A novel highly enantio- and diastereoselective synthesis of vitamin e side-chain

Article abstract of DOI:10.1016/j.tetlet.2014.12.081

A novel highly enantioselective (>99% ee) and diastereoselective (>98% de) method for the synthesis of chiral C₁₅ vitamin E side-chain 1 was developed. ZACA-lipase-catalyzed acetylation protocol to provide a key α,ω-dioxyfunctional C₅

Full text of DOI:10.1016/j.tetlet.2014.12.081

Accepted Manuscript
A novel highly enantio- and diastereoselective synthesis of vitamin E side-chain
Yohei Matsueda, Shiqing Xu, Ei-ichi Negishi
PII:
S0040-4039(14)02147-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.081
TETL 45605
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 December 2014
12 December 2014
14 December 2014
Please cite this article as: Matsueda, Y., Xu, S., Negishi, E-i., A novel highly enantio- and diastereoselective synthesis
of vitamin E side-chain, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.081
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
A novel highly enantio- and diastereoselective
synthesis of vitamin E side-chain
Leave this area blank for abstract info.
Yohei Matsueda, Shiqing Xu, Ei-ichi Negishi

Tetrahedron Letters
journal homepage: www.elsevier.com
A novel highly enantio- and diastereoselective synthesis of vitamin E side-chain
Yohei Matsueda, Shiqing Xu, Ei-ichi Negishi
Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN 47907-2084, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel highly enantioselective (>99% ee) and diastereoselective (>98% de) method for the
synthesis of chiral C15 vitamin E side-chain 1 was developed. ZACA–lipase-catalyzed
acetylation protocol to provide a key α,ω-dioxyfunctional C5 synthon 6 (≥99% ee), and two
subsequent Cu-catalyzed alkyl–alkyl cross-coupling reactions of enantiomerically pure C5 iodide
1
Available online
4 were employed as key steps. H NMR analysis of MαNP ester was found to be a convenient
method for measuring the enantiomeric purity of the C15 vitamin E side-chain 1.
Keywords:
vitamin E
2014 Elsevier Ltd. All rights reserved.
isoprenoid
ZACA
Cu-catalyzed cross-coupling
asymmetric catalysis
Saturated isoprenoids represent a large and diverse class of
naturally occurring organic compounds including vitamins,1
pheromones,2 antioxidants,3 marine natural products,4 and
archaebacterial lipids.5 The saturated isoprenoids play widely
varying roles in the physiological processes in living organisms
such as archaea, bacteria, and human. Archaea are distinct from
bacteria and eukaryotes. One characteristic feature of archaea is
the chemical structure of its core membrane lipids consisting of
saturated isoprenoid chains connected to glycerol through ether
linkages.6
related antioxidants.9 It has also been identified as a precursor of
many isoprenoid compounds in plants,10 geological sediments,11
and archaebacterial lipids in archea.12 Thus, numerous synthetic
strategies have been developed for the synthesis of such
important building block. Current synthetic approaches include
chiral auxiliary-based methods,13 chiral pool synthesis,14 and
enzymatic protocols.15 However, these methods have several
disadvantages including long and multi-step processes, the use of
stoichiometric quantities of chiral reagents, and low
stereoselectivity. At present, only a very few transition metal-
catalyzed methods are known, of which catalytic asymmetric
hydrogenation by Noyori16 and Pfaltz17 are noteworthy. We also
developed a concise and efficient synthesis of 1 via Zr-catalyzed
asymmetric carboalumination of alkenes (ZACA).18 However, all
these methods lack high (≥98%) stereoselectivity leading to
diastereomeric mixtures which are very difficult to purify.
(3R,7R)-3,7,11-Trimethyldodecanol 1 is a very important
saturated isoprenoid derivative, which can be used as a versatile
intermediate for the syntheses of vitamin E,7 vitamin K1,8 and
We recently developed highly enantioselective (≥99% ee) and
catalytic routes to a wide range of 1-alkanols including those of
isotopic cryptochirality via ZACA–Cu- or Pd-catalyzed cross-
coupling.19-21 The development of these methods relied on the
following four critical findings: (i) ZACA–in situ iodinolysis of
allyl alcohol to produce either (S)- or (R)-ICH2CH(R)CH2OH in
80–90% ee,19 (ii) ZACA–in situ oxidation of TBS-protected ω-
alkene-1-ols to afford both (R)- and (S)-α,ω-dioxyfunctional
intermediates in 80–86% ee,20,21 (iii) enantiomeric purification by
lipase-catalyzed acetylation (LICA) of the above functionally
rich intermediates to the ≥99% ee level through exploitation of
their high selectivity factors (E),22 and (iv) essentially perfect
(>99%) stereochemical fidelity with retention observed widely in
the subsequent Cu- or Pd-catalyzed cross-coupling reactions.18e,23
Herein we report a highly reliable and predictable method for the
Figure 1. Some natural products containing chiral saturated
isoprenoid units.
———
 Corresponding authors. Tel: (+1)-765-494-5301; fax: (+1)-765-494-0239;
E-mail addresses: xu197@purdue.edu (S. Xu); negishi@purdue.edu (E. Negishi)

preparation of both enantiomerically and diastereomerically pure
C15 vitamin E side-chain 1 using our ZACA–Cu-catalyzed cross-
coupling strategy.
Enantiomeric purification of α,ω-dioxyfunctional intermediate
6 obtained by the ZACA reaction was carried out by lipase-
catalyzed acetylation. Thus, crude intermediate 6 (81% ee) was
readily purified to the level of ≥99% ee in 52% recovery yield by
Amano lipase PS-catalyzed acetylation with vinyl acetate in 1,2-
dichloroethane. The high enantiomeric purity of 6 was evidenced
by Mosher ester analysis25 as shown in Figure 2. Two
diastereomeric Mosher esters of β-chiral alcohol 6 showed the
expected chemical shift differences. The absence of peaks at 4.23
ppm of MTPA ester 9 derived from alcohol 6 and (R)-MTPA-Cl
indicated the high enantiomeric purity of alcohol 6 (Figure 2).
A retrosynthetic scheme for preparation of the C15 vitamin E
side-chain 1 is shown in Scheme 1. It was planned to couple C5
iodide 4 and C10 Grignard reagent 5 through Cu-catalyzed alkyl–
alkyl cross-coupling reaction.23 Segment 5 should be readily
prepared by another Cu-catalyzed alkyl–alkyl cross-coupling
reaction of isopentylmagnesium bromide with iodide 4, which, in
turn, should be derived from the key α,ω-dioxyfunctional chiral
C5 subunit 6. We envisioned that a highly enantioselective
synthesis of chiral C5 synthon 6 could be achieved via our
ZACA–LICA protocol. If the key C5 subunit 6 could be obtained
in high enantiomeric purity (≥99% ee), the subsequent Cu-
catalyzed cross-coupling reactions would proceed with
essentially full (>99%) retention of all carbon skeletal features of
key C5 synthon 6 to provide 1 with excellent enantiomeric and
diastereomeric purity (ee > 99%, de > 98%).
Figure 2. 1H NMR spectra of two diastereomeric MTPA esters of
β-chiral alcohol 6 (CDCl3, 600MHz).
With the enantiomerically pure C5 intermediate 6 in hand, we
proceeded to investigate the synthesis of C15 vitamin E side-chain
1 by using 6 as the key building block. Thus, the chiral C5
alcohol
6
was readily converted to iodide
4
with
triphenylphosphine, imidazole and iodine in CH2Cl2. Next,
CuCl2-catalyzed alkyl–alkyl cross-coupling reaction23 between
iodide 4 and isopentylmagnesium bromide proceeded efficiently
in the presence of 1-phenylpropyne as an additive, followed by
desilylation with TBAF, providing C10 alcohol intermediate 10 in
93% yield, which was further transformed to the corresponding
bromide 11 in 96% yield using Ph3P/NBS. The desired C15
vitamin E side-chain 1 was prepared in 70% yield via another
round of CuCl2/1-phenylpropyne-catalyzed alkyl–alkyl cross-
coupling reaction23 between C5 iodide 4 and the Grignard reagent
derived from C10 bromide 11, followed by desilylation with
TBAF.
Scheme 1. Retrosynthetic analysis of C15 vitamin E side-chain 1.
The α,ω-dioxyfunctional C5 synthon 6 (≥99% ee) was
prepared as shown in Scheme 2. 3-Buten-1-ol 7 was protected
with TBSCl and was subjected to ZACA reaction. A solution of
1 mol% of (+)-bis(neomenthylindenyl)zirconium dichloride [(+)-
(NMI)2ZrCl2]24 in CH2Cl2 was treated with trimethylaluminum
(2 equiv) and H2O (1 equiv), then TBS-protected 3-buten-1-ol 8
was added to the above solution for asymmetric
methylalumination. After the completion of methylalumination,
the initial alkylalane intermediate was oxidized in-situ with O2 to
provide 6 in 88% yield and 81% ee.
Scheme 3. The synthesis of C15 vitamin E side-chain 1.
Scheme 2. The synthesis of key α,ω-dioxyfunctional C5 synthon
6 (≥99% ee).

We then wanted to determine the enantiomeric purity of the
C15 vitamin E side-chain 1. Mosher ester analysis of γ-chiral
alcohol 1 proved to be ineffective for determining the optical
purity of 1. We recently demonstrated that 2-methoxy-2-(1-
naphthyl)propionic acid (MαNP acid)26 ester analysis is a widely
applicable and powerful method for chiral discrimination of
various β- and more-remotely chiral primary alcohols including
those of isotopomers.20,21 As expected, two diastereomeric MαNP
esters 12a and 12b derived from γ-chiral alcohol 1 showed
significantly different chemical shifts. In particular, the γ-methyl
groups of these two diastereomers 12 showed completely
References
1. (a) Mercier, C.; Chabardes, P. Pure Appl. Chem. 1994, 66, 1509; (b)
Dowd, P.; Hershline, R.; Ham. S. W.; Naganathan, S. Nat. Prod. Rep.
1994, 11, 251.
2. (a) Nakamura, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2175; (b) Aldrich,
J. R.; Oliver, J. E.; Lusby, W. R.; Kochansky J. P.; Borges, M. J. J.
Chem. Ecol. 1994, 20, 1103.
3. Bennett, C. J.; Caldwell, S. T.; McPhail, D. B.; Morrice, P. C.; Duthie,
G. G.; Hartley, R. C. Bioorg. Med. Chem. 2004, 12, 2079.
4. (a) Minale, L. In Marine Natural Products: Chemical and Biological
Perspectives; Scheuer, P. J., Ed.; Academic Press, 1978, Vol. 1, pp
175–240; (b) Sankaranarayanan, S.; Sharma A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 2002, 13, 1373.
1
separate H NMR signals (Figure 3), which indicated that the
5. Zhang, D.; Poulter, C. D. J. Am. Chem. Soc. 1993, 115, 1270.
6. (a) Heathcock, C. H.; Finkelstein, B. L.; Aoki, T.; Poulter, C. D. Science
1985, 229, 862; (b) Zillig, W. Curr. Opin. Genet. Dev. 1991, 1, 544.
7. (a) Cohen, N.; Schaer, B. J. Org. Chem. 1992, 57, 5783; (b) Hübscher,
J.; Barner, R. Helv. Chim. Acta 1990, 73, 1069; (c) Netscher, T. Chimia
1996, 50, 563.
enantiomeric excess of alcohol 1 is greater than 99%. In addition,
the diastereomeric purity of alcohol 1 was also confirmed to be
greater than 99% by 13C NMR analysis.
8. (a) Fujisawa, T.; Sato, T.; Kawara T.; Ohashi, K. Tetrahedron Lett.
1981, 22, 4823; (b) Schmid, R.; Antoulas, S.; Rüttimann, A.; Schmid,
M.; Vecchi, M.; Weiser, H. Helv. Chim. Acta 1990, 73, 1276.
9. (a) Lee, H.; Lee, Y.; Kim, D.; Son, M.; Nam, T.; Jeong, B. Tetrahedron
Lett. 2014, 55, 5895; (b) Chapelat, J.; Hengartner, U.; Chougnet, A.;
Liu, K.; Huebbe, P.; Rimbach, G.; Woggon, W.-D. ChemBioChem.
2011, 12, 118.
10. Threlfall, D. R. In Secondary Plant Products; Bell, E. A.; Charlwood,
B. V., Eds.; Springer, Berlin, 1980, pp 292–298.
11. Rowland, S. J.; Robson, J. N. Mar. Environ. Res. 1990, 30, 191.
12. Mancuso, C. A.; Odham, G.; Westerdahl, G.; Reeve, J. N.; White, D.
C.; J. Lipid Res. 1985, 26, 1120.
13. (a) Chan, K.; Cohen N.; De Noble, J. P.; Specian, A. C. Jr.; Saucy, G. J.
Org. Chem. 1976, 41, 3497; (b) Koreeda, M.; Brown, L. J. Org. Chem.
1983, 48, 2122; (c) Fujiwara, J.; Fukutani, Y.; Hasegawa, M.; Maruoka,
K.; Yamamoto, H. J. Am. Chem. Soc. 1984, 106, 5004; (d) Berkowitz,
W. F.; Wu, Y. Tetrahedron Lett. 1997, 38, 8141.
14. (a) Scott, J. W.; Bizzarro, F. T.; Parrish, D. R.; Saucy, G. Helv. Chim.
Acta 1976, 59, 290; (b) Takabe, K.; Sawada; Satani, T.; Yamada, T.;
Katagiri, T.; Yoda, H. Bioorg. Med. Chem. Lett. 1993, 13, 157; (c)
Chen, Y. C.; Nagumo, S.; Akita, H. Chem. Pharm. Bull. 1996, 44, 2153;
(d) Fleming, I.; Maiti, P.; Ramarao, C. Org. Biomol. Chem. 2003, 1,
3989.
1
Figure 3. H NMR spectra of diastereomeric MαNP esters of γ-
chiral alcohol 1 (CDCl3, 600MHz).
15. (a) Leuenberger, H. G. W.; Boguth, W.; Barner, R.; Schmid, M.; Zell,
R. Helv. Chim. Acta 1979, 62, 455; (b) Schmid, M.; Barner, R. Helv.
Chim. Acta 1979, 62, 464; (c) Zell, R. Helv. Chim. Acta 1979, 62, 474;
(d) Fuganti, C.; Grasselli, P. J. Chem .Soc. Chem. Commun. 1979, 995;
(e) Nozawa, M.; Takahashi, K.; Kato, K.; Akita, H. Chem. Pharm. Bull.
2000, 48, 272.
16. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc. 1987, 109, 1597.
17. Wang, A.; Wüstenberg, B.; Pfaltz, A. Angew. Chem. Int. Ed. 2008, 47,
2298.
18. (a) Huo, S.; Shi, J.; Negishi, E. Angew. Chem. Int. Ed. 2002, 41, 2141;
For the discovery of the ZACA reaction, see: (b) Kondakov, D.;
Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771; (c) Kondakov, D. Y.;
Negishi, E. J. Am Chem. Soc.1996, 118, 1577; For the recent reviews of
the ZACA reaction, see: (d) Negishi, E. Arkivoc 2011, viii, 34; (e)
Negishi, E. Angew. Chem. Int. Ed. 2011, 50, 6738; (f) Xu, S.; Negishi,
E. Heterocycles 2014, 88, 845.
19. Xu, S.; Lee, C. T.; Wang, G.; Negishi, E. Chem. Asian J. 2013, 8, 1829.
20. Xu, S.; Oda, A.; Kamada, H.; Negishi, E. Proc. Natl. Acad. Sci. USA,
2014, 111, 8368.
In summary, we have developed a highly enantioselective
(>99% ee) and diastereoselective (>98% de) route to chiral C15
vitamin E side-chain 1 via ZACA–Cu-catalyzed cross-coupling
from 3-buten-1-ol. The key α,ω-dioxyfunctional C5 synthon 6
(≥99% ee) was readily prepared by ZACA–LICA protocol, which
can be further functionalized at both ends. Two sequential Cu-
catalyzed alkyl–alkyl cross-coupling reactions of the
enantiomerically pure C5 iodide 4 were employed as the key
steps for preparing the C15 vitamin E side-chain 1. In addition, we
demonstrated that 1H NMR analysis of MαNP ester is a
convenient method for measuring the optical purity of the C15
vitamin E side-chain 1. It should be noted that various (R)- and
(S)-α,ω-difunctional compounds have been successfully prepared
as enantiomerically pure (≥99% ee) substances by ZACA–LICA
protocol.19-21 This novel approach promises to provide a reliable
method for highly enantioselective and diastereoselective
syntheses of various possible stereoisomers of chiral isoprenoid
natural products and analogues. Further studies along this line are
currently ongoing in our laboratories.
21. Xu, S.; Oda, A.; Negishi, E. Chem. Eur. J. 2014, 20, 16060.
22. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 104, 7294.
23. Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew.
Chem. Int. Ed. 2007, 46, 2086.
24. (a) Erker, G.; Aulbach, M.; Knickmeier, M.; Wingbermühle, D.;
Kürger, C.; Nolte, M.; Werner, S. J. Am. Chem. Soc. 1993, 115, 4590;
(b) (+)–(NMI)2ZrCl2 (CAS number: 641627-68-1) and (–)–(NMI)2ZrCl2
(CAS number: 148347-88-0) are available from Sigma-Aldrich and
Wako Pure Chemicals.
Acknowledgments
25. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512; (b)
Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451.
26. (a) Harada, N.; Watanabe, M.; Kuwahara, S.; Sugio, A.; Kasai, Y.;
Ichikawa, A. Tetrahedron: Asymmetry 2000, 11, 1249; (b) Kasai, Y.;
Sugio, A.; Sekiguchi, S.; Kuwahara, S.; Matsumoto, T.; Watanabe, M.;
Ichikawa, A.; Harada, N. Eur. J. Org. Chem. 2007, 1811.
We thank the Negishi-Brown Institute, Purdue University and
Teijin Limited for support of this research. We also thank Sigma-
Aldrich, Albemarle, and Boulder Scientific for their support.