Synthesis of γ-Lactones via the kowalski homologation reaction: Protecting-group-free divergent total syntheses of eupomatilones-2,5,6, and 3- epi-eupomatilone-6

Article abstract of DOI:10.1021/acs.orglett.9b02848

A highly efficient synthesis of functionalized chiral γ-butyrolactone scaffolds has been described. The basis of the approach is the Kowalski ester homologation that is modified for our proposed transformation. The newly developed methodology combines a d

Full text of DOI:10.1021/acs.orglett.9b02848

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of γ‑Lactones via the Kowalski Homologation Reaction:
Protecting-Group-Free Divergent Total Syntheses of Eupomatilones-
2,5,6, and 3-epi-Eupomatilone‑6
Hosam Choi,† Hanho Jang,† Hyoungsu Kim,‡ and Kiyoun Lee*,†
†Department of Chemistry, The Catholic University of Korea, Bucheon 14662, Korea
‡College of Pharmacy, Ajou University, Suwon 16499, Korea
S
* Supporting Information
ABSTRACT: A highly efficient synthesis of functionalized chiral γ-butyrolactone scaffolds has been described. The basis of the
approach is the Kowalski ester homologation that is modified for our proposed transformation. The newly developed
methodology combines a divergent synthetic strategy to permit a straightforward protecting-group-free asymmetric total
syntheses of eupomatilones-2,5,6, and 3-epi-eupomatilone-6 in five or six steps from commercial starting materials, making it
one of the shortest syntheses reported to date.
any structurally complex chiral γ-butyrolactones exhibit
the γ-position.4 Despite impressive advances in the field of γ-
butyrolactone synthesis, successful protocols are thus far
largely limited in terms of substrate scope diversity, stereo-
selectivity, and starting material availability. Moreover, to date,
many asymmetric methods have focused on the generation of
one stereogenic center, while strategies providing access to
optically active γ-butyrolactones possessing β,γ-two vicinal
stereogenic centers have rarely been reported.5
M
a wide range of biological properties1 and often serve as
key synthetic intermediates within the context of natural
product syntheses (Figure 1).2 Intrigued by the diversity of this
Consequently, further developments are needed to address
the generally limited substrate scope and moderate stereo-
selectivity. In order to access a broader range of structurally
diverse chiral lactones in a step-economical and versatile
fashion, a new synthetic approach is required. Herein, we
disclose studies on the development of a concise synthesis of γ-
butyrolactones with access to two chiral functional groups with
the necessary stereochemistry based on a slightly modified
Kowalski ester homologation reaction in which an effective
intramolecular ring closure occurs.
This efficient approach was applied to the synthesis of
protecting-group-free divergent total syntheses of three
members of natural eupomatilones-2,5,6 and one 3-epi-
eupomatilone-6. Even though the Kowalski ester homologation
reaction is a robust and valuable method for new carbon−
carbon bond forming reactions,6,7 its application in natural
product synthesis is extremely rare.8 Additionally, to the best of
Figure 1. Natural products containing γ-butyrolactones.
naturally occurring motif, in the past decades, significant efforts
have been made on the development of synthetic approaches
toward the enantioselective construction of γ-butyrolactone-
s.1a,3 There are several representative conventional methods for
the synthesis of γ-butyrolactones, including intramolecular
substitutions or halolactonization based on either inherent
electrophilic or nucleophilic characteristics of substituents at
Received: August 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02848
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Organic Letters
Letter
our knowledge, this work presents one of the shortest
asymmetric total syntheses of eupomatilones reported to date.
On the basis of a simplified mechanism of the Kowalski
reaction, as depicted in Scheme 1, we hypothesized that it
Scheme 2. Synthesis of γ-Lactones via the Aldol/Kowalski
Homologation Sequence
Scheme 1. Proposed Strategy for the Synthesis of the γ-
Butyrolactone Framework
a
b
Isolated yield of major diastereomer. Reaction conditions: 0.3−0.6
mmol of 2a−c and 5. (i) LiTMP (4.0 equiv), CH2Br2 (4.4 equiv),
−78 °C, (ii) LiHMDS (2.0 equiv), LiOEt (1.0 equiv), −78 to −20
°C, (iii) s-BuLi (2.0 equiv), −78 to −20 °C, (iv) n-BuLi (4.0 equiv),
−78 °C, (v) acidic MeOH. NMP = N-methyl-2-pyrrolidone;
LiHMDS = lithium bis(trimethylsilyl)amide.
would be possible to accomplish the construction of an
optically active β,γ-disubstituted γ-butyrolactone motif if the
Kowalski ester homologation reaction was combined with a
chiral auxiliary-mediated asymmetric aldol reaction, followed
by in situ intramolecular ring closure in a tandem manner.
The proposed transformation mechanism is as follows9,10
(Scheme 1): upon treatment with dibromomethyllithium, the
chiral auxiliary bearing starting material I could be converted
to a tetrahedral intermediate. Subsequent treatment with
silazide base (LiHMDS) and lithium ethoxide results in the
formation of di- and monobromoketone enolates II and III.
The key halogen−metal exchange rearrangement occurs upon
treatment with sec-butyllithium leading to ynolate anion IV at
low temperature. This is followed by the addition of n-
butyllithium, which acts as a base to regenerate LiTMP and
deprotonate the remaining enolate III to complete the
rearrangement and convert residual enolate III to ynolate IV.
In turn, quenching the resulting ynolate anion by acidic alcohol
might generate the desired chiral γ-butyrolactone, presumably
through the intramolecular ring closure of the ketene
intermediacy V. Additionally, it was anticipated that the
stereochemical outcome of the two vicinal stereogenic centers
in γ-butyrolactones would be retained under those reaction
conditions. Furthermore, it should be noted that all β,γ-
stereoisomers would be accessible by taking advantage of the
high stereofacial selectivity of auxiliary-mediated asymmetric
aldol reactions.
initial attempt was successful, it afforded the desired γ-
butyrolactone 3 in an unsatisfactory yield (16%). Replacing the
N-acyloxazolidinone with an oxazolidinethione in syn-aldol
product 2b and subsequently subjecting it to the one-carbon
homologated intramolecular lactonization improved the yield
but only to 36%.
We hypothesized that these results could be attributed to the
inherent electrophilic nature of the C1 carbonyl carbon in 2a−
c and the consequent inhibition of the initial dibromoketone
enolate formation. Therefore, we expected that substrates with
reduced electrophilic character at C1 and auxiliaries, which
could be cleaved more easily than oxazolidinones or
oxazolidinethiones, would be advantageous in achieving more
effective ring closure.11,15,17 After searching for alternative
chiral auxiliaries and fine-tuning the reaction parameters,
including bases and temperature, we were delighted to find
that the use of asymmetric syn-aldol products bearing N-
acylthiazolidinethione with a Bn or an i-Pr (Scheme 2) moiety
proved to be more effective leading to a higher conversion
(64%) along with 4 in 20% yield. It is of note that the
developed reaction proceeds with complete retention of the
stereochemistry in 3 (see the Supporting Information). An
additional attribute of this approach is that the isolated 4, the
one-carbon homologated intermediate γ-hydroxy ester, under-
went cyclization upon treatment with DBU in THF to deliver
the desired 3 (66%), revealing a significant benefit of the
present methodology.
To test this hypothesis, syn-aldol adduct 2a was prepared
using an Evans type auxiliary-mediated aldol protocol,11−14
following the procedure described by Crimmins.15,16 Com-
pound 2a was then subjected to the modified Kowalski ester
homologation reaction conditions (Scheme 2). While this
B
DOI: 10.1021/acs.orglett.9b02848
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Letter
Now that the chiral auxiliary had served its intended purpose
in the formation of the syn-aldol product 2c, we sought to
address the intramolecular ring closure with a simpler ester
functionality by removal of the chiral auxiliary. This was
performed by methanolysis (DMAP (20 mol %), MeOH (1.5
equiv), CH2Cl2, 25 °C, 4 h, 88%) and subsequent one-carbon
homologated intramolecular cyclization, which proceeded to
provide 3 in 58% yield, suggesting that a direct mode of
homologated ring closure from an intermediate such as 2c may
constitute a more effective approach than a two-step process
through intermediate 5.
compounds bearing aryl and aliphatic substituents was
prepared and found to undergo the desired γ-butyrolactoniza-
tion in good to moderate conversions. Electron-neutral and
electron-rich aryl substituents were well tolerated (Scheme 3,
7a−g), while slightly lower yields were observed with
substrates containing electron-deficient substituents (4-CN
(7h) and 4-CF3 (7i)).
These experiments have shown that the reaction conditions
were compatible with a range of functional groups and that
aromatic substrates were generally slightly more effective than
aliphatics (7j−l). It is of note that the current strategy
produced the shortest total synthesis of the optically active
natural products (+)-cis-cognac lactone (7k) and (+)-cis-
whisky lactone (7l) reported to date18,19 (two steps in total
from commercially available 1c), demonstrating the applic-
ability of this strategy in natural product synthesis.
Given the interest in facilitating access to the desired γ-
butyrolactone 3, we set out to explore the scope and the
limitations of this transformation. Representative examples are
summarized in Scheme 3. A series of β-hydroxy carbonyl
To demonstrate the synthetic utility of this methodology, we
tackled the synthesis of three members of the eupomatilone
family (eupomatilones-2,5,6) and one 3-epi-eupomatilone-6.
Eupomatilones 1−7 (Figure 2) are natural products isolated
from the Australian shrub Eupomatia bennettii in 1991 by
Carroll and Taylor, and they are members of a structurally
intriguing class of lignans.20
Scheme 3. Substrate Scope of the Kowalski One-Carbon
Homologative Lactonization.
a
Figure 2. Eupomatilones 1−7.
Due to their unique structural features, including the chiral
γ-butyrolactone motifs and the highly oxygenated biaryl
skeletons, several elegant and concise syntheses have been
accomplished by different groups, such as the Hall group’s
efficient construction of γ-butyrolactone in ( )-eupomatilone-
6 employing a Brønsted acid catalyzed allylboration,21e the
Buchwald group’s asymmetric synthesis of eupomatilone-3 via
dynamic kinetic resolution,21f and the Rovis group’s asym-
metric synthesis of eupomatilones-4,7 and 3-epi-eupomatilone-
6 utilizing the rhodium catalyzed desymmetrization of succinic
anhydrides.21i
While there have been a number of prior syntheses
reported,21 many utilize a biaryl linkage via a cross-coupling
reaction in the first stage of the synthesis and a late stage
stereoselective formation of the γ-lactone core.21c,d,f−h,j−l It
should be noted that our synthetic route, in contrast, provides
the rapid stereoselective formation of the γ-lactone core and
potentially allows ready manipulation of the biaryl functionality
a
Reaction conditions: (i) LiTMP (4.0 equiv), CH2Br2 (4.4 equiv),
−78 °C, (ii) LiHMDS (2.0−4.0 equiv), LiOEt (1.0 equiv for 7a−i
and no LiOEt was used for 7j−l), −78 to −20 °C, (iii) s-BuLi (2.0−
4.0 equiv), −78 to −20 °C, (iv) n-BuLi (2.0−4.0 equiv), −78 °C, (v)
acidic MeOH. (For details, see the Supporting Information.)
b
c
Isolated yields of 7 and 8. Not determined.
C
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Letter
which ultimately permits a concise divergent assembly of
eupomatilones, thereby effectively enhancing the synthetic
utility of the present methodology.
The total syntheses of eupomatilone-2 (10) and eupoma-
tilone-5 (13) is illustrated in Scheme 4. An asymmetric aldol
lones family of lignans. Toward this end, bromination of 17 by
treatment with NBS in DMF provided the aryl bromide 19 in
high yield (98%). The Suzuki cross-coupling of the resulting
common intermediate 19 and 3,4,5-trimethoxyphenylboronic
acid (20) (Pd(PPh3)4, K3PO4, dioxane, 100 °C) smoothly
proceeded to provide 22 (89%).
Similarly, the Suzuki coupling of 19 with 3,4-
(methylenedioxy)phenylboronic acid 21 resulted in 23 in
excellent yield (97%). Subsequent installation of the α-exo-
methylene moiety of 10 upon treatment of 22 with
Eschenmoser’s salt (LiHMDS, THF, −78 °C, 1 h) and its
subsequent in situ elimination (m-CPBA, CH2Cl2, 25 °C, 5
min) afforded the eupomatilone-2 (10) in 67% yield. The
synthesis of eupomatilone-5 (13) was accomplished in a
similar fashion in 62% yield which proved to be identical in all
respects with the reported properties of the natural product
(Scheme 4).
Scheme 4. Divergent Total Synthesis of Eupomatilone-2 and
Eupomatilone-5
With straightforward access to (+)-eupomatilones-2 and -5,
the synthesis of eupomatilone-6 (14) was realized upon
treatment of the lactone enolate of 23 with iodomethane
(LiHMDS, THF, 5 min, −78 °C) as a single diastereomer
(Scheme 5). Furthermore, the diastereoselective hydrogena-
Scheme 5. Total Synthesis of Eupomatilone-6 and 3-epi-
Eupomatilone-6
tion of the α-exo-methylene lactone 13 was best effected with
Wilkinson’s catalyst in toluene, in which the facial selectivity is
governed by the C-4 methyl, providing 3-epi-eupomatilone-6
(24) in good conversion and diastereoselectivity (95%, dr
>8.8:1), thereby providing access to three members of
eupomatilones family and one 3-epi-analogue in only five
steps (for eupomatilones-2,5,6) and six steps (for 3-epi-
eupomatilone-6) from commercially available thiazolidine-
thione propionate (+)-1c, which proved our approach is
comparable in length to the shortest asymmetric syntheses of
eupomatilones reported by the Rovis group,21i highlighting the
efficiency of our approach.
In summary, we have demonstrated an efficient synthesis of
γ-butyrolactones via a combination of the asymmetric aldol/
Kowalski ester homologation reaction. The strategy enables
the straightforward preparation of a range of γ-butyrolactones
bearing two vicinal functional groups and requisite stereo-
chemistry in a single step. The applicability of this trans-
formation was demonstrated in a protecting-group-free
divergent total syntheses of eupomatilones-2,5,6 and 3-epi-
a
Reaction conditions: 0.5−1.0 mmol of 16. (i) LiTMP (4.0 equiv),
CH2Br2 (4.4 equiv), −78 °C, (ii) LiHMDS (4.0 equiv), LiOEt (1.0
equiv), −78 to −20 °C, (iii) s-BuLi (4.0 equiv), −78 to −20 °C, (iv)
n-BuLi (4.0 equiv), −78 °C, (v) acidic MeOH.
addition of chlorotitanium enolate of thiazolidinethione
propionate ent-(+)-1c with 3,4,5-trimethoxybenzaldehyde
afforded the syn-aldol adduct 16 in 98% yield, which was
subjected to a modified Kowalski ester homologation reaction
to provide the desired γ-butyrolactone 17 (66%) along with
the γ-hydroxy ester 18 (19%). The isolated intermediate 18
underwent ring closure upon treatment with DBU in THF to
provide 17 (67%).
Having successfully secured the γ-butyrolactone 17, we
continued our investigation to the formation of the biaryl
skeleton and completion of four members of the eupomati-
D
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P.; Segura, J. Recent Developments in γ-Lactone Synthesis. Mini-Rev.
Org. Chem. 2009, 6, 345−358.
eupomatilone-6. This represents one of the shortest asym-
metric syntheses of eupomatilones family of lignans reported to
date. The extension of this transformation in furthering the
exploration of natural products is in progress, and the
continued examination for more concise and facile access to
chiral γ-lactones and tetrahydrofurans will be disclosed in due
course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02848.
Full experimental details and copies of 1H and 13C NMR
spectra (PDF)
(6) (a) Kowalski, C. J.; Fields, K. W. Alkynolate Anions via a New
Rearrangement: The Carbon Analogue of the Hofmann Reaction. J.
Am. Chem. Soc. 1982, 104, 321−323. (b) Kowalski, C. J.; Haque, M.
S.; Fields, K. W. Ester Homologation via α-Bromo α-Keto Dianion
Rearrangement. J. Am. Chem. Soc. 1985, 107, 1429−1430.
(c) Kowalski, C. J.; Haque, M. S. Aldehydes, Alcohols, and Enol
Acetates via Reductive Homologation of Esters. J. Am. Chem. Soc.
1986, 108, 1325−1327. (d) Kowalski, C. J.; Lal, G. S. 1-Acetoxy and
1-Silyloxy-1,3-dienes via Reductive Homologation of α,β-Unsaturated
Esters. Tetrahedron Lett. 1987, 28, 2463−2466. (e) Kowalski, C. J.;
Lal, G. S.; Haque, M. S. Ynol Silyl Ethers via O-Silylation of Ester-
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(f) Kowalski, C. J.; Reddy, R. E. Ester Homologation Revisited: A
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kiyoun@catholic.ac.kr.
ORCID
Hyoungsu Kim: 0000-0002-2774-8727
Kiyoun Lee: 0000-0003-4940-5044
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by National Research Foundation
of Korea (NRF) grants funded by the Korea government
(MSIT; No. 2019R1H1A1079670).
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the Preparation of α’-Chloroketones of N-Carbamate Protected-α-
Aminoacids. Tetrahedron Lett. 1997, 38, 3175−3178. (b) Gray, D.;
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DOI: 10.1021/acs.orglett.9b02848
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