Short eight-steps total synthesis of racemic asteriscunolide C

Article abstract of DOI:10.1080/00397911.2017.1365907

A concise total synthesis of racemic asteriscunolide C in eight steps has been described starting from neopentane diol involving an efficient Yamaguchi esterification using an aldehyde-acid, intramolecular Horner–Wittig–Emmons olefination, and a late stage ring-closing metathesis to construct the strained 11-membered ring with one Z- and two E-double bonds.

Full text of DOI:10.1080/00397911.2017.1365907

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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A short eight-steps total synthesis of racemic
asteriscunolide C
Rodney A. Fernandes , Vijay P. Chavan & Arpita Panja
To cite this article: Rodney A. Fernandes , Vijay P. Chavan & Arpita Panja (2017): A short
eight-steps total synthesis of racemic asteriscunolide C, Synthetic Communications, DOI:
10.1080/00397911.2017.1365907
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Date: 21 August 2017, At: 19:24

A short eight-steps total synthesis of racemic asteriscunolide
C
Rodney A. Fernandes
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai,
Maharashtra, India
Vijay P. Chavan
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai,
Maharashtra, India
Arpita Panja
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai,
Maharashtra, India
These authors contributed equally.
Address correspondence to Rodney A. Fernandes. E-mail: rfernand@chem.iitb.ac.in
ABSTRACT
A concise total synthesis of racemic asteriscunolide C in eight steps has been described
starting from neopentane diol involving an efficient Yamaguchi esterification using an aldehyde-
1

acid, intramolecular Horner-Wittig-Emmons olefination and a late stage ring-closing metathesis
to construct the strained 11-membered ring with one Z- and two E-double bonds.
GRAPHICAL ABSTRACT
KEYWORDS: asteriscunolides, Horner-Wittig-Emmons, macrolide, racemic synthesis, ring-
closing metathesis
Introduction
San Feliciano et al.[1] isolated the sesquiterpene lactones asteriscunolides A-D, 1-4
(Figure 1) from Asteriscus aquaticus L. Asteriscunolides possess the humulene 5 skeleton with a
strained 11-membered ring. (−)-Asteriscunolide A 1 induces apoptosis[2] (programmed cell
death) of human melanoma, leukemia and cells that overexpress antiapoptotic proteins, namely
Bcl-2 and Bcl-x(L). All cell lines were sensitive to this compound, with IC50 values of
approximately 5 M. The cyctotoxicity levels of asteriscunolides were much higher than those of
the common antitumor agent like Cisplatinum for the cancer cell lines, namely human lung
carcinoma (A-549), human colon carcinoma (HT-29) and human melanoma (MEL-28).[3]
Asteriscunolide D 4 was most potent followed by A 1 and C 3.
The synthetic attempts on these molecules are rather scarce.[4] The first total synthesis of
asteriscunolide D was reported by Trost and co-workers[4a] employing a thionium ion mediated
formal aldol reaction followed by thioether activation-elimination sequence to generate the final
C-6 E-double bond of asteriscunolide D. Subsequently, a chiral pool D-pentolactone based
2

synthesis involving ring-contracting ring-closing metathesis (RCM) was employed by us in the
synthesis of (−)-ateriscunolide C.[4b] Recently, the asteriscunolides and related molecules are
synthesized efficiently by Li et al. based on a metathesis cascade.[4c]
The inherent ring strain to accommodate one or more E-double bonds in the macrocycle
imposes a major impediment in the synthesis of these medium ring compounds. Ring-closing
metathesis (RCM)[5] is a reaction of choice to generate olefinic bonds in macrocycle synthesis.[6]
The outcome of olefin geometry depends largely on ring size and in most cases with medium
rings favouring the Z-olefin stereochemistry. Thus, it should be possible to generate either of the
two Z-bonds in asteriscunolide A or the Z-bonds in asteriscunolides B and C (Figure 1).
Results and Discussion
We designed a non-chiral pool approach to the synthesis of racemic asteriscunolide C
starting from neopentanediol 11 which has the gem-dimethyl group that is required in the target
molecule as shown in our retrosynthetic analysis in Scheme 1. The alcohol 9 was designed by
phosphonate addition to ester 10 which in turn could be easily derived from neopentane diol 11.
The phosphonate 7 was planned through Yamaguchi esterification of alcohol 9 and aldehyde-
acid 8. The bicyclic and highly strained 11-membered ring in 3 was visualized from
macrolactone 6 through RCM. The 12-membered macrolactone 6 could be achieved from
phosphonate 7 through intramolecular Horner-Wittig-Emmons (HWE)-olefination. The use of
ester-aldehyde 8 circumvents any protecting group manipulations unlike in our earlier
synthesis[4b] and hence compound 7 could be directly taken for HWE-olefination.
The forward synthesis was initiated from neopentanediol 11. Diol 11 was oxidized to
dialdehyde and subsequent same pot selective HWE-olefination with triethylphosphonoacetate
3

efficiently delivered compound 12 (72%) in one step. The dialdehyde from 11 was quite stable,
perhaps the gem dimethyl group possibly prevented aldol-type reaction. Selective addition of
vinyl-Grignard delivered 10inꢀ 88% yield. MOM-ether protection of free hydroxyl group to 13
(90%) and successive two steps: n-BuLi mediated addition of (EtO)2P(O)CH2CH3[7] followed by
MOM-ether deprotection, led to alcohol fragment 9 (13 to 9, 81%). For subsequent reaction we
considered a aldehyde-acid 8 as the esterification partner (Scheme 2). The latter was prepared
from commerically available -valerolactone 14. α-Methylenation[8] of 14 gave 15 (70%) and
subsequent hydrolysis and alcohol oxidation provided 8 as an equilibrium mixture of 8a and 8b
(1.5:1, 68% overall).[9] The Yamaguchi esterification[10] of aldehyde-acid 8 with alcohol 9
provided the ester 7inꢀ 74% yield which on direct intramolecular HWE-olefination[11] under
dilution provided the inseparable mixture of 6a/6b (1:1) in 77% yield. Unlike our earlier
approach[4b] the use of compound 8 directly for the synthesis of the aldehyde 7 circumvents any
protecting group involvement and hence 7 can be used for direct HWE-olefination without
involving deprotection-oxidation steps. The final step was similar to our earlier approach[4b]
leading to asteriscunolide 3inꢀ overall 8 steps from 11. The final RCM[12] reaction was attempted
on the mixture of 6a/6b using Grubbs IInd generation catalyst which delivered only (±)-
asteriscunolide C 3inꢀ 42% yield (84% based on the presence of 6b in the substrate mixture).
Astericunolide D was not obtained, neither could we isolate the precursor 6a from the RCM
reaction. The spectral and analytical data of 3 were in excellent agreement with that reported in
literature.[1b]
Conclusion
In summary, a concise total synthesis of racemic asteriscunolide C has been achieved in
eight steps. Neopentanediol served as the source for preparation of intermediate 9 with the
4

gemdimethyl group. The acid-aldehyde partner 8 for esterification was prepared from -
valerolactone and could give directly the aldehyde 7 for subsequent intramolecular HWE-
olefination. The late stage RCM reaction led to the strained 11-membered ring. The synthesis is
completed in 8 steps and 11.0% overall yield.
Experimental
Experimental Procedure for the synthesis of
2-Methylene-5-oxopentanoic acid (8a) and 6-hydroxy-3-methylenetetrahydro-
2H-pyran-2-one (8b)
To the lactone 15 (0.2gꢀ, 1.78 mmol, 1.0 equiv), LiOH.H2O (1.79gꢀ, 42.8 mmol, 24.0
equiv), MeOH (16mLꢀ), THF (8mLꢀ) and H2O (4mLꢀ) were added and the reaction mixture was
then stirred for 24hꢀ at room temperature. Then MeOH and THF were evaporated in vacuum and
the resulting residue was diluted with cold H2O (5.0mLꢀ) and EtOAc (5.0mLꢀ). After
acidification with 2Nꢀ HCl (pH 4-5), the solution was extracted with EtOAc (3  10mLꢀ). The
combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated. The
crude residue was purified by silica gel column chromatography using petroleum ether/EtOAc
1
(1:1) as eluent to give the acid-alcohol (0.2gꢀ, 87%) as gummy solid. H NMR (CDCl3,
400MHzꢀ): δ 6.19 (s, 1H) 6.59 (s, 1H) 3.65−3.53 (m, 2H) 2.36−2.25 (m, 2H) 1.72−1.62 (m, 2H);
13Cꢀ NMR (CDCl3, 100MHzꢀ): δ 171.3, 139.6, 126.8, 61.4, 30.9, 27.6.
The acid-alcohol (0.2gꢀ, 1.54 mmol, 1.0 equiv) was treated with Dess-Martin periodinane
(0. 978gꢀ, 2.31 mmol, 1.5 equiv) in dry CH2Cl2 (15mLꢀ) at 0°C. The resulting mixture was stirred
at room temperature for 3hꢀ. After completion of the reaction (checked by TLC), the mixture was
5

filtered through celite pad and then concentrated. The residue was passed through a short pad of
silica gel and eluted with petroleum ether/EtOAc (1:1) to give the equilibrium mixture 8
1
(0.154gꢀ, 78%) as colorless oil. Data for 8a: H-NMR (400MHzꢀ, CDCl3): 9.78 (s, 1H) 6.35 (s,
13
1H) 5.73 (s, 1H) 2.69−2.59 (m, 4H); Cꢀ-NMR (100MHzꢀ, CDCl3): 201.2, 172.2, 139.1, 128.5,
1
42.5, 29.7; Data for 8b: H-NMR (400MHzꢀ, CDCl3): 6.31 (s, 1H) 5.68 (s, 1H) 4.88 (t, J =
5.1Hzꢀ, 1H) 2.46−2.38 (m, 2H) 1.92−1.85 (m, 2H); 13Cꢀ NMR (CDCl3, 100MHzꢀ): δ 171.5,
138.1, 127.4, 100.7, 32.7, 24.3.
(6E,9E)-7,11,11-Trimethyl-3-methylene-12-vinyloxacyclododeca-6,9-diene-2,8-
dione (6a) (1:1) mixture with (6Z,9E)-7,11,11-Trimethyl-3-methylene-12-
vinyloxacyclododeca-6,9-diene-2,8-dione (6b)
To a solution of K2CO3 (77mgꢀ, 0.558 mmol, 6.0 equiv) and 18-crown-6 (0.296gꢀ, 1.12
mmol, 12.0 equiv) in toluene (50mLꢀ) at 60 C was added a solution of aldehyde 7 (40mgꢀ, 0.093
mmol) in toluene (15mLꢀ) over period of 4hꢀ. The resulting solution was stirred at 60 C for 12hꢀ.
It was then quenched with sat. aq. NH4Cl (5mLꢀ) and the solution extracted with EtOAc (3 
20mLꢀ). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated.
The residue was purified by silica gel column chromatography using petroleum ether/EtOAc
(4:1) as eluent to give a mixture of 6a:6b (1:1, by 1H-NMR, 20.9mgꢀ, 77%) as colorless oil.
Data of mixture: 1H NMR (CDCl3, 400MHzꢀ): δ 6.68 (d, J = 16.2Hzꢀ, 1H) 6.29−6.21 (m,
3H) 6.03−5.99 (m, 3H) 5.96−5.77 (m, 2H) 5.62 (s, 1H), 5.51−5.47 (m, 2H) 5.42 (d, J = 6.8Hzꢀ,
1H) 5.36−5.29 (m, 4H), 5.03 (d, J = 6.8Hzꢀ, 1H) 2.91−2.85 (m, 1H), 2.61−2.10 (m, 7H) 1.87 (s,
3H) 1.79 (s, 3H) 1.15 (s, 3H) 1.12 (s, 3H) 1.09 (s, 3H) 1.08 (s, 3H); IR (CHCl3, cm-1): 3018,
6

2924, 2856, 1722, 1640, 1465, 1371, 1288, 1184, 1146, 1102, 1021, 990, 940, 669; HRMS
(ESI): calcd for C17H23O3 [M + H] + 275.1647; found 275.1656.
(±)-Asteriscunolide C (3)[4b]
To a stirred mixture of 6a and 6b (15mgꢀ, 0.055 mmol, 1.0 equiv) in dry and degassed
toluene (10mLꢀ) was added Grubb’s IInd generation catalyst (4.6mgꢀ, 10molꢀ%). The resulting
solution was refluxed for 24hꢀ and Grubb’s IInd generation catalyst (2.3mgꢀ, 5molꢀ%) was added
and stirred for another 48hꢀ. The reaction mixture was concentrated and the residue purified by
silica gel column chromatography using petroleum ether/EtOAc (7:3) as eluent to give (±)-3
(5.65mgꢀ, 84% based on the proportion of 6b in substrate mixture) as white solid. mp 160−161
oC; (lit.[3] 164 oC); 1H NMR (CDCl3, 400MHzꢀ): δ 6.97 (s, 1H) 6.28 (d, J = 16.5Hzꢀ, 1H) 5.91 (d,
J = 16.5Hzꢀ, 1H) 5.48 (bd, J = 11.6Hzꢀ, 1H) 4.71 (s, 1H) 2.54−1.76 (m, 4H) 1.87 (s, 3H) 1.37 (s,
3H) 1.27 (s, 3H); 13Cꢀ NMR (CDCl3, 100MHzꢀ): δ 202.6, 173.7, 156.4, 149.7, 138.6, 135.6,
129.5, 128.5, 85.6, 40.7, 33.8, 24.6, 22.8, 21.1, 21.0; IR (CHCl3, cm-1): 3022, 2927, 1762, 1655,
1460, 1451, 1368, 1312, 1182, 1053, 895, 855, 669; HRMS (ESI): calcd for C15H19O3 [M + H] +
247.1334; found 247.1328.
Acknowledgements
We thank the Board of Research in Nuclear Sciences (BRNS), Government of India
(Basic Sciences, Grant No. 2013/37Cꢀ/59/BRNS/2443) for financial support. V.P.S. thanks
Council of Scientific and Industrial Research (CSIR), New Delhi, India for research fellowship.
A.P. thank Indian Institute of Technology Bombay for postdoctoral fellowship.
Supporting Information
7

1
13
Full experimental detail, H and Cꢀ NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
References
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[9] See Supporting Information for spectra of 8a/8b mixture.
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8

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9

Figure 1. Asteriscunolides A-D 1-4 and related molecule humulene 5.
10

Scheme 1. Retrosynthetic route to ()-asteriscunolide C 3.
11

Scheme 2. Synthesis of ()-asteriscunolide C 3.
12