A convenient and asymmetric protocol for the synthesis of natural products containing chiral alkyl chains via Zr-catalyzed asymmetric carboalumination of alkenes. Synthesis of phytol and vitamins E and K.

Article abstract of DOI:10.1021/ol010142d

[reaction: see text]. A convenient and asymmetric protocol for the synthesis of chiral oligoisoprenoids is described. Typically, a C14 vitamin E side chain 5 was synthesized in 47% yield over four steps. Isomeric purity of 5 was upgraded to >99% R at C-2 and 97% R at C-6 by the statistical formation of stereoisomeric p-phenylenebisurethanes and their diastereomeric separation. In addition, phytol and vitamin K were synthesized in 21% and 28% overall yields, respectively, over five steps from 1.

Full text of DOI:10.1021/ol010142d

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3253-3256
A Convenient and Asymmetric Protocol
for the Synthesis of Natural Products
Containing Chiral Alkyl Chains via
Zr-Catalyzed Asymmetric
Carboalumination of Alkenes. Synthesis
of Phytol and Vitamins E and K†
Shouquan Huo and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907-1393
negishi@purdue.edu
Received June 26, 2001 (Revised Manuscript Received September 10, 2001)
ABSTRACT
A convenient and asymmetric protocol for the synthesis of chiral oligoisoprenoids is described. Typically, a C14 vitamin E side chain 5 was
synthesized in 47% yield over four steps. Isomeric purity of 5 was upgraded to >99% R at C-2 and 97% R at C-6 by the statistical formation
of stereoisomeric p-phenylenebisurethanes and their diastereomeric separation. In addition, phytol and vitamin K were synthesized in 21%
and 28% overall yields, respectively, over five steps from 1.
We describe herein a novel, highly efficient, and enantio-
selective protocol for the synthesis of natural products
containing chiral alkyl chains via the Zr-catalyzed asym-
metric carboalumination of alkenes1-3 and the Cu-catalyzed
homoallylation or homopropargylation4 of â-branched chiral
alkyl iodides or sulfonates.
Of various natural products of terpenoid origin, those
containing saturated and flexible chiral chains, such as
vitamins E and K,5 have presented one of the ultimate
synthetic challenges from the methodological viewpoint.
Highly desirable is a synthetic protocol permitting high
efficiency including high product yields and high selectivity,
especially high enantioselectivity,6 while simultaneously
satisfying various other requirements. One of the current
benchmark syntheses is that of a C15 side chain of vitamins
E and K reported by Noyori,5h which appears to satisfy the
† This paper is dedicated to Professor Herbert C. Brown, a pioneer in
organometallic enantioselective synthesis, on the occasion of his 90th
birthday.
(1) (a) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771.
(b) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577.
(2) A recent report that addition of H2O accelerates the Zr-catalyzed
methylalumination is notheworthy: Wipf, P.; Ribe, S. Org. Lett. 2000, 2,
1713. See also: Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503.
(3) For Zr-catalyzed asymmetric carbomagnesation of allylically hetero-
substituted alkenes, which evidently proceeds via cyclic carbozirconation
and is therefore discrete from the reaction discussed herein, see: (a) Morken,
J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6697.
(b) Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35,
1262.
(4) (a) Tamura, M.; Kochi, J. Synthesis 1971, 303. (b) Fouquet, G.;
Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 82. (c) Schlosser, M.
Angew. Chem., Int. Ed. Engl. 1974, 13, 701.
10.1021/ol010142d CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

above-mentioned requirements reasonably well. Even so,
asymmetric construction of the chiral centers in the reported
cases requires stereodefined allylically heterosubstituted
alkenes that must be synthesized and purified for subsequent
asymmetric operations.
yield for each stereoisomer. It is noteworthy that two and
three successive and independent (lacking internal chiral
recognition) enantioselective operations of 85% and 70%
ee’s, respectively, are sufficient to provide chiral compounds
of ca. 99% ee, while permitting maximum possible chemical
yields of 86.1% and 61.8%, respectively10 (Table 1).
We recently reported a novel Zr-catalyzed enantioselective
carbon-carbon bond formation of simple, unactivated,
terminal alkenes,1 which represents an as yet rare example
of high enantioselection of one-point binding. While the ee
figures observed with alanes containing Et and higher alkyls
are typically g90%, those observed with the singularly
important methylalanes are about 75%.7 Along with our
efforts to improve the ee figures for methylalumination,8 we
were attracted by the statistical principle of enantiomeric
amplification (Horeau principle)9 through iteration of two
or more asymmetric operations or combination of two or
more chiral compounds. Thus, in the absence of internal
chiral recognition, the overall % ee after multiple asymmetric
operations (and/or synthetic combinations) may be readily
predicted from the coefficients of the general mathematical
expression (a1R + b1S)(a2R + b2S)..., where an and bn are
molar fractions of the nth R and S molecules or molecular
moieties. This also indicates the maximum possible chemical
Table 1. Statistical Enantiomeric Amplification in Iterative
Enantioselective Processes
dimeric products
trimeric products
% ee of
each cycle
max yield (%)
% ee
max yield (%)
% ee
70
75
80
85
74.5
78.1
82.0
86.1
94.0
96.0
97.6
98.8
61.8
67.2
73.0
79.2
98.9
99.4
99.7
99.9
With this statistical principle in mind, efficient syntheses
of phytol and vitamins E and K without protection-
deprotection or redox manipulation shown in Scheme 1 were
devised. We believe that these are the most direct and shortest
syntheses of vitamin E and K side chains and phytol reported
to date. The reaction of 1 with Me3Al (1 molar equiv) and
2 mol % of (-)-(NMI)2ZrCl211 in CH2Cl2 at 23 °C1 followed
by treatment with I2 (4 molar equiv) in Et2O produced iodide
2 in 72% yield. Oxidation of the carboalumination product
with O2 similarly gave the corresponding alcohol 3 in 79%
yield. Analysis of the 1H NMR spectra of its Mosher esters
obtained by using both (R)- and (S)-R-methoxy-R-trifluoro-
methylphenylacetyl chlorides (MTPA) and pyridine indicated
3 to be 74% ee. Either 2 or 3 was readily converted to 4 via
Cu-catalyzed coupling with 3-butenylmagnesium bromide in
93% or 78% yield, respectively, as shown in Scheme 1.
Conversion of 4 into 5 was carried out in 76% yield as in
the conversion of 1 into 3.
(5) (a) Scott. J. W.; Bizzarro, F. T.; Parrish, D. R.; Saucy, G. HelV. Chim.
Acta 1976, 59, 290. (b) Chan, K. K.; Cohen, N.; De Noble, J. P.; Specian,
A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497. (c) Cohen, N.; Eichel,
W. F.; Lopresti, R. J.; Neukom, C.; Saucy, G. J. Org. Chem. 1976, 41,
3505. (d) Fuganti, C.; Grasselli, P. J. Chem. Soc., Chem. Commun. 1979,
995. (e) Trost, B. M.; Klun, T. P. J. Am. Chem. Soc. 1981, 103, 1864. (f)
Fujiwara, J.; Fukutani, Y.; Hasegawa, M.; Maruoka, K.; Yamamoto, H. J.
Am. Chem. Soc. 1984, 106, 5004. (g) Takabe, K.; Uchiyama, Y.; Okisaka,
K.; Yamada, T.; Katagiri, T.; Okazaki, T.; Oketa, Y.; Kumobayashi, H.;
Akutagawa, S. Tetrahedron Lett. 1985, 26, 5153. (h) Takaya, H.; Ohta, T.;
Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori,
R. J. Am. Chem. Soc. 1987, 109, 1596. (i) Inoue, S.; Ikeda, H.; Sato, S.;
Horie, K.; Ota, T.; Miyamoto, O.; Sato, K. J. Org. Chem. 1987, 52, 5495.
(j) Takano, S.; Yoshimitsu, T.; Ogasawara, K. Synlett 1994, 119.
(6) The term enantioselectivity is used here to indicate the extent of
preferential formation of one enantiomeric molecule or molecular moiety
from a prochiral molecule or molecular moiety.
1
Analysis of the H NMR spectra of the Mosher esters of
(7) Although the origin of this significant difference is not clear, the
possibility that Et and higher alkyls might exert a secondary chiral induction
stemming from R-agostic interaction, which is uniquely absent in the case
of Me, is an attractive notion to be pursued. For a recent discussion of the
effect of R-agostic interaction in alkene polymerization, see: Grubbs, R.
H.; Coates, G. W. Acc. Chem. Res. 1996, 29, 85.
5 indicated that the second Zr-catalyzed carboalumination
step to be 74% ee. It may therefore be concluded that the
second carboalumination step is essentially unaffected by the
first asymmetric carbon center. Although the NMR analysis
mentioned above failed to directly establish the overall ee
of 5, the statistical analysis discussed above indicated that
the overall ee should be 95.6%.12 The calculated diastereo-
meric ratio, i.e., (R,R + S,S)/(R,S + S,R), of 3.42 agreed
well with the experimental value of 3.3 obtained from the
relative intensities of 13C NMR signals for the C atoms of
the CH3 groups bonded to the C-2 and C-6 atoms.
(8) The ee figures for methylalumination observed by Negishi1 and Wipf2
are as follows. Negishi-Kondakov protocol: RCH2CHdCH2, 70-81% ee;
ArCHdCH2, 85% ee; c-C6H11CHdCH2, 65% ee. Wipf-Ribe modifica-
tion: RCH2CHdCH2, 75-86% ee; ArCHdCH2, 89-90% ee; c-C6H11CHd
CH2, 55-74% ee. Judging from these data, addition of H2O or MAO does
appear to improve the ee for methylalumination by several %. For the
preparation of highly pure stereoisomers, however, either subsequent
purification or further substantial improvement in ee would be needed.
(9) For recent reviews and general discussions with pertinent references,
see: (a) Rautenstrauch, V. Bull. Soc. Chim. Fr. 1994, 131, 515. (b) El Baba,
S.; Sartor, K.; Poulin, J. C.; Kagan, H. B. Bull. Soc. Chim. Fr. 1994, 131,
525. For applications of the statistical asymmetric amplification-purifica-
tion, see: (c) Vigneron, J. P.; Dhaenens, M.; Horeau, A. Tetrahedron 1973,
29, 1055. (d) Toda, F.; Tanaka, K. Chem. Latt. 1986, 1905. (e) Fleming, I.;
Ghosh, S. K. J. Chem. Soc., Chem. Commun. 1994, 99. The references list
below are several earlier and representative examples among many that
explicitly discuss the statistical asymmetric amplification in synthesis: (f)
Kogure, T.; Eliel, E. L. J. Org. Chem. 1984, 49, 578. (g) Midland, M. M.;
Gabriel, J. J. Org. Chem. 1985, 50, 1144. (h) Hoye, T. R.; Suhadolnik, J.
C. J. Am. Chem. Soc. 1985, 107, 5312. (i) Mori, K.; Senda, S. Tetrahedron
1985, 41, 541.
Noting in the literature13 that all four diastereomers of
vitamin E can be separately seen by 13C NMR spectroscopy,
(10) See Table 1 compiled by using the mathematical expression: (a1R
+ b1S)(a2R + b2S) (a3R + b3S).
(11) This compound was originally synthesized by G. Erker and co-
workers: Erker, G.; Aulbach, M.; Knickmeier, M.; Wingbermu¨hle, D.;
Kru¨ger, C.; Nolte, M.; Werner, S. J. Am. Chem. Soc. 1993, 115, 4590.
(12) Compound 3 of 74% ee ) 0.87R + 0.13S and compound 5 of 74%
ee at C-2 ) 0.87R + 0.13S gives the following statistical expression (0.87R
+ 0.13S)2 ) 0.7569R,R + 0.0169S,S + 0.1131R,S + 0.1131S,R. The
statistically predicted overall % ee of 5 ) ((0.7569-0.0169)/(0.7569 +
0.0169)) × 100 ) 95.6%. The diastereomeric ratio of 5 ) (0.7569 +
0.0169)/(2 × 0.1131) ) 3.42.
3254
Org. Lett., Vol. 3, No. 21, 2001

Scheme 1
we decided to use the optically pure R isomer (g99% R) of
Although the % ee of the final product, i.e., vitamin E, was
not experimentally determined in this experiment,15 it now
seems very safe to predict that the statistical cross-coupling
(vide supra) of 6 (96.7% ee) with 7 (g98% ee) must have
produced vitamin E of >99.9% ee. It should also be noted
that the observation of the highest field signal of the four
signals for the C-3′ atom as the major one, to which the
R,R,R (and S,S,S) isomers were previously assigned,13 further
confirms the assignment of the R and R,R configurations to
2-4 and 5 (or 6), respectively.
a chroman derivative 75a in Scheme 1 obtained via resolution
as a reagent for determining the overall ee of 5. To this end,
5 was converted into 6 in 95% yield and then into vitamin
E in 50% yield by the reported procedure,5b as shown in
Scheme 1. Assuming that the final cross-coupling step is
essentially statistical, the R,R,R:R,S,S:(R,R,S + R,S,R) ratio
for vitamin E may be calculated to be 75.7:1.7:(11.3 + 11.3).
13C NMR analysis of the C-3′ signals indicated the experi-
mental ratio to be 75.2:1.2:(10.3 + 13.3), which is in
excellent agreement with the calculated ratio, strongly
suggesting that the cross-coupling step producing vitamin E
must indeed be essentially statistical. Furthermore, the above-
indicated R,R,R to R,S,S ratio of vitamin E observed
experimentally permits determination of the overall ee of 5
to be 96.7%,14 which once again is in excellent agreement
with the statistically predicted value of 95.6% (vide supra).
Having established the feasibility of efficiently synthesiz-
ing flexible chiral compounds such as 5 and 6 in high ee,
we then turned our attention to no less challenging issue of
(14) The experimental overall % ee of 5 ) ((75.21 - 1.25)/(75.21 +
1.25)) × 100 ) 96.7%.
(15) It has been reported that a combination of capillary GLC and HPLC
using a chiral column distinguishes all eight stereoisomers of vitamin E:
Vecchi, M.; Walther, W.; Glinz, E.; Netscher, T.; Schmid, R.; Lalonde,
M.; Vetter, W. HelV. Chim. Acta 1990, 73, 782.
(13) Bremser, W.; Vogel, F. G. M. Org. Magn. Reson. 1980, 14, 155.
Org. Lett., Vol. 3, No. 21, 2001
3255

stereoisomeric separation for isolation of the desired single
stereoisomer. In addition to the classical resolution technique
requiring pure chiral reagents, we were also attracted by the
feasibility of using bi- and multifunctional achiral reagents
for statistical enantiomeric or asymmetric amplification.9c-e
This has been reported only in a few papers since Horeau’s
original publication in 1973.9c Furthermore, the substrates
have been restricted to relatively rigid secondary and tertiary
alcohols in which the chiral center is at the HO-bearing C
atom.
Treatment of 3 (74% ee) with p-phenylene diisocyanate
(PPDI) in a 2:1 molar ratio in benzene in the presence of
2% DABCO at 60 °C over 4 h produced the corresponding
bisurethane (11) in quantitative yield as a crystalline
compound, which could be readily recrystallized from MeOH
(Scheme 2). After four cycles of recrystallization requiring
the first example of separation-purification of primary
alcohols resorting to statistical asymmetric amplification.
For the synthesis of (R,R)-phytol, which is a widely used
key intermediate for the synthesis of both vitamin E5a,i,j and
vitamin K,18 the methylalumination product obtained from
4 was converted to iodide 8. After its Cu-catalyzed cross-
coupling with Me3SiCtC(CH2)2MgBr and desilylation with
methanolic KOH to give 9, its methylalumination with
Me3Al-Cp2ZrCl2 followed by evaporation of the volatiles,
ate complexation with n-BuLi, and treatment with (CH2O)n
in THF19 afforded g99% (E)-phytol in 65% yield, the yield
based on 1 over five steps being 21%. In fact, vitamin K
was preparable more directly by alkenylation with alkenyl-
alanes20 of a naphthoquinone derivative 1021 in 86% yield
(28% over five steps).
In summary, the preliminary results reported above have
established the feasibility of developing an efficient protocol
with minimal or no protection-deprotection and redox
manipulations for the synthesis of phytol and vitamins E and
K, which promises to be applicable to many other related
syntheses. It has been demonstrated that the statistical
asymmetric amplification principle permits the synthesis of
flexible primary alcohols of high stereoisomeric purity
containing two or more asymmetric carbon atoms even if
each stereogeneric process is of modest stereoselectivity. Not
only synthetic iteration or combination but also stereo-
isomeric purification based on statistical asymmetric ampli-
fication can be exploited in their syntheses. At the same time,
however, the results point to the desirability of further
improving the enantioselectivity in each stereogeneric syn-
thetic step for higher practical synthetic values. Our efforts
along this line are in progress.
Scheme 2
<1 day, the crystals recovered in 43% were treated with
NaOEt in EtOH under reflux for 0.5 h to give a 95% yield
of 3, which was 93% ee by Mosher ester analysis. Prompted
by these initial results, we then subjected 5, which was 87%
R and 13% S, i.e., 74% ee, at both C-2 and C-6, to the
treatment with PPDI and recrystallization from MeOH. To
our delight, the bisurethane readily crystallized, and its
recrystallization from MeOH required only 0.5-1 h for each
cycle. We also learned that the progress of asymmetric
enrichment could be readily checked by monitoring the ratios
of diastereomeric bisurethane by 13C NMR spectroscopy.
After nine cycles of recrystallization, reductive cleavage of
the urethane with LiAlH4 in THF at 50 °C for 1 h in 98%
Acknowledgment. We thank the National Science Foun-
dation (CHE-0080795), the National Institutes of Health (GM
36792), and Purdue University for supports of this research.
We also thank Albemarle, Boulder Chemical, and Johnson-
Matthey for assistances in the procurement of Al, Zr, and
Pd compounds, respectively. Information on the analysis of
vitamin E provided by Drs. D. Burdick, T. Netscher, A.
Ru¨ttimann, and R. Schmid of Hoffmann-La Roche (Basel)
is thankfully acknowledged. We also acknowledge Professors
H. Kagan, R. Noyori, and D. Seebach for useful suggestions
and information.
yield provided 5 ([R]23 +9.21; lit. max value +9.365a),
D
which was recovered in 33% overall yield, as compared with
the statistically estimated maximum recovery of 57.3%.16 On
the basis of a reasonable assumption that the formation of
the bisurethane 12 is statistical, the desired R,R,R,R isomer
is predicted to be 99.9% ee.17 The Mosher ester analysis
indicated that the stereoisomeric purity at C-2 to be well
over 99%. Furthermore, the stereoisomeric purity at C-6 was
also determined to be 97% (or 94% ee at C-6) by 13C NMR
analysis of the C-12 and C-13 signals. Thus, the C14 chain
moiety of vitamins E and K as well as of phytol, i.e., 5, has
been synthesized in 97% overall isomeric purity, providing
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL010142D
(18) (a) Tso, H.; Chen, Y. J. Chem. Res. Synop. 1995, 104. (b) Schmid,
R.; Antoulas, S.; Ru¨ttimann, A.; Schmid, M.; Vecchi, M.; Weiser, H. HelV.
Chim. Acta 1990, 73, 1276. (c) Ru¨ttimann, A. Chimia 1986, 40, 290 and
references therein.
(19) Okukado, N.; Negishi, E. Tetrahedron Lett. 1978, 19, 2357.
(20) (a) Matsushita, H.; Negishi, E. J. Am. Chem. Soc. 1981, 103, 2882.
(b) Negishi, E.; Matsushita, H.; Okukado, N. Tetrahedron Lett. 1981, 22,
2715.
(16) The maximum yield can be predicted from the following expres-
sion: (0.87R + 0.13S)4, i.e, (0.874 + 0.134) × 100 ) 57.3.
(17) The statistically predicted overall % ee ) ((0.874 - 0.134)/(0.874
+ 0.134)) × 100 ) 99.9%.
(21) Lipshutz, B. H.; Kim, S.; Mollard, P.; Stevens, K. L. Tetrahedron
1998, 54, 1241.
3256
Org. Lett., Vol. 3, No. 21, 2001