Total synthesis of danshenspiroketallactone

Article abstract of DOI:10.1055/s-0031-1290082

Described herein is the first synthesis of the monobenz-annulated 5,5-spiroketals danshenspiroketallactone and epi-danshen-spiroketallactone, two components of the traditional Chinese medicine Danshen. Key features of the synthesis include a directed metallation-lactonisation sequence to install the isobenzofuranone moiety and an oxidative radical cyclisation to afford the monobenz-annulated 5,5-spiroketal. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1290082

128
LETTER
Total Synthesis of Danshenspiroketallactone
Total
S
ynthesis of
a
D
anshensp
n
iroketallacton
i
e
el F. Chorley, Jack Li-Yang Chen, Daniel P. Furkert, Jonathan Sperry, Margaret A. Brimble*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
E-mail: m.brimble@auckland.ac.nz
Received 3 October 2011
to extend this methodology toward the synthesis of danshen-
spiroketallactone (1) and its retrosynthesis is based on this
strategy (Scheme 1).
Abstract: Described herein is the first synthesis of the monobenz-
annulated 5,5-spiroketals danshenspiroketallactone and epi-danshen-
spiroketallactone, two components of the traditional Chinese
medicine Danshen. Key features of the synthesis include a directed
metallation–lactonisation sequence to install the isobenzofuranone
moiety and an oxidative radical cyclisation to afford the monobenz-
annulated 5,5-spiroketal.
O
O
O
O
O
Me
O
Key words: Danshen, spiroketal, oxidative radical cyclisation, nat-
ural product
Me
Me
Me
danshenspiroketallactone (1)
epi-danshenspiroketallactone (2)
Several diverse spiroketal-containing natural products
have been isolated over the years,1 but compounds of this
class that contain aryl rings fused to the spiroketal moiety
are relatively rare.2 Two such examples are danshen-
spiroketallactone (1) and epi-danshenspiroketallactone
(2), monobenzannulated 5,5-spiroketals isolated from
Danshen, the traditional Chinese medicine consisting of
dried roots of Chinese sage, Salvia miltiorrhiza that is
used to treat renal failure, heart disease, and strokes.3 Al-
though 1 and 2 are epimeric at the spirocentre, subjecting
1 to prolonged acidic conditions has proven that 2 is a nat-
ural product and not an artefact of the isolation procedure.
However, subjecting 2 to acidic conditions effects epimer-
ization to 1, suggesting that some (or all) of 1 is produced
during isolation and purification of the natural product(s)
on silica gel.4 Further analysis of this medicinal plant af-
forded cryptoacetalide (3) and epi-cryptoacetalide (5),5
and the acetone extract of the closely related folk medi-
cine Salvia aegyptiaca has been shown to contain 6-meth-
ylcryptoacetalide (4) and 6-methyl-epi-cryptoacetalide
(6,6 Figure 1).
O
O
O
O
O
Me
O
Me
Me Me
R
R = H, cryptoacetalide (3)
R = Me, 6-methylcryptoacetalide (4) R = Me, 6-methyl-epi-cryptoacetalide (6)
Me Me
R
R = H, epi-cryptoacetalide (5)
Figure 1 Naturally occurring monobenzannulated 5,5-spiroketals
O
O
Me
OH
O
O
oxidative
radical
cyclisation
O
(R)
Me
Me
Me
1
7
i. lactonisation
ii. hydrogenolysis
O
NEt2
NEt2
O
i. directed
metallation
ii. (R)-10
OH Me
Due to an ongoing project aimed at identifying the com-
pounds responsible for the therapeutic effect in traditional
Chinese medicines, combined with our continued interest
in the synthesis of benzannulated spiroketal natural prod-
ucts,7 we decided to initiate a synthesis of danshen-
OBn
Me
9
Me
O
Me
8
OBn
H
spiroketallactone (1). Furthermore,
a recent total
(R)-10
synthesis of cryptoacetalide (3, along with its epimer 5)8
Scheme 1 Retrosynthetic analysis of danshenspiroketallactone (1)
prompts us to disclose our own efforts in this area.
Recently, we demonstrated that the oxidative radical
cyclisation9 of various benzofurans and chromans con-
taining a hydroxyalkyl side chain could be used to con-
struct a series of monobenzannulated spiroketals.10
Encouraged by these promising model studies, we aimed
We planned a late-stage spiroketalisation by oxidative
radical cyclisation of alcohol 7 which in turn was to be ob-
tained by lactonisation of intermediate 8. Directed metal-
lation of naphthalene amide 9 followed by addition of R-
aldehyde 1011 was proposed as the key carbon–carbon
bond-forming step to deliver 8 (Scheme 1).
SYNLETT 2012, 23, 128–130
x
x.
x
x.
2
0
1
1
Advanced online publication: 28.11.2011
DOI: 10.1055/s-0031-1290082; Art ID: D50911ST
© Georg Thieme Verlag Stuttgart · New York
Thus, our initial attention was aimed towards the synthe-
sis of the two coupling partners 9 and 10. The synthesis of

LETTER
Total Synthesis of Danshenspiroketallactone
129
naphthalene 9 commenced with the regioselective the crude product 8 (as a mixture of rotameric diastere-
bromination12 of 1-naphthoic acid 11, delivering 5-bro- omers) which was immediately subjected to lactonisation
monaphthoic acid 12 which underwent facile diethyl- with anhydrous HCl in dioxane, delivering the desired
amide formation giving 13. Finally, Suzuki coupling of 13 isobenzofuranone 16 in moderate yield (Scheme 4).14
with methylboronic acid delivered the desired naphtha-
lene fragment 9 in good overall yield (Scheme 2).
O
NEt2
O
OH
O
OH
Br2
AcOH
reflux
i. s-BuLi
NEt2
OH Me
O
Me
THF, –78 °C
9
48%
ii. 10
–78 °C to r.t.
(2 equiv)
OBn
11
Br
+
12
O
Me
i. (COCl)2
DMF (cat.)
THF
ii. Et2NH
THF
OBn
Me
H
91%
O
10
8
Pd(dba)2
S-Phos
MeB(OH)2
Cs2CO3
dioxane
reflux
HCl
dioxane
O
Me
NEt2
O
NEt2
OBn
O
38%
(2 steps)
96%
Me
Br
Me
16
13
9
Scheme 4 Synthesis of isobenzofuranone 16
Scheme 2 Synthesis of naphthalene amide 9
With the successful synthesis of the key isobenzofuranone
16 completed, we were keen to complete the total synthe-
sis of danshenspiroketallactone (1). Hydrogenolysis of the
benzyl ether in 16 proceeded smoothly, affording the key
radical cyclisation precursor 7 and setting the scene for
the key spiroketalisation. Gratifyingly, subjecting 7 to the
standard radical cyclisation conditions9,10 afforded dan-
shenspiroketallactone (1) along with its epimer 2 in a
1.5:1 ratio15 (Scheme 5). A lack of stereocontrol from the
anomeric effect contributed to the formation of a mixture
of 5,5-spiroketals.16 The spectroscopic data of synthetic 1
With a scalable synthesis of arene 9 successfully complet-
ed, attention turned to the synthesis of aldehyde (R)-10.
Although an asymmetric synthesis of (R)-10 exists,11 we
chose to develop a new route. This goal was ultimately
achieved using Evans’ auxiliary based conjugate addition
of methylmagnesium bromide to oxazolidinone 14,13 af-
fording 15 with a diastereomeric ratio of 94:6 which could
be improved to >99:1 with a single recrystallisation. Re-
ductive cleavage of the oxazolidinone followed, and oxi-
dation of the resultant alcohol with Dess–Martin
periodinane (DMP) delivered the desired R-aldehyde 10
21
20
{[a]D +10.4 (c 0.7, CHCl3); (lit.11 [a]D +10.7 (c 0.7,
O
O
Me
Me
CHCl3)} (Scheme 3).
OBn
OH
O
O
H2
Pd(OH)2
EtOAc–MeOH
MeMgBr
CuBr⋅SMe2
THF–Me2S
(3:2)
O
O
O
O
Me
63%
OBn
OBn
O
N
O
N
Me
Me
7
16
98%
(dr = 99:1)
hν, I2
Ph
Ph
PhI(OAc)2
14
15
cyclohexane
i. LiBH4
THF–H2O
ii. DMP
47%
1/2 = 1.5:1
O
Me
CH2Cl2
OBn
O
O
H
53%
(2 steps)
O
O
10
O
Me
+
Scheme 3 Synthesis of R-aldehyde 10
O
Me
Next, the key coupling of fragments 9 and 10 could be
conducted. Directed lithiation of the naphthalene amide 9
at –78 °C for one hour was followed by addition of the al-
dehyde 10. When the reaction was complete, workup gave
Me
Me
1
2
Scheme 5 Total synthesis of danshenspiroketallactone (1) and epi-
danshenspiroketallactone (2)
© Thieme Stuttgart · New York
Synlett 2012, 23, 128–130

130
D. F. Chorley et al.
LETTER
(16) Kirby, J. A. The Anomeric Effect and Related
and 2 were in excellent agreement with that reported for
the natural products.4,17
Stereoelectronic Effects at Oxygen; Springer: New York,
1983.
In conclusion, we have completed the first total syntheses
of the naturally occurring monobenzannulated 5,5-
spiroketals danshenspiroketallactone (1) and epi-danshen-
spiroketallactone (2). This synthesis has provided suffi-
cient material for biological study to assess whether 1 and
2 are responsible for any of the therapeutic effects of the
traditional Chinese medicine Danshen.
(17) Synthesis of Danshenspiroketallactone (1) and epi-
Danshenspiroketallactone (2)
A mixture of alcohol 7 (50 mg, 0.19 mmol), PhI(OAc)2 (119
mg, 0.37 mmol), and iodine (108 mg, 0.43 mmol) in anhyd
cyclohexane (15.3 mL) was degassed with nitrogen at r.t. for
15 min. The resulting solution was cooled in an ice-water
bath (10 °C) and irradiated with a desk lamp (60 W) for 3.5
h. The solution was poured onto a mixture of sat. aq Na2S2O3
(20 mL) and sat. aq NaHCO3 (20 mL) and diluted with Et2O
(100 mL). The organic layer was separated and the aqueous
layer further extracted with Et2O (2 × 100 mL). The organic
fractions were combined and dried over anhyd MgSO4,
filtered, and the solvent was removed under reduced
pressure. The crude product was purified by flash chroma-
tography on silca gel using hexanes–EtOAc (3:1, Rf = 0.52)
as eluent to afford the title compounds 1 and 2 (23.3 mg, 0.09
mmol, 47%; Figure 2) as an orange solid and an inseparable
mixture of diastereomers (1.5:1). IR (neat): nmax = 2957,
2928, 2876, 1925, 1749, 1601, 1588, 1526, 1470, 1454,
1375, 1342, 1322, 1254, 1211, 1183, 1159, 1136, 1110,
1083, 1070, 1047, 1003, 981, 950, 928, 915, 882, 847, 811,
777, 769, 737, 700, 684, 658, 646, 628 cm–1. 1H NMR (400
MHz, CDCl3): d = 1.26 (1.5 H, d, J = 7.0 Hz, H-17), 1.32 (1.5
H, d, J = 7.0 Hz, H-17*), 2.11 (0.5 H, dd, J = 10.5, 13.0 Hz,
H-16a), 2.22 (0.5 H, dd, J = 4.7, 13.2 Hz, H-16b*), 2.53 (0.5
H, dd, J = 7.0, 13.0 Hz, H-16b), 2.70 (0.5 H, dd, J = 9.5, 13.4
Hz, H-16a*), 2.74 (3 H, s, H-18, H-18*), 2.76 (0.5 H, m, H-
15*), 2.95 (0.5 H, m, H-15), 3.82 (0.5 H, t, J = 8.2 Hz, H-
14a), 3.93 (0.5 H, dd, J = 7.2, 8.2 Hz, H-14b*), 4.42 (0.5 H,
t, J = 7.8 Hz, H-14a*), 4.47 (0.5 H, t, J = 8.2 Hz, H-14b), 7.46
(1 H, dd, J = 1.0, 7.0 Hz, H-3, H-3*), 7.53 (0.5 H, d, J = 8.8
Hz, H-7*), 7.57 (0.5 H, d, J = 8.4 Hz, H-7), 7.60 (1 H, dd,
J = 7.0, 8.5 Hz, H-2, H-2*), 8.34 (1 H, m, H-6, H-6*), 8.87
(1 H, d, J = 8.4 Hz, H-1, H-1*). 13C NMR (100 MHz,
CDCl3): d = 17.4 (CH3, C-17), 18.2 (CH3, C-17*), 19.9
(2 × CH3, C-18, C-18*), 32.6 (CH, C-15), 33.5 (CH, C-15*),
44.6 (CH2, C-16*), 45.4 (CH2, C-16), 77.37, 77.39 (2 × CH2,
C-14, C-14*), 113.2 (2 × C, C-13, C-13*), 118.1 (ArH, C-
7*), 118.2 (ArH, C-7), 121.7 (C, C-9*), 122.1 (ArH, C-1),
122.17 (ArH, C-1*), 122.21 (C, C-9), 128.5 (2 × ArH, C-3,
C-3*), 129.0 (2 × ArH, C-2, C-2*), 129.2 (ArH, C-10*),
129.3 (ArH, C-10), 131.9 (ArH, C-6), 132.0 (ArH, C-6*),
133.4 (C, C-5*), 133.5 (C, C-5), 135.1 (2 × C, C-4, C-4*),
147.1 (C, C-8), 147.8 (C, C-8*), 168.4 (2 × C=O, C-11, C-
11*). MS (ESI+): m/z (%) = 291 (100) [M + Na]+, 259 (29),
214 (18), 165 (22), 89 (27). HRMS: m/z calcd for
Acknowledgment
We thank the New Zealand Foundation for Research, Science and
Technology (FRST) for financial support through the International
Investment Opportunities Fund (IIOF). Victoria Mackay is thanked
for conducting preliminary experiments.
References and Notes
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H. Chem. Lett. 1990, 1885.
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Int. Ed. 2011, 50, 8350. (d) McLeod, M. C.; Wilson, Z. E.;
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(8) The total synthesis of cryptoacetalide involves a similar
oxidative cyclisation to that reported herein: Zou, Y.;
Dieters, A. J. Org. Chem. 2010, 75, 5355.
(9) For a review on the use of the oxidative radical cyclisation
approach to spiroketal natural products, see: Sperry, J.; Liu,
Y.-C.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 29.
(10) (a) Liu, Y.-C.; Sperry, J.; Rathwell, D. C. K.; Brimble, M. A.
Synlett 2009, 793. (b) Sperry, J.; Liu, Y.-C.; Wilson, Z. E.;
Hubert, J. G.; Brimble, M. A. Synthesis 2011, 8, 1383.
(11) Hansen, D. B.; Starr, M.-L.; Tolstoy, N.; Joullié, M. M.
Tetrahedron: Asymmetry 2005, 16, 3623.
(12) Short, W. F.; Wang, H. J. Chem. Soc. 1950, 991.
(13) Nakamura, S.; Kikuchi, F.; Hashimoto, S. Tetrahedron:
Asymmetry 2008, 18, 1059.
(14) The full results of the extensive optimisation study
conducted to ensure the satisfactory reaction between 9 and
10 will be reported in due course.
(15) At the conclusion of the previously reported total synthesis
of a member of this family of natural products, crypto-
acetalides 3 and 5 were obtained as an inseparable 2:1
mixture of spiroketal epimers, respectively (ref. 8).
C17H16O3Na: 291.0992; found: 291.0991 [M + Na]+. The
spectroscopic data are in full agreement with that reported in
the literature.3,4
O
O
11
11
17
Me
16
O
13
O
13
O
14
15
1
1
9
9
15
14
10
10
2
3
2
3
8
7
8
7
O
16
Me
5
5
17
4
4
6
6
Me
Me
18
18
danshenspiroketallactone
epi-danshenspiroketallactone
(1)
(2)
Figure 2
Synlett 2012, 23, 128–130
© Thieme Stuttgart · New York

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