"One-pot" reductive lactone alkylation provides a concise asymmetric synthesis of chiral isoprenoid targets

Article abstract of DOI:10.1021/ol401801g

An efficient method, based on nucleophilic addition to lactones followed by modified in situ Clemmensen reduction, provides a short synthetic route to chiral isoprenoid targets. The efficacy of this method has been exemplified through the synthesis of several targets including the commercial fragrance Rosaphen, the side chain of Zaragozic acid C, the cotton leaf sex pheromone, and the side chains of vitamin E.

Full text of DOI:10.1021/ol401801g

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4327–4329
“One-Pot” Reductive Lactone Alkylation
Provides a Concise Asymmetric
Synthesis of Chiral Isoprenoid Targets
Jia Cao and Patrick Perlmutter*
School of Chemistry, Monash University, Clayton VIC 3800, Australia
patrick.perlmutter@monash.edu
Received June 26, 2013
ABSTRACT
An efficient method, based on nucleophilic addition to lactones followed by modified in situ Clemmensen reduction, provides a short synthetic
route to chiral isoprenoid targets. The efficacy of this method has been exemplified through the synthesis of several targets including the
commercial fragrance Rosaphen, the side chain of Zaragozic acid C, the cotton leaf sex pheromone, and the side chains of vitamin E.
Chiral isoprenoid units are important structural frag-
ments in natural products, such as pheromones, fragrances,
and vitamins. Previous approaches have employed chiral
auxiliaries,1 biocatalysis,2,3 transition metal catalysis,4,5 or
the chiral pool.6 Despite significant reports on the synthesis
of chiral isoprenoid compounds, considering the numerous
natural products with such moieties and the disadvantages
of existing methods, there is still room to explore more
efficient approaches for general methyl-branched com-
pounds with short synthetic routes, cheap starting materials,
and feasible scale-up procedures.
The proposed process is outlined in Scheme 1. This
involves monoaddition of an organometallic reagent to a
lactone carbonyl followed by in situ reduction of the
intermediate keto-alcohol.
Scheme 1. Proposed “One-Pot” Reductive Alkylation of Chiral
Lactones
(1) Yadav, J. S.; Gayathri, K. U.; Thrimurtulu, N.; Prasad, A. R.
Tetrahedron 2009, 65, 3536.
(2) Hoegberg, H. E.; Hedenstroem, E.; Faegerhag, J.; Servi, S. J. Org.
Chem. 1992, 57, 2052.
(3) Ferraboschi, P.; Grisenti, P.; Manzocchi, A.; Santaniello, E.
J. Org. Chem. 1990, 55, 6214.
(4) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa,
S.; Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc. 1987, 109,
1596.
(5) Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117,
10771.
Additions of both Grignard reagents and alkyllithiums
were evaluated. This apparently simple process is often
plagued by overaddition leading to tertiary alcohols. This
is especially so for Grignard additions. We found that Xu’s
method gave the monoadduct reproducibly in acceptable
yields.7 However this required the use of 8 equiv of amine
(6) Liu, X. Y.; Stocker, B. L.; Seeberger, P. H. J. Am. Chem. Soc.
2006, 128, 3638.
(7) Yang, S. B.; Gan, F.-F.; Chen, G. J.; Xu, P. F. ChemInform 2009,
40, 2532–2534.
r
10.1021/ol401801g
2013 American Chemical Society
Published on Web 08/19/2013

salt, N,O-dimethylhydroxylamine HCl. In our hands, em-
3
ploying alkyllithiums, either commercially available or
generated from the iodide and t-BuLi,8 gave the mono-
adduct, reproducibly, in good yields.
Table 1. Reductive Alkylation of Sample Lactonesa
The more problematic step involved the in situ reduction
of the adduct. The generated keto-alcohol can undergo
deoxygenation under the modified Clemmensen reduction
as reported by Arimoto and co-workers,9 ultimately giving
the best results. Unlike their original report, which re-
quired 100 equiv of TMSCl and Zn dust, we found that
10 equiv were more than satisfactory giving the corre-
sponding reduction products in >95% yields.
As outlined in Scheme 2 the initial adduct is in equili-
brium withthe ring-closed, lithiatedacetal. Asthe reducing
system requires access to the free ketone, it is possible that
the cyclic acetal is not present in appreciable amounts and/or
the silylated derivative is able to rearrange to the free
ketone prior to reduction.
yield
(%)
entry
1
n
R1
R2
R
4
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1c
1d
1
1
1
1
1
2
3
Me
Me
Me
Me
H
H
i-Bu
4a
4b
4c
4d
4e
4f
79
73
75
78
79
76
83
H
n-Pr
H
n-Hex
n-Oct
n-Bub
Ph
H
Me
H
Me
H
H
n-Bub
4g
a Reagents and conditions: (i) t-BuLi (2.2 equiv), Et2O, À78 °C, 1 h;
(ii) 1 (1.1 equiv), Et2O, À78 °C, 3 h; (iii) TMSCl (10 equiv), Zn (10 equiv),
MeOH/Et2O (3:1), 0 °C, 1 h. b Commercial 1 M solution of n-BuLi in
hexanes was used.
Scheme 2. Nucleophilic Addition to Lactones, Followed by in
Situ Silylation and Modified ArimotoÀClemmenson Reduction
results for comparison.13 The absence of peaks at 4.15 ppm
indicated the high enantiomeric purity of alcohol 4a.
Table 1 lists examples of the reductive alkylation proce-
dure outlined in Scheme 1. In all cases the overall yields for
a one-pot sequence of lithiation, addition, and reduction
are excellent. For alkyllithiums which are not commer-
cially available, the corresponding iodides were converted
to their alkyllithiums by reacting with t-BuLi (2.2 equiv) at
À78 °C in Et2O for 1 h, followed by warming to rt for
30 min. During warming, the Et2O served as a scavenger to
consume any excess t-BuLi, generating the corresponding
alkyllithium in >95% yield. The two homochiral lactones
used, (R)-3-methylbutyrolactone and (R)-4-methyl-δ-
valerolactone, can be derived from tigogenin, a byproduct
from sisal industrial waste.10,11 The (R)-3-methylbutyro-
lactone also can be prepared via asymmetric synthesis, as
reported by Helmchen.12
It is noteworthy that this process works well for five-,
six-, and seven-membered lactones (Table 1).
Each alcohol synthesized from 1a and 1c was produced
in high enantiomeric purity evidenced by, for example,
Mosher ester analysis of 4a shown in Figure 1 with Negishi’s
Figure 1. Spectroscopic analysis of the Mosher ester of 4a.13
(a) The 1H NMR spectrum reported by Negishi for the mixture
of the R-enantiomer (I, major) and S-enantiomer (II, minor).
(b) The 1H NMR spectrum of the crude ester from our alcohol
4a synthesized from the “one-pot” procedure.
(8) Cavicchioli, S.; Savoia, D.; Trombini, C.; Umani-Ronchi, A.
J. Org. Chem. 1984, 49, 1246.
(9) Xu, S.; Toyama, T.; Nakamura, J.; Arimoto, H. Tetrahedron Lett.
2010, 51, 4534.
(10) Cheng, L. L.; Gu, C. Y.; Li, M.; Jin, R. H.; Lin, J. R.; Tian, W. S.
Huaxue Shiji 2010, 32, 305.
(11) Yu, S.; Pan, X.; Lin, X.; Ma, D. Angew. Chem., Int. Ed. 2005, 44,
135.
(12) Ostermeier, M.; Brunner, B.; Korff, C.; Helmchen, G. Eur. J.
Org. Chem. 2003, 3453.
Alcohol 4c is an advanced intermediate in the total
synthesis of tuberculostearic acid, (R)-10-methylstearic acid
originally isolated from Mycobacterium tuberculosis.14
(13) Huo, S. Q.; Negishi, E. I. Org. Lett. 2001, 3, 3253.
4328
Org. Lett., Vol. 15, No. 17, 2013

Scheme 3. Synthesis of the Cotton Leafworm Sex Pheromone
Scheme 5. Synthesis of the Vitamin E Side Chain
Scheme 4. Synthesis of the C6 Side Chain of Zaragozic Acid C
in a Kocienski-modified Julia olefination (Scheme 4).19
This provided alkene 6, the C6 side chain of Zaragozic acid
C, a potent inhibitor of squalene synthase isolated from a
sterile fungal culture of Leptodontium elatius,20 in 81%
yield and 98% ee over the two steps.
Given the occurrence of repeating chiral isoprene units
in Nature, it was of obvious interest to establish whether or
not our reductivealkylation methodologycould be applied
in an iterative manner to the undecanol 7. This was chosen
as a representative target, as it is the side chain moiety
employed by Noyori’s group in their total synthesis of
R,R,R-R-tocopherol.3 Thus conversion of 2a into its cor-
responding iodide, employing Appel’s procedure followed
bylithiation, providedthe nucleophile requiredtoenter the
next reductive alkylation cycle (Scheme 5). This process
gave 8 in 41% overall yield from 2a.
Significantly, 4f is the commercially important fragrance
(R)-Rosaphen which has been prepared previously by
several groups.15À17
Simple activation of the alcohol produced in our proce-
dure allows for the direct incorporation of the chiral
isoprene unit in other natural product targets. For example,
tosylation of 4d, followed by Cu(II)-catalyzed displacement
with n-heptylmagnesium bromide, provides (S)-9-methyl-
nonadecane, 5 (>99% ee), in a total of three steps from
(R)-3-methylbutyrolactone (Scheme 3). Product 5 is the
major sex pheromone of female moths and larvae of the
cotton leafworm (Alabama argillacea),18 pests which feed
on cotton leaves, twigs, and buds. Our synthesis of 5
(3 steps, 57%) is a substantial improvement over a previous
synthesis (15 steps, 6%).14
In summary, we have developed a very short, two-step
protocol for reductively alkylating lactones employing a
sequence of nucleophilic addition followed by modified in
situ Clemmensenreduction. Thishasprovided the basisfor
a simple and versatile method for synthesizing enantio-
merically pure chiral isoprenoids.
Alternatively, Dess-Martin oxidation of 4f gave the
corresponding aldehyde, which was used without purification
(14) Anderson, R. J.; Chargaff, E. J. Biol. Chem. 1929, 85, 77.
(15) Santini, C.; Ball, R. G.; Berger, G. D. J. Org. Chem. 1994, 59,
2261.
(16) Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 17281.
(17) Matteoli, U.; Beghetto, V.; Scrivanti, A.; Aversa, M.; Bertoldini,
Acknowledgment. J.C. is grateful to the China Scholar-
ship Council and Monash University for financial support.
M.; Bovo, S. Chirality 2011, 23, 779.
(18) Lamers, Y. M. A. W.; Rusu, G.; Wijnberg, J. B. P. A.; de Groot,
A. Tetrahedron 2003, 59, 9361.
(19) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Supporting Information Available. Experimental pro-
1
cedures and H NMR spectra for 4aÀ4f, 5À9 as well as
13C NMR spectra for 9. This material is available free of
charge via the Internet at http://pubs.acs.org.
Synlett 1998, 1998, 26.
(20) Dufresne, C.; Wilson, K. E.; Zink, D.; Smith, J.; Bergstrom,
J. D.; Kurtz, M.; Rew, D.; Nallin, M.; Jenkins, R.; Bartizal, K.; Trainor,
C.; Bills, G.; Meinz, M.; Huang, L.; Onishi, J.; Milligan, J.; Mojena, M.;
Pelaez, F. Tetrahedron 1992, 48, 10221.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
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