Platinum-catalyzed tandem diboration/intramolecular allylboration: Diastereoselective access to cyclohexanes bearing 1,3-diols

Article abstract of DOI:10.1055/s-2004-822379

A tandem reaction sequence consisting of platinum-catalyzed diboration of 1,3-dienes followed by intramolecular allylboration and oxidative hydrolysis has been developed for constructing cyclic structures that bear a 1,3-diol. This methodology has proven effective for synthesizing cyclohexanes from dienals in good yields (44-64%) to generate diols containing two new vicinal stereocenters, one of which is quaternary. The products are obtained in high regio- and diastereomeric ratios (>19:1). A preexisting stereocenter on the substrate can provide high levels of asymmetric induction in the product.

Full text of DOI:10.1055/s-2004-822379

PAPER
1321
Platinum-Catalyzed Tandem Diboration/Intramolecular Allylboration:
Diastereoselective Access to Cyclohexanes Bearing 1,3-Diols
P
latinum-Catalyz
.
edTandem
E
iboration/Intra
r
m
olecul
i
a
r
Ally
c
lboration Ballard, James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,
27599-3290, USA
Fax +1(919)9622388; E-mail: morken@unc.edu
Received 15 April 2004
Abstract: A tandem reaction sequence consisting of platinum-cat-
alyzed diboration of 1,3-dienes followed by intramolecular allylbo-
ration and oxidative hydrolysis has been developed for constructing
cyclic structures that bear a 1,3-diol. This methodology has proven
effective for synthesizing cyclohexanes from dienals in good yields
(44–64%) to generate diols containing two new vicinal stereo-
centers, one of which is quaternary. The products are obtained in
high regio- and diastereomeric ratios (>19:1). A preexisting stereo-
center on the substrate can provide high levels of asymmetric induc-
tion in the product.
Key words: diboration, diene, platinum, allylboration, quaternary
stereocenter
Scheme 1
Addition of intermetallic reagents across the multiple
bonds of organic substrates generates synthetically useful
dimetallic species. To date, intermetallic reagents have
been added across alkynes, enones, imines, alkenes, and
dienes.1 Recently our laboratory began a program in this
area and demonstrated the first enantioselective addition
of a diboron reagent across a simple olefin.2 In addition,
we have investigated the tandem 1,4-diboration/allylation
Scheme 2
involving chiral diborons and 1,3-dienes.3–5 This reaction
proceeds though the intermediacy of an allyl(bis)metal in-
Dienal 3 was chosen to initiate investigation on the tan-
dem diboration/stereoselective intramolecular allylation
termediate and we considered that if the precursor diene
were tethered to the carbonyl, a useful carbocyclic ring-
reaction. Synthesis of the substrate proceeded as shown in
forming reaction may result (Scheme 1).6 This reaction
Scheme 3. Finkelstein reaction of commercially available
would provide two new stereocenters and, depending on
5-chloropentyne followed by enolate alkylation gave ester
the connectivity of the tether and the regioselectivity of
the allylation, may introduce a quaternary stereocenter as
well.
1.7 The alkyne was converted to the 1,3-diene by enyne
metathesis using conditions developed by Diver.8 Reduc-
tion of the ester followed by oxidation to the aldehyde
provided 3 in reasonable yield.
Concerned that the tethered aldehyde may react faster
than the diene under diboration conditions thereby pre-
With 3 in hand, development of the tandem reaction se-
cluding development of the tandem reaction process, we
quence was commenced. Initial investigations surveyed
first examined the diene diboration in the presence of an
four diboron reagents: bis(diethyltartrato)diboron, bis(pi-
aldehyde. Exposure of isoprene, cyclohexanecarboxalde-
nacolato)diboron, bis(neopentylglycolato)diboron and
hyde and bis(diethyl-L-tartrateglycolato)diboron to 5
bis(catecholato)diboron [B2(cat)2]. We also surveyed a
mol% (Ph3P)2Pt(ethylene) for 14 hours at 80 °C smoothly
number of late transition metal complexes which are
provided the derived tandem diboration/allylation product
known to catalyze diboration and silaboration (see
(75% conversion), indicating that the aldehyde does not
Table 1). Catalyst 4 has proven effective for addition of
interfere with diboration but will undergo allylation reac-
tions with the allyl(bis)metal intermediate (Scheme 2).
silaboranes across dienes5b while complex 5 is known for
the diboration of simple olefins.2 Complexes 6–8 have
proven effective for diboration of dienes.3,4b Among the
four diboron reagents investigated, only bis(catechola-
SYNTHESIS 2004, No. 9, pp 1321–1324
Advanced online publication: 18.05.2004
DOI: 10.1055/s-2004-822379; Art ID: C02304ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4
to)diboron exhibited reactivity with any of the transition
metal complexes. As shown in Table 1, catalysts 7 and 8
were effective for the transformation of model substrate 3

1322
C. E. Ballard, J. P. Morken
PAPER
Scheme 4
the methyl group than between Ha and Hb. These observa-
tions indicate that the methyl group and the vicinal alco-
hol bear a trans relationship. The NOESY experiment
indicated closer proximity between Ha and the protons of
Scheme 3
into diol 9 (entries 4 and 5) in the presence of bis(catecho- the vinyl group than between Ha and the carbinol protons
lato)diboron. Notably, in both cases the six-membered cy- of the hydroxymethyl group. This indicates a cis relation-
clic diol was produced to the exclusion of the seven- ship between the secondary hydroxyl group and the hy-
membered ring product and the level of stereoinduction droxymethyl group.
was >19:1 as determined by 1H NMR analysis. Optimiza-
tion of reaction conditions indicated that the reaction pro-
ceeded equally well in THF at 60 °C and with 1.1
equivalents of bis(catecholato)diboron.
The major diastereomer produced in the tandem dibora-
tion/intramolecular allylation reaction is as depicted in
Figure 1
Scheme 4. The assignment was determined by analysis of
1H NMR coupling constants in conjunction with NOESY
In order to determine the effect of substitution at an alter-
nate location and the effect of alternate tether lengths, we
examined other substrates. Using a similar reaction se-
quence as described in Scheme 2, the substrates depicted
in Scheme 5 were prepared. Compounds 11, 13 and 15,
which have the same tether length between the aldehyde
and the diene as the model substrate 3, were each efficient
substrates for the reaction and all provided the six-mem-
bered carbocycle with a high level of stereoselection. The
data. The major product diastereomer appears to arise
from a Z-selective [1,4]-diboration of the 1,3-diene fol-
lowed by allylation through a six-membered transition
structure wherein the methyl group occupies an equatorial
position. The relative stereochemistry of product 9 was
assigned as follows (Figure 1). The coupling constant be-
tween Ha and Hb was 10.0 Hz, implying that they lie in an
axial-axial orientation.9 A NOESY experiment indicated
there was a shorter distance between Ha and the protons of
Table 1 a Screening of Catalysts for the Diene Diboration/Intramolecular Allylboration
Entry
Catalyst
Conditions
% Yield
9:10 (dr)
1
2
3
4
5
Ni(acac)2/DIBAL (4)
(nbd)Rh(acac)/quinap (5)
Pt(dba)2 (6)
toluene, 80 °C, 20 h
THF, r.t., 14 h
0
0
–
–
benzene, 80 °C, 24 h
benzene, 80 °C, 24 h
benzene, 80 °C, 24 h
0
–
Pt(dba)2/PCy3 (7)
(Ph3P)2Pt(CH2=CH2) (8)
30
64
>19:1 (>19:1)
>19:1 (>19:1)
a Experiments were conducted with 1.5 equiv of bis(catecholato)diboron.
Synthesis 2004, No. 9, 1321–1324 © Thieme Stuttgart · New York

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Platinum-Catalyzed Tandem Diboration/Intramolecular Allylboration
1323
TMS with the solvent resonance as the internal standard (CDCl3:
7.26 ppm). Data are reported as follows: chemical shift, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br =
stereoinduction from the existing stereocenter in sub-
strates 13 and 15 was also high (>19:1). The sense of in-
duction was ascertained for compound 16 by X-ray
structure analysis and for 14 by analogy with the chair-
like transition state model as described above. Dienal 17,
with one less carbon in the tether, may react to form either
a five-membered or six-membered ring product and ap-
pears to provide exclusively the cyclohexyl derivative.
While the yield for this transformation is low, the stereo-
selection still remains high. When the tether length is in-
creased such that either a seven-membered or eight-
membered ring may result, the reaction fails to provide the
tandem reaction product.
broad, m = multiplet), coupling constants (Hz) and assignment. 13
C
NMR spectra were recorded on a Bruker 400 MHz (100 MHz) spec-
trometer with complete proton decoupling. Chemical shifts are re-
ported in ppm from TMS with the solvent as the internal standard
(CDCl3: 77.0 ppm). IR spectra were obtained of solutions of ana-
lytes dissolved in CH2Cl2 using a Nicolet 560 infrared spectrometer.
Liquid chromatography was performed using forced flow (flash
chromatography) on silica gel (SiO2, 32–63 mm) purchased from
Scientific Absorbents or Sorbent Technologies. TLC was per-
formed on EM science 0.25 mm silica gel 60 plates. Visualization
was achieved with phosphomolybdic acid in EtOH followed by
heating. All reactions were conducted in oven and flame dried
glassware under an inert atmosphere of dry nitrogen or dry argon.
Deuterated solvents were used as received. Benzene was distilled
from CaH2 and freeze-pump-thaw degassed. Toluene was passed
through activated basic alumina. Anhydrous THF was purchased
from Aldrich Chemical Companies and used as received. Pt(dba)2
was synthesized by a literature procedure.10 All other reagents were
purchased from Aldrich Chemical Companies and used directly.
Diboration/Intramolecular Allylboration; General Procedure
Under an atmosphere of argon, the dienal (0.1 mmol) was dissolved
in anhyd THF (0.8 mL). Bis(catecholato)diboron (1.1 equiv) and
ethylenebis(triphenylphosphine)platinum(0) (0.05 equiv) were add-
ed. The reaction vial was capped and magnetically stirred in a 60 °C
oil bath for 24 h. The reaction mixture was diluted with anhyd THF
(2 mL) and NaOH (3 M, 0.4 mL) and H2O2 (30%, 0.4 mL) were
added dropwise. The mixture was stirred at r.t. for 3 h. The oxida-
tion was quenched by cautious addition of sat. Na2S2O3 (3 mL). The
presence of peroxide was checked with starch/KI paper. This mix-
ture was diluted with deionized water (10 mL) and extracted with
Et2O (3 × 10 mL). The combined organic extracts were washed with
NaOH (0.5 M, 2 × 5 mL), dried (MgSO4), filtered, rotary evaporat-
ed, and purified by flash chromatography (EtOAc–hexanes, 1:1).
Compound 9
IR: 3614, 3502, 2931, 2858, 2871, 2339, 1721, 1636, 1480, 1463,
1437, 1395, 1378, 1368, 1339, 1152, 1098, 1048, 1005 cm–1.
1H NMR (CDCl3): d = 6.05 (dd, J = 17.6, 11.0 Hz, 1 H), 5.28 (dd,
J = 17.6, 1.0 Hz, 1 H), 5.23 (dd, J = 11.0, 1.0 Hz, 1 H), 4.21 (d, J =
11.4 Hz, 1 H), 3.62 (d, J = 11.4 Hz, 1 H), 3.21 (d, J = 10.0 Hz, 1 H),
2.91 (br s, 1 H), 2.73 (br s, 1 H), 1.98–1.85 (m, 2 H), 1.79–1.72 (m,
1 H), 1.63–1.35 (m, 3 H), 1.22–1.11 (m, 1 H), 1.17 (d, J = 6.2 Hz, 3
H).
13C NMR (CDCl3): d = 144.0, 114.2, 82.1, 64.9, 45.5, 34.6, 33.9,
33.7, 21.0, 19.0.
HRMS–FAB: m/z [M + Li] calcd for C10H18O2Li: 177.1467; found:
177.1462.
Scheme 5
Compound 12
IR: 3610, 3498, 3083, 3056, 2939, 2865, 2667, 2358, 2341, 2254,
In conclusion, we have developed a tandem diene dibora-
tion/intramolecular allylboration that allows stereoselec-
tive access to cyclohexanes bearing 1,3-diols from linear
dienals. Preexisting stereocenters on the tether can be
used to control the stereochemistry of the new chiral cen-
ters. Efforts directed toward catalytic asymmetric dimeta-
lation reactions continue in our laboratory
1733, 1636, 1451, 1418, 1376, 1046, 1000, 990, 924, 911 cm–1.
1H NMR (CDCl3): d = 5.81 (dd, J = 17.8, 11.4 Hz, 1 H), 5.26 (dd,
J = 11.4, 1.0 Hz, 1 H), 5.21 (dd, J = 17.8, 1.0 Hz, 1 H), 3.88 (dd,
J = 6.4, 3.0 Hz, 1 H), 3.92–3.86 (m, 1 H), 3.82 (d, J = 11.4 Hz, 1 H),
3.57 (d, J = 11.4 Hz, 1 H), 2.48 (s, 2 H), 1.81–1.58 (m, 3 H), 1.50–
1.21 (m, 4 H).
13C NMR (CDCl3): d = 142.4, 115.4, 74.3, 67.6, 45.4, 30.2, 29.5,
21.9, 21.1.
1H NMR spectra were recorded on Bruker DRX (400 MHz or 300
MHz) spectrometers. Chemical shifts are reported in ppm from
HRMS–FAB: m/z [M + Li] calcd for C9H16O2Li: 163.1310; found:
163.1306.
Synthesis 2004, No. 9, 1321–1324 © Thieme Stuttgart · New York

1324
C. E. Ballard, J. P. Morken
PAPER
Compound 14
Acknowledgment
IR: 3606, 3491, 3083, 3054, 2939, 2865, 2362, 2342, 2331, 1731,
1636, 1609, 1463, 1451, 1434, 1422, 1380, 1345, 1326, 1194, 1138,
1065, 1042, 1001, 990, 947, 919 cm–1.
1H NMR (CDCl3): d = 5.81 (ddd, J = 17.9, 11.0, 1.0 Hz, 1 H), 5.46
(dd, J = 17.9, 1.0 Hz, 1 H), 5.40 (dd, J = 11.0, 1.0 Hz, 1 H), 4.23 (d,
J = 11.4 Hz, 1 H), 3.86 (d, J = 11.4 Hz, 1 H), 3.69–3.63 (m, 1 H),
3.12 (br s, 1 H), 2.81 (br s, 1 H), 1.99–1.62 (m, 3 H), 1.50–1.16 (m,
4 H), 0.80 (d, J = 6.7 Hz, 3 H).
This work was supported by the NIH (GM 59417-03). JPM is an Al-
fred P. Sloan Research Fellow and a Packard Foundation Fellow
and thanks AstraZeneca, Bristol-Myers Squib and GlaxoSmithKli-
ne for support.
References
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Norman, N. C. Top. Catal. 1998, 5, 63. (b) Suginome, M.;
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Miyaura, N. J. Organomet. Chem. 2000, 611, 392.
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13C NMR (CDCl3): d = 143.0, 116.4, 78.7, 61.5, 48.4, 39.0, 29.6,
29.3, 24.0, 16.0.
HRMS–FAB: m/z [M + Li] calcd for C10H18O2Li: 177.1467; found:
177.1461.
Compound 16
IR: 3946, 3755, 3693, 3157, 3054, 2987, 2686, 2522, 2306, 2256,
1794, 1638, 1561, 1422, 1272, 1158, 1096 cm–1.
1H NMR (CDCl3): d = 6.04 (dd, J = 17.6, 11.0 Hz, 1 H), 5.28 (dd,
J = 17.6, 1.0 Hz, 1 H), 5.23 (dd, J = 11.0, 1.0 Hz, 1 H), 4.26 (dd,
J = 11.6, 3.4 Hz, 1 H), 3.72–3.61 (m, 2 H), 2.50 (d, J = 4.7 Hz, 1 H),
2.33–2.32 (m, 1 H), 1.88–1.87 (m, 1 H), 1.79–1.52 (m, 3 H), 1.25
(s, 1 H), 0.95–0.84 (m, 2 H), 0.85 (d, J = 6.2 Hz, 3 H).
13C NMR (CDCl3): d = 143.8, 114.5, 76.7, 64.7, 45.9, 42.2, 33.5,
30.6, 27.2, 22.2.
Compound 18
IR: 3610, 3502, 3076, 3054, 2939, 2867, 2362, 2342, 2323, 1733,
1684, 1646, 1449, 1439, 1420, 1391, 1200, 1171, 1154, 1048, 1013,
984 cm–1.
1H NMR (CDCl3): d = 4.91 (s, 1 H), 4.79 (s, 1 H), 4.13–4.01 (m, 2
H), 3.78 (dd, J = 11.1, 5.6 Hz, 1 H), 2.58–2.52 (m, 1 H), 2.37 (br s,
2 H), 2.17–2.02 (m, 2 H), 1.86–1.66 (m, 4 H), 1.58–1.47 (m, 1 H).
(7) Cookson, R. C.; Liverton, N. J. J. Chem. Soc., Perkin Trans.
1 1985, 1589.
(8) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271.
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ed.; New York: Wiley, 1991, 221.
(10) Cherwinski, W. J.; Johnson, B.; Lewis, J. J. Chem. Soc.,
Dalton Trans. 1974, 1404.
13C NMR (CDCl3): d = 146.2, 110.5, 71.4, 62.3, 50.1, 33.9, 31.8,
23.2.
HRMS–FAB: m/z [M + Li] calcd for C8H14O2Li: 149.1154; found:
149.1157.
Synthesis 2004, No. 9, 1321–1324 © Thieme Stuttgart · New York