Asymmetric total synthesis of (+)-isocryptotanshinone and formal synthesis of (?)-cryptotanshinone

Article abstract of DOI:10.1016/j.tet.2019.05.069

The first asymmetric total synthesis of (+)-isocryptotanshinone was achieved in 12 linear steps with 12% overall yield from commercially available dihydrobenzopyrone. The key step was a base-mediated cyclization reaction. In addition, the synthetic strate

Full text of DOI:10.1016/j.tet.2019.05.069

Accepted Manuscript
Asymmetric total synthesis of (+)-isocryptotanshinone and formal synthesis of (−)-
cryptotanshinone
Xiang Shi, Xiaoyu Liu, Feilong Yang, Yong Wang, Zhenwei Wang, Xiaozhen Jiao,
Ping Xie
PII:
S0040-4020(19)30631-3
https://doi.org/10.1016/j.tet.2019.05.069
TET 30390
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 April 2019
Revised Date: 29 May 2019
Accepted Date: 31 May 2019
Please cite this article as: Shi X, Liu X, Yang F, Wang Y, Wang Z, Jiao X, Xie P, Asymmetric total
synthesis of (+)-isocryptotanshinone and formal synthesis of (−)-cryptotanshinone, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.05.069.
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Asymmetric Total Synthesis of (+)-Isocryptotanshinone
and Formal Synthesis of (-)-Cryptotanshinone
Leave this area blank for abstract info.
Xiang Shi, Xiaoyu Liu, Feilong Yang, Yong Wang,
Zhenwei Wang, Xiaozhen Jiao* and Ping Xie*.
No. 2, Nanwei Road, Xicheng District, Beijing

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Tetrahedron
journal homepage: www.elsevier.com
Asymmetric Total Synthesis of (+)-Isocryptotanshinone and Formal Synthesis of (-)-
Cryptotanshinone
Xiang Shi, Xiaoyu Liu, Feilong Yang, Yong Wang, Zhenwei Wang, Xiaozhen Jiao and Ping Xie
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first asymmetric total synthesis of (+)-isocryptotanshinone was achieved in 12 linear steps
with 12% overall yield from commercially available dihydrobenzopyrone. The key step was a
base-mediated cyclization reaction. In addition, the synthetic strategy included the formal
synthesis of (-)-cryptotanshinone.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
(+)-isocryptotanshinone
asymmetric total synthesis
(-)-cryptotanshinone
STAT3 inhibitor
base-mediated cyclization
———
Corresponding author. E-mail: jiaoxz@imm.ac.cn, xp@imm.ac.cn;
Tel.: +86 10 63165242; fax: +86 10 63017757.

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Salvia miltiorrhiza Bunge (dan-shen in Chinese) is an
important herb in Chinese traditional medicine and has been
widely used in Asia to treat various diseases, such as
inflammation, diabetes, atherogenesis [1], allergic asthma, and
cardiovascular disease [2]. Tanshinones, which are abietane
diterpene pigments with a 1,2- or 1,4-naphthoquinone skeleton,
are major lipophilic bioactive constituents of dan-shen[3,8]. (+)-
isocryptotanshinone (1), (+)-neocryptotanshinone (2), (-)-
cryptotanshinone (3), tanshinone IIA (4), tanshinone I (5), (-)-
[4-6]
Scheme 1. Inouye and Kakisawa’s Diels–Alder reaction
strategy for the synthesis of raemic cryptotanshinone.
dihydrotanshinone I (6), and miltirone (7)
examples of tanshinones (Figure 1).
are well-known
Based on the promising potential of these tanshinones, we
developed an asymmetric synthesis of 1, which included a formal
synthesis of 3.
2. Results and discussion
The retrosynthetic analysis for 3 and 1 are shown in Scheme
2. Natural product 3 could be obtained from 1 in two steps
according to the reported method [6, 27]. And then we anticipated
that an oxidation reaction would transform compound 17 into
natural product 1. Compound 17, the key intermediate, could be
constructed via the new base-mediated cyclization strategy
reported by Tsai et al. by simply heating compound 16 with
NaOMe [17]. In addition, the Sonogashira coupling of intermediate
15 and (S)-2-methylpent-4-yn-1-ol (20) would provide
compound 16. Tetralin triflate ester 15 could be obtained through
a series of conventional reactions by using commercially
available dihydrobenzopyrone (8) as the starting material and the
Figure 1. Structures of (+)-isocryptotanshinone (1), (+)-
neocryptotanshinone (2), (-)-cryptotanshinone (3), tanshinone
IIA (4), tanshinone I (5), (-)-dihydrotanshinone I (6), and
miltirone (7).
Among these tanshinones, cryptotanshinone, which contains a
1,2-naphthoquinone skeleton, displays several interesting
pharmacological properties. For example, it is an effective
inhibitor of signal transducer and activator of transcription 3
(STAT3) [7] and exhibits significant cytotoxicity against a number
of cultured human tumor cell lines [8]. Due to its remarkable
bioactivities, cryptotanshinone has attracted considerable
attention from organic chemists. Several total syntheses of
chiral side chain (20) could be generated from 18 [18,19]
.
cryptotanshinone have already been reported, but most chemical
[9,10,11,16]
syntheses provide only the racemic form
and the only
asymmetric syntheses of 3, which used photochemical aromatic
annulation, was reported by Danheiser et al. in 1995 [6]. In
addition to 1,2-naphthoquinone skeleton tanshinones, (+)-
isocryptotanshinone (1) is a lipophilic component with a 1,4-
naphthoquinone skeleton isolated from dan-shen. Because of its
1,4-naphthoquinone skeleton, 1 is a more potent STAT3 inhibitor
than 3 [12]. 1 inhibits STAT3 signal proteins by inhibiting the
MAPK pathway and JAK-STAT signaling pathway, and thus has
a strong inhibitory effect on the growth of A549 and MCF-7
cancer cells [12,13]. Furthermore, 1 can also inhibit gastric cancer
cell proliferation by inducing G1/G0 cell cycle arrest and
apoptosis via inhibiting the STAT3 signaling pathway [14]. The
STAT3 pathway is a new target associated with cancer. However,
Scheme 2. Retrosynthetic analysis of 1 and 3.
Our synthesis commenced with known intermediate 9, which
[20, 21]
was prepared through
a
reported protocol
from
commercially available dihydrocoumarin (8) (Scheme 3).
Treatment of compound 9 with MeI and K2CO3 afforded 10 in
moderate yield. Using the method reported by Danheiser et al. [6]
,
despite its attractive biological activity, the limited availability of
[15]
1 from natural sources
has seriously hampered further
tetrahydronaphthalen-1-ol (11) could be synthesized from 10 in
good overall yield. Formylation of 11 with paraformaldehyde and
Et3N in the presence of anhydrous MgCl2 gave 12 [22]. To prepare
cyanide 13, we initially treated salicylaldehyde 12 with
hydroxylamine hydrochloride in the presence of FeCl3 to afford
cyanide 13 [23]. However, a mixture of desired cyanide 13 and by-
product amide 13a (~1:1) was produced.
biological research and development. To our knowledge, no
asymmetric total synthesis of 1 has been reported and only
Inouye and Kakisawa have reported the synthesis of racemic
isocryptotanshinone via
a
Diels−Alder reaction as an
intermediate while studying the total synthesis of racemic 3 in
1969 (Scheme 1) [16]. Though Inouye and Kakisawa’s synthesis is
concise, an inherent drawback associated with their synthesis is
the lack of enantioselectivity. Hence, the development of an
efficient, scalable asymmetric synthetic strategy is worth
exploring.

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Scheme 3 Synthesis of intermediates 13 and 13a.
To avoid the formation of 13a, another synthetic strategy was
adopted (Scheme 4). According to the synthetic method for
nitriles reported by Sardarian et al. [24], oxime 14 was synthesized
by the reaction of 12 with hydroxylamine hydrochloride at room
temperature in excellent yield. 14 underwent a dehydration
reaction with diethyl chlorophosphate to give 13 in great yield
(90%).
Scheme 6. Synthesis of intermediate 17.
Scheme 7. Proposed mechanism for the formation of 17b.
Table 1. Optimization of the Base and Temperature for the
Cyclization Reaction of 17
Scheme 4. Synthetic route for intermediate 13.
The chiral chain (S)-2-methylpent-4-yn-1-ol (20) was
prepared by Evans alkylation (Scheme 5). Thus, acylation of 4-
pentynoic acid and oxazolidinone produced compound 18 in a
good yield [18]. Then treatment of compound 18 with MeI and
NaHMDS at -40oC afforded 19 in a moderate yield. The
reduction of compound 19 gave the chiral chain 20 following the
reported protocol [19]
.
Entry
Catalyst
Temp.
ꢀ
Time
(h)
NaOMe
(eq.)
Yield
(17b/17)%
1
2
-
-
140
140
0.5
0.5
1.5
1.0
42/26
27/44
3
4
5
-
100
100
100
1.0
1.0
1.0
1.5
1.0
1.0
24/60
-/79
Scheme 5. Synthetic route for intermediate 20
18-Crown-5
-/77
Then the key intermediate 17 was tried to synthesized
(Scheme 6). Compound 13 was treated with Tf2O in the presence
of pyridine at room temperature to give intermediate 15 in
excellent yield [25]. Subsequently, the Sonogashira coupling of
compound 15 and (S)-2-methylpent-4-yn-1-ol (20) gave
compound 16 in good yield [26]. Treating 16 with 1.5 N NaOMe in
DMSO at 140 °C [17] (Table 1, Entry 1) afforded only a small
amount of desired product 17 along with a large amount of by-
product 17b, a ring-opened product of target compound 17. The
proposed mechanism for the ring-opening of 17 to 17b is shown
in Scheme 7. The compound 17b was probably formed via an E2
elimination reaction from compound 17. Excess MeONa was
likely the main reason to cause the formation of byproduct 17b.
To improve the yield of the cyclization reaction, different
reaction conditions were screened (Table 1). The best yield (79%)
was achieved with 1 N NaOMe at 100 °C (Table 1, Entry 4).
With compound 17 in hand, we continued to synthesize
natural product 1 (Scheme 8). Oxidation of 17 with Fremy’s salt
in acetone/H2O afforded natural product 1 in moderate yield. The
present route also includes the formal total synthesis of 3 from 1
in two steps [6, 27]
.
Scheme 8. Synthesis of 1 and 3.

4
Tetrahedron
ACCEPTED MANUSCRIPT
3. Conclusion
extracted with EtOAc (3×300 mL). The combined organics were
washed with brine (200 mL) and dried over anhydrous Na2SO4.
The dried solution was filtered and the filtrate was concentrated
in vacuo. The crude product was purified by flash
chromatography on a silica gel column (EtOAc/PE = 1/30) to
afford compound 12 (15.6 g, 76%) as a yellow oil. Rf (12) = 0.54
(EtOAc/PE = 1/20). IR (neat): 3275, 3045, 2948, 2856, 2749,
2673, 1896, 1649, 1573, 1382, 1308, 1229, 875, 746, 712, 658
cm-1; 1H NMR (400 MHz, CDCl3 ) δ 11.41 (s, 1H, CHO), 9.80 (s,
1H, OH), 7.33 (dt, J = 0.5 Hz, 8.2 Hz, 1H, Ar-H), 7.01 (d, J = 8.2
Hz, 1H, Ar-H), 2.70 (t, J = 6.5 Hz, 2H, CH2), 1.78-1.83 (m, 2H,
CH2), 1.65-1.68 (m, 2H, CH2), 1.30 (s, 6H, CH3×2). 13C NMR
(100 MHz, CDCl3) δ 196.1, 159.8, 156.1, 130.1, 125.4, 118.1,
117.4, 38.5, 34.8, 31.1, 23.1, 18.5. HRMS (ESI): calcd. for
C13H17O2 [M+H]+, 205.1223; found 205.1220.
In conclusion, we performed the first asymmetric total
synthesis of the natural product (+)-isocryptotanshinone (1). The
synthesis was achieved with a Wittig reaction, Friedel–Crafts
cyclization, Sonogashira coupling, and alkali-mediated
cyclization of an o-cyanophenylalkenyl alcohol as the key steps.
The strategy developed here includes the formal synthesis of (-)-
cryptotanshinone (3) and can be used to provide sufficient
amounts of 1 and 3 for further biological activity research.
4. Experimental section
4.1. General description
All reagents were obtained from commercial sources and used
without further purification. All NMR experiments were carried
out on a Mercury 400 or Bruker AV500 spectrometer using
CDCl3 or DMSO-d6 as the solvent with tetramethylsilane as the
internal standard. Coupling constants are given in Hz and
chemical shifts are expressed as δ values in ppm. The following
multiplicity abbreviations are used: (s) singlet, (d) doublet, (t)
triplet, (q) quartet, (m) multiplet, (br) broad, (dd) double doublet,
(dt) double triplet. High-resolution mass spectra (HRMS) were
obtained with Thermo Exactive Orbitrap plus spectrometer.
Optical rotations were measured with a PerkinElmer Polarimeter
341LC at 589 nm and 20 ºС. IR spectra were recorded on a
4.4. (E)-1-hydroxy-5,5-dimethyl-5,6,7,8-
tetrahydronaphthalene-2-carbaldehyde oxime (14)
To a solution of hydroxylamine hydrochloride (6.1 g, 88.1
mmol) in water (100 mL) was added a solution of sodium
hydroxide (3.5 g, 88.1 mmol) in water (100 mL) at 0 ºС. After
stirring for 10 min at 0 ºС, a solution of 12 (15.0 g, 73.4 mmol)
in ethanol (100 mL) was added. The reaction mixture was
allowed to stir for 3 h at room temperature. The resulting solution
was poured into water (200 mL). The aqueous phase was
extracted with EtOAc (3×300 mL), The organic layers were
washed with water, saturated NaHCO3 solution and brine, dried
over anhydrous Na2SO4. The dried solution was filtered and the
filtrate was concentrated in vacuo to give compound 14 (15.8 g,
98%) as a red solid. which was used in the next step without
further purification. Rf (14) = 0.31 (EtOAc/PE = 1/3). IR (neat):
3396, 3226, 3069, 2941, 2867, 1640, 1615, 1564, 1455, 1402,
1302, 1285, 998, 815, 748, 651 cm-1; 1H NMR (400 MHz,
CDCl3 ) δ 10.48 (br, 1H, OH), 8.38 (br, 1H, OH), 8.20 (s, 1H,
CH=N), 7.00 (d, J = 8.4 Hz, 1H, Ar-H), 6.97 (d, J = 8.4 Hz, 1H,
Ar-H), 2.76 (t, J = 6.4 Hz, 2H, CH2), 1.82-1.86 (m, 2H, CH2),
1.65-1.68 (m, 2H, CH2), 1.31 (s, 6H, CH3×2); 13C NMR δ (100
MHz, CDCl3) δ 154.5, 153.0, 149.9, 127.7, 124.5, 118.2, 112.8,
38.7, 34.2, 31.6, 23.8, 18.8; HRMS (ESI): calcd. for C13H18NO2
[M+H]+, 220.1332; found 220.1325.
Thermo
Nicolet
5700
FT-IR
microscope
Centaurs
spectrophotometer. Column chromatography was carried out on
silica gel (100-200 mesh). Thin-layer chromatography was
performed using commercially available HSGF 254 precoated
plates.
4.2. 1-methoxy-2-(4-methylpent-3-en-1-yl)benzene (10)
To a solution of 9 (30.6 g, 173.6 mmol) in DMF (300 mL)
was added anhydrous potassium carbonate (35.2 g, 254.6 mmol)
and iodomethane (15.6 mL, 250.1 mmol). The mixture was
stirred under an Ar atmosphere for 12 h at 80 ºС before being
cooled to room temperature. The resulting mixture was poured
into water (500 mL) and the aqueous phase was extracted with
EtOAc (3×300 mL). The combined organic layers were washed
with brine (200 mL) and dried over anhydrous Na2SO4. The dried
solution was filtered and the filtrate was concentrated in vacuo to
give compound 10 (23.4 g, 72%) as a yellow oil, which was used
in the next step without further purification. Rf (10) = 0.47
(EtOAc/PE = 1/30). IR (neat): 2959, 2925, 2856, 1601, 1589,
4.5. 1-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-
carbonitrile (13)
To a solution of 14 (14.8 g, 67.5 mmol) in toluene (200 mL)
was heated to reflux under Ar atmosphere, a solution of diethyl
chlorophosphate (29.4 mL, 202.5 mmol) in toluene (100 mL) was
added. The reaction mixture was allowed to stir for 8 h at 120 ºС.
After that, the resulting solution was cooled to room temperature
and poured into water (200 mL). The aqueous phase was
extracted with EtOAc (3×300 mL), The organic layers were
washed with water, saturated NaHCO3 solution and brine, dried
over anhydrous Na2SO4. The dried solution was filtered and the
filtrate was concentrated in vacuo. The crude product was
purified by flash chromatography on a silica gel column
(EtOAc/PE = 1/5) to afford compound 13 (12.3 g, 90%) as white
solid. Rf (13) = 0.51 (EtOAc/PE = 1/3). IR (neat): 3321, 2963,
2942, 2872, 2228, 1606, 1561, 1483, 1442, 1384, 1336, 1240,
1
1494, 1463, 1440, 1377, 1243, 1176, 1036, 806, 751 cm-1; H
NMR (400 MHz, CDCl3) δ 7.17 (dt, J = 1.8 Hz, 7.6 Hz, 1H, Ar-
H), 7.13 (dt, J = 1.8 Hz, 7.4 Hz, 1H, Ar-H), 6.87 (dt, J = 1.1 Hz,
7.4 Hz, 1H, Ar-H), 6.83 (d, J = 8.1 Hz, 1H, Ar-H), 5.18-5.23 (m,
1H, C=CH), 3.82 (s, 3H, OCH3), 2.62 (t, J = 8.1 Hz, 2H,
CH2CH2Ar), 2.24 (dd, J = 7.2 Hz, 8.1 Hz, 2H, CH2CH2Ar), 1.69
(d, J = 7.2 Hz, 1.1 Hz, 3H, CH3), 1.57 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 157.6, 131.8, 130.9, 129.9, 127.0, 124.4,
120.4, 110.2, 55.2, 30.7, 28.5, 25.8, 17.6; HRMS (ESI): calcd. for
C13H19O [M+H]+, 191.1443; found 191.1447.
4.3. 1-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-
carbaldehyde (12)
1
1213, 816, 619 cm-1; H NMR (400 MHz, CDCl3) δ 7.25 (d, J =
To a solution of 11 (17.6 g, 99.8 mmol) in anhydrous THF
(200 mL) was added anhydrous MgCl2 (14.3 g, 150.2 mmol),
Et3N (52.6 mL, 38.1 mmol) and paraformaldehyde (61.6 g, 678.6
mmol) at room temperature. The reaction mixture was stirred at
reflux for 24 h under an Ar atmosphere. After completion of the
reaction (monitored by TLC), the mixture was cooled to room
temperature and quenched with 1M aqueous HCl solution. The
organic layers were separated and the aqueous layer was
8.3 Hz, 1H, Ar-H), 6.97 (d, J = 8.3 Hz, 1H, Ar-H), 6.32 (br, 1H,
OH), 2.65 (t, J = 6.4 Hz, 2H, CH2), 1.80-1.83 (m, 2H, CH2),
1.62-1.65 (m, 2H, CH2), 1.26 (s, 6H, CH3×2); 13C NMR (100
MHz, CDCl3) δ 156.3, 153.7, 128.6, 124.7, 119.3, 117.1, 95.1,
37.9, 34.3, 31.1, 31.1, 23.6, 18.3; HRMS (ESI): calcd. for
C13H16NO [M+H]+, 202.1226; found 202.1219.

4.6. 1-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-
carboxamide (13a)
4.9. (S)-2-methylpent-4-yn-1-ol (20)
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To a solution of compound 19 (9.0 g, 33.2 mmol) in
anhydrous Et2O (100 mL) was added anhydrous EtOH (0.2 mL)
and LiBH4 (ca. 2.0 M THF solution, 18.3 mL, 36.5 mmol) at 0 o C.
The resulting solution was stirred under Ar atmosphere at 0 o C
for 1.5 h. The reaction was quenched with 1M NaOH and poured
into water (200 mL).The aqueous phase was extracted with Et2O
(3×100 mL), The organic layers were combined and dried over
anhydrous Na2SO4. The dried solution was filtered and the filtrate
was concentrated in vacuo. The crude product was purified by
flash chromatography on a silica gel column (Et2O) to afford
Compound 13a as a red solid. Rf (13a) = 0.23 (EtOAc/PE =
1/3). IR (neat): 3447, 3329, 3216, 2954, 2939, 2920, 2863, 1638,
1
1585, 1489, 1458, 1403, 1360, 1257, 798, 740 cm-1; H NMR
(400 MHz, CDCl3) δ 7.16 (d, J = 8.5 Hz, 2H, Ar-H), 6.85 (d, J =
8.5 Hz, 2H, Ar-H), 2.69 (t, J = 6.4 Hz, 2H, CH2), 1.77-1.84 (m,
2H, CH2), 1.62-1.65 (m, 2H, CH2), 1.27 (s, 6H, CH3×2); 13C
NMR (100 MHz, CDCl3) δ 172.9 (C=O), 160.0, 153.3, 126.2,
122.9, 116.6, 109.0, 38.4, 34.3, 31.2 (CH3 × 2), 23.5, 18.6;
HRMS (ESI): calcd. for C13H18NO2 [M+H]+, 220.1332; found
220.1328.
D
compound 20 (1.56 g, 48 %) as a colorless oil. [α]25 = -12.8 (c
D
1
1.1, CHCl3)(lit 29. [α]20 = -11.1 (c 1.05, CHCl3) ); H NMR
(CDCl3, 400 MHz) δ 3.58 (d, J = 6.2 Hz, 2H, CH2OH), 2.18-2.32
(m, 2H, CHCH2CCH), 1.98 (t, J = 2.6 Hz, 1H, CꢁCH), 1.85-
1.94 (m, 1H, CHCH2CCH), 1.62 (br, 1H, OH), 1.01 (d, J = 6.7
Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 82.5, 69.5, 66.7,
34.8, 22.1, 16.0; GC-MS (EI): 98.03.
4.7. (S)-4-benzyl-3-(pent-4-ynoyl)oxazolidin-2-one (18)
To a solution of 4-pentynoic acid (10.1 g, 102.9 mmol) in
THF (400 mL) was added triethylamine (27.5 mL, 198.0 mmol)
and PivCl (11.7 mL, 95.0 mmol) at 0 o C. The mixture was stirred
at 0 ºС under Ar atmosphere for 1 h, and then LiCl (3.7 g, 87.1
mmol) and (S)-4-benzyloxazolidin-2-one (14.0 g, 79.2 mmol)
were added . After that, the reaction mixture was allowed to
warm to room temperature and stirred for 6 h. The reaction
mixture was poured into water (500 mL) and the aqueous phase
was extracted with EtOAc (3×400 mL). The combined organic
layers were washed with 1M HCl, sat. NaHCO3 and brine, dried
over anhydrous Na2SO4. The dried solution was filtered and the
filtrate was concentrated in vacuo. The residue was purified by
flash chromatography on a silica gel column (EtOAc/PE = 1/3) to
afford compound 18 (15.9 g, 78%) as a white solid. Rf (18) =
4.10. 2-cyano-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl
trifluoromethanesulfonate (15)
To a solution of 13 (12.0 g, 59.6 mmol), pyridine (9.6 mL,
119.2 mmol) and DMAP (0.7 g, 5.9 mmol) in CH2Cl2 (300 mL)
was added Tf2O (15.1 mL, 89.4 mmol) at 0 ºС. After that, the
reaction mixture was allowed to warm to room temperature and
stirred for 12 h. The resulting solution was poured into ice-water
(300 mL). The aqueous phase was extracted with EtOAc (3×300
mL), The organic layers were washed with water, saturated
NaHCO3 solution and brine, dried over anhydrous Na2SO4. The
dried solution was filtered and the filtrate was concentrated in
vacuo. The crude product was purified by flash chromatography
on a silica gel column (EtOAc/Pe = 1/30) to afford compound 15
(18.4 g, 93%) as a yellow oil. Rf (15) = 0.55 (EtOAc/PE = 1/10).
IR (neat): 2962, 2870, 2237, 1610, 1553, 1460, 1414, 1216, 1136,
818, 748 cm-1; 1H NMR (400 MHz, CDCl3 ) δ 7.52 (d, J = 8.2 Hz,
1H, Ar-H), 7.47 (d, J = 8.2 Hz, 1H, Ar-H), 2.86 (t, J = 6.3 Hz, 2H,
CH2), 1.80-1.86 (m, 2H, CH2), 1.69-1.71 (m, 2H, CH2), 1.32 (s,
6H, CH3×2); 13C NMR (100 MHz, CDCl3) δ 155.5, 147.3, 132.7,
131.2, 127.4, 120.0, 116.8, 114.3, 104.6, 37.7, 35.0, 31.5, 25.3,
18.3; HRMS (ESI): calcd. for C14H15F3NO3S [M+H]+, 334.0719;
found 334.0722.
D
0.35 (EtOAc/PE = 1/3). [α]21 = +98.2 (c 1.4, CH2Cl2) (lit 28.
D
1
[α]20 = +98.6 (c 1.8, CH2Cl2) ), H NMR (CDCl3, 400 MHz) δ
7.26-7.35 (m, 3H, Ar-H), 7.20-7.22 (m, 2H, Ar-H), 4.66-4.72 (m,
1H, CH of Ozazolidone), 4.17-4.25 (m, 2H, CH2 of Ozazolidone),
3.30 (dd, J = 3.2 Hz, 13.4 Hz, 1H, CH of CH2Ph), 3.12-3.27 (m,
2H, CHꢁCCH2CH2), 2.79 (dd, J = 9.6 Hz, 13.4 Hz, 1H, CH of
CH2Ph), 2.59 (dt, 2H, J = 7.1 Hz, 2.6 Hz, CHꢁCCH2CH2), 2.00
(t, J = 2.6 Hz, 1H, CꢁCH); 13C NMR (CDCl3, 100 MHz) δ 171.1,
153.3, 135.0, 129.3, 128.9, 127.3, 82.5, 68.9, 66.3, 55.0, 37.7,
34.7, 13.5; HRMS (ESI): calcd. for C15H16NO3 [M+H]+,
258.1113; found 258.1125.
4.8. (S)-4-benzyl-3-((S)-2-methylpent-4-ynoyl)oxazolidin-2-one
(19)
4.11. (S)-1-(5-hydroxy-4-methylpent-1-yn-1-yl)-5,5-dimethyl-
5,6,7,8- tetrahydronaphthalene-2-carbonitrile (16)
To a solution of compound 18 (15.2 g, 59.1 mmol) in THF
(400 mL) was add NaHMDS (ca. 2.0 M THF solution, 44.3 mL,
o
88.6 mmol) at -78 C. After 30 min, MeI (7.3 mL, 118.2 mmol)
To a solution of 15 (2.0 g, 6.0 mmol) in anhydrous DMF (20
mL) was added bis(triphenylphosphine)palladium(II)chloride
(0.1 g, 0.14 mmol), compound 20 (1.47 g, 15.0 mmol) and Et3N
(1 mL, 7.0 mmol) in room temperature. The mixture was stirred
at 80 ºС for 3 h under Ar atmosphere before being cooled to
room temperature. The resulting solution was poured into water
(20 mL). The aqueous phase was extracted with EtOAc (3×30
mL). The organic layers were washed with brine and dried over
anhydrous Na2SO4, The dried solution was filtered and the filtrate
was concentrated in vacuo. The crude product was purified by
flash chromatography on a silica gel column (EtOAc/PE = 1/2) to
afford compound 16 (1.4 g, 86%) as a yellow oil. Rf (16) = 0.32
(EtOAc/PE = 1/3). [α]25D = +5.6 (c 1.0, CHCl3); IR (neat): 3347,
2960, 2932, 2872, 2229, 1725, 1667, 1581, 1460, 1413, 1387,
o
was added. The mixture was allowed to warm to -40 C and
stirred under Ar atmosphere for 25 h. After completion of the
reaction, the mixture was quenched with AcOH (10 mL) and
poured into water (500 mL), the aqueous phase was extracted
with EtOAc (3×400 mL). The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4. The
dried solution was filtered and the filtrate was concentrated in
vacuo. The crude product was purified by flash chromatography
on a silica gel column (EtOAc/PE = 1/5) to afford 19 (9.3 g, 58%,
1
d. r. > 95:1 determined by H-NMR) as a yellow oil. Rf (19) =
D
0.37 (EtOAc/PE = 1/5). [α]21 = +107.5 (c 1.0, CHCl3);1H NMR
(CDCl3, 400 MHz) δ 7.27-7.35 (m, 3H, Ar-H), 7.20-7.21 (m, 2H,
Ar-H), 4.68-4.74 (m, 1H, CH of Ozazolidone), 4.17-4.25 (m, 2H,
CH2 of Ozazolidone), 3.88-3.97 (m, 1H, CHCH2), 3.27 (dd, J =
2.9 Hz, 13.3 Hz, 1H, CH of CH2Ph), 2.77 (dd, J = 13.3 Hz, 9.5
Hz, 1H, CH of CH2Ph), 2.38-2.61 (m, 2H, CHCH2), 1.99 (t, J =
2.6 Hz, 1H, CꢁCH), 1.33 (d, J = 6.9 Hz, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) δ 175.2, 153.0, 135.1, 129.4, 128.9, 127.4,
81.6, 69.8, 66.2, 55.3, 37.9, 37.5, 22.2, 17.1; HRMS (ESI): calcd.
for C16H18NO3 [M+H]+, 272.1284; found 272.1281.
1
1040, 829, 756, 692, 646 cm-1; H NMR (400 MHz, CDCl3) δ
7.40 (d, J = 8.1 Hz, 1H, Ar-H), 7.32 (d, J = 8.1 Hz, 1H, Ar-H),
3.68 (dd, J = 4.1 Hz, 6.7 Hz, 2H, CH2CHCH2OH), 2.87 (t, J = 6.5
Hz, 2H, CH2), 2.60 (d, J = 6.1 Hz, 2H, CH2CHCH2OH), 2.01-
2.07 (m, 1H, CH2CH(CH3)CH2OH), 1.81-1.84 (m, 2H, CH2),
1.74 (br, 1H, OH), 1.63-1.66 (m, 2H, CH2), 1.27 (s, 6H, CH3×2),
1.10 (d, J = 6.7 Hz, CH3) ; 13C NMR (100 MHz, CDCl3) δ 151.4,

6
Tetrahedron
ACCEPTED MANUSCRIPT
139.5, 129.3, 127.5, 126.3, 118.8, 112.6, 99.9, 77.8 (CN), 66.7,
Hz, 9.4 Hz, 1H, CH), 3.63-3.69 (m, 1H, CH), 3.24 (t, J = 6.5 Hz,
38.2, 35.2, 34.6, 31.4, 29.5, 23.5, 19.0, 16.4; HRMS (ESI): calcd.
2H, CH2), 1.79-1.82 (m, 2H, CH2), 1.64-1.67 (m, 2H, CH2), 1.38
(d, J = 6.9 Hz, 3H, CH3), 1.31 (d, J = 1.7 Hz, 6H, CH3×2); 13C
NMR (100 MHz, CDCl3) δ 182.3 (C=O), 180.6 (C=O), 160.9,
153.1, 141.0, 132.9, 132.6, 128.8, 125.5, 124.2, 80.3, 37.8, 35.6,
34.9, 32.0, 31.9, 30.0, 19.3, 18.9; HRMS (ESI): calcd. for
C19H21O3 [M+H]+, 297.1485; found 297.1479.
for C19H24NO [M+H]+, 282.1852; found 282.1850.
4.12. (S)-4,4,8-trimethyl-1,2,3,4,8,9-
hexahydrophenanthro[3,2-b]furan-7- amine (17)
To a solution of 16 (1.4 g, 4.9 mmol) in anhydrous DMSO (10
mL) was added NaOMe (0.26 g, 4.9 mmol). The mixture was
stirred at 100 ºС under Ar atmosphere for 1 h. After completion
of the reaction (monitored by TLC), the mixture was poured into
water (20 mL) and the aqueous phase was extracted with EtOAc
(3×30 mL). The combined organic layers were washed with
water and brine, dried over anhydrous Na2SO4. The dried
solution was filtered and the filtrate was concentrated in vacuo.
The crude product was purified by flash chromatography on a
4.15. (+)-neocryptotanshinone (2)
To a solution of (+)-isocrytotanshinone (1) (0.5 g, 1.7 mmol)
in EtOH (10 mL) was added KOH (1.6 g, 28.9 mmol), The
mixture was stirred at room temperature for 8 h. After completion
of the reaction (monitored by TLC), the mixture was poured into
1N HCl (100 mL) at 0 ºС and the aqueous phase was extracted
with EtOAc (3×30 mL). The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4. The
dried solution was filtered and the filtrate was concentrated in
vacuo. The crude product was purified by flash chromatography
on a silica gel column (EtOAc/PE = 1/3) to afford 2 (0.49 g, 92%,
98.8% ee, determined by HPLC) as an orange-red solid. Rf (2) =
silica gel column (EtOAc/PE = 1/3) to afford compound 17 (1.1 g,
79%) as a pink solid. Rf (17) = 0.38 (EtOAc/PE = 1/2). [α]24
D
=
+54.9 (c 1.2, CHCl3); IR (neat): 3481, 3389, 3239, 3054, 2948,
2865, 2828, 1883, 1731, 1632, 1592, 1452, 1430, 1384, 804, 741
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.9 Hz, 1H, Ar-
H), 7.32 (d, J = 8.9 Hz, 1H, Ar-H), 6.85 (s, 1H, Ar-H), 4.67 (t, J
= 8.5 Hz, 1H, CH), 4.27 (dd, J = 3.5 Hz, 8.5 Hz, 1H, CH), 4.11
(br, 2H, NH2), 3.50-3.58 (m, 1H, CH), 3.00 (t, J = 6.4 Hz, 2H,
CH2), 1.93-1.99 (m, 2H, CH2), 1.73-1.76 (m, 2H, CH2), 1.38 (d, J
= 6.4 Hz, 6H, CH3×3), 1.37 (d, J = 6.9 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 159.1, 142.7, 138.2, 134.5, 130.1, 121.1,
118.0, 117.6, 114.1, 91.9, 78.7, 38.7, 34.4, 34.0, 31.4, 31.3, 27.3,
D
0.45 (EtO Ac/PE = 1/2). [α]20 = +6.1 (c 1.0, CHCl3); IR (neat):
3335, 2962, 2932, 2873, 1642, 1564, 1458, 1413, 1380, 1328,
1202, 1028, 803, 759, 732 cm-1; H NMR (500 MHz, CDCl3) δ
1
8.09 (br, 1H, OH), 7.98 (d, J = 8.1 Hz, 1H, Ar-H), 7.73 (d, J =
8.1 Hz, 1H, Ar-H), 3.81-3.95 (m, 2H, (CH3)CHCH2OH), 3.41-
3.48 (m, 1H, (CH3)CHCH2OH), 3.23 (t, J = 6.4 Hz, 2H, CH2),
2.41 (br, 1H, OH), 1.80-1.85 (m, 2H, CH2), 1.64-1.68 (m, 2H,
CH2), 1.31 (s, 6H, CH3×2), 1.26 (d, J = 7.0 Hz, 3H,
(CH3)CHCH2OH); 13C NMR (125 MHz, CDCl3) δ 185.4 (C=O),
182.9 (C=O), 154.1, 152.9, 140.9, 133.5, 132.6, 126.4, 125.1,
122.9, 65.5, 37.7, 34.8, 33.0, 31.8, 29.9, 19.1, 14.6; HRMS (ESI):
calcd. for C19H23O4 [M+H]+, 315.1591; found 315.1598.
19.5, 18.3; HRMS (ESI): calcd. for C19H24NO [M+H]+
282.1852; found 282.1848.
,
4.13. 1-amino-8,8-dimethyl-2-(prop-1-en-2-yl)-5,6,7,8-
tetrahydrophenanthren-3-ol (17b)
Compound 17b as a red solid. Rf (17b) = 0.42 (EtOAc/PE =
Acknowledgments
1/2). IR (neat): 3477, 3388, 3317, 3200, 2961, 2926, 2865, 1680,
1
1650, 1589, 1561, 1422, 827, 783 cm-1; H NMR (400 MHz,
This investigation was supported by CAMS Innovation Fund
for Medical Sciences (CIFMS, 2016-I2M-3-009) and the Drug
Innovation Major Project (2018ZX09711-001-005).
DMSO-d6) δ 9.14 (s, 1H, OH), 7.73 (d, J = 8.9 Hz, 1H, Ar-H),
7.14 (d, J = 8.9 Hz, 1H, Ar-H), 6.55 (s, 1H, Ar-H), 5.36 (s, 1H,
C=CH2), 5.09 (s, 2H, NH2), 4.87 (s, 1H, C=CH2), 2.78 (t, J = 6.2
Hz, 2H, CH2), 1.98 (s, 3H, CH3 ), 1.84-1.87 (m, 2H, CH2), 1.63-
1.65 (m, 2H, CH2), 1.28 (s, 6H, CH3×2); 13C NMR (100 MHz,
DMSO-d6) δ 153.8, 141.9, 141.5, 141.1, 132.9, 127.7, 120.7,
119.8, 116.5, 115.8, 112.9, 94.7, 38.6, 33.8, 31.3, 26.7, 23.2, 19.3;
HRMS (ESI): calcd. for C19H24NO [M+H]+, 282.1852; found
282.1851.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://
4.14. (+)-isocrytotanshinone (1)
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mixture was stirred at room temperature for 10 min, and then
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