of the enantiomeri-
cally pure homoallylic alcohols.
The required homoallylic alcohols (R ) Me, 30, and Pr,
31) were prepared via asymmetric allylboration in g99%
ee.9 Application of the stepwise hydroboration protocol
using (()-IpcBCl2 as shown in Scheme 3 provided, after
DCME reaction and hydrogen peroxide oxidation, the
unsymmetrical ketone 35 (R ) Pr) in 75% yield along
with about 5% of the symmetrical ketones. Pure ketone
35 was readily obtained by column chromatography,
which on treatment with aqueous HF in CH3CN pro-
vided, as expected, spiroketal 29 as a single diastereomer
in g99% ee.30 Taking into account the anomeric effect11
and the known absolute configurations of the starting
homoallylic alcohols, the product is the undoubtedly the
required (2S,6R,8S) isomer.
Con clu sion s
A new and stepwise hydroboration methodology based
on the use of (()-IpcBCl2 has been developed for the
synthesis of unsymmetrical ketones and enantiomerically
pure spiroketals. Notable features of this methodology
are the following: (i) (()-IpcBCl2 can be prepared in one
step from inexpensive (()-R-pinene and is stable at room
temperature for extended periods of time when stored
under a nitrogen atmosphere. (ii) Both the hydridation
steps can be completed in less than 30 min at 0 °C, and
a little excess of the hydride reagent does not adversely
affect the reaction. (iii) All the steps can be carried out
in one-pot in a matter of 10-12 h, and the unsymmetrical
ketones are obtained in high yields and purity. We
believe that this methodology can be extended to the
synthesis of more highly substituted optically active
spiroketals 37 by making use of the ready availability of
variously substituted homoallylic alcohols 7 and allylic
alcohols 36 in high enantiomeric excess.
The homoallylic alcohol 30 (R ) Me) required for the
synthesis of 28 was prepared in g99% ee using our well-
established allylboration methodology (eq 3).9 It was
then protected as the TBS ether derivative 32 and
converted into ketone 34 (R ) Me) in 79% yield using
stepwise hydroboration (Scheme 3). Deprotection of the
two TBS groups of 34 with aqueous HF in CH3CN
provided only the required diastereoisomer of 28. Fur-
1
ther analysis of 28 by capillary GC and H and 13C NMR
revealed the formation of the desired diastereoisomer 28
in the reaction. Comparison of the specific rotation with
the literature value29 indicated that the spiroketal 28 was
of g99% ee, confirming that no racemization had taken
place under the reaction conditions.30
To test this methodology for unsymmetrically substi-
tuted spiroketal synthesis, we decided to synthesize
spiroketal 29. This is one of the many spiroketals
present in the mandibular gland secretion of female
Andrena haemorrhoa.4c It occurs in nature as a single
diastereoisomer having both the C-O bonds in an axial
orientation and the alkyl groups in equatorial positions.
Even though this relative configuration was known, the
specific rotation and absolute configuration i.e., whether
it is (2R,6S,8R) or (2S,6R,8S) was not known. We
Exp er im en ta l Section
All reaction flasks and equipment were dried at 150 °C for
several hours prior to use and assembled hot under a stream
of nitrogen. Special techniques for handling air-sensitive
materials are described elsewhere.31 Boiling points reported
are uncorrected. All 1H NMR were recorded at 300 MHz, while
all 13C NMR were recorded at 50.1 MHz in CDCl3 with TMS
as internal standard. Chemical shifts in the H and 13C NMR
1
spectra are reported as parts per million (ppm) downfield from
TMS. Flash chromatography was performed on silica gel
(230-400 mesh, Merck). Preparative gas chromatography was
performed on a 6 ft × 0.25 in. column packed with 10% SE-30
on chromosorb W (100-120 mesh, AW DMCS). Specific
rotations [R] were determined at the sodium D line at 25 °C.
(30) We expect it to be of g99% ee since the starting homoallylic
alcohols were of g99% ee and it was established in the preparation of
28 that no racemization takes place under the reaction conditions. This
is confirmed by the absence of other diastereomers of 28 in the 1H
and 13C NMR since any racemization would have resulted in the
formation of diastereomers of 28. Further, the enantiomeric purity of
the spiroketal 29 was confirmed by chiral capillary GC in comparison
with the racemic spiroketal.
(31) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis via Boranes; Wiley-Interscience: New York, 1975.
A reprinted edition of Vol. 1, Aldrich Chemical Co., Inc., Milwaukee,
WI, 1997, is currently available.

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 63, No. 20, 1998 7035
Unless otherwise mentioned, the reagents and starting
materials were purchased from commercial sources and used
directly. Pentane was stored over 4-Å molecular sieves and
used directly in all experiments. THF was dried by distillation
over sodium-benzophenone ketyl. Enantiomerically pure
homoallylic alcohols 30 and 31 (R ) Me, Pr) were prepared
according to the literature procedure in >99% ee using 2-dIcr2-
BAllyl.9 Silyl ethers 2032 and 3033 (R ) Me) were also prepared
using literature procedures.
(()-Isop in oca m p h eyld ich lor obor a n e [(()-Ip cBCl2]. To
the cold (-78 °C) solution of BCl3 (1.0 M, 10 mmol) in pentane,
a cold (-78 °C) mixture of precondensed Me3SiH (10 mmol)
and (()-R-pinene (10 mmol) was added slowly. The reaction
mixture was stirred for 10 min at that temperature and then
allowed to warm to ambient temperature. The 11B NMR
showed complete formation of (()-IpcBCl2 (singlet at δ 64).
The volatiles of the reaction mixture were removed (15 mmHg,
room temperature, 0.5 h), and residual liquid was purified by
distillation under reduced pressure: bp 60-5 °C (0.2 mmHg);
1H NMR δ 1.80-2.40 (m, 6H), 1.20 (s, 3H), 1.12 (d, I ) 7.2 Hz,
3H), 1.06 (s, 3H), 0.86 (d, J ) 9.6 Hz, 1H); 13C NMR 47.63,
40.87, 38.61, 33.13, 29.64, 28.15, 22.89, 22.64.
to half the volume and diluted with EtOH (5.0 mL). It was
then subjected to oxidation by adding 3 M NaOAc (10.0 mL,
30% H2O2, 4.5 mL, 40.0 mmol), and heating was continued at
70 °C for 2 h with vigorous stirring.
The reaction mixture was then diluted with ether (40.0 mL),
and the aqueous layer was discarded. The organic layer was
washed with water (2 × 25 mL), dried over anhydrous MgSO4,
and concentrated. After removal of Et3COH and other low-
boiling impurities from the reaction mixture by heating at 100
°C in an oil bath (12 mmHg), the product was distilled at 0.2
mmHg in a Kugelrohr apparatus to provide crude ketone 23
in approximately 90% purity. It was further purified by flash
chromatography (98:2 hexane/ethyl acetate) to give pure 23
as a colorless oil (2.77 g, 81%): 1H NMR δ 3.43 (q, J ) 5.4 Hz,
1H), 2.38 (t, J ) 7.5 Hz, 4H), 1.44-1.78 (m, 5H), 1.22-1.40
(m, 8H), 0.80-0.92 (m, 18H), 0.033 (s, 3H), -0.028 (s, 3H);
13C NMR δ 211.40, 76.62, 43.06, 42.06, 42.99, 42.75, 32.64,
31.64, 28.96, 25.95, 23.86, 22.52, 20.00, 18.16, 18.01, 14.04,
-4.26, -4.47.
7-P en ta d eca n on e (17):34 1H NMR δ 2.38 (t, J ) 7.5 Hz,
4H), 1.45-1.61 (m, 4H), 1.27 (bs, 16H), 0.88 (t, J ) 6.6 Hz,
6H).
3-((ter t-Bu tyld ip h en ylsilyl)oxy)-1-p en ten e (26). To a
solution of tert-butyldiphenylsilyl chloride (7.56 g, 27.5 mmol),
imidazole (3.88 g, 57.0 mmol), and DMAP (0.06 g, 0.5 mmol)
in DMF (13.5 mL) was added 1-penten-3-ol (2.15 g, 25.0 mmol),
and the reaction mixture was stirred at room temperature for
16 h. It was worked up by adding hexane (50 mL) followed
by washing with 1 N HCl (2 × 25 mL), and water (25 mL).
The organic layer was concentrated and fractionated under
reduced pressure to give 26 (7.45 g, 92%) in >95% purity. A
small sample was purified by flash chromatography (98:2
hexane/ethyl acetate): colorless oil; 1H NMR δ 7.61-7.75 (m,
4H), 7.30-7.46 (m, 6H), 5.71-5.84 (m, 1H), 4.92-5.04 (m, 2H),
4.06-4.15 (m, 1H), 1.40-1.60 (m, 2H), 1.07 (s, 9H), 0.77 (t,
3H); 13C NMR δ 140.53, 135.96, 135.88, 134.57, 134.33, 129.47,
129.40, 127.41, 127.31, 114.34, 75.66, 30.28, 27.04, 19.38, 8.74.
(4S)-4-((ter t-Bu tyld im eth ylsilyl)oxy)-1-h ep ten e (33, R
) P r ). Prepared from 1-hepten-4-ol by a procedure similar
to that of 26 using TBSCl instead of TBDPSCl: colorless oil,
bp 110-5 °C (26 mmHg); 1H NMR δ 5.70-5.90 (m, 2H), 4.97-
5.09 (m, 2H), 3.63-3.73 (m, 1H), 2.15-2.24 (m, 2H), 1.20-
1.47 (m, 4H), 0.85-0.93 (m, 12H), 0.05 (s, 6H); 13C NMR δ
135.51, 116.51, 71.82, 42.01, 39.13, 25.91, 18.61, 18.61, 18.16,
14.26, -4.37, -4.54.
7-Meth yl-9-p en ta d eca n on e (18): colorless oil; 1H NMR δ
2.32-2.42 (m, 3H), 2.19 (dd, J ) 8.1, 15.9 Hz, 1H), 1.91-2.07
(m, 1H), 1.50-1.61 (m, 2H), 1.10-1.40 (bs, 16H), 0.83-0.92
(m, 9H); 13C NMR δ 211.53, 50.36, 43.42, 37.00, 31.87, 31.64,
29.46, 29.27, 28.95, 26.95, 23.79, 22.66, 22.52, 19.91, 14.10,
14.04. Anal. Calcd for C16H32O: C, 79.93; H, 13.41. Found:
C, 79.99; H, 13.42.
1-(3-Cycloh exen yl)-3-n on a n on e (19): colorless oil; 1H
NMR δ 5.65 (bs, 2H), 2.36-2.48 (m, 4H), 1.98-2.13 (m, 3H),
1.43-1.78 (m, 7H), 1.15-1.35 (m, 7H), 0.88 (t, J ) 6.6 Hz, 3H);
13C NMR δ 211.68, 127.04, 126.23, 42.86, 40.33, 33.32, 31.65,
31.63, 30.44, 28.96, 28.71, 25.15, 23.90, 22.51, 14.04. Anal.
Calcd for C15H26O: C, 81.02, H, 11.78. Found: C, 80.65; H,
11.51.
3-(ter t-Bu tyld ip h en ylsiloxy)-6-d od eca n on e (27): color-
less oil; 1H NMR δ 7.63-7.70 (m, 4H), 7.32-7.46 (m, 6H),
3.63-3.72 (m, 1H), 2.15-2.45 (m, 4H), 1.55-1.80 (m, 2H),
1.36-1.54 (m, 4H), 1.17-1.37 (m, H), 1.05 (s, 9H), 0.88 (t, J )
6.9 Hz, 3H), 0.76 (t, J ) 7.5 Hz, 3H); 13C NMR δ 211.44, 135.87,
134.54, 134.38, 129.55, 129.51, 127.52, 127.45, 42.75, 38.19,
31.60, 29.30, 29.23, 28.90, 27.07, 23.86, 22.50, 19.42, 14.04,
9.29. Anal. Calcd for C28H42O2Si: C, 76.66, H, 9.65. Found:
C, 77.02; H, 9.80.
(2R,6R,8S)-2,8-Dim eth yl-1,7-d ioxa sp ir o[5.5]u n d eca n e
(28). Ketone (2S,10S)-2,10-bis-(tert-butyldimethylsiloxy)-6-
undecanone (34, R ) Me) was prepared in 79% yield using
the same procedure as described for 27 except that alkene 32
was used in both the hydroboration steps (2.00 g, 10.0 mmol,
was used in each step): colorless oil; [R]D ) 13.1° (c 1.10,
CHCl3); 1H NMR δ 3.72-3.84 (m, 2H), 2.39 (t, J ) 7.2 Hz,
4H), 1.46-1.73 (m, 4H), 1.28-1.45 (m, 4H), 1.12 (d, J ) 6.0
Hz, 6H), 0.88 (s, 18H), 0.44 (s, 12H); 13C NMR δ 211.18, 68.37,
42.77, 39.15, 25.90, 23.73, 20.15, 18.13, -4.38, -4.71.
Conversion of ketone 34 (2.37 g, 5.5 mmol) to spiroketal 28
was achieved by simply treating 34 with HF/CH3CN (33.8 mL
of a 5% solution of 48% aqueous HF solution in CH3CN, 44.0
mmol) for 12 h at room temperature. The reaction mixture
was then treated with saturated aqueous K2CO3 (20 mL) and
diluted with ether (30 mL). The aqueous layer was discarded,
and the organic layer was dried over anhydrous MgSO4. It
was then carefully concentrated using a Vigruex column, and
the residue was chromatographed using flash column chro-
matography (1:9 ether/hexane) to give spiroketal 28 (0.52 g,
51%) (the high volatility of 28 is responsible for the low
yield): colorless oil. Capillary GC and 1H and 13C NMR
analyses of a crude sample established the formation of the
desired diastereoisomer. 1H NMR: δ 3.62-3.76 (m, 2H), 1.80-
1.98 (m, 2H), 1.46-1.63 (m, 6H), 1.31-1.43 (m, 2H), 1.08-
1.24 (m, 8H). 13C NMR: δ 96.17, 65.01, 35.22, 32.81, 21.89,
18.95. The spectral properties agreed very well with those
reported in the literature.29c [R]D ) -57.6° (c 1.04, pentane)
(lit.29c [R]D ) -56.0° (c 1.40, pentane).
Gen er a l P r oced u r e for th e P r ep a r a tion of Un sym -
m etr ica l Keton es 17-19, 23, a n d 27. The procedure de-
scribed for the preparation of 3-((tert-butyldimethylsilyl)oxy)-
2-methyl-7-tridecanone (23) is representative.
To a stirred solution of (()-IpcBCl2 (2.19 g, 10.0 mmol) in
pentane (8.0 mL) and ether (2.09 mL, 20.0 mmol) at 0 °C was
added alkene 20 (2.19 g, 10.0 mmol). To this solution was
immediately added precooled (-78 °C) Me3SiH (1.11 g, 15.0
mmol) via a double-ended needle and stirred for 10 min.
1-Hexene (0.88 g, 10.5 mmol) was added, followed by a
dropwise addition of LAH (1.0 M solution in ether, 3.25 mL,
3.25 mmol). The ice bath was removed after 4 min, and the
reaction mixture was brought to room temperature (30 min).
Solvents and other volatiles were removed under reduced
pressure (12 mmHg, 30 min), and the residue was diluted with
ether (10.0 mL) and cooled to 0 °C. Isobutyraldehyde (0.86 g,
12.0 mmol) was added, and the reaction mixture was stirred
for 1 h. Ether and excess aldehyde were removed under
reduced pressure (12 mmHg, room temperature), and the
residue was dissolved in THF (10.0 mL) and cooled to -10 °C.
To this solution was added R,R-dichloromethyl methyl ether
(2.87 g, 25 mmol) followed by a dropwise addition of Et3COLi
(25.0 mmol, prepared by reaction of Et3COH and BuLi) over
10 min. The reaction mixture stirred for 30 min then warmed
to room temperature (LiCl precipitated out), and it was further
stirred for 2 h. The reaction mixture was then concentrated
(32) Hoffman, R. W.; Bewersdorf, M. Chem. Ber. 1991, 124, 1259.
(33) Kalivretenos, A.; Stille, J . K.; Hegedus, L. S. J . Org. Chem.
1991, 56, 2883.

7036 J . Org. Chem., Vol. 63, No. 20, 1998
Brown et al.
(2R ,6R ,8S )-2-Me t h y l-8-p r o p y l-1,7-d io x a s p ir o [5.5]-
u n d eca n e (29). Ketone (2S,10S)-2,10-bis(tert-butyldimeth-
ylsiloxy)-6-tridecanone (35, R ) Pr) was prepared in 75% yield
using the same procedure as described for 27 except that in
the first hydroboration alkene 33 (2.00 g, 10.0 mmol) and in
the second hydroboration alkene 32 (2.39 g, 10.5 mmol) were
used: colorless oil; [R]D ) 7.3° (c 1.00, CHCl3); 1H NMR δ 3.76
(sextet, J ) 6.3 Hz, 1H), 3.64 (pentet, J ) 6.3 Hz, 1H), 2.38 (t,
J ) 7.2 Hz, 4H), 1.21-1.72 (m, 12H), 1.20 (d, J ) 6.3 Hz, 3H),
0.84-0.92 (m, 21H), 0.05 (s, 6H), 0.04 (s, 6H); 13C NMR δ
211.17, 71.86, 68.37, 42.93, 42.77, 39.32, 39.15, 36.57, 25.93,
23.74, 20.16, 19.72, 18.51, 18.13, 14.32, -4.38, -4.43, -4.71.
Ketone 35 (2.11 g, 4.6 mmol) was stirred for 12 h at room
temperature with HF/CH3CN (28.3 mL of a 5% solution of 48%
aqueous HF solution in CH3CN, 36.8 mmol), and the reaction
mixture worked up as described for 28 provided pure 29 (0.85
g, 87%) as a colorless oil. The enantiomeric purity (g99%) of
29 was determined by analyzing it on chiral capillary GC
(Chiraldex GTA, 23 m, 65 °C, isothermal) under conditions
where the racemic spiroketal 29 (prepared from the corre-
sponding racemic homoallylic alcohols and relevant spiroketal
diastereoisomers isolated by preparative GC) had shown an
3.60 (m, 2H), 1.08-1.63 (m, 17H), 0.92 (t, J ) 7.2 Hz, 3H).).
13C NMR: δ 95.96, 68.69, 65.06, 38.77, 35.56, 35.36, 32.88,
31.42, 21.85, 19.15, 19.02, 18.95, 14.26. Anal. Calcd for
C13H24O2: C, 73.34, H, 11.39. Found: C, 73.31; H, 11.61. The
spectral properties agreed well with those reported in the
literature35 for racemic 29.
Ack n ow led gm en t. We gratefully acknowledge the
financial support of this research by the National
Institutes of Health (Grant GM 10937) and the Borane
Research Fund.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds described in the Experimental
Section (16 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O980989W
(34) Smith, K.; Pelter, A.; J in, Z. Angew. Chem., Int. Ed. Engl. 1994,
33, 851.
(35) O’Shea, M. G.; Kitching, W. Tetrahedron 1989, 45, 1177.
almost 1:1 ratio of the two well-resolved enantiomers. [R]D
)
-78.1°(c 1.71, CHCl3). 1H NMR: δ 3.64-3.77 (m, 1H), 3.49-