Asymmetric reduction of Diynones and the total synthesis of (S)-Panaxjapyne A

Article abstract of DOI:10.1021/ol4032123

The asymmetric transfer hydrogenation of a series of diynones has been achieved in high conversion and enantiomeric induction. When R¹ is a phenyl group, a competing alkyne reduction takes place; however, when R ¹ is an alkyl group, this side-reaction is not observed. The application of the reduction to the total synthesis of the natural product (S)-panaxjapyne A in high enantiomeric excess is described.

Full text of DOI:10.1021/ol4032123

Letter
pubs.acs.org/OrgLett
Asymmetric Reduction of Diynones and the Total Synthesis of
(S)‑Panaxjapyne A
Zhijia Fang and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, U.K.
S
* Supporting Information
ABSTRACT: The asymmetric transfer hydrogenation of a series of
diynones has been achieved in high conversion and enantiomeric
induction. When R1 is a phenyl group, a competing alkyne reduction
takes place; however, when R1 is an alkyl group, this side-reaction is not
observed. The application of the reduction to the total synthesis of the
natural product (S)-panaxjapyne A in high enantiomeric excess is
described.
iynols are found in a number of natural products, some of
which exhibit potent anticancer and anti-HIV properties.1
Notable examples are strongylodiols A−C, isolated from the
sponge genus Strongylophora, which possesses cytotoxic
activities against tumor cells (DLD-1 and MOLT-4).2 Diynol-
containing natural products panaxjapyne A−C (Figure 1) were
(S,S)-ProPhenol ligand.6 An amino-alcohol ligand system
D
established by Wang et al. was also applied to the total
synthesis of strongylodiols.7 Trost el al. found that low yields in
additions to low molecular weight aldehydes were caused by a
competing aldol reaction, but were able to obtain a product of
94% ee in up to 78% yield through slow addition of excess
aldehyde.8 A recently reported 1,1′-binaphth-2-ol (BINOL)/
ZnEt2/Ti(OiPr)4 system gave excellent results in this trans-
formation, across a wide range of substrates.9
Although the addition of diynes to aldehydes is an effective
method for the synthesis of diynols in high ee, it is often
necessary to employ an excess of either a diyne or aldehyde. It
therefore seemed desirable to develop an alternative approach
to these valuable targets. The asymmetric transfer hydro-
genation (ATH)10 of ketones adjacent to an alkyne is known to
proceed in high enantioselectivity and yield when Ru(II)
complexes 2 and 3 (Figure 2) are employed as catalysts.11 To
our knowledge, however, no report has yet been published on
the synthesis of enantiomerically eniched diynols via the
asymmetric reduction of diynones.
Figure 1. Structures of panaxjapynes A−C.
The synthesis of diynones required the use of the well
established and efficient Cadiot-Chodkiewicz cross-coupling.12
In this reaction, racemic 1-yne-3-ols, which are either
isolated as secondary metabolites from the roots of Panax
japonicus C. A. Meyer var. major. Potent yeast α-glucosidase
activity inhibitory effects have been reported for these three
compounds, although to date a total synthesis of only
panaxjapyne C has been reported; L-ascorbic acid was used as
the source of chirality in this synthesis.3
Reported approaches to the asymmetric synthesis of diynols
have predominantly involved the addition of 1,3-diynes to
aldehydes. The first example was reported by Carreira et al.,
who employed a Zn(OTf)2/N-methylephedrine ligand for the
total syntheses of (R)-strongylodiols A and B4 in 82 and 80%
ee, respectively. A modified protocol was reported by
Tykwinski et al.5 Trost et al. published a systematic study of
catalytic 1,3-diyne asymmetric additions to aldehydes using an
Figure 2. Tethered asymmetric reduction catalysts.
Received: November 7, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol4032123 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
commercially available or easily accessible, were used as
coupling reagents. Eight racemic diynols 4a−h were prepared12
(Table 1) in good to excellent yields (72−98%). After
purification, the resulting diynols were oxidized by activated
MnO2 powder, which is commonly used to oxidize ynols to
ynones.13
Table 2. ATH of Diynones
ab
abc
, ,
,
entry
R1
R2
yield
25
%
ee
94
%
Table 1. Synthesis of Diynones
1
2
3
4
5
6
7
8
C6H5
CH3 (4a)
BnO(CH3)2C
n-C4H9
CH3 (4b)
86 (82)
94 (75)
91 (95)
89 (96)
90 (92)
85 (76)
79 (95)
94 (93)
97 (97)
97 (98)
CH3 (4c)
n-C4H9
n-C3H7 (4d)
CH3 (4e)
HO(CH2)4
n-C4H9
>90 (>90)
97 (98)
CH2C6H5 (4f)
CH3 (4g)
BnO(CH2)5C
BnO(CH3)2C
95 (90)
i-C3H7 (4h)
96 (99)
a
b
Isolated yield and ee using catalyst (S,S)-2. Reaction time 3 h. ee
c
values were determined by chiral HPLC. Figures in brackets are yields
a
a
entry
R1
R2
CH3
step 1 yield
%
step 2 yield %
and ees achieved by using catalyst (S,S)-3. Reaction time 1 h.
1
2
3
4
5
6
7
8
C6H5
90 (4a)
98 (5a)
85 (5b)
BnO(CH3)2C
n-C4H9
CH3
79 (4b)
69 (4c)
88 (4d)
98 (4e)
72 (4f)
97 (4g)
73 (4h)
yield (up to 95%) and ee (up to 99%). In the example shown in
entry 5, even with a free hydroxyl group on the side of the R1
group, neither the conversion nor the selectivity of the
reduction was compromised. In one case (4c), the sign of
the optical rotation matched that previously reported,14 serving
to confirm the (S) configuration that was anticipated on the
basis of the reduction of ynones.11 The configurations of the
other products were assigned by analogy.
b
CH3
− (5c)
n-C4H9
n-C3H7
CH3
82 (5d)
90 (5e)
25 (5f)
71 (5g)
98 (5h)
HO(CH2)4
n-C4H9
CH2C6H5
CH3
BnO(CH2)5C
BnO(CH3)2C
i-C3H7
a
b
Isolated yield. This compound was not isolated.
A route to panaxjapyne A 13a was developed, via 1,4-diyne
intermediate 615 (Scheme 1). 1-Iodo-2-decyne 7 was prepared
With the exception of entry 6, clean diynones 5a−h were
formed as the only products, and these were easily isolated
using silica gel column chromatography. Activated MnO2
powder oxidizes diynols preferentially without breaking the
electron-rich 1,3-diyne bond or oxidizing a terminal hydroxyl
group (entry 5). In entry 6 the resulting ketone is more likely to
enolize, which may explain why the yield is lower than the
others. In entry 3 pure diynone was not separated because of its
high volatility and was used as a CH2Cl2 solution in the next
step.
Scheme 1. Synthesis of Skipped Diyne 6
Initially, 6-phenyl-3,5-hexadiyn-2-one 5a was selected for
testing in the ATH reaction.10,11 It was found that the ATH of
this compound was problematic. The ketone was prone to
decomposition in both TEA and HCO2Na, and during the
reduction reaction, a side reaction was detected (Table 2, entry
in high yield using the combination of I2, PPh3, and imidazole.
The resulting product was combined with ethynyltrimethylsi-
lane using the procedure reported by Prati et al.16 It was found
1
that the product was formed as a single regioisomer by H
1
1). Peaks were observed in the H NMR spectrum of the
NMR and in good yield. The skipped diyne 6, however, is
unstable and therefore needs to be used freshly or stored in
hexane at low temperature.
product at 5.72 and 6.64 ppm (see Supporting Information).
TLC analysis showed a spot close to that of 6-phenyl-3,5-
hexadiyn-ol. This suggested that a competing hydrogen transfer
process takes place on the dialkyne to give a number of alkyne
reduction products. Although the isolated yield of 4a was low
(25%), its ee was 94%. It was thought that a bulky group at the
end of the diyne might slow down the rate of alkyne reduction.
In the event, the ketone bearing a BnO(CH3)2C group (entry
2) exhibited greater stability in HCO2H/TEA 5:2 CH2Cl2
solution. Furthermore, during the ATH reduction, only a trace
amount (<5%) of the alkyne reduction product was detected in
the 1H NMR spectrum. The relatively low reactivities of
diynones 5 required the catalyst loading to be increased to 10
mol % to allow the reaction to finish within a short reaction
time (3 h when (S,S)-2 was used, 1 h when (S,S)-3 was used).
At lower loadings, longer times were required, and some
decomposition was observed. The reduction of diynones
containing an aliphatic chain gave products in both excellent
A regio- and Z-selective hydrogenation using a P-2 Ni
catalyst was adopted to prepare (4Z)-4-dodecen-1-ynyltrime-
thylsilane 8.17 To achieve a good yield and Z/E selectivity, it
was found that the in situ generated P-2 Ni has to be poisoned
by ethylenediamine for at least 1.5 h and the reaction must be
complete in 1 h. The yield decreased (33%) when the reaction
time was extended to 3.5 h, probably because of the base
sensitivity of the TMS acetylene. The highest Z/E selectivity
measured by 1H NMR was Z/E = 23/1. Decreasing the
poisoning time caused a drop in the Z/E selectivity. Subsequent
AgF and NBS-mediated desilylbromination gave the corre-
sponding bromoalkyne 9 in excellent yield.18
A Cadiot−Chodkiewicz cross-coupling12 was used to link
bromoalkyne 9 and 1-pentyn-3-ol 11 together. Under the
conditions modified by Marino and Nguyen,12b the coupling
was completed within 30 min. The MnO2 oxidation was clean,
B
dx.doi.org/10.1021/ol4032123 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K.; Yagyu, T.; Yoshioka, Y.; Fujiwara, T.; Kanamoto, A.; Okamoto, T.;
Ojika, M. Tetrahedron 2013, 69, 101−106.
(2) (a) Watanabe, K.; Tsuda, Y.; Yamane, Y.; Takahashi, H.; Iguchi,
K.; Naoki, H.; Fujita, T.; Van Soest, R. W. M. Tetrahedron Lett. 2000,
41, 9271−9276. (b) Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.;
Baldwin, J. E. Tetrahedron 2005, 61, 7219−7932.
and only product 10 could be detected by TLC. From the ATH
reaction of 10, enantiomerically enriched (S)-panaxjapyne A 1
was isolated in 85% yield and 96% ee (Scheme 2), as
determined by analysis of racemic panaxjapyne A and chiral
HPLC of the panaxjapyne A 4-methoxybenzonate.
(3) (a) Chan, H. H.; Sun, H. D.; Reddy, M. V. B.; Wu, T. S.
Phytochemistry 2010, 7, 1360−1364. (b) Thakur, P.; Kumaraswamy,
B.; Reddy, G. R.; Bandichhor, R.; K. Mukkanti, K. Tetrahedron Lett.
2012, 53, 3703−3705.
Scheme 2. Completion of the Synthesis of (S)-Panaxjapyne
A 1
(4) Reber, S.; Knopfel, T. F.; Carreira, E. M. Tetrahedron 2003, 59,
̈
6813−6817.
(5) Graham, E. R.; Tykwinski, R. R. J. Org. Chem. 2011, 76, 6574−
6583.
(6) Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010,
132, 5186−5192.
(7) Zheng, B.; Li, S.-N.; Mao, J.-Y.; Wang, B.; Bian, Q.-H.; Liu, S.-Z.;
Zhong, J.-C.; Guo, H.-C.; Wang, M. Chem.Eur. J. 2012, 18, 9208−
9211.
(8) Trost, B. M.; Quintard, A. Angew. Chem., Int. Ed. 2012, 51, 6704−
6708.
(9) Turlington, M.; Du, Y.; Ostrum, S. G.; Santosh, V.; Wren, K.; Lin,
T.; Sabat, M.; Pu, L. J. Am. Chem. Soc. 2011, 133, 11780−11794.
(10) (a) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem.
Rev. 2004, 248, 2201−2237. (b) Gladiali, S.; Alberrico, E. Chem. Soc.
Rev. 2006, 35, 226−236. (c) Ikariya, T.; Murata, K.; Noyori, R. Org.
Biomol. Chem. 2006, 4, 393−406. (d) Ikariya, T.; Blacker, A. J. Acc.
Chem. Res. 2007, 40, 1300−1308. (e) Wang, C.; Wu, X.; Xiao, J.
Chem.Asian J. 2008, 3, 1750−1770. (f) Hashiguchi, S.; Fujii, A.;
Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
7562−7563. (g) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521−2522. (h) Haack, K. J.;
Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed.
1997, 36, 285−288. (i) Handgraaf, J.-W.; Meijer, E. J. J. Am. Chem. Soc.
2007, 129, 3099−3103. (j) Soni, R.; Cheung, F. K.; Clarkson, G. C.;
Martins, J. E. D.; Graham, M. A.; Wills, M. Org. Biomol. Chem. 2011, 9,
3290−3294. (k) Steward, K. M.; Gentry, E. C.; Johnson, J. S. J. Am.
Chem. Soc. 2012, 134, 7329−7332. (l) Cheung, F. K.; Lin, C.; Minissi,
The experimental data for synthetic panaxjapyne A, including
1H NMR, 13C NMR, optical rotation and Mosher ester, were
consistent with that reported for the natural material (see
Supporting Information). The absolute configuration of 1 was
1
assigned as (S) by comparing the H NMR spectra of the
Mosher ester derivatives of our racemic and enantiomerically
enriched panaxjapyne A samples (see Supporting Informa-
tion).19
In summary, we have demonstrated, for the first time, that
diynones are suitable substrates for asymmetric transfer
hydrogenation in high ee and conversion. The value of this
methodology has been demonstrated in its application to the
total synthesis of panaxjapyne A.
́
F.; Lorente Criville, A.; Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett.
2007, 9, 4659−4662. (m) Soni, R.; Collinson, J.-M.; Clarkson, G. J.;
Wills, M. Org. Lett. 2011, 13, 4304−4307. (n) Hems, W. P.; Jackson,
W. P.; Nightingale, P.; Bryant, R. Org. Process Res. Dev. 2012, 16, 461−
463.
(11) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738−8739. (b) Druais, V.; Meyer, C.; Cossy, J.
Org. Lett. 2012, 14, 516−519. (c) Dias, L. C.; Ferreira, M. A. B. J. Org.
Chem. 2012, 77, 4046−4062. (d) Gallon, J.; Esteban, J.; Bouzbouz, S.;
Campbell, M.; Reymond, S.; Cossy, J. Chem.Eur. J. 2012, 18,
11788−11797. (e) Mi, X.; Wang, Y.; Zhu, L.; Wang, R.; Hong, R.
Synthesis 2012, 44, 3432−3440. (f) Arai, N.; Satoh, H.; Utsumi, N.;
Murata, K.; Tsutsumi, K.; Ohkuma, T. Org. Lett. 2013, 15, 3030−3033.
(g) Raghavan, S.; Vinoth Kumar, V. Org. Biomol. Chem. 2013, 11,
2847−2858. (h) Kesava Reddy, N.; Chandrasekhar, S. J. Org. Chem.
2013, 78, 3355−3360. (i) Trost, B. M.; Bartlett, M. J. Org. Lett. 2012,
14, 1322−1325.
(12) (a) Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci.
1955, 241, 1055−1057. (b) J. P. Marino, J. P.; Nguyen, H. N. J. Org.
Chem. 2002, 67, 6841−6844. (c) García-Domínguez, P.; Alvarez, R.;
De Lera, A. R. Eur. J. Org. Chem. 2012, 4762−4782. (d) Gung, B. W.;
Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2004, 15, 3973−3977.
(e) Sabitha, G.; Reddy, C. S.; Yadav, J. S. Tetrahedron Lett. 2006, 47,
4513−4516. (f) Gung, B. W.; Craft, D. T.; Truelove, J. Tetrahedron:
Asymmetry 2007, 18, 1284−1287. (g) Domnin, I. N.; Remizova, L. A.
Russ. J. Org. Chem. 2009, 45, 1123−1127. (h) Bonney, K. J.; Braddock,
D. C. J. Org. Chem. 2012, 77, 9574−9584.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and analytical data including NMR
spectra and chiral HPLC analyses. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: m.wills@warwick.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Warwick University for partial support of Y.F. and
Johnson Matthey (Cambridge) for a generous gift of catalyst 3.
■
(13) Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979−982.
(14) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859−4861.
(15) Caruso, T.; Spinella, A. Tetrahedron: Asymmetry 2002, 13,
2071−2073.
REFERENCES
■
(1) (a) Gung, B. W. C. R. Chim. 2009, 12, 489−505. (b) Yamaguchi,
M.; Park, H.; Hirama, M. Chem. Lett. 1997, 535−536. (c) Horikawa,
C
dx.doi.org/10.1021/ol4032123 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(16) Morandi, S.; Pellati, F.; Benvenuti, S.; Prati, S. F. Tetrahedron
2008, 64, 6324−6328.
(17) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226−2230.
(18) Lee, T.; Kang, H. R.; Kim, S.; Kim, S. Tetrahedron 2006, 62,
4081−4085.
(19) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092−4096. (b) Dale, J. A.; Mosher, H. S. J. Am.
Chem. Soc. 1973, 95, 512−519.
D
dx.doi.org/10.1021/ol4032123 | Org. Lett. XXXX, XXX, XXX−XXX