Single-Step Construction of the anti-Deoxypropionate Motif from Propylene: Formal Total Synthesis of the Cuticular Hydrocarbons Isolated from Antitrogus parvulus

Article abstract of DOI:10.1002/anie.201804711

Reported herein is the single-step construction of an anti-configured deoxypropionate motif by syndiospecific propylene oligomerization catalyzed by a C_s-symmetric zirconocene complex. After oligomerization, oxidation of the oligomers by oxygen afforded oligopropylene alcohols in a single step. This strategy was applied to the single-step preparation of rel-(2R,4S,6R,8S)-2,4,6,8-tetramethylundecan-1-ol, the racemic mixture of the synthetic fragment of the cuticular hydrocarbons isolated from the cane beetle Antitrogus parvulus.

Full text of DOI:10.1002/anie.201804711

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Single-step construction of the anti-deoxypropionate motif from
propylene: Formal total synthesis of the cuticular hydrocarbons
isolated from Antitrogus parvulus
Authors: Toshiki Murayama and Kyoko Nozaki
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804711
Angew. Chem. 10.1002/ange.201804711
Link to VoR: http://dx.doi.org/10.1002/anie.201804711
http://dx.doi.org/10.1002/ange.201804711

10.1002/anie.201804711
Angewandte Chemie International Edition
COMMUNICATION
Single-step construction of the anti-deoxypropionate motif from
propylene: Formal total synthesis of the cuticular hydrocarbons
isolated from Antitrogus parvulus
Toshiki Murayama and Kyoko Nozaki*
Abstract: Herein we report the single-step construction of anti-
configured deoxypropionate motif by syndiospecific propylene
oligomerization catalyzed by CS-symmetric zirconocene complex.
After oligomerization, oxidation of the oligomers by oxygen afforded
oligopropylene alcohols in a single step. This strategy was applied to
minimize the number of unstable conformations,[12] there are
several naturally occurring examples featuring the anti-
configured deoxypropionate motif. Therefore, the expansion of
our methodology into anti-configured deoxypropionate motif is
indeed important.
the
single-step
preparation
of
rel-(2R,4S,6R,8S)-2,4,6,8-
tetramethylundecan-1-ol, the racemic mixture of the synthetic
fragment of the cuticular hydrocarbons isolated from the cane beetle
Antitrogus parvulus.
The deoxypropionate motif (i.e., 1,3,...,(n−1)-polymethylalkyl
chain) is
a common structure found in natural products
synthesized by bacteria, fungi, and plants (Fig. 1a).[1] Because of
the abundance of this motif in natural products and the range of
biological activities they are related to, its synthesis has received
a great amount of attention.[2,3] To construct the structure
consisting of repeating units containing stereocenter but no
functionalities, the majority of the conventional syntheses of the
deoxypropionate motif employ iterative stereoselective reactions
including functional group interconversions. The examples
include enolate alkylation,[4,5] carboalumination,[6] organocuprate
displacement,[7] homologation of boronic esters,[8] and conjugate
addition.[9] Although these reactions proceed with high
stereoselectivity, long reaction sequences of 3–6 steps per
repeating unit are typically necessary. Consequently, long
reaction routes toward the natural products are required.
To construct the deoxypropionate motif in a single step, we
previously
reported
asymmetric
isospecific
propylene
oligomerization catalyzed by optically active C2-symmetric
zirconocene complex in the presence of diethylzinc (Fig. 1b).[10]
This
strategy
utilized
coordinative
chain
transfer
polymerization,[11] where excess amount of alkylmetal species is
used as a chain transfer agent in order to control the chain
length. In the previous paper, 2000–5000 equivalents of
diethylzinc was added to the system as a chain transfer agent,
which result in selective formation of oligopropylenes,
maintaining high isospecificity. We demonstrated the three-step
synthesis of
a
natural product (2R,4R,6R,8R)-2,4,6,8-
tetramethyldecanoic acid (1), which as previously reported,[6,9]
was conventionally synthesized over at least ten steps. However,
the product was limited to syn-configured deoxypropionate motif
owing to the isospecificity provided by C2-symmetric zirconocene
catalyst. Although the significant majority of the deoxypropionate
motifs found in natural products have syn-configuration to
Figure 1. a) Selected examples of natural products containing
deoxypropionate motif. b) Asymmetric isospecific propylene oligomerization
and total synthesis of 1.[10] c) Syndiospecific propylene oligomerization and
formal
total
synthesis
of
2
and
3
(this
work).
EBTHI,
Dichloro[ethanediylbis(4,5,6,7-tetrahydro-1H-inden-1-yl)]zirconium. RP-HPLC,
reversed phase high performance liquid chromatography. CpOct,
Dichloro[(cyclopentadienyl)(diphenylmethylene)(1,2,3,4,7,8,9,10-octahydro-
1,1,4,4,7,7,10,10-octamethyl-12H-dibenzo[b,h]fluoren-12-yl)zirconium
dichloride.
[*]
T. Murayama, Prof. K. Nozaki
Department of Chemistry and Biotechnology, Graduate School of
Engineering, The University of Tokyo
Herein we expand our strategy to construct the anti-configured
deoxypropionate motif, utilizing Cs-symmetric zirconocene
complex in the presence of dialkylzinc (Fig. 1c). This strategy
was applied to the facile formal total synthesis of the major
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: nozaki@chembio.t.u-tokyo.ac.jp
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201804711
Angewandte Chemie International Edition
COMMUNICATION
oligomer and Figure 2 for the yield distribution. [b] Percentage of the main
diastereomer of hexamer determined by GC analysis.
cuticular hydrocarbons isolated from the cane beetle Antitrogus
parvulus,
(4S,6R,8R,10S,16R,18S)-4,6,8,10,16,18-
hexamethyldocosane (2) and (4S,6R,8R,10S,16S)-4,6,8,10,16-
pentamethyldocosane (3).[13,14] The racemic mixture of the
common synthetic intermediate of 2 and 3, rel-(2R,4S,6R,8S)-
2,4,6,8-tetramethylundecan-1-ol ((±)-4),[15–19] was successfully
obtained in a single step.
We chose the Cs-symmetric zirconocene complex 5[20] as an
oligomerization catalyst since it exhibited high activity and
stereoregularity in syndiospecific propylene polymerization
(Table 1 and Figure 2). In a similar manner to the previous
report of isospecific propylene oligomerization,[10] reaction was
carried out at 1 µmol Zr scale in the presence of 1000
equivalents of methylaluminoxane (MAO) as a cocatalyst, 2000
equivalents of diethylzinc as a chain transfer agent under 0.2
MPa of propylene. Reaction was carried out at 10 °C for 16
hours and quenched with hydrochloric acid. Analysis of the
reaction mixture was carried out by GC and GC-MS. The yield of
each oligomer was calculated based on peak area of GC trace
on mass basis. We found that Zirconocene 5 successfully
catalyzed
syndiospecific
oligomerization
with
high
stereoregularity (entry 1); the percentage of the main
diastereomer of hexamer was calculated to be 92% (by GC).
This high diastereoselectivity was further confirmed by
comparison
with
the
oligomerization
catalyzed
by
bis(cyclopentadienyl)zirconium dichloride 6, which produces
atactic polypropylenes.[21] GC trace of the reaction mixture of
entry 1 showed virtually single peaks for each oligomer (Figure 3,
bottom), whereas the use of 6 resulted in the formation of
multiple peaks (Figure 3, top).[10]
Table 1. Syndiospecific propylene oligomerization in the presence of
diethylzinc.[a]
Entry
Variation
d.p./%[b]
1
2
3
4
5
6
7
n/a
92
88
94
95
95
90
74
0.4 MPa
Figure 2. Yield distribution of the main diastereomer of each oligomer in the
oligomerization in the presence of diethylzinc (top: percentage based on
diethylzinc; bottom: equivalent to 5). Yield of 7-, 8-, 9-mer in entry 7 was not
determined.
0.4 MPa, 5 mmol Zn
0.4 MPa, 10 mmol Zn
−20 °C
Same as entry 3, ×5 scale
Same as entry 3, 1-hexene, 4.0 mL
[a] Reaction conditions: 5 (1.0 mL, 1.0 mM in toluene, 1.0 µmol), MAO (0.30 g,
8.9 wt% Al in toluene, 1.0 mmol Al), diethylzinc (2.0 mL, 1.0 M in toluene, 2.0
mmol), propylene (0.2 MPa) at 10 °C for 16 h. After quenched by hydrochloric
acid, organic phase was analyzed by GC to determine the yield and the
diastereomer percentages. See Supporting Information for the yield of each
This article is protected by copyright. All rights reserved.

10.1002/anie.201804711
Angewandte Chemie International Edition
COMMUNICATION
Entry
Variation
d.p./%[b]
65
1
2
3
4
5
n/a
2 mmol Zn
58
10 mmol Zn
90
−20 °C
74
Figure 3. GC traces of the oligomerization products catalyzed by 6[10] (top)
and 5 (bottom, Table 1, entry 1).
Neat di(n-propyl)zinc, 5 mmol
94
Following up on these results, we optimized reaction conditions.
Contrary to expectations, increase in propylene pressure from
0.2 MPa to 0.4 MPa (entry 2) led to steep decrease in oligomer
yields. We attributed such dependence to rapid propagation
rates, leading to the increased probability to form longer
oligomers. To oppose rapid propagation rate via an increase in
the rate of chain transfer, the ratio of diethylzinc to 5 was raised
from 2000 to 5000 or 10000 (entries 3 and 4, respectively).
[a] Reaction conditions: 5 (1.0 mL, 1.0 mM in toluene, 1.0 µmol), MAO (0.30 g,
8.9 wt% Al in toluene, 1.0 mmol Al), di(n-propyl)zinc (5.0 mL, 1.0 M in toluene,
5.0 mmol), propylene (0.4 MPa) at 10 °C for 16 h. After quenched by
hydrochloric acid, organic phase was analyzed by GC to determine the yield
and the diastereomer percentages. See Supporting Information for the yield of
each oligomer and Figure 3 for the yield distribution. [b] Percentage of main
diastereomer of hexamer.
Gratifyingly,
oligomer
yields,
together
with
the
diastereoselectivity were improved. We also found that
decreasing the reaction temperature down to −20 °C (entry 5)
has virtually no effect on diastereoselectivity, rather only
decreased oligomer yields were observed. We concluded that
entry
3 was the best condition for the production of
oligopropylenes in combined view of both oligomer yield and
diastereoselectivity. To investigate the scalability of this reaction,
the oligomerization was carried out at 5 times larger scale under
the same condition as entry
3 (entry 6). As a result,
oligopropylenes were successfully obtained with negligibly lower
yield and diastereoselectivity. This strategy was also applicable
to α-olefins other than propylene. When 4 mL of 1-hexene was
used as a monomer, oligohexenes were obtained (entry 7).
After optimizing the reaction conditions in the 5/MAO/ZnEt2
system, we switched our focus to the natural product synthesis
in order to demonstrate the synthetic utility of our new strategy.
The target alcohol (±)-4, which was previously synthesized over
at least 11 steps,[15,16,18,19] can be synthesized in a single step by
syndiospecific propylene oligomerization using di(n-propyl)zinc
as a chain transfer agent and subsequent oxidation after
oligomerization.
When 1.0 M solution of di(n-propyl)zinc in toluene was used
as a chain transfer agent, although good selectivity for short
oligomers and no solid polymers were observed under
previously optimized reaction conditions (Table 2 and Figure 4,
entry 1), diastereoselectivity was significantly lower compared to
the case of diethylzinc.
Table 2. Syndiospecific propylene oligomerization in the presence of di(n-
propyl)zinc.[a]
This article is protected by copyright. All rights reserved.

10.1002/anie.201804711
Angewandte Chemie International Edition
COMMUNICATION
of dissolved propylene in solvent is constant (Henry’s Law), a
possible reason for the higher yield of short oligomers is that
smaller amount of the solvent decreased the ratio of
concentrations of propylene to di(n-propyl)zinc.
Finally, propylene oligomerization in the presence of di(n-
propyl)zinc and oxidation were carried out in series (Scheme 1).
After oligomerization reaction under the optimized condition,
propylene was vented and a mixture of oligopropylene zinc
species was subjected to oxidation by oxygen stream at 0 °C for
2 hours. Reaction was then quenched with hydrochloric acid,
and the separated organic layer was treated with
triphenylphosphine to convert any remaining alkyl hydroperoxide
into alcohol. GC analysis of the reaction mixture revealed that
conversion of the oxidation reaction was 76%. Alkanes deriving
from unoxidized oligopropylene zinc species, triphenylphosphine,
and triphenylphosphine oxide were removed by silica gel column
chromatography, and mixture of oligopropylene alcohols were
successfully
separated
by
reversed-phase
liquid
chromatography to afford the tetramer alcohol, which is the
target alcohol (±)-4, in 3.8% yield based on di(n-propyl)zinc. The
1
product was characterized by H and 13C NMR analyses. Thus,
single-step synthesis of (±)-4 is achieved and this sequence is
the shortest ever reported. Consequently, the formal total
syntheses of 2 (over 11 steps with longest linear sequence of 9
steps)[15,16] and 3 (over 12 steps with longest linear sequence of
9 steps)[18,19] were also achieved. It is worth noting that both
sequences are the shortest ever reported.
Scheme 1. One-step synthesis of (±)-4.
Figure 4. Yield distribution of the main diastereomer of each oligomer in the
oligomerization in the presence of di(n-propyl)zinc (top: percentage based on
di(n-propyl)zinc; bottom: equivalent to 5).
In conclusion, we have successfully utilized syndiospecific
oligomerization of propylene followed by oxidation to afford
hydroxy-terminated anti-configured deoxypropionate motif in a
single step. Cs-symmetric zirconocene complex 5 catalyzed
propylene oligomerization in highly syndiospecific manner, and
resultant oligomers were converted into alcohols by oxygen
stream. A mixture of oligopropylene alcohols were separated by
reversed-phase HPLC to afford Single-step synthesis of rel-
Thus, it was necessary to optimize reaction conditions to obtain
oligomers with comparable diastereoselectivity to that obtained
when using diethylzinc. We first examined the variation in the
ratio of di(n-propyl)zinc to 5. In the presence of 2000 equivalents
of di(n-propyl)zinc, diastereoselectivity remained almost the
same (entry 2). With increased amount of 10000 equivalents of
di(n-propyl)zinc, diastereoselectivity was improved (entry 3).
However, in both cases, yield was lower than entry 1. Lower
reaction temperature of −20 °C resulted in lower yield and
diastereoselectivity (entry 4). Among various reaction conditions
tested with different concentrations of di(n-propyl)zinc, the best
result with improved oligomer yield and diastereoselectivity was
observed when di(n-propyl)zinc was added as neat liquid (entry
5) instead of 1.0 M solution in toluene. Since the concentration
(2R,4S,6R,8S)-2,4,6,8-tetramethylundecan-1-ol
(±)-4,
the
racemic mixture of the synthetic fragment of cuticular
hydrocarbons isolated from the cane beadle Antitrogus parvulus.
Combined with our previous report on the single-step synthesis
of syn-configured deoxypropionate motif by isospecific
propylene oligomerization,[10] these results prove the broad
scope of deoxypropionate motif synthesis by propylene
oligomerization, further demonstrating the successful application
This article is protected by copyright. All rights reserved.

10.1002/anie.201804711
Angewandte Chemie International Edition
COMMUNICATION
of polymerization catalysts to synthetic chemistry, which has
been an active field of research .[22] Installation of a functional
moiety into the initiating group and the use of alternative chain-
end functionalization are currently being investigated in our
laboratory towards realization of cyclic natural products.
[1]
C. Khosla, R. S. Gokhale, J. R. Jacobsen, D. E. Cane, Annu. Rev.
Biochem. 1999, 68, 219–253.
[2]
[3]
S. Hanessian, S. Giroux, V. Mascitti, Synthesis 2006, 1057–1076.
B. ter Horst, B. L. Feringa, A. J. Minnaard, Chem. Commun. 2010,
46, 2535–2547.
[4]
A. Abiko, O. Moriya, S. A. Filla, S. Masamune, Angew. Chem. Int.
Ed. Engl. 1995, 34, 793–795.
Experimental Section
[5]
D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs, R. Zahler, J. Am.
Chem. Soc. 1990, 112, 5290–5313.
Rel-(2R,4S,6R,8S)-2,4,6,8-tetramethylundecan-1-ol
((±)-4)[16–19]
A
[6]
B. Liang, T. Novak, Z. Tan, E. Negishi, J. Am. Chem. Soc. 2006,
128, 2770–2771.
mixture of 5[20] (1.0 mL, 1.0 mM in toluene, 1.0 µmol), MAO (0.30 g, 8.9
wt% Al in toluene, 1.0 mmol Al), di(n-propyl)zinc[23] (0.75 g, 5.0 mmol)
was stirred under propylene (0.40 MPa) in a 50-mL stainless steel
autoclave for 16 h at 10 °C. Following propylene venting, the reaction
vessel was cooled to 0 °C. Additional toluene (10 mL) was added to the
reaction mixture, and oxygen stream was applied for 2 h at 0 °C.
Reaction was then quenched with hydrochloric acid, and
triphenylphosphine was added to the separated organic phase. The
mixture was concentrated for purification by silica gel column
chromatography (Hex/EtOAc = 10:1 v/v), and then by reversed phase
HPLC (MeOH) to afford 43.6 mg (3.8% yield from di(n-propyl)zinc) of (±)-
4 as a colorless oil. 1H NMR (500 MHz, CDCl3): δ=3.48 (dd, 2J(H,H)=10.4
[7]
S. Hanessian, N. G. Cooke, B. DeHoff, Y. Sakito, J. Am. Chem. Soc.
1990, 112, 5276–5290.
[8]
S. Balieu, G. E. Hallett, M. Burns, T. Bootwicha, J. Studley, V. K.
Aggarwal, J. Am. Chem. Soc. 2015, 137, 4398–4403.
B. ter Horst, B. L. Feringa, A. J. Minnaard, Chem. Commun. 2007,
489–491.
[9]
[10]
[11]
Y. Ota, T. Murayama, K. Nozaki, Proc. Natl. Acad. Sci. U. S. A.
2016, 113, 2857–2861.
A. Valente, A. Mortreux, M. Visseaux, P. Zinck, Chem. Rev. 2013,
113, 3836–3857.
Hz, 3J(H,H)=5.7 Hz, 1H; 1-CH2), 3.40 (dd, J(H,H)=10.4 Hz, 3J(H,H)=6.7
2
Hz, 1H; 1-CH2), 1.78–1.68 (m, 1H; 2-CH), 1.65–1.54 (m, 2H; CH), 1.53–
1.44 (m, 1H; CH), 1.38–0.97 (m, 11H; CH2 and OH), 0.90 (d, 3J(H,H)=6.7
Hz, 3H; 2′-CH3), 0.88 (t, 3J(H,H)=7.3 Hz, 3H; 11-CH3), 0.82 (d,
[12]
[13]
R. W. Hoffmann, Angew. Chem. Int. Ed. 2000, 39, 2054–2070.
M. T. Fletcher, S. Chow, L. K. Lambert, O. P. Gallagher, B. W. Cribb,
P. G. Allsopp, C. J. Moore, W. Kitching, Org. Lett. 2003, 5, 5083–
5086.
3J(H,H)=6.5 Hz, 3H; CH3), 0.82 (d, J(H,H)=6.6 Hz, 3H; CH3), 0.80 ppm
3
(d, 3J(H,H)=6.5 Hz, 3H; CH3); 13C NMR (126 MHz, CDCl3): δ=69.07,
46.53, 45.50, 41.32, 40.22, 33.20, 29.71, 27.29, 27.16, 20.09, 19.60,
19.52, 19.39, 16.45, 14.40 ppm.
[14]
S. Chow, M. T. Fletcher, L. K. Lambert, O. P. Gallagher, C. J. Moore,
B. W. Cribb, P. G. Allsopp, W. Kitching, J. Org. Chem. 2005, 70,
1808–1827.
[15]
[16]
[17]
[18]
C. Herber, B. Breit, Angew. Chem. Int. Ed. 2005, 44, 5267–5269.
C. Herber, B. Breit, Eur. J. Org. Chem. 2007, 3512–3519.
J. Zhou, Y. Zhu, K. Burgess, Org. Lett. 2007, 9, 1391–1393.
N. B. Basar, H. Liu, D. Negi, H. M. Sirat, G. A. Morris, E. J. Thomas,
Org. Biomol. Chem. 2012, 10, 1743.
Acknowledgements
We are grateful to Dr. Yusuke Ota (ETH, Zürich) for helpful
discussions and Dr. Shrinwantu Pal (University of British
Columbia) for proofreading. This work was supported by Grant-
in-Aid for Scientific Research (B) (No. JP15H03807) from JSPS
and partially by Grant-in-Aid for Scientific Research on
Innovative Areas “Precise Formation of a Catalyst Having a
Specified Field for Use in Extremely Difficult Substrate
Conversion Reactions” (No. JP15H05796) from MEXT. T.M. is
grateful to Program for Leading Graduate Schools "Materials
Education program for the future leaders in Research, Industry
and Technology (MERIT)" from JSPS.
[19]
N. Basar, K. Damodaran, H. Liu, G. A. Morris, H. M. Sirat, E. J.
Thomas, D. P. Curran, J. Org. Chem. 2014, 79, 7477–7490.
S. A. Miller, J. E. Bercaw, Organometallics 2004, 23, 1777–1789.
W. Kaminsky, K. Kulper, S. Niedoba, Makromol. Chem., Macromol.
Symp. 1986, 3, 377–387.
[20]
[21]
[22]
[23]
C. Chen, Nat. Rev. Chem. 2018, 2, 6–14.
C. R. Noller, Org. Synth. Coll. 1943, 2, 184–187
Keywords: deoxypropionate motif • propylene • oligomerization
• natural product synthesis
This article is protected by copyright. All rights reserved.

10.1002/anie.201804711
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
T. Murayama, K. Nozaki
Page No. – Page No.
Single-step construction of the anti-
deoxypropionate motif from
propylene: Formal total synthesis of
the cuticular hydrocarbons isolated
from Antitrogus parvulus
One giant leap: Herein we report the single-step construction of anti-configured
deoxypropionate motif by syndiospecific propylene oligomerization. This strategy
was applied to the single-step preparation of rel-(2S,4R,6S,8R)-2,4,6,8-
tetramethylundecan-1-ol, the racemic mixture of the synthetic fragment of the
cuticular hydrocarbons isolated from the cane beadle Antitrogus parvulus.
This article is protected by copyright. All rights reserved.