Bidirectional Asymmetric Allylboration. A Convenient Asymmetric Synthesis of C2-Symmetric 3-Methylenepentane-1,5-diols and Rapid Access to C2-Symmetric Spiroketals

Article abstract of DOI:10.1021/jo991205x

The double allylboration of aldehydes using 1,3-bis(diisopinocampheylboryl)-2-methylenepropanes (R,R)-3 and (S,S)-3 under Brown's salt-free conditions provides C₂-symmetric 3-methylenepentane-1,5-diols 1 in excellent enantiomeric excess. The absolute stereochemistry of the products was confirmed by a single-crystal X-ray study of bis-Mosher ester 6g. Desymmetrization and further functionalization of diol 1a were achieved by treatment of the bis-BOC carbonate 13 with IBr in toluene at -80°C to give cyclic iodocarbonate 14 as a single diastereomer. This methodology is also applicable in natural product synthesis; enantiomerically pure spiroketals 1,7-dioxaspiro[5.5]-undecanes 18 and 25, the latter representing an expedient synthesis of the AB ring system of the spongistatins 20, were easily accessed from simple starting materials in excellent yields and selectivities.

Full text of DOI:10.1021/jo991205x

J . Org. Chem. 2000, 65, 375-380
375
Bid ir ection a l Asym m etr ic Allylbor a tion . A Con ven ien t Asym m etr ic
Syn th esis of C2-Sym m etr ic 3-Meth ylen ep en ta n e-1,5-d iols a n d
Ra p id Access to C2-Sym m etr ic Sp ir ok eta ls
Anthony G. M. Barrett,* D. Christopher Braddock, Pieter D. de Koning,
Andrew J . P. White, and David J . Williams
Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, U.K.
Received J uly 28, 1999
The double allylboration of aldehydes using 1,3-bis(diisopinocampheylboryl)-2-methylenepropanes
(R,R)-3 and (S,S)-3 under Brown’s salt-free conditions provides C2-symmetric 3-methylenepentane-
1,5-diols 1 in excellent enantiomeric excess. The absolute stereochemistry of the products was
confirmed by a single-crystal X-ray study of bis-Mosher ester 6g. Desymmetrization and further
functionalization of diol 1a were achieved by treatment of the bis-BOC carbonate 13 with IBr in
toluene at -80 °C to give cyclic iodocarbonate 14 as a single diastereomer. This methodology is
also applicable in natural product synthesis; enantiomerically pure spiroketals 1,7-dioxaspiro[5.5]-
undecanes 18 and 25, the latter representing an expedient synthesis of the AB ring system of the
spongistatins 20, were easily accessed from simple starting materials in excellent yields and
selectivities.
Sch em e 1
C2-symmetric 3-methylenepentane-1,5-diols 1 are po-
tentially versatile synthetic intermediates,1 but to date
their utility has been hampered by the fact that the
available synthetic methods afford 1:1 mixtures of the
desired C2-symmetric rac-1 and meso-2 isomers.2 As an
extension of the Brown allylboration reaction,3 we have
recently communicated the use of the enantiomeric bis-
(diisopinocampheylborane)s (S,S)- and (R,R)-3 in bidi-
Resu lts a n d Discu ssion
Double deprotonation of 2-methylpropene 4 with n-Bu-
Li-TMEDA, as reported,2a,5 followed by condensation
with 2 equiv of either antipode of commercially available
B-chlorodiisopinocampheylborane afforded the corre-
sponding bis(diisopinocampheylborane)s (S,S)- and (R,R)-
3. Initial in situ reaction with 2 equiv of benzaldehyde
followed by an alkaline H2O2 workup afforded an insepa-
rable mixture of 3-methylenepentane-1,5-diols 1a and 2a
(R ) Ph) (60%) accompanied by the product of monoal-
lylboration, 3-methyl-1-phenylbut-3-en-1-ol (5a ) (30%)
(Scheme 1). The diastereomeric ratio (dr) of the mixture
of diols 1a and 2a (R ) Ph) was estimated to be 8:2 (by
1H NMR spectroscopy) in favor of the desired C2-sym-
metric isomer 1a . The reaction was then optimized. First
the initially formed 1,3-dilithio-2-methylenepropane was
isolated by filtration (35-50%) to remove any monoanion
present in solution, as this is known to provide the
product of monoallylboration.6 Second the reaction was
conducted under Brown’s “salt-free” conditions7 to im-
prove the selectivity. Gratifyingly, these modifications
afforded the desired product 1a (R ) Ph) in good yield
(55% from the dianion) and diastereoselectivity and
excellent enantioselectivity (see Table 1, entry 1), and
reduced the yield of the alcohol byproduct 5a to <5%.
A range of achiral aldehydes were then allowed to react
with both enantiomers of reagent 3 under the optimized
conditions to afford the corresponding C2-symmetric
3-methylenepentane-1,5-diols 1b-h in moderate yields
rectional asymmetric allylboration reactions, providing
the first access to highly diastereo- and enantiomerically
enriched C2-symmetric 3-methylenepentane-1,5-diols 1.4
Herein we report full experimental details for this
method and the application to the synthesis of C2-
symmetric spiroketals.
(1) Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1997, 38, 2187.
(2) (a) Bates, R. B.; Beavers, W. A.; Gordon, B. J . Org. Chem. 1979,
44, 3800. (b) Klein, J .; Medlik-Balan, A.; Meyer, A. Y.; Chorev, M.
Tetrahedron 1976, 32, 1839. (c) Bubnov, Y. N.; Gurskii, M. E.; Pershin,
D. G. Bull. Acad. Sci., USSR, Div. Chem. Sci. 1987, 36, 1107. (d) Imai,
T.; Nishida, S. Synthesis 1993, 395. (e) Go´mez, C.; Ramo´n, D. J .; Yus,
M. Tetrahedron 1993, 49, 4117. (f) Kang, S.-K.; Park, D.-C.; Park, C.-
H.; J ang, S.-B. Synth. Commun. 1995, 25, 1359. (g) Majetich, G.;
Nishidie, H.; Zhang, Y. J . Chem. Soc., Perkin Trans. 1 1995, 453. (h)
Li, C.-J . Tetrahedron Lett. 1995, 36, 517. (i) Masuyama, Y.; Kagawa,
M.; Kurusu, Y. Chem. Commun. 1996, 1585. (j) Krief, A.; Dumont, W.
Tetrahedron Lett. 1997, 38, 657 and references therein.
(3) (a) Brown, H. C.; J adhav, P. K. J . Am. Chem. Soc. 1983, 105,
2092. (b) Roush, W. R. Allyl Organometallics. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon Press: New York, 1991; Vol. 2, pp 1-53 and references
therein. (c) Barrett, A. G. M.; Wan, P. W. H. J . Org. Chem. 1996, 61,
8667 and references therein.
(5) Bahl, J . J .; Bates, R. B.; Beavers, W. A.; Mills, N. S. J . Org. Chem.
1976, 41, 1620.
(6) Brown, H. C.; J adhav, P. K.; Perumal, P. T. Tetrahedron Lett.
1984, 25, 5111.
(4) Barrett, A. G. M.; Braddock, D. C.; de Koning, P. D. Chem.
Commun. 1999, 459.
(7) Racherla, U. S.; Brown, H. C. J . Org. Chem. 1991, 56, 401.
10.1021/jo991205x CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/29/1999

376 J . Org. Chem., Vol. 65, No. 2, 2000
Barrett et al.
Ta ble 1. P r ep a r a tion of C2-Sym m etr ic
Sch em e 2
3-Meth ylen ep en ta n e-1,5-d iols 1
the diols 1a -h . The absolute stereochemical outcome of
the reaction was determined by an X-ray crystallographic
analysis of the bis-(S)-MTPA ester 6g (R ) 4-MeO-C6H4)
(see the Supporting Information) derived from the action
of (S,S)-3 on p-methoxybenzaldehyde, which unequivo-
cally established both the relative and absolute stere-
ochemistries of this compound and, by inference, all the
diols in Table 1. Additional confirmation of the absolute
stereochemical control of the double allylboration reaction
was obtained through ozonolysis of the hexanal derived
diol 1e to dihydroxy ketone 7 (97%). The optical rotation
observed {[R]25 +45.8° (c 0.2; CHCl3)} had the sign
D
opposite to that reported for the antipode {[R]25 -40.4°
D
(c 0.2; CHCl3)}.9 Thus, the reagent (S,S)-3 gives rise to
the central 3-methylenepentane-1,5-diol core with the
absolute configuration A as depicted in Scheme 2, while
the (R,R)-3 reagent gives rise to the opposite configura-
tion B (note that the absolute configurational descriptors
in the adducts, R,R vs S,S, are dependent on the nature
of the R group). These results are in full accord with the
established stereoselectivities of other Brown allylborane
and aldehyde condensation reactions.3
a
Reagent (S,S)-3 derives from (+)-B-chlorodiisopinocamphey-
lborane. (R,R)-3 derives from (-)-B-chlorodiisopinocampheylbo-
rane. b All yields are quoted relative to the amount of dianion used.
c Both the dr and % ee are estimated from the corresponding bis-
d
Mosher esters.8 (R,R) configuration. e (S,S) configuration. f The
central 3-methylenepentanediol entity of the major diastereoiso-
g
mer has the (R,R) configuration. The central 3-methylenepen-
tanediol entity of the major diastereoisomer has the (S,S) config-
uration.
(Table 1, entries 2-9), but with good diastereoselectivities
(dr > 91:9) and excellent enantioselectivities (>95% ee).
In all examples, the product of monoallylboration 5 was
observed but not isolated as it coeluted with the diiso-
pinocampheylborane-derived isopinocampheol. Both 2-ni-
trobenzaldehyde and pivaldehyde failed to react, pre-
sumably on account of SET chemistry or steric congestion.
Reaction with homochiral aldehydes (Table 1, entries 10-
12) proceeded with substantial reagent control; largely
a single isomer was isolated in both the mismatched
(entry 10) and matched (entry 11) cases. As expected,
when the stereocenter was one atom further removed
from the aldehyde, it had no significant influence on the
reaction outcome (Table 1, entry 12), the diastereoselec-
tivity being similar to that observed with achiral alde-
hydes.
The bis(diisopinocampheylborane) reagents (S,S)- and
(R,R)-3 would be much more versatile synthons if they
could be reacted successively with two different alde-
hydes, RCHO and R′CHO, to give mixed adducts of type
8. A number of experiments were conducted utilizing
benzaldehyde and isobutyraldehyde as two representa-
tive aldehydes: (i) the reagent (S,S)-3 was treated with
1 equiv of benzaldehyde under the normal reaction
conditions followed, after 1 h, by 2 equiv of isobutyral-
dehyde; (ii) the order of addition (and the stoichiometry)
was reversed; (iii) the two aldehydes (1.5 equiv) were
added as a mixture; (iv) the reaction was conducted with
just benzaldehyde, in a limiting quantity (1 equiv). The
results from these experiments are as follows. Experi-
ments 1 and 2 yielded both the symmetrical adducts 1a
(15%, 15%) and 1b (29%, 12%) as the major products
along with a small amount of mixed adduct 9 (10%, 4%),
respectively. Experiment 3 yielded an approximately
statistical distibution of products (41% isolated yield). In
the final experiment the bisadduct 1a was isolated in 27%
While in principle the diastereoselectivity could be
1
determined directly from the H NMR of the (chromato-
graphed) inseparable diol mixture 1 and 2, it was found
1
that more accurate ratios could be garnered from the H
NMR of their bis-(S)-Mosher (MTPA) esters.8 This also
allowed for determination of the enantiomeric excess of
(8) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(9) Annunziata, R.; Cinquini, M.; Cozzi, F.; Restelli, A. J . Chem. Soc.,
Perkin Trans. 1 1985, 2293.

Biredirectional Asymmetric Allylboration
J . Org. Chem., Vol. 65, No. 2, 2000 377
Sch em e 3
Sch em e 4
Sch em e 5
yield with only 1.7% of monoadduct 5a present. These
results clearly show that all things being equal the second
allylboration proceeds faster than the first, and the
reagents (R,R)-3 and (S,S)-3 appear to be unsuitable for
the practical synthesis of nonsymmetrical diols 8 in this
manner. A possible explanation for this finding is that
bis(diisopinocampheylborane) 3 is stabilized relative to
the presumed monoallylboration adduct intermediate 10
by degenerate 1,3-boron migrations. This type of migra-
tion has been observed in the analogous achiral 1,3-bis-
(dipropylboryl)-2-methylenepropane,2c where the three
methylene groups were found to be equivalent by 1H
NMR spectroscopy.
In light of our inability to prepare diols of type 8, a
method for the efficient desymmetrization of diol 1 via
intramolecular attack of the central methylene unit by
the suitably derivatized alcohol was pursued. Exposing
diol 1a (R ) Ph) to iodocarbonate cyclization conditions10
employing 2.2 equiv of n-BuLi, followed by CO2 and I2,
afforded the desymmetrized cyclic carbonate 11 in a
reasonable yield (61%, Scheme 3), but without any
selectivity at the quaternary carbon (ca.. 1:1 mixture of
diastereoisomers by 1H NMR). The acyclic monoprotected,
desymmetrized alcohol 12 was obtained by silylation of
11 followed by treatment with zinc in acetic acid (40%,
Scheme 3). While this method had indeed achieved the
desired desymmetrization, the lack of selectivity in the
iodocyclization step and the poor yield clearly limit its
utility. Fortunately, Smith’s excellent modification11
utilizing IBr on the bis-BOC carbonate 13 in toluene at
-80 °C afforded iodocarbonate 14 in good isolated yield
(82%). In this case the diastereoselectivity was excellent;
essentially a single isomer was observed by 1H NMR. The
structural assignment was confirmed by NOE measure-
ments, the diagnostic evidence being the presence of an
NOE enhancement between the two protons R to the
carbonates, firmly placing the phenyl and iodomethylene
groups cis on the six-membered ring.
3-(Tetrahydro-2H-pyran-2-yl)oxypropanal (15)14 was re-
acted with (S,S)-3 under the standard reaction conditions
to give C2-symmetric diol 16 (45%, Scheme 4). Due to the
presence of the THP protecting groups it proved impos-
sible to determine the diastereomeric excess at this stage.
Ozonolysis to dihydroxy ketone 17, followed by treatment
with DOWEX 50WX8-400 resin in methanol, chroma-
tography, and recrystallization afforded the known
1
spiroketal 1813 as a single diastereoisomer by 13C and H
NMR spectroscopy in ca. 33% yield from aldehyde 15.
Although the melting point was slightly lower than that
reported, the observed optical rotation and other spec-
troscopic data were identical to the literature values.13
Spiroketal 18 was previously synthesized from (S)-malic
acid in 10 steps and in ca. 10% overall yield; this
procedure therefore represents a significant improve-
ment.
As a further demonstration of the power of this
methodology, we assayed the synthesis of the AB spiroket-
al fragment of the spongistatins 20.15 These extremely
potent inhibitors of cancer cell growth are isolated in
miniscule quantities from marine sponges and have been
the subject of numerous synthetic efforts,16 culminating
in two total syntheses.17 A previously published retrosyn-
thetic analysis18 had shown that a differentially protected
hydroxyketone 21 should be a suitable precursor for this
product. In addition, an excellent method for the desym-
The double allylboration strategy also lends itself to
the preparation of enantiomerically pure spiroketals, a
widely occurring motif in natural products.12 4,10-Dihy-
droxy-1,7-dioxaspiro[5.5]undecane (18) was selected as
a target, which has been converted into both enantiomers
of 1,7-dioxaspiro[5.5]undecane (19), the major compo-
nents of the sex pheromones of the olive fruit fly.13
(14) (a) Danieli, B.; Lesma, G.; Palmisano, G.; Tollari, S. J . Chem.
Soc., Perkin Trans. 1 1984, 1237. (b) Adamczyk, M.; Reddy, R. E.
Tetrahedron 1996, 52, 14689.
(15) (a) Pettit, G. R. Pure Appl. Chem. 1994, 66, 2271. (b) Pettit, G.
R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt, J . M.;
Hooper, J . N. A. J . Org. Chem. 1993, 58, 1302. (c) Fusetani, N.;
Shinoda, K.; Matsunaga, S. J . Am. Chem. Soc. 1993, 115, 3977.
(16) Pietruszka, J . Angew. Chem., Int. Ed. Engl. 1998, 37, 2629.
(17) (a) Evans, D. A.; Coleman, P. J .; Dias, L. C. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2737. (b) Evans, D. A.; Trotter, B. W.; Coˆte´, B.;
Coleman, P. J . Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. (c) Evans,
D. A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J .; Dias, L. C.; Tyler, A. N.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2744. (d) Guo, J .; Duffy, K. J .;
Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y.
Angew. Chem., Int. Ed. Engl. 1998, 37, 187. (e) Hayward, M. M.; Roth,
R. M.; Duffy, K. J .; Dalko, P. I.; Stevens, K. L.; Guo, J .; Kishi, Y. Angew.
Chem., Int. Ed. Engl. 1998, 37, 190.
(10) (a) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J . Chem. Soc.,
Chem. Commun. 1981, 465. (b) Bongini, A.; Cardillo, G.; Orena, M.;
Porzi, G.; Sandri, S. J . Org. Chem. 1982, 47, 4626. (c) Bartlett, P. A.;
Meadows, J . D.; Brown, E. G.; Morimoto, A.; J ernstedt, K. K. J . Org.
Chem. 1982, 47, 4013.
(11) Duan, J . J .-W.; Smith, A. B. J . Org. Chem. 1993, 58, 3703.
(12) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.
(13) (a) Mori, K.; Uematsu, T.; Watanabe, H.; Yanagi, K.; Minobe,
M. Tetrahedron Lett. 1984, 25, 3875. (b) Mori, K.; Uematsu, T.; Yanagi,
K.; Minobe, M. Tetrahedron 1985, 41, 2751.
(18) Paquette, L. A.; Zuev, D. Tetrahedron Lett. 1997, 38, 5115.

378 J . Org. Chem., Vol. 65, No. 2, 2000
Barrett et al.
Exp er im en ta l Section
All solvents were redistilled prior to use. 2,3-O-Isopropy-
lidene-D-glyceraldehyde,21 3-(tetrahydro-2H-pyran-2-yl)oxypro-
panal (15),14 and (3R)-4-(4-methoxybenzyloxy)-3-(tetrahydro-
2H-pyran-2-yl)oxybutanal (22)18 were prepared according to
reported procedures. 1,3-Dilithio-2-methylenepropane‚2TMEDA
was prepared as reported2a,5 and isolated by filtration (35-
50% yield). All other reagents were purchased from commercial
sources and used without further purification. Scalemic 3-me-
thylenepentane-1,5-diols were prepared from 1,3-dilithio-2-
methylenepropane‚2TMEDA as reported.2a
Column chromatography was performed on BDH silica gel
60, 230-400 mesh ASTM. Analytical thin-layer chromatog-
raphy (TLC) was perfomed on precoated glass-backed plates
(Merck Kieselgel 60 F254) and visualized with ultraviolet light
(254 nm), vanillin, or potassium permanganate, as appropriate.
Gen er a l P r oced u r e for th e Dou ble Asym m etr ic Al-
lylbor a tion of Ald eh yd es u sin g (S,S)-3 or (R,R)-3 for th e
P r epar ation of 3-Meth ylen epen tan e-1,5-diols 1a -k (Table
1). A solution of (+)-B-chlorodiisopinocampheylborane or (-)-
B-chlorodiisopinocampheylborane (5.4 g, 16.8 mmol) in Et2O
(20 mL) was added to a cooled (0 °C) suspension of 1,3-dilithio-
2-methylenepropane‚2TMEDA (2.3 g, 7.7 mmol) in Et2O (20
mL), and the resulting yellow solution was stirred for 3 h at
this temperature, during which time a heavy white precipitate
was deposited. The solvent was evaporated under reduced
pressure, and the residue was dissolved in dry pentane (50
mL). The solution was filtered under an argon atmosphere,
and the residue was washed with a further aliquot of pentane
(50 mL). The pentane was evaporated (1 mmHg), and the
resulting foam was dissolved in Et2O (50 mL). This solution
was cooled to -78 °C, the aldehyde (20.5 mmol) was added
dropwise, and the reaction mixture was stirred for 3 h at this
temperature. Hydrogen peroxide (27 wt %, 4 mL, 32 mmol)
and aqueous NaOH (4M, 4 mL, 32 mmol) were added simul-
taneously, and the reaction mixture was allowed to stir for a
further 18 h with slow warming to room temperature. H2O (5
mL) was added, and the reaction mixture was extracted with
Et2O. The combined organic phase was washed with water and
brine, dried (MgSO4), concentrated in vacuo, and chromato-
graphed. Full characterization data for the 3-methylenepen-
tane-1,5-diols 1a -k can be found in the Supporting Informa-
tion.
metrization of a C2-symmetric analogue of 21 has been
published.19 We sought to prepare a C2-symmetric version
of the spiroketal intermediate 21. (3R)-4-(4-Methoxyben-
zyloxy)-3-(tetrahydro-2H-pyran-2-yl)oxybutanal (22) was
prepared from commercially available (S)-glycidol fol-
lowing the literature procedure,18 and was treated with
(S,S)-3 to give olefin 23 (48%, Scheme 5). Once again,
due to the presence of the THP groups, the diastereomeric
ratio could not be ascertained at this point. Dihydroxy-
lation followed by oxidative cleavage provided dihydroxy
ketone 24 in excellent yield (85%). One-pot deprotection
and subsequent spirocyclization were accomplished by
treatment with DOWEX 50WX8-400 resin in methanol.
Careful chromatography afforded the C2-symmetric
spiroketal 25 (58%), accompanied by three other diaste-
reoisomers (two inseparable) which could not be identi-
fied (25% combined). The stereochemistry of the spiro-
center in 25 was assigned by analogy with that observed
in the spirocyclization of a number of closely related
compounds,16-20 and is supported by the fact that the
Deter m in a tion of Dia ster eom er ic Ra tios a n d En a n -
tiom er ic Excesses. To determine the diastereomeric and
enantiomeric excesses of diols 1a -h , they were converted into
their bis-(S)-Mosher (MTPA) esters8
6 using (R)-Mosher
chloride. Their 1H NMR spectra were compared with the bis-
MTPA esters of the corresponding 1:1 mixture of diols 1 and
2 (meso) prepared by condensation of 1,3-dilithio-2-methyl-
enepropane with the appropriate aldehyde,2a and the dr and
ee were determined by integration of the signals for the olefinic
protons (see the Supporting Information).
(6S,10S)-(+)-6,10-Dih ydr oxypen tadecan -8-on e (7). Ozone
was bubbled though a solution of diol 1e (78 mg, 0.30 mmol)
in CH2Cl2 (5 mL) at -78 °C until the solution turned a pale
blue (ca. 15 min). The ozone generator was turned off, and O2
was bubbled through the solution until the color had dis-
charged (ca. 5 min). Me2S (3 mL) and EtOH (3 mL) were added,
and the reaction mixture was allowed to warm to ambient
temperature and stirred for 18 h. The solvent was removed
under reduced pressure, and the residue was chromatographed
(1:4 EtOAc/hexanes) to afford dihydroxy ketone 7 as a white
amorphous solid (75 mg, 97%): TLC Rf 0.10 (1:4 EtOAc/
1
signal for the hydroxyl protons in the H NMR spectrum
appears at δ 4-4.3 ppm, which has been shown to be
diagnostic for an axial hydroxyl proton in related sys-
tems.20
This study further expands the utility of pinene-
derived compounds in asymmetric synthesis. The direct
conversion of aldehydes into highly enantiomerically
enriched C2-symmetric 3-methylenepentane-1,5-diols, sup-
ported by the desymmetrization procedure developed,
should be of considerable application in organic synthesis.
To demonstrate the utility of this method, we have
synthesized the AB fragment of the spongistatin nucleus
and have completed a formal total synthesis of both
enantiomers of 1,7-dioxaspiro[5.5]undecane.
hexanes); [R]23 +45.8° (c 0.2, CHCl3) [lit.9 [R]25D, (-)-(R,R)
D
isomer, -40.4° (c 0.2, CHCl3)]; IR (CHCl3) 3552, 3008, 2958,
1
2931, 2860, 1699 cm-1; H NMR (300 MHz, CDCl3) δ 4.09-
4.02 (m, 2H), 3.17 (br s, 2H), 2.55 (d, 4H, J ) 5.5 Hz), 1.49-
1.28 (m, 16H), 0.87 (t, 6H, J ) 6.7 Hz); 13C NMR (75 MHz,
CDCl3) δ 212.5, 67.6, 50.2, 36.6, 31.7, 25.1, 22.6, 14.0 (also
present from the minor diastereoisomer 50.3, 67.8); MS (CI,
(19) Claffey, M. M.; Heathcock, C. H. J . Org. Chem. 1996, 61, 7646.
(20) Menges, M.; Bru¨ckner, R. Liebigs Ann. 1995, 365.
(21) Schmid, C. R.; Bryant, J . D. Org. Synth. 1993, 72, 6.

Biredirectional Asymmetric Allylboration
J . Org. Chem., Vol. 65, No. 2, 2000 379
NH3) m/z 276 (M + NH4)+, 259 (M + H)+; HRMS (CI, NH3)
calcd for C15H31O3 (M + H)+ 259.2273, found (M + H)+
259.2279.
C28H40NO6 (M + NH4)+ 486.2856, found (M + NH4)+ 486.2846.
Anal. Calcd for C28H36O6: C, 71.77; H, 7.74. Found: C, 71.85;
H, 7.73.
(1R,5R)-6-Met h yl-1-p h en yl-3-m et h ylen eh ep t a n e-1,5-
d iol (9): as a 3:5 mixture with 1b; TLC Rf 0.33 (2:3 EtOAc/
hexanes); 1H NMR (300 MHz, CDCl3) 7.40-7.28 (m, 5H), 5.12
(s, 1H), 5.09 (s, 1H), 5.04 (s, 3.33H), 4.89-4.80 (m, 1H), 3.59-
3.48 (m, 4.33H), 2.58-2.40 (m, 2H), 2.35-2.31 (m, 4.33H),
2.10-2.03 (m, 4.33H), 1.75-1.67 (m, 4.33H), 0.99-0.97 (m,
26H).
(4S,6R)-4-[(2-ter t-Bu t yloxy)ca r b on yloxy)-(2R)-p h en -
eth yl]-4-iod om eth yl-6-p h en yl-1,3-d ioxa n -2-on e (14). IBr
(1.0 M in CH2Cl2, 0.3 mL, 0.3 mmol) was slowly added to a
solution of dicarbonate 13 (100 mg, 0.21 mmol) in PhMe (5
mL) at -80 to -85 °C (CO2-Et2O bath), and the mixture was
stirred at this temperature for 4 h. A mixture of aqueous
NaHCO3 and Na2S2O3 was added, the solution was allowed to
warm to room temperature and extracted with Et2O. The
combined organic phase was washed with H2O, dried, evapo-
rated under reduced pressure, and chromatographed (1:9 Et2O/
pentane) to furnish iodolactone 14 as an off-white foam (93
(6R)-4-(2-H yd r oxy-2R-p h en ylet h yl)-4-iod om et h yl-6-
p h en yl-1,3-d ioxa n -2-on e (11). n-BuLi (2.4 M in hexanes, 0.5
mL, 1.2 mmol) was added to a solution of (1R,5R)-1a (140 mg,
0.52 mmol) in THF (10 mL), and after 1 h at room temperature
CO2 was bubbled through the solution for 1 min, a solution of
I2 (400 mg, 1.57 mmol) in THF (5 mL) was added, and the
mixture was stirred for 18 h at room temperature. The solution
was poured into water and extracted with Et2O. The combined
organic phase was washed with water, dried (MgSO4), con-
centrated under reduced pressure, and chromatographed (1:4
EtOAc/hexanes) to give 11 as a clear oil (138 mg, 61% as a 1:1
mixture of diastereoisomers): TLC Rf 0.4 (2:3 EtOAc/hexanes);
mg, 82%): TLC Rf 0.25 (1:4 EtOAc/hexanes); [R]23 +0.75° (c
D
6.7, CHCl3); IR (CHCl3) 3033, 2978, 2930, 2856, 1746 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.45-7.35 (m, 10H), 5.43 (dd,
1H, J ) 11.9, 2.9 Hz), 5.43 (dd, 1H, J ) 11.9, 2.9 Hz), 3.50 (d,
1H, J ) 10.9 Hz), 3.42 (d, 1H, J ) 10.9 Hz), 2.78 (dd, 1H J )
15.2, 8.6 Hz), 2.49 (m, 2H), 2.24 (dd, 1H, J ) 14.5, 12.2 Hz),
1.47 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 152.4, 148.3, 139.8,
137.0, 129.1, 129.0, 128.7, 126.2, 125.7, 83.2, 81.3, 76.7, 74.2,
44.1, 39.7, 27.7, 13.8; MS (CI, NH3) m/z 556 (M + NH4)+;
HRMS (CI, NH3) calcd for C24H31INO6 (M + NH4)+ 556.1196,
found (M + NH4)+ 556.1216. Anal. Calcd for C24H27IO6: C,
53.54; H, 5.06. Found: C, 53.60; H, 4.88.
1
IR (film) 3442, 3062, 3031, 2956, 2927, 2871, 1739 cm-1; H
NMR (300 MHz, CDCl3) δ 7.45-7.35 (m, 10H), 5.65-5.45 (m,
1H), 5.16-5.06 (m, 1H), 4.10-3.45 (m, 3H), 2.87-2.10 (m, 4H);
MS (CI, NH3) m/z 471 (M + H - H2O)+, 453 (M + H - 2H2O)+.
(1R,5R)-(+)-5-(ter t-Bu tyldim eth ylsily)oxy-1,5-diph en yl-
3-m eth ylen e-1-p en ta n ol (12). A solution of iodocarbonate 11
(99 mg, 0.23 mmol), imidazole (25 mg, 0.37 mmol), and tert-
butyldimethylsilyl chloride (50 mg, 0.33 mmol) in DMF (1 mL)
was stirred at room temperature for 18 h. H2O was added (10
mL) and the solution extracted with Et2O. The ethereal
extracts were washed with dilute HCl, water, and brine, dried
(MgSO4), evaporated, and chromatographed to yield the in-
termediate silyl carbonate. This was dissolved directly in
glacial AcOH (3 mL) and stirred vigorously while zinc dust
was added (50 mg, 0.76 mmol). After 0.5 h saturated aqueous
NaHCO3 was added until effervescence ceased, and the
mixture extracted with Et2O. The combined extracts were
washed with H2O, dried, concentrated, and chromatographed
on silica gel (1:19 EtOAc/hexanes) to give alcohol 12 (35 mg,
40%): TLC Rf 0.43 (1:4 EtOAc/hexanes); [R]23D +48.1° (c 1.65,
CHCl3); IR (CHCl3) 3422, 3065, 3029, 2953, 2929, 2887, 2857,
1643 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.30 (m, 10H),
5.02 (s, 1H), 5.00 (s, 1H), 4.81-4.78 (m, 2H), 2.60-2.40 (m,
4H), 2.25 (br s, 1H), 0.89 (s, 9H), 0.03 (s, 3H), -0.15 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 145.1, 144.1, 142.7, 128.4, 128.1,
127.5, 127.2, 126.0, 125.8, 116.7, 74.5, 71.5, 47.1, 47.0, 25.9,
18.3, -4.6, -4.9 (also present from the minor diastereoisomer
143.2, 116.2, 47.5); MS (CI, NH3) m/z 383 (M + H)+; HRMS
(CI, NH3) calcd for C24H35O2Si (M + H)+ 383.2403, found (M
+ NH4)+ 383.2403. Anal. Calcd for C24H35O2Si: C, 75.34; H,
8.96. Found: C, 75.20; H, 8.82.
(1R ,5R )-(+)-1,5-Di[(t er t -b u t yloxy)ca r b on yloxy]-1,5-
d ip h en yl-3-m eth ylen ep en ta n e (13). To a solution of 1a (350
mg, 1.31 mmol) in THF (3.5 mL) at 0 °C was added dropwise
a solution of n-BuLi (2.4 M in hexanes, 1.5 mL, 3.6 mmol),
and the mixture was stirred for 30 min. A solution of 2-(tert-
butoxycarbonylimino)-2-phenylacetonitrile (BOC-ON) (890
mg, 3.6 mmol) in THF (5 mL) was added, and the mixture
was warmed to room temperature and stirred for 18 h. The
solution was poured into aqueous NaOH (0.4M, 30 mL) and
extracted with Et2O. The ether layer was washed with brine,
and the aqueous phase was back-extracted with Et2O. The
combined organic phase was dried (MgSO4), concentrated
under reduced pressure, and chromatographed (1:19 EtOAc/
hexanes), furnishing dicarbonate 13 as an off-white solid (460
(3R,7R)-1,9-Di[(t et r a h yd r op yr a n -2-yl)oxy]-5-m et h yl-
en en on a n e-3,7-d iol (16). Following the general procedure for
double asymmetric allylboration using (S,S)-3 and 1514 gave
16 as a colorless oil (45% as an inseparable mixture of
diastereoisomers (ratio not determined)): TLC Rf 0.08 (2:3
EtOAc/hexanes); IR (film) 3428, 3073, 2940, 2872, 1643 cm-1
;
1H NMR (300 MHz, CDCl3) δ 4.97 (s, 2H), 4.59 (m, 2H), 4.00-
3.80 (m, 6H), 3.65-3.43 (m, 4H), 3.32 (br s, 2H), 2.30-2.15
(m, 4H), 1.85-1.50 (m, 16H); 13C NMR (75 MHz, CDCl3) δ
143.7, 115.2, 99.1, 99.0, 68.9, 68.8, 68.5, 68.5, 65.9, 65.8, 62.6,
62.3, 44.1, 36.4, 30.7, 30.5, 25.3, 19.6, 19.5; MS (CI, NH3) m/z
388 (M + NH4)+, 373 (M + H)+; HRMS (CI, NH3) calcd for
C20H37O6 (M + H)+ 373.2590, found (M + H)+ 373.2592. Anal.
Calcd for C20H36O6: C, 64.49; H, 9.74. Found: C, 64.68; H,
9.89.
(3S,7S)-3,7-Dih yd r oxy-1,9-d i[(t et r a h yd r op yr a n -2-yl)-
oxy]n on a n -5-on e (17). From 16 (300 mg, 0.81 mmol) the
procedure described for 7 gave 17 as a colorless oil (295 mg,
97%): TLC Rf 0.32 (1:24 MeOH/CHCl3); IR (film) 3427, 3008,
2944, 2875, 1708 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.48 (br
s, 2H), 4.23-4.15 (m, 2H), 3.87-3.71 (m, 4H), 3.53-3.41 (m,
6H), 2.63-2.47 (m, 4H), 1.76-1.42 (m, 16H); 1H NMR (300
MHz, CD3OD) δ 4.61 (br s, 2H), 4.25 (m, 2H), 3.92-3.84 (m,
4H), 3.48-3.58 (m, 4H), 3.33 (m, 2H), 2.66 (s, 4H), 1.86-1.54
(m, 16H); 13C NMR (75 MHz, CDCl3) δ 210.8, 210.7, 210.7,
99.0, 99.0, 66.3, 66.1, 64.9, 64.8, 62.5, 62.3, 50.5, 36.2, 30.6,
30.5, 25.3, 19.6, 19.5; MS (CI, NH3) m/z 392 (M + NH4)+;
HRMS (CI, NH3) calcd for C19H38NO7 (M + NH4)+ 392.2648,
found (M + NH4)+ 392.2654. Anal. Calcd for C19H34O7: C,
60.94; H, 9.15. Found: C, 61.00; H, 9.26.
(4S,6S,10S)-(+)-1,7-Dioxa sp ir o[5.5]u n d eca n -4,10-d iol
(18).13 A solution of ketone 17 (795 mg, 2.13 mmol) in MeOH
(10 mL) was stirred at room temperature with freshly washed
DOWEX 50WX8-400 resin (50 mg) for 18 h. The mixture was
filtered, and the resin was washed with further MeOH. The
combined organic phase was concentrated to give a solid
residue. Chromatography (1:19 MeOH/CHCl3) gave first an
unidentified mixture of products, followed by spiroketal 18 as
a white solid (300 mg, 75%): mp 119-120 °C (Me2CO) (lit.13
mp 153-154 °C); TLC Rf 0.07 (1:19 MeOH/CHCl3); [R]23
D
+124.5° (c 0.4, Me2CO) (lit.13 [R]D +121.4° (c 0.5, Me2CO)); IR
mg, 75%): mp 79-80 °C; TLC Rf 0.46 (1:4 EtOAc/hexanes);
(CHCl3) 3376, 2951, 2879 cm-1 1H NMR (300 MHz, (CD3)2-
;
1
[R]23 +35.7° (c 0.8, CHCl3); IR (CHCl3) 2987, 1738 cm-1; H
D
CO) δ 4.00-3.90 (m, 2H), 3.74 (m, 2H), 3.63-3.53 (m, 4H),
1.98-1.91 (m, 2H), 1.85-1.77 (m, 2H), 1.45-1.22 (m, 4H); 1H
NMR (300 MHz, CD3OD) δ 4.03-3.92 (m, 2H), 3.69-3.55 (m,
6H), 2.02-1.95 (m, 2H), 1.88-1.82 (m, 2H), 1.51-1.27 (m, 4H);
13C NMR (75 MHz, (CD3)2CO) δ 99.0, 63.2, 58.5, 45.3, 35.2;
NMR (300 MHz, CDCl3) δ 7.35-7.30 (m, 10H), 5.72-5.62 (m,
2H), 4.91 (s, 2H), 2.65-2.40 (m, 4H), 1.45 (s, 18H); 13C NMR
(75 MHz, CDCl3) δ 152.9, 140.1, 132.9, 128.5, 128.0, 126.4,
117.1, 82.1, 65.9, 43.2, 27.8 (also present from the minor
diastereoisomer 129.3, 127.5, 27.7); HRMS (CI, NH3) calcd for

380 J . Org. Chem., Vol. 65, No. 2, 2000
Barrett et al.
MS (CI, NH3) m/z 206 (M + NH4)+, 189 (M + H)+; HRMS (CI,
NH3) calcd for C9H17O4 (M+H)+ 189.1123, found (M + H)+
189.1127.
3.77 (s, 3H), 3.66-3.42 (m, 8H), 2.67-2.46 (m, 4H), 1.78-1.42
(m, 16H); 13C NMR (75 MHz, CDCl3) δ 210.4, 210.3, 159.2,
130.3, 130.2, 130.2, 129.4, 129.2, 113.8, 113.8, 99.7, 99.5, 99.0,
98.9, 77.4, 75.6, 75.3, 75.0, 74.8, 73.0, 72.4, 72.3, 67.2, 66.9,
65.8, 65.5, 64.5, 64.3, 62.7, 60.6, 55.2, 51.1, 50.8, 50.7, 50.5,
39.0, 38.8, 38.7, 31.3, 31.1, 25.4, 25.2, 21.0, 20.9, 20.8, 19.7;
MS (electrospray) m/z 697.2 (M + Na)+. Anal. Calcd for
(2R,4R,8R,10R)-1,11-Di(4-m et h oxyb en zyloxy)-2,10-d i-
[(t et r a h yd r op yr a n -2-yl)oxy]-6-m et h ylen eu n d eca n e-4,8-
d iol (23). Following the general procedure for double asym-
metric allylboration using (S,S)-3 and 2218 gave 23 as a
colorless oil (48% as an inseparable mixture of diastereoiso-
mers (ratio not determined)): TLC Rf 0.06 (2:3 EtOAc/
hexanes); [R]23D +4.1° (c 3.9, CHCl3); IR (film) 3423, 3071, 2972,
C
37H54O11: C, 65.85; H, 8.07. Found: C, 65.97; H, 8.15.
(2R,4S,6R,8R,10S)-2,8-Di(4-m eth oxyben zyloxym eth yl)-
1,7-d ioxa sp ir o[5.5]u n d eca n -4,10-d iol (25). From 24 (650
mg, 0.96 mmol) the procedure described for 18 gave 25 as a
pale yellow oil (271 mg, 58%): TLC Rf 0.22 (3:2 EtOAc/
1
2854, 1642 cm-1; H NMR (300 MHz, CDCl3) δ 7.24 (m, 4H),
6.88 (m, 4H), 4.96 (m, 2H), 4.74 (m, 2H), 4.51-4.45 (m, 4H),
4.15-3.92 (m, 6H), 3.83 (s, 3H), 3.81 (s, 3H), 3.71-3.41 (m,
8H), 2.25-2.20 (m, 4H), 1.87-1.45 (m, 16H); 13C NMR (75
MHz, CDCl3) δ 159.2, 143.7, 130.4, 130.2, 130.2, 129.4, 129.2,
115.0, 113.8, 99.9, 99.5, 99.3, 99.2, 99.0, 76.6, 76.2, 75.8, 75.4,
75.3, 72.9, 72.5, 72.4, 69.4, 68.8, 67.9, 67.4, 65.9, 64.4, 64.2,
62.7, 55.3, 44.7, 44.4, 44.1, 43.7, 39.1, 39.0, 31.2, 25.4, 25.2,
25.2, 20.9, 20.8, 19.7; MS (Electrospray) m/z 690.2 (M + H2O)+,
673.1 (M + H)+; Anal. Calcd for C38H56O10: C, 67.83; H, 8.39.
Found: C, 67.72; H, 8.41.
hexanes); [R]23 -21.5° (c 3.0, CHCl3); IR (film) 3523, 2930,
D
1
2861 cm-1; H NMR (300 MHz, CDCl3) δ 7.24 (d, 4H, J ) 8.6
Hz), 6.86 (d, 4H, J ) 8.6 Hz), 4.51-4.48 (m, 4H), 4.34-4.29
(m, 2H), 4.30-4.00 (br s, D2O exchange, 2H), 4.15-4.05 (m,
2H), 3.78 (s, 6H), 3.45-3.42 (m, 4H), 1.93-1.85 (m, 2H), 1.75-
1.63 (m, 4H), 1.54-1.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
159.2, 130.2, 129.2, 113.8, 100.1, 72.8, 72.4, 64.3, 55.2, 39.4,
33.7; MS (CI, NH3) m/z 506 (M + NH4)+, 489 (M + H)+; HRMS
(CI, NH3) calcd for C27H40NO8 (M + NH4)+ 506.2754, found
(M + NH4)+ 506.2765.
(2R,4S,8S,10R)-4,8-Dih yd r oxy-1,11-d i(4-m eth oxyben z-
yloxy)-2,10-d i[(t e t r a h yd r op yr a n -2-yl)oxy]u n d e ca n -6-
on e (24). A solution of OsO4 (4 wt % in H2O, 2 mL) was added
to alkene 23 (1.07 g, 1.6 mmol) and NMO (380 mg, 3.2 mmol)
in t-BuOH/THF/H2O (42 mL, 10:3:1) at room temperature, and
the reaction mixture was stirred for 72 h, during which time
the color faded from dark brown to pale yellow. To this solution
were added H2O (10 mL) and NaIO4 (1.08 g, 5.05 mmol), and
the mixture was stirred for 20 h at room temperature. The
mixture was filtered and extracted with Et2O (100 mL), and
the aqueous phase was treated with saturated aqueous
Na2S2O3 (50 mL) and concentrated in vacuo to about half-
volume. The mixture was extracted with Et2O (2 × 50 mL)
and CH2Cl2 (2 × 50 mL), and the combined organic extracts
were washed with H2O and brine, dried, concentrated, and
chromatographed (2:3 EtOAc/hexanes and then 1:99 MeOH/
CHCl3) to give 24 as a clear oil (0.92 g, 85%): TLC Rf 0.55
Ack n ow led gm en t. We thank Parke Davis Warner
Lambert for generous support of this program of re-
search, Glaxo Wellcome Research Ltd. for the generous
research endowment (to A.G.M.B.), the Wolfson Foun-
dation for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College, and
the EPSRC.
Su p p or t in g In for m a t ion Ava ila b le: Spectral data for
3-methylenepentane-1,5-diols 1a -k , copies of 1H NMR and 13C
NMR spectra of diols 1b, 1c, 1d , 9 (1H NMR only, as a mixture
with 1b), iodocarbonate 11, and spiroketals 18 and 25, 1H
NMR spectra of bis-Mosher esters derived from diols 1a -h ,
NOE measurements on iodocarbonate 14, and X-ray crystal-
lographic data for Mosher ester 6g. This material is available
free of charge via the Internet at http://pubs.acs.org.
(1:99 MeOH/CHCl3); IR (film) 3480, 2945, 2856, 1709 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.24 (m, 4H), 6.84 (m, 4H), 4.47
(m, 2H), 4.52-4.44 (m, 4H), 4.43-3.89 (m, 6H), 3.78 (s, 3H),
J O991205X