Highly effective transition structure designed catalyst for the enantio- and position-selective dihydroxylation of polyisoprenoids.

Article abstract of DOI:10.1021/ol016577i

[structure: see text] The chiral monocinchona derivative shown, synthesized in one step from two efficiently prepared chiral building blocks, was designed under mechanistic guidance as a catalyst for the enantio- and position-selective dihydroxylation of the terminal isopropylidene group of polyisoprenoids. Its efficacy as a synthetic reagent for this purpose was demonstrated for several different substrates.

Full text of DOI:10.1021/ol016577i

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3211-3214
Highly Effective Transition Structure
Designed Catalyst for the Enantio- and
Position-Selective Dihydroxylation of
Polyisoprenoids
E. J. Corey* and Junhu Zhang
Department of Chemistry and Chemical Biology HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received August 14, 2001
ABSTRACT
The chiral monocinchona derivative shown, synthesized in one step from two efficiently prepared chiral building blocks, was designed under
mechanistic guidance as a catalyst for the enantio- and position-selective dihydroxylation of the terminal isopropylidene group of polyisoprenoids.
Its efficacy as a synthetic reagent for this purpose was demonstrated for several different substrates.
The biscinchona alkaloid catalyzed dihydroxylation of olefins
is remarkable because of its broad utility, fundamental
mechanistic complexity, and uniqueness.1,2 Despite the
availability of extensive experimental evidence in favor of
a highly organized [3 + 2] mechanistic pathway, as il-
lustrated by pre-transition state assembly 1 for styrene and
a bisdihydroquinidine catalyst,3-7 and a rejection6b,8 of the
originally advanced9,10 [2 + 2] pathway, there remains an
impression of uncertainty regarding the asymmetric dihy-
droxylation that is not easily dispelled.11,12 Perhaps the best
measure of the value of a transition state model such as 1
(5) (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1995, 117, 10805. (b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C.
Tetrahedron Lett. 1995, 36, 3481. (c) Corey, E. J.; Noe, M. C.; Ting, A.
Tetrahedron Lett. 1996, 37, 1735. (d) Corey, E. J.; Noe, M. C.; Lin, S.
Tetrahedron Lett. 1995, 36, 8741. (e) Corey, E. J.; Noe, M. C.; Guzman-
Perez, A. J. Am. Chem. Soc. 1995, 117, 10817.
(1) For a review of the catalytic asymmetric dihydroxylation of olefins,
see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(2) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(6) (a) Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996,
37, 4899. See also: (b) DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless,
K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc.
1997, 119, 9907.
(7) Corey, E. J.; Sarshar, S.; Azimioara, M. D.; Newbold, R. C.; Noe,
M. C. J. Am. Chem. Soc. 1996, 118, 7851.
(3) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
(4) (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579.
(b) Corey, E. J.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, 35, 2861.
(c) Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1994, 35,
6427. (d) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (e)
Corey, E. J.; Noe, M. C.; Sarshar, S. J. Am. Chem. Soc. 1993, 115, 3828.
(8) (a) Dapprich, S.; Ujaque, G.; Maseras, F.; Lledo´s, A.; Musaev, D.
G.; Morokuma, K. J. Am. Chem. Soc. 1996, 118, 11660. (b) Pidun, U.;
Boehme, C.; Frenking, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2817.
(c) Torrent, M.; Deng, L.; Duran, M.; Sola, M.; Ziegler, T. Organometallics
1997, 16, 13.
(9) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263.
10.1021/ol016577i CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

Scheme 1
(Criegee, Corey, Noe; CCN model3) is its predictive power.
serves as a conformationally fixed activating ligand for OsO4,
which holds it in a suitable position for reaction with the
substrate in the binding pocket. The N-benzhydryl/benzoyl
domain caps the top of the binding pocket and limits
penetration of the substrate up into that region of the pocket
while providing a upper binding surface. Finally, the (R)-
tert-butyl-9-anthryl carbinol domain places the 9-anthryl
In this paper we describe the successful application of the
CCN model3 to the design of a new catalyst (2) for the
enantio- and position-selective dihydroxylation of a variety
of polyolefinic substrates of the isoprenoid type. Our
expectation was that the reactive complex 2‚OsO4 would
react selectively with the terminal isopropylidine unit of a
polyprenoid substrate via the pre-transition state assembly
represented by 3 to form the corresponding terminal dihy-
droxylation product with >90% enantioselectivity. Presented
herein is a full confirmation of this prediction and, in
addition, evidence that catalyst 2 is an exceedingly useful
and practical new reagent.
In pre-transition state assembly 3 there are four key
domains of the ligand part, which are all important to catalyst
function and are integrated in a conformationally organized
way. The 1,4-dioxanaphthopyridazine domain in the center
has several functions: (1) it serves as a distance-critical
spacer for the domains on the left and right and as a binding
surface for the R portion of the substrate, and (2) it maintains
the attached domains to the left and right with fixed cisoid,
coplanar C-O-pyridazine-O-C geometry at a proper distance
for substrate intercalation. The dihydroquinidine domain
(10) (a) Norrby, P.-O.; Kolb, H. C.; Sharpless, K. B. Organometallics
1994, 13, 344. (b) Norrby, P.-O.; Kolb, H. C.; Sharpless, K. B. J. Am.
Chem. Soc. 1994, 116, 8470. (c) Becker, H.; Ho, P. T.; Kolb, H. C.; Loren,
S.; Norrby, P.-O.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 7315. (d)
Norrby, P.-O.; Becker, H.; Sharpless, K. B. J. Am. Chem. Soc. 1996, 118,
35. (e) Sharpless, K. B.; Teranishi, A. Y.; Ba¨ckvall, J.-E. J. Am. Chem.
Soc. 1977, 99, 3120. (f) Jørgensen, K. A.; Schiøtt, B. Chem. ReV. 1990,
90, 1483.
(11) Chem. Eng. News. 1997, 75 (Nov 3), 23.
(12) Nelson, D. W.; Gypser, A.; Ho, P. T.; Kolb, H. C.; Kondo, T.;
Kwong, H.-L.; McGrath, D. V.; Rubin, A. E.; Norrby, P.-O.; Gable, K. P.;
Sharpless, K. B. J. Am. Chem. Soc. 1997, 119, 1840.
3212
Org. Lett., Vol. 3, No. 20, 2001

group in the vertical arrangement shown in 3 so that it
functions as the right-hand wall of the binding pocket. In
previous work 1-anthryl-4c and 9-anthrylmethyl5c groups have
been used successfully as binding surfaces in structure-based
catalyst design for enantioselective OsO4-mediated dihy-
droxylation of olefins. However, these specific groups are
not suited to the present application.
Farnesyl and geranylgeranyl acetates (13 and 14) are
known to undergo oxidation by OsO4 and the standard
Sharpless (DHQD)2-PYDZ ligand with poor selectivity with
respect to dihydroxylation at the terminal isopropylidene
group vs the internal olefinic linkage(s).5d,18 In contrast, as
shown in Scheme 3 catalyst 2 (1 mol %) affords the highest
The synthetic pathway for the assembly of catalyst 2 is
outlined in Scheme 1. Catalytic reduction of tert-butyl-9-
anthryl ketone (4) by BH3-THF in the presence of the chiral
(R)-oxazaborolidine 5 (20 mol %) in toluene at reflux for
25 min (CBS method)13 afforded the corresponding (R)-
alcohol 6 (99% ee after one recrystallization). Conversion
of 6 to the potassium alkoxide (KH, THF, 0.5 h) and reaction
with 1,4-dichloronaphthopyridazine (7)14 at 23 °C for 0.5 h
produced the monoether 8. Coupling of 8 with the potassium
salt of the dihydroquinidine derivative 9 (110 °C, 0.5 h) gave
catalyst 2 in good yield. The synthesis of 9 was accomplished
by the straightforward reaction sequence shown in Scheme
2 starting with dihydrocupreidine (10), prepared by dem-
Scheme 3
Scheme 2
selectivity observed thus far in dihydroxylation of 13 and
14. In the case of 13 the (R)-terminal diol 15 of 97% ee can
be isolated in 72% yield (84% based on recovered starting
material (brs)) with only ca. 4% of internal diol being
formed.19 To investigate the minor internal dihydroxylation
pathway further, the dihydroxylation of farnesyl 4-methoxy-
benzoate was studied with catalyst 2. In addition to the major
terminal isopropylidene oxidized diol (86% yield brs, 95%
ee) ca. 4% of internal diol was obtained of 57% ee as
determined by HPLC analysis using a Chiral Technologies
AS column. The low ee of the minor product indicates that
it is probably formed by dihydroxylation modes not involving
(i.e., outside of) the binding pocket. The dihydroxylation of
geranylgeranyl acetate (14) at the terminal isopropylidene
unit also proceeded selectively with catalyst 2 to give (R)-
diol 16 (95% ee, 70% brs). The yields of 15 and 16 obtained
with 2 are higher than those obtained with the Noe-Lin
catalyst,5d a biscinchona type, in side by side experiments,
and also the reactions of 2 are considerably faster, i.e., more
strongly accelerated. It should be emphasized that the product
diols 15 and 16 possess the (R) configuration as expected.
Also, catalyst 2 could be recovered from these reactions for
reuse with at least 90% efficiency.20,21
ethylation of dihydroquinidine in aqueous HBr.15 Conversion
of 10 to the phenolic triflate16 followed by silylation to 11
and amination17 gave 12. The transformation of 12 to 9 was
accomplished in three steps without purification of interme-
diates in 85% overall yield.
(18) Crispino, G. A.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 4273.
(19) Enantiomeric purities, unless indicated otherwise, were determined
by 500 MHz 1H NMR analysis of the mono-(S)-MTPA (Mosher) ester using
racemic mono Mosher ester as standard.
(20) The diols 15 and 16 are readily converted via the corresponding
secondary mesylates (MeSO2Cl-py, then base) to the corresponding (S)-
epoxides, which are useful for the enantioselective synthesis of many
polycyclic natural products. See, for example: (a) Huang, A. X.; Xiong,
Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999. (b) Corey, E. J.; Lin,
S. J. Am. Chem. Soc. 1996, 118, 8765. (c) Corey, E. J.; Luo, G.; Lin, S. J.
Am. Chem. Soc. 1997, 119, 9927. (d) Corey, E. J.; Lee, J. J. Am. Chem.
Soc. 1993, 115, 8873. (e) Corey, E. J.; Lee, J.; Liu, D. R. Tetrahedron
Lett. 1994, 35, 9149.
(13) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(14) Hill, J. H. M.; Ehrlich, J. H. J. Org. Chem. 1971, 36, 3248.
(15) Heidelberger, M.; Jacobs, W. A. J. Am. Chem. Soc. 1919, 41, 817.
(16) Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T. Tetrahedron
1994, 50, 11827.
(17) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S.
L. Tetrahedron Lett. 1997, 38, 6367.
Org. Lett., Vol. 3, No. 20, 2001
3213

K2OsO4 (1 mol %), K3Fe(CN)6, K2CO3, CH3SO2NH2, and
Bu4NOH in 1:1:0.3 t-BuOH/H2O/methylcyclohexane at 0 °C
for 20 h, the terminal diol (R)-19 was obtained of 90% ee in
38% yield (53% brs, 90% recovery of 2), the major
byproduct being tetraol 20. By doubling the amount of
oxidant mixture (to 7 equiv) of K2Fe(CN)6 and eliminating
methylcyclohexane as cosolvent, squalene could also be
converted into the (R)-tetraol 20 after 3 h at 0 °C in 40%
isolated yield after silica gel chromatography (99% ee and
92% de as measured by HPLC analysis with a Chiral
Technologies AS column). Similarly the acetonide of (R)-
2,3-squalene diol could be dihydroxylated to the (R,R)-tetraol
monoacetonide 21 of 98% ee, 95% de in 50% yield (60%
brs, 92% recovery of 2) after 3 h at 0 °C. These syntheses
of 19, 20 and 21, which in our judgment are the most
efficient and convenient to date, emphasize the effectiveness
of catalyst 2.
In summary, the design, synthesis, and testing of catalyst
2, as described above, provides additional strong support for
the CCN transition state model for chiral ligand-catalyzed
dihydroxylation of olefins. In addition, the facile synthesis
of 2, its efficacy as a catalytic ligand at 1 mol % levels, and
its efficient recovery for reuse (90% or better) underscore
the value and practicality of 2 as a synthetic reagent. Further,
the elaborate binding pocket and design elements of 2 lend
confidence that organic chemistry can advance the frontier
of molecular catalysis toward enzyme-like performance with
greater versatility and much lower complexity. Also, we have
discovered an excellent new way of accelerating the dihy-
droxylation of water insoluble substrates in t-Bu4NOH as a
surfactant. Finally, the utility of reagent 2 in multistep
synthesis has been demonstrated by a synthesis of serran-
tenediol (as described in the paper that follows).
As anticipated the dihydroxylation of (E)-nerolidol (17)
using 2 as catalyst (1 mol %) gave the (R)-dihydroxylation
product 18 with 94% π-facial selectivity and high position
selectivity for the terminal isopropylidine group (isolated
yield 78%; 96% brs).
(S)-2,3-Oxidosqualene, a very important precursor in the
biosynthesis of triterpenoids and sterols, is readily prepared
from inexpensive commercial squalene using 2 as catalyst
via diol 19. In this case, because squalene is only very
slightly soluble in aqueous t-BuOH, the dihydroxylation is
slow at 0 °C. However, we have discovered that the reaction
is accelerated by the use of 0.5 equiv of n-Bu4NOH as
surfactant (relative to squalene). Thus, using 2 (1 mol %),
(21) Procedure for Synthesis of 15. A mixture of ligand 2 (32.0 mg,
31.3 µmol), K2OsO4‚2H2O (5.9 mg, 15.7 µmol), K3Fe(CN)6 (3.10 g, 9.42
mmol), K2CO3 (1.30 g, 9.42 mmol), CH3SO2NH2 (299 mg, 3.14 mmol),
and 2,6-(E,E)-farnesyl acetate (829 mg, 3.14 mmol) in 32 mL of 1:1
t-BuOH/H2O was stirred at 0 °C for 4 h. The reaction mixture was treated
with 10 mL of saturated aqueous Na2SO3 and 10 mL of saturated Na2S2O3
at 0 °C, allowed to warm to 23 °C, and stirred for 45 min. After removal
of t-BuOH under reduced pressure, the reaction mixture was extracted four
times with 50 mL of ethyl acetate. The combined extracts were washed
with 15 mL of 1 N NaOH, followed by 20 mL of brine, dried over Na2-
SO4, and concentrated in vacuo. The residue was purified by silica gel
chromatography (20-40% EtOAc in hexanes) to give 124 mg of unreacted
farnesyl acetate (15%), 37.4 mg of 6,7-dihydroxy-6,7-dihydrofarnesylacete
(4%), and 674 mg of (10R)-10,11-dihydroxy-10,11-dihydrofarnesyl acetate
(84%, 72% uncorrected for recovered farnesyl acetate). Elution with 20%
EtOH in EtOAc provided 38.0 mg (4%) of tetraol and 29.5 mg (92%) of
recovered ligand 2. The spectroscopic data of the terminal diol agreed with
those reported. The ee of (10R)-10,11-dihydroxy-10,11-dihydrofarnesyl
Acknowledgment. This research was supported by a
Canadian NSERC postdoctoral fellowship and by Pfizer Inc.
Supporting Information Available: Procedures for the
synthesis of 2 and for its use as a catalyst for enantio- and
position-selective dihydroxylation of selected substrates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
acetate was determined as 97% by H NMR analysis of its corresponding
mono-(S)-MTPA ester: 1H NMR (500 MHz, C6D6) δ 3.54 (s, 3H) for the
R enantiomer; δ 3.47 (s, 3H) for the S enantiomer, corresponding to the
R-methoxy group of the ester.
OL016577I
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Org. Lett., Vol. 3, No. 20, 2001