Intramolecular [2 + 2] Cycloadditions of Alkyl(phenylthio)ketenes: Total Synthesis of (+)-Sphaerodiol

Article abstract of DOI:10.1021/acs.orglett.8b00407

Asymmetric total synthesis of (+)-sphaerodiol (2) has been achieved. A key step is an intramolecular [2 + 2] cycloaddition of alkyl(phenylthio)ketene for rapid assembly of the decalin ring.

Full text of DOI:10.1021/acs.orglett.8b00407

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Intramolecular [2 + 2] Cycloadditions of Alkyl(phenylthio)ketenes:
Total Synthesis of (+)-Sphaerodiol
,†
†
†
,‡
Xiang Wu,* Hai-Jun Wang, Yong-Shuang Huang, and Wei-Dong Z. Li*
†Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009, China
‡
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
*
S Supporting Information
ABSTRACT: Asymmetric total synthesis of (+)-sphaerodiol (2) has been achieved. A key step is an intramolecular [2 + 2]
cycloaddition of alkyl(phenylthio)ketene for rapid assembly of the decalin ring.
he Asteraceae family contains over 1000 eudesmanes, with
Scheme 1. [2 + 2] Cycloaddition of (Phenylthio)ketenes
T
almost every conceivable oxidation pattern within the
carbon framework. Considerable efforts have been devoted to
1
the total synthesis of eudesmane sesquiterpenoids over the past
2
decades, in which the rigid decalin skeleton 1 possessing
multiple hydroxyl functions (i.e., euonyminol) posed a
significant synthetic challenge. It is thus highly desirable to
develop a facile and diversified strategy for the total synthesis of
eudesmane sesquiterpenes.
The natural eudesmane sesquiterpene compound
3
(
+)-sphaerodiol (2) with C1, C14-dihydroxyl was isolated
intramolecular cycloaddition of those type of ketenes has not
been explored systematically. Therefore, it is in our interest to
explore the intramolecular [2 + 2] cycloaddition of alkyl-
from polyachyrus sphaerocephalus by Bohlmann and co-workers
4
in 1991. In continuation of our ongoing studies on the total
5
synthesis of bioactive sesquiterpenoids, we report herein the
(
phenylthio)ketene for the construction of the decalin ring
development of a novel method of intramolecular [2 + 2]
cycloaddition of alkyl(phenylthio)ketene to construct the
decalin ring (Scheme 1B) and its application in the total
synthesis of (+)-sphaerodiol (2).
system of typical eudesmanes (Scheme 1B).
10
Previous studies by Ghosez and co-workers have shown
that the ketenes prepared by the treatment of acid chloride 3a
and 3e (entries 1 and 5, Table 1) with Et N provided the
The cycloaddition of ketenes to alkenes is a generally popula6r
method for the synthesis of cyclobutanone derivatives.
Although the intramolecular [2 + 2] cycloadditions of ketenes
to alkenes generate synthetically useful polycyclic compounds
3
11
cycloadducts 4a, e in only 3% yield both. When the
phenylthio group was introduced to the α position of carbonyl
acid chloride 3b, the yield of the cycloadduct 4b was only
slightly increased to 6% (entry 2, Table 1). Therefore, we set
out to investigate other substrates for the cycloaddition.
7
with a high degree of regio- and stereocontrol, this method has
been applied by a few groups for the synthesis of natural
8
products. Heterosubstituted ketenes, such as the alkyl(phenyl-
thio)ketenes, have shown enhanced reactivity toward functional
groups (Scheme 1A). To the best of our knowledge, the
Received: February 4, 2018
9
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00407
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Table 1. Intramolecular Ketene [2 + 2] Cycloaddition of 3
Table 2. Intramolecular Ketene [2 + 2] Cycloaddition of 5
a
Method A: Ketenes were generated by adding the solution of Et N to
3
b
the solution of acid chloride in refluxing CH Cl . Method B: Ketenes
2
2
were generated by adding the solution of carboxylic acid to a solution
of Et N and 2-chloro-N-methylpyridinium iodide in refluxing CH CN.
3
3
c
Isolated yield.
It has been reported that activation of carboxylic acid with
Mukaiyama’s reagent is superior to the corresponding acid
chloride for the in situ generation of ketene and subsequent
a
b
1
c
8
f
Isolated yield. Determined by H NMR. Determined by separation
cyclization. Mukaiyama’s reagent (2-chloro-N-methyl-
12
through chromatography.
pyridinium iodide) is an effective reagent to generate ketenes
1
3
in situ for subsequent [2 + 2] cycloadditions with alkenes,
1
4
15
16
17
allenes, aldehydes, imines, and hydrazones. Although
initial studies on the acid 3c with Mukaiyama’s reagent failed to
yield desired intramolecular cycloadduct 4a, when the phenyl-
thio-substituted acid 3d and 3f were added to a solution of
Mukaiyama’s reagent and Et N in refluxing CH CN, cyclo-
not afford any cycloadduct. Moreover, the methylthio-
substituted acid 5c (entry 3) could also produce tricyclic
adduct 6c with the same diastereoselectivity but in a lower yield
of 57%. As illustrated in entries 1−3, the reactivity of
phenylthio-substituted ketene is superior to that of methyl-
thio-substituted ketene, probably because the phenyl group
works as an inductively withdrawing group when bonding with
the sulfur atom which could stabilize the ketene more
effectively and avoid the side reactions. Further modified
substrates 5d and 5e can also be converted to the cycloadducts
in excellent yields (entries 4 and 5); however, 5f gave the
corresponding product 6f with excellent diastereoselectivity
3
3
adducts 4b and 4f were obtained as single diastereomers in 70%
and 62% yields, respectively (entries 4 and 6, Table 1). Based
on these results, it could be inferred that the introduction of
phenylthio-substituent to ketene can enhance the reactivity and
the phenylthio-substituted ketene could be generated efficiently
by the reaction of acid with Mukaiyama’s reagent.
8i
Then, in order to construct the decalin ring of eudesmane,
some elaborated substrates were employed. The cycloaddition
was carried out under the optimal conditions as described
above. Results are summarized in Table 2. The α-phenylthio
acid 5b, which has a four-carbon-atom tether conformationally
restricted by a six-membered ring, was investigated to give the
19
albeit in a low yield (entry 6).
As an example, the α-phenylthio acid 5d as the key
intermediate to the synthesis of (+)-sphaerodiol (2) was
prepared as follows (Scheme 2). (S)-Perillyl bromide 7,
obtained from commercially available (S)-perillyl aldehyde,
reacted with the aldehyde 8 to give the alcohol 9 via a Barbier-
20
18
tricyclic cycloadduct 6b in 70% yield with 2.5:1 dr. For
comparison, the acid 5a without a phenythio-substituent could
21
type reaction. Alcohol 9 was a diastereomeric mixture that
B
DOI: 10.1021/acs.orglett.8b00407
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Acid 5d
hydroxyl group was introduced to the α position of lactone 12
by the reaction of enolate with Davis’ oxaziridine. Then the
23
compound was reduced with LiAlH to give diastereomeric
4
lactols. Without separation, the resultant lactols underwent
oxidative cleavage using NaIO to furnish a formate aldehyde.
4
The formate aldehyde residue was further reduced with LiAlH4
to give C1, C14-diol. Deprotection of the ketal group using 1 M
HCl afforded 13 in 69% yield over five steps. The cis-fused
decalin ring system of 13 was confirmed according to the X-ray
crystallographic analysis of a single crystal of ester derivative 17
(
see SI). Ketone 13 could be epimerized under basic conditions
to give a mixture of 13 and trans-14(a, b) in a ratio of 4:1.
Thus, by a repeated epimerization−separation sequence,
undesired ketone 13 was mostly converted to a mixture of
ketone 14a and hemiketal 14b. Wittig reaction of 13 with
Ph PMeBr and t-BuOK gave compound 15 (5-epi-2), and
3
Wittig reaction of 14 furnished target compound 2. 14-Acetoxy-
lα-hydroxy-5,10-bis-epi-eudesma-4(15),11(13)-diene (16) was
obtained after acylation of the 14-hydroxy of compound 2. The
24
1
13
synthetic product 2 ( H NMR, C NMR, IR and HRMS)
was converted to ketones 10 and 11 by Dess-Martin
1
2
2
and 16 ( H NMR, IR) were identical spectroscopically to the
natural products as previously reported.
oxidation. Compound 10 was then separated by column
chromatography. Protection of the ketone in 10 and
introduction of phenylthio group, followed by hydrolysis of
ester, provided acid 5d in 71% yield.
25
In summary, we have described the intramolecuar [2 + 2]
cycloaddition of alkyl(phenylthio)ketene prepared from the
corresponding acids to construct a decalin ring, and
demonstrated the utility of the strategy for the first asymmetric
total synthesis of (+)-sphaerodiol (2) in 6% yield via 15 steps.
The cycloadduct 6d derived from acid 5d underwent smooth
desulfurization upon exposure to activated Zn dust and NH Cl
4
in MeOH under reflux, and was then oxidized by H O , which
2
2
gave five-membered lactone 12 in 73% yield over two steps
Scheme 3). The structure of 12 was confirmed by single
crystal X-ray analysis (see Supporting Information (SI)). A
(
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00407.
Scheme 3. Total Synthesis of (+)-Sphaerodiol (2)
Experimental procedures, X-ray structures of 12 and 17,
and spectral data (PDF)
Accession Codes
CCDC 1588362 and 1588364 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
*
*
E-mail: wuxiang@hfut.edu.cn.
E-mail: wdli@cqu.edu.cn.
ORCID
Xiang Wu: 0000-0001-5428-9063
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (NNSFC) (Grant 21672049 and
2
1672030). This paper is in memory of Yan-Jun Guo for his
supportive contribution to this project.
C
DOI: 10.1021/acs.orglett.8b00407
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
9) (a) Bellus,
̌
D. Helv. Chim. Acta 1975, 58, 2509. (b) Minami, T.;
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Org. Lett. XXXX, XXX, XXX−XXX