Total synthesis of xiamenmycin C and all of its stereoisomers: stereochemical revision

Article abstract of DOI:10.1080/10286020.2016.1188808

Xiamenmycin C, a potent anti-fibrotic natural product, and all of its stereoisomers have been synthesized and their structures were fully characterized. Based on this study, the originally proposed structure of xiamenmycin C has been accordingly revised to be 2R,3S.

Full text of DOI:10.1080/10286020.2016.1188808

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
Total synthesis of xiamenmycin C and all of its
stereoisomers: stereochemical revision
Yang-Yang Yao, Xiao-Yu Liu, Xiao-Yu Li, Hong-Guang Yang, Li Li, Xiao-Zhen
Jiao & Ping Xie
To cite this article: Yang-Yang Yao, Xiao-Yu Liu, Xiao-Yu Li, Hong-Guang Yang, Li Li,
Xiao-Zhen Jiao & Ping Xie (2016): Total synthesis of xiamenmycin C and all of its
stereoisomers: stereochemical revision, Journal of Asian Natural Products Research, DOI:
10.1080/10286020.2016.1188808
To link to this article: http://dx.doi.org/10.1080/10286020.2016.1188808
Published online: 03 Jun 2016.
Submit your article to this journal
Article views: 15
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ganp20
Download by: [University of California, San Diego]
Date: 29 June 2016, At: 13:13

Journal of asian natural Products research, 2016
http://dx.doi.org/10.1080/10286020.2016.1188808
Total synthesis of xiamenmycin C and all of its stereoisomers:
stereochemical revision
Yang-Yang Yao, Xiao-Yu Liu, Xiao-Yu Li, Hong-Guang Yang, Li Li, Xiao-Zhen Jiao and
Ping Xie
state Key laboratory of Bioactive substance and function of natural Medicines, Beijing Key laboratory of
active substance discovery and druggability evaluation, institute of Materia Medica, chinese academy of
Medical science & Pecking union Medical college, Beijing 100050, china
ABSTRACT
ARTICLE HISTORY
received 14 March 2016
accepted 9 May 2016
Xiamenmycin C, a potent anti-fibrotic natural product, and all of its
stereoisomers have been synthesized and their structures were fully
characterized. Based on this study, the originally proposed structure
of xiamenmycin C has been accordingly revised to be 2R,3S.
KEYWORDS
Xiamenmycin c; total
synthesis; stereochemical
revision
1. Introduction
A series of benzopyran derivatives with the benzopyran skeleton and a prenylated side chain,
named xiamenmycins A–D (Figure 1), were isolated from mangrove-derived Streptomyces
xiamenensis as potential drug candidates against excessive fibrotic diseases by Xu’s group.
eir absolute configurations were elucidated as (2S,3S) based on the analysis of the spec-
troscopic data, Mosher’s method, Marfey’s reagent, and NOESY correlation [1–4].
As promising drug candidates for treating excessive fibrotic diseases, xiamenmycins
have triggered our efforts to establish a flexible and efficient approach to their synthesis. In
our previous studies, the structure of xiamenmycin A has been revised [5]. As a continued
program for biological research, a rapid access to all the isomers of 3-chromanol core of
all the xiamenmycins is needed. Herein, we report the synthesis of the xiamenmmycin C,
which possessed the related simple structure, and all of its stereoisomers.
2. Results and discussion
Our initial retrosynthetic analysis of xiamenmycin C (1) is outlined in Scheme 1. e amide
moiety of xiamenmycin C could be synthesized from substituted methyl benzoate 6 via
hydrolysis and amidation [6,7], while the key intermediate 6 might be formed through a
highly regio- and diastereoselective oxidative cyclization [8] from 5, which, in turn, could
be accessed from organoboron 3 via Suzuki-Miyaura coupling [9,10].
CONTACT Xiao-Zhen Jiao
jiaoxz@imm.ac.cn
© 2016 informa uK limited, trading as taylor & francis Group

2
Y.-Y. Yao et aL.
O
OH
R
3
2
O
CO2H
NH
HO
R=
xiamenmycin B
R=-OH
xiamenmycin A
xiamenmycin C
H3C
CO2CH3
NH
HO
R=
R=-NH2
xiamenmycin D
H3C
Figure 1. structures of xiamenmycins a–d.
Our synthesis started with the commercially available neryl acetate 2, which could be con-
verted into the key intermediate benzoate Z-5 in two steps. us, treatment of neryl acetate 2
with bis(pinacolato)diboron (B2Pin2) in the presence of catalytic amount of bis(1,5-cyclooc-
tadiene)nickel(0) (Ni(cod)2) and tricyclohexylphosphine (PCy3) [9] afforded the organob-
oron 3, which was subjected to the Suzuki-Miyaura coupling with MOM-protected methyl
3-bromo-4-hydroxybenzoate using [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalla-
dium(II) (Pd(dppf)Cl2) [10] as catalyst to give the benzoate Z-5 in good yield.
With benzoate Z-5 in hand, we initially tried to establish a direct formation of the 3-chro-
manol through a vanadium-catalyzed asymmetric epoxidation of benzoate Z-5 followed
by regio- and diastereo-selective cyclization. Unfortunately, using bishydroxamic acid as a
ligand [11], only low stereoselectivity was observed (ee=14%). Based on this result, we had
to first synthesize the racemic xiamenmycin C and then try to isolate each isomer [12]. For
this purpose, followed a literature procedure [8,13,14], treatment of the Z-5 with tert-Butyl
hydroperoxide (t-BuOOH), vanadyl acetylacetonate (VO(acac)2) in the presence of TFA,
the required ( ) 6 along with a small amount of the 5-exocyclization by-product 6a (6:1)
was achieved. Finally, afer hydrolysis and subsequent amidation using Boc2O/NH4HCO3
[6,7], compound ( ) 8, which has the originally proposed structure of xiamenmycin C,
was obtained (Scheme 2).
As expected, a pseudo-SN2 epoxide opening resulted in the trans orientation between
3-OH and 2-CH3 in compound ( ) 8 [15,16], which is also confirmed by the NOE analyses.
e coupling constants of 3-H (J3-H=6.7, 5.2 Hz) showed that 3-H occupied the equatorial
orientation (Scheme 2). Besides, it was found that 2-CH3 was at the axial position because
of the NOE correlation between the 4-Hax (δ 2.93) and 2-CH3 (δ 1.22). Based on the above
analysis, the relative configuration at C-2 and C-3 in ( ) 8 were found to be (2S*,3S*).
However, the comparison of NMR spectral data of compound ( ) 8 with the reported nat-
ural xiamenmycin C showed that there were large deviations in the 13C-NMR spectra for
the 9-position carbon atom (Δδ=4.9 ppm) and 15-position carbon atom (Δδ=2.5 ppm)
(Table 1). e results suggested that the stereochemistry of the proposed xiamenmycin C
may be incorrect [1,5].
To fully elucidate the stereoconfiguration of C-2, we further synthesized the epimer ( )
15 with a similar method using E-geranyl acetate (9) as the starting material (Scheme 2).
e structure of ( ) 15 was determined by 1H NMR and NOESY analyses, which showed

JouRnaL of aSian natuRaL PRoduCtS ReSeaRCH
3
O
NH2
hydrolysis,
amidation
4
6
3
OH
4a
14
12
OH
O
O
1'
10
2
O
8a O
9
13
8
11
15
6
1
oxidative cyclization
OH
Suzuki-Miyaura
coupling
Br
OH
+
O
B
O
O
O
O
O
24
3
5
Scheme 1. retrosynthetic analysis of xiamenmycin c.
O
OMOM
OH
b
a
c
O
O
O
B
65%
78%
74%
O
O
4
O
O
3
2
5
O
OH
NH2 Heq Hax
OH
e
OH
d
f
OH
NOE
O
O
O
Heq
79%
O
98%
78.0%
O
O
(2S*, 3S*)
8
6
(2S*, 3S*)
7
(2S*, 3S*)
O
OMOM
OH
c
a
b
O
O
B
O
62%
54%
61%
9
10
O
O
O
O
11
12
O
O
O
Heq
Hax
e
OH
d
f
OH
OH
Hax
O
HO
H2N
NOE
80%
97%
98%
O
(2R*, 3S*)
O
O
13
14
(2R*, 3S*)
(2R*, 3S*)
15
Scheme 2. synthesis of racemic xiamenmycin c. reagents and conditions: (a) B2Pin2, ni(cod)2, Pcy3, acoet;
(b) methyl 3-bromo-4-hydroxybenzoate, Pd(dppf)cl2, csco3, 1,4-dioxane; (c) d-camphorsulfonic acid,
Meoh; (d) Vo(acac)2, tBhP, tfa, dcM; (e) 4 n naoh, ch3oh; (f) Boc2o, pyridine, nh4hco3, 1,4-dioxane.
the 3-H and 2-CH3 were in axial orientation. e 1H and 13C-NMR data of ( ) 15 (2R*,3S*)
were in accordance with those reported [1] for xiamenmycin C (Table 1).
AfercompletingthetotalsynthesisoforiginallyproposedstructureofxiamenmycinC( )8
and the revised xiamenmycin C ( ) 15, we found both racemates could be efficiently
resolved by their (S)-O-methyl mandelic acid ester [17]. Reaction ( ) 8 with (S)-O-methyl
mandelic acid provided a pair of diastereomeric esters 16 (Rf=0.4, 1:1 DCM/EtOAc) and

4
Y.-Y. Yao et aL.
Table 1. comparison of 1h and 13c nMr spectral data of compounds ( ) 8, ( ) 15 and reported natural
xiamenmycin c.
natural xiamenmycin C1
Compound 15
δH (J in Hz)
Compound 8
δH (J in Hz)
Position
δH (J in Hz)
δC
δC
δC
1
2
3
4
–
–
–
–
–
–
–
–
3.74,dd (7.4, 5.2)
2.66,dd (17.3, 7.4)
2.93, dd (17.3, 5.2)
–
7.63, d (1.8)
–
7.60, dd (8.4,1.8)
6.74, d (8.4)
–
79.7 c
79.5 c
66.0 ch
79.1 c
66.3 ch
31.3 ch2
–
120.4 c
130.2 ch
126.3c
127.4 ch
116.5 ch
156.0c
38.0 ch2
3.74, dt (7.8, 5.2)
2.65, dd (16.6, 7.8) 30.9 ch2
2.92, dd (16.6, 5.3)
3.73, dt (6.7, 5.2)
2.65, dd (16.9, 6.8)
2.93, dd (16.9, 5.2)
67.1 ch
30.6 ch2
–
120.0 c
129.8 ch
125.8 c
126.8 ch
116.0 ch
155.4 c
33.1 ch2
–
4a
5
6
7
8
8a
9
–
7.62, s
–
7.58, d (8.0)
6.73, d (8.4)
–
120.2 c
130.0 ch
125.8 c
127.2 ch
116.3 ch
155.8 c
37.6 ch2
–
7.62, s
–
7.58, d (8.5)
6.72, d (8.0)
–
1.59, m
1.60–1.58, m
1.68–1.64, m; 1.49–1.45,
m
2.10–1.95, m
5.07, t (7.5)
–
10
11
12
13
14
15
1′
2.10, m
5.10,t (7.3)
–
1.56, s
1.63, s
1.16, s
–
21.6 ch2
124.8 ch
131.3c
18.0 ch3
25.9 ch3
18.8 ch3
168.0 c
–
2.12–2.06, m
5.10, t (7.3)
21.4
124.5 ch
131.2 c
17.7 ch3
25.7 ch3
18.7 ch3
168.1 c
–
21.3 ch2
124.4 ch
130.7 c
17.4 ch3
25.4 ch3
21.3 ch3
167.5c
–
–
1.55, s
1.62, s
1.15, s
–
1.53, s
1.61, s
1.22, s
–
co-nh2
8.38,brs
7.71, brs 7.07, brs
7.73, brs 7.09, brs
17 (Rf=0.5, 1:1 DCM/EtOAc). Afer chromatography separation, each diastereomer was
hydrolyzed using sodium methoxide [8] to afford (2S,3S)-20 and (2R,3R)-21. Similarly, the
stereoisomers (2S,3R)-22, (2R,3S)-23 were obtained from ( ) 15 (Scheme 3). Structures
and stereochemistry of 20, 21, 22, 23 were determined by 1H, 13C NMR spectra and NOE
experiments, and comparison of the experimental CD spectra with the calculated spectra
using TDDFT method [18,19] (Figure 2). e data of (2R,3S)-23 were in agreement with
those reported [1] for the natural product. us, the absolute configurations of xiamenmycin
C were revised to be 2R,3S rather than 2S,3S (Figure 3).
In summary, we have accomplished the first total synthesis of xiamenmycin C and all
of its stereoisomers in nine steps. eir stereoconfigurations were elucidated by 1H-NMR
spectra, 13C NMR spectra, NOESY analyses, and calculated CD method. Furthermore, the
stereoconfigurations of the initially proposed xiamenmycin C were revised to be 2R,3S
through comparison of physicochemical properties of the synthetic stereoisomers with
the isolated natural compound. e biological evaluation of xiamenmycin C and all of its
stereoisomers is in progress.
3. Experimental
3.1. General experimental procedures
Melting points were measured on an MP-J3 micro-melting apparatus (Yanaco, Kyoto, Japan).
Optical rotations were measured on PE341 (PerkinElmer, Fremont, CA, USA). NMR spec-
tra were recorded on Mercury 400-plus (Varian, Palo Alto, CA, USA), Mercury 500-plus
(Varian, Palo Alto, CA, USA) or else on a Varian Inova-600 NMR spectrometer (Varian,
Palo Alto, CA, USA). HR-ESI-MS were obtained on orbitrap mass spectrometer (ermo,
Waltham, USA). ECD analysis was carried out using JASCO J-815 (JASCO, Tokyo, Japan).

JouRnaL of aSian natuRaL PRoduCtS ReSeaRCH
5
O
O
OR2
OH
83%
H2
N
H2N
38%
R1
R1
MeO
COOH
Ph
O
O
O
20 (2S, 3S)
16 (2S, 3S, S)
OH
(S)-
H2
N
R1
O
O
O
OR2
R1
OH
R1
8
(2S*, 3S*)
H2
N
96%
91%
H2
N
41%
O
O
21
(2R, 3R)
17 (2R, 3R, S)
O
O
OH
OR2
R1
H2
N
H2
N
44%
MeO COOH
R1
O
O
O
Ph
(S)-
18
22
(2S, 3R)
OH
R1
(2S, 3R, S)
H2
N
O
O
O
15
(2R*, 3S*)
OR2
R1
OH
R1
92%
H2
N
H2
N
37%
O
O
19 (2R, 3S, S)
23
(2R, 3S)
O
MeO
R1=
R2=
Ph
Scheme 3. synthesis of the xiamenmycin c and its stereoisomers.
Figure 2. the theoretical cd spectra and experimental cd spectra of 20, 21, 22, 23.
Solvents were distilled under positive pressure of dry argon before use and dried by standard
procedures. All reagents and solvents were purchased from commercial suppliers (Beijing,
China). Column chromatography was carried out on silica gel (160–200 mesh). Reactions
were monitored using thin-layer silica gel chromatography (TLC) using GF254 (Qingdao
Marine Chemical Inc. Qingdao, China).

6
Y.-Y. Yao et aL.
NH2
O
NH2
OH
OH
O
3
3
2
2
O
O
CH3
CH3
23
1
C2-epimer (corrected structure)
(2R, 3S)
originally proposed structure
(2S, 3S)
Figure 3. the structure of the proposed xiamenmycin c (1) and the corrected xiamenmycin c (23).
3.2. (Z)-2-(3,7-Dimethylocta-2,6-dien-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane (3)
To a solution of neryl acetate (12.60 g, 64.28 mmol) and bis(pinacolato)diboron (16.32 g,
64.28 mmol) in AcOEt (125 ml), bis(1,5-cyclooctadiene)nickel(0) (0.88 g, 3.21 mmol) and
tricyclohexylphosphine (0.90 g, 3.21 mmol) were added carefully under argon atmosphere.
e mixture was stirred at 60 °C for 10.5 h and then concentrated and purified by column
chromatography using PE:AcOEt (200:1) to afford 3 (11 g, 65%) as a colorless oil.
1H NMR (500 MHz, CDCl3) δ (ppm): 5.62–5.10 (m, 1H), 4.36–4.23 (m, 1H), 2.06–
2.03(m, 2H), 1.79–1.61 (m, 7H), 1.43–1.13 (complex, 18H).
3.3. (Z)-Methyl 3-(3,7-dimethylocta-2,6-dien-1-yl)-4-(methoxymethoxy)
benzoate (4)
To a solution of 3 (1.65 g, 6.24 mmol) in 1,4-dioxane (50 ml) methyl 3-bromo-4-(methox-
ymethoxy)benzoate (1.14 g, 4.16 mmol), CsCO3 (4.06 g, 12.47 mmol), Pd(dppf)Cl2 (0.30 g,
0.42 mmol) was added under argon atmosphere. Afer being heated to reflux for 14 h, the
reaction mixture was filtered by short column chromatography, and then concentrated
under reduced pressure. e residue was purified by column chromatography using PE/
DCM(3/1) as eluent affording 4 (1.07 g, 78%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ (ppm): 7.91–7.79 (m, 2H), 7.06 (d, J=9.0 Hz, 1H), 5.31 (t,
J=7.4 Hz, 1H), 5.26 (s, 2H), 5.16–5.10 (m, 1H), 3.88 (s, 3H), 3.48 (s, 3H), 3.36 (d, J=7.3 Hz,
2H), 2.18–2.09 (m, 4H), 1.74 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H).
3.4. (Z)-Methyl 3-(3,7-dimethylocta-2,6-dien-1-yl)-4-hydroxybenzoate (5)
To a solution of 4 (973 mg, 2.93 mmol) in MeOH (25 ml), CSA (136 mg, 0.59 mmol) was
added, then the mixture was stirred at room temperature for one week before quenched
with six drops of Et3 N. e reaction mixture was extracted with CH2Cl2, washed with water
and brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure.
e residue was purified by column chromatography using PE:AcOEt (20:1) to afford 5
(625 mg, 74%) as a colorless oil.
1H NMR (500 MHz, CDCl3) δ (ppm): 7.82–7.81 (m, 2H), 6.82 (d, J=8.9 Hz, 1H), 5.67
(s, 1H), 5.31 (t, J=7.0 Hz, 1H), 5.14 (t, J=6.9 Hz, 1H), 3.88 (s, 3H), 3.39 (d, J=6.9 Hz, 2H),
2.22–2.20 (m, 2H), 2.16–2.14 (m, 2H), 1.78 (s, 3H), 1.69 (s, 3H), 1.62 (s, 3H).

JouRnaL of aSian natuRaL PRoduCtS ReSeaRCH
7
3.5. (2S*,3S*)-Methyl 3-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-
6-carboxylate (6) and (R*)-methyl 2-((R*)-2-hydroxy-6-methylhept-5-en-2-yl)-2,3-
dihydrobenzofuran-5-carboxylate (6a)
To a solution of 5 (700 g, 2.43 mmol) in DCM (10 ml), VO(acac)2 (10 mg, 0.037 mmol) was
added under argon atmosphere, and the mixture was stirred at room temperature. Afer
5 min, TBHP (4 N, 0.79 ml) and TFA (36 μl, 0.49 mmol) were added. e solution was stirred
at 40 °C for 3 h. e solvents were removed under reduced pressure, diluted with CH2Cl2,
then washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduce pressure. e residue was purified by column chromatography using PE/
AcOEt (20/1) as eluent affording 6 (584 mg, 79%) and 6a (97 mg, 13%) as a colorless oil.
Compound 6: 1H NMR (500 MHz, CDCl3) δ (ppm): 7.80 (s, 2H), 6.85 (d, J=6.4 Hz, 1H),
5.13 (s, 1H), 3.90 (s, 1H), 3.87 (s, 3H), 3.08(d, J=16 Hz, 1H), 2.85(d, J=16 Hz, 1H), 2.14–2.10
(m, 2H), 1.78–1.70 (m, 3H), 1.68 (s, 3H), 1.66–1.63 (m, 1H), 1.60 (s, 3H), 1.57–1.55 (m,
1H), 1.29 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm): 167.0, 157.0, 132.3, 132.0, 129.5,
123.8, 122.3, 118.9, 117.2, 79.5, 77.3, 77.0, 76.8, 68.3, 51.8, 34.7, 30.8, 25.6, 21.8, 21.6, 17.6.
HR-ESI-MS: m/z 305.1742 [M+H]+ (calcd for C18H25O4, 305.1747). Compound 6a: 1H NMR
(600 MHz, CDCl3) δ 7.86 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.7 Hz, 1H), 5.15 (t, J=7.3 Hz,
1H), 4.75 (t, J=9.1 Hz, 1H), 3.87 (s, 3H), 3.24–3.23 (m, 1H), 3.16–3.12 (m, 1H), 2.15–2.13
(m, 2H), 1.76–1.71 (m, 1H), 1.69 (s, 3H), 1.64 (s, 3H), 1.62–1.58 (m, 1H), 1.17 (s, 3H). 13
C
NMR (150 MHz, CDCl3) δ 166.9, 163.6, 132.1, 131.0, 129.9, 127.6, 126.7, 124.0, 122.8, 108.9,
89.5, 77.2, 77.0, 76.8, 73.6, 51.8, 38.9, 29.9, 25.7, 22.3, 21.1, 17.7. HR-ESI-MS: m/z 305.1744
[M+H]+ (calcd for C18H25O4, 305.1747).
3.6. (2S*,3S*)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxylic acid (7)
To a solution of 6 (254 mg, 0.84 mmol) in MeOH (25 ml), aqueous NaOH (4 N, 1.0 ml)
was added dropwise. e mixture was stirred at room temperature for 36 h. e solvents
were removed under reduced pressure, diluted with water, and washed with EtOAc. e pH
was adjusted to 1~2, and extracted with EtOAc. e combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under
reduced pressure affording 7 (237 mg, 98%) as a white solid.
1
m. p. 145–148 °C. H NMR (400 MHz, acetone-d6) δ (ppm): 7.76 (s, 2H), 6.80 (d,
J=8.4 Hz, 1H), 5.14–5.10 (m, 1H), 3.94–3.91(m, 1H), 3.10–3.05 (m, 1H), 2.84–2.79 (m,
1H), 2.18–2.09 (m, 2H), 1.82–1.76 (m, 1H), 1.63 (s, 3H), 1.59 (s, 1H), 1.56 (s, 3H), 1.34
(s, 3H). 13C NMR (150 MHz, acetone-d6) δ (ppm): 167.3, 158.1, 132.9, 131.7, 129.8, 125.1,
122.8, 121.1, 117.4, 80.3, 68.6, 34.1, 31.4, 25.6, 22.4, 22.3, 17.4. HR-ESI-MS: m/z 291.1588
[M+H]+ (calcd for C17H23O4, 291.1591).
3.7. (2S*,3S*)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxamide (8)
To a solution of 7 (200 mg, 0.69 mmol) in 1,4-dioxane (20 ml), azabenzene (0.50 ml) and
di-tert-butyl dicarbonate (2556 mg, 11.70 mmol) were added, then the mixture was stirred at
room temperature for 15 min, and ammonium bicarbonate (927 mg, 11.70 mg) was added.

8
Y.-Y. Yao et aL.
e solution was stirred at room temperature for 3 h, then quenched with saturated aqueous
NaHCO3 (50 ml), extracted with EtOAc and dried over anhydrous Na2SO4, filtered, and the
filtrate was concentrated under reduced pressure. e residue was purified by column chro-
matography using DCM/ AcOEt (5/1) as eluent affording 8 (155 mg, 78%) as a white solid.
m. p. 150–151 °C. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.73 (s, 1H), 7.62 (s, 1H),
7.58 (d, J=8.5 Hz, 1H), 7.09 (s, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.13 (d, J=5.0 Hz, 1H), 5.07 (t,
J=7.5 Hz, 1H), 3.73 (dt, J=6.7, 5.2 Hz, 1H), 2.93 (dd, J=16.9, 5.2 Hz, 1H), 2.64 (dd, J=16.9,
6.8 Hz, 1H), 2.10–1.95 (m, 2H), 1.68–1.64 (m, 1H), 1.61 (s, 3H), 1.53 (s, 3H), 1.49–1.45
(m, 1H), 1.22 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 167.5, 155.4, 130.7, 129.8,
126.8, 125.8, 124.4, 120.0, 116.0, 79.1, 67.1, 33.1, 30.6, 25.4, 22.0, 21.3, 17.4. HR-ESI-MS:
m/z 293.1389 [M+H]+ (calcd for C17H17ON4, 293.1397).
3.8. (E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborol
ane (10)
10 (9.13 g, 54%) was prepared from geranyl acetate (12.60 g, 64.28 mmol) following the
procedure described for 3.
1H NMR (400 MHz, CDCl3) δ (ppm): 5.64–5.61 (m, 2H), 2.37–1.93 (m, 5H), 1.86–1.54
(m, 6H), 1.52–1.31 (m, 4H), 1.27–1.19 (m, 12H).
3.9. (E)-Methyl 3-(3,7-dimethylocta-2,6-dien-1-yl)-4-(methoxymethoxy)benzo
ate (11)
11 (811 mg, 61%) was prepared from 10 (1.58 g, 6.0 mmol) following the procedure
described for 4.
1H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, 2H), 7.07 (d, J=9.2 Hz, 1H), 5.33–5.29 (m,
1H), 5.26 (s, 2H), 5.10 (s, 1H), 3.88 (s, 3H), 3.48 (s, 3H), 3.36 (d, J=7.3 Hz, 2H), 2.09–2.03
(m, 4H), 1.73 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H).
3.10. (E)-Methyl 3-(3,7-dimethylocta-2,6-dien-1-yl)-4-hydroxybenzoate (12)
12 (320 mg, 62%) was prepared from 11 (660 mg, 1.99 mmol) following the procedure
described for 5.
1H NMR (400 MHz, CDCl3) δ (ppm): 7.91–7.74 (m, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.13
(s, 1H), 5.32 (t, J=7.1 Hz, 1H), 5.07 (d, J=6.0 Hz, 1H), 3.88 (s, 3H), 3.40 (d, J=7.1 Hz, 2H),
2.15–2.09 (m, 4H), 1.77 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H).
3.11. (2R*,3S*)-Methyl 3-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-
6-carboxylate (13)
13 (800 mg, 80%) was prepared from 12 (1 g, 3.47 mmol) following the procedure described
for 6.
1H NMR (500 MHz, CDCl3) δ (ppm): 7.80 (d, J=6.9 Hz, 2H), 6.84 (d, J=8.9 Hz, 1H),
5.09–5.07 (m, 1H), 3.92–3.89 (m, 1H), 3.87 (s, 3H), 3.08 (dd, J=16.7, 4.6 Hz, 1H), 2.82 (dd,
J=16.7, 6.0 Hz, 1H), 2.17–2.11 (m, 2H), 1.76–1.74 (m, 1H), 1.68 (s, 3H), 1.64–1.60 (m,
1H), 1.58 (s, 3H), 1.34 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm): 166.9, 157.1, 132.3,

JouRnaL of aSian natuRaL PRoduCtS ReSeaRCH
9
132.2, 129.5, 123.7, 122.4, 118.9, 117.2, 79.7, 67.8, 51.8, 37.3, 30.9, 25.6, 21.6, 19.2, 17.6.
HR-ESI-MS: m/z 305.1733 [M+H]+ (calcd for C18H25O4, 305.1747).
3.12. (2R*,3S*)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxylic acid (14)
14 (46 mg, 98%) was prepared from 13 (49 mg, 0.16 mmol) following the procedure
described for 7.
m. p. 146–148 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.87 (d, J=7.2 Hz, 2H), 6.87 (d,
J=8.6 Hz, 1H), 5.10–5.07 (m, 1H), 3.93 (t, J=5.6 Hz, 1H), 3.10 (dd, J=16.9, 5.1 Hz, 1H),
2.85 (dd, J=16.9, 6.1 Hz, 1H), 2.18–2.11 (m, 2H), 1.67 (s, 3H), 1.64–1.62 (m, 2H), 1.59 (s,
3H), 1.36 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm): 200.6, 171.3, 157.9, 132.9, 132.4,
130.2, 123.6, 121.4, 119.0, 117.4, 79.8, 67.7, 37.3, 30.9, 25.7, 21.6, 19.2, 17.6. HR-ESI-MS:
m/z 291.1574 [M+H]+ (calcd for C17H23O4, 291.1591).
3.13. (2R*,3S*)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxamide (15)
15 (48 mg, 97%) was prepared from 14 (50 mg, 0.17 mmol) following the procedure
described for 8.
m. p. 123–125 °C. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.71 (s, 1H), 7.62 (s, 1H),
7.58 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.16 (d, J=4.9 Hz, 1H), 5.10
(t, J=7.3 Hz, 1H), 3.74 (dt, J=7.8, 5.2 Hz,1H), 2.92 (dd, J=16.6, 5.3 Hz, 1H), 2.65 (dd,
J=16.6, 7.8 Hz, 1H), 2.12–2.06 (m, 2H), 1.62 (s, 3H), 1.60–1.58 (m, 2H), 1.55 (s, 3H), 1.15
(s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.1, 155.8, 131.2, 130.0, 127.2, 125.8,
124.5, 120.2, 116.3, 79.5, 66.0, 37.6, 30.9, 25.7, 21.4, 18.7, 17.7. HR-ESI-MS: m/z 290.1735
[M+H]+ (calcd for C17H24O3 N, 290.1751).
3.14. (S)-(2S,3S)-6-Carbamoyl-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-3-
yl 2-methoxy-2-phenylacetate (16) and (S)-(2R,3R)-6-carbamoyl-2-methyl-2-(4-
Methyl-pent-3-en-1-yl)chroman-3-yl 2-methoxy-2-phenylacetate (17)
Toasolutionof8(76mg, 0.26mmol)indrydichloromethane(8ml), (S)-methoxyphenylacetic
acid (48 mg, 0.29 mmol), dicyclohexylcarbodiimide (70 mg, 0.34 mmol) and 4-(dimeth-
ylamino)pyridine (4 mg, 0.0057 mmol) were added, and the mixture was stirred at room
temperature for 1 h. en, the reaction mixture was filtered, and the filtrate was concentrated
under reduced pressure. e residue was purified by column chromatography using DCM/
AcOEt (20/1) as eluent affording 16 (44 mg, 38%) and 17 (47 mg, 41%) as colorless oils.
Compound 16:[ꢀ]2D0 +4.2 (c 0.5, MeOH); 1H NMR (600 MHz, CDCl ) δ (ppm): 7.58–7.56
3
(m, 2H), 7.38–7.36 (m, 2H), 7.34–7.32 (m, 3H), 6.86–6.84 (m, 1H), 5.05 (t, J=4.8 Hz, 1H),
4.70 (s, 1H), 4.66 (t, J=7.2 Hz, 1H), 3.36 (s, 3H), 3.12 (dd, J=17.4, 4.8 Hz, 1H), 2.87 (dd,
J=17.4, 4.7 Hz, 1H), 1.66 (m, 2H), 1.61 (s, 3H), 1.48 (s, 3H), 1.34–1.32 (m, 2H), 1.08 (s, 3H).
13C NMR (150 MHz, CDCl3) δ (ppm): 170.0, 168.9, 156.1, 135.9, 131.6, 129.8, 128.9, 128.7,
127.3, 127.1, 125.4, 123.4, 118.3, 117.3, 82.2, 77.8, 70.2, 57.1, 34.8, 28.0, 25.6, 21.5, 21.4, 17.5.
20
HR-ESI-MS: m/z 438.2258 [M+H]+ (calcd for C26H32O5 N, 438.2275). Compound 17: [α]D
+59.3 (c 1.0, MeOH); 1H NMR (600 MHz, CDCl3) δ (ppm): 7.56 (dd, 1H, J=8.4, 1.8 Hz),

10
Y.-Y. Yao et aL.
7.26–7.23 (m, 3H), 7.18–7.15 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.11 (t, J=4.4, 1.0 Hz, 1H),
5.05 (m, 1H), 4.73 (s, 1H), 3.36 (s, 3H), 2.94 (dd, J=17.4, 4.4 Hz, 1H), 2.47 (dd, J=17.4,
4.2 Hz, 1H), 2.10–2.06 (m, 2H), 1.72–1.68 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H).
13C NMR (150 MHz, CDCl3) δ (ppm): 170.1, 168.7, 155.9, 135.6, 132.2, 129.6, 128.6, 128.4,
127.1, 126.6, 125.2, 123.5, 117.9, 117.1, 82.2, 77.7, 70.2, 57.3, 35.6, 27.5, 25.7, 21.8, 21.6, 17.6.
HR-ESI-MS: m/z 438.2262 [M+H]+ (calcd for C26H32O5 N, 438.2275).
3.15. (S)-(2S,3R)-6-Carbamoyl-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-3-
yl 2-methoxy-2-phenylacetate (18) and (S)-(2R,3S)-6-carbamoyl-2-methyl-2-(4-
methylpent-3-en-1-yl)chroman-3-yl 2-methoxy-2-phenylacetate (19)
18 (30 mg, 44%) and 19 (25 mg, 37%) were prepared from 15 (45 mg, 0.16 mmol) following
the procedure described for 16.
Compound 18: [ꢀ]2D0 +13.6 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.56
(d, J=8.5 Hz, 1H), 7.30 (s, 1H), 7.26 (s, 3H), 7.23–7.21 (m, 2H), 7.21–7.19 (m, 1H), 6.84 (d,
J=8.5 Hz, 1H), 5.81 (s, 2H), 5.12 (t, J=4.7 Hz, 1H), 5.01–4.96 (m, 1H), 4.76 (s, 1H), 3.39 (s,
3H), 2.98 (dd, J=17.2, 4.3 Hz, 1H), 2.45 (dd, J=17.2, 4.8 Hz, 1H), 2.11–2.04 (m, 3H), 1.68
(s, 2H), 1.64 (s, 3H), 1.54 (s, 3H), 1.53–1.46 (m, 2H), 1.32 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ (ppm): 170.1, 168.7, 156.0, 135.7, 132.4, 129.6, 128.6, 128.5, 127.1, 126.7, 125.2,
123.2, 118.0, 117.1, 82.2, 77.7, 77.2, 77.0, 76.8, 70.1, 57.3, 37.1, 29.7, 27.5, 25.6, 21.5, 20.2,
17. 6. HR-ESI-MS: m/z 438.2264 [M+H]+ (calcd for C26H32O5 N, 438.2275). Compound 19:
[ꢀ]2D0 +74.2 (c 0.5, MeOH); 1H NMR (500 MHz, acetone-d ) δ (ppm): 7.71 (d, J=8.0 Hz, 1H),
6
7.68 (s, 1H), 7.39–7.41 (m, 2H), 7.36–7.34 (m, 3H), 7.26 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.42
(s, 1H), 5.10–5.07 (m, 1H), 4.91–4.88 (m, 1H), 4.85 (s, 1H), 3.36 (s, 3H), 3.20 (dd, J=5.5 Hz,
1H), 2.87–2.85 (m, 1H), 2.03–1.93 (m, 1H), 1.59 (s, 3H), 1.49 (s, 3H), 1.41–1.34 (m, 2H),
1.05 (s, 3H). 13C NMR (150 MHz, acetone-d6) δ (ppm): 170.4, 168.3, 156.2, 137.7, 132.0,
129.3, 129.2, 128.1, 128.1, 127.5, 124.4, 119.0, 117.3, 82.9, 78.3, 70.4, 70.4, 57.3, 37.5, 28.6,
25.6, 21.9, 19.7, 17.5. HR-ESI-MS: m/z 438.2263 [M+H]+ (calcd for C26H32O5 N: 438.2275).
3.16. (2S,3S)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxamide (20)
To a solution of 16 (20 mg, 0.046 mmol) in MeOH (2 ml), a solution of MeONa in MeOH
(25% w/w, 16 μL, 0.069 mmol) was added at 0 °C, and the mixture was stirred at room
temperature for 3 h. e reaction mixture was quenched with HCl (2 N, 1 ml), and the
product was extracted with EtOAc. e combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced
pressure. en, the crude material was purified by column chromatography using DCM/
MeOH (20/1) as eluent affording 20 (11 mg, 83%) as a colorless solid.
Compound 20: m. p. 41–43 °C. [ꢀ]2D0 −16.99 (c 0.206, MeOH); H NMR (600 MHz,
1
DMSO-d6) δ (ppm): 7.72 (s, 1H), 7.62 (s, 1H), 7.59 (dd, J=8.5, 2.0 Hz, 1H), 7.07 (s, 1H),
6.72 (d, J=8.5 Hz, 1H), 5.11 (d, J=4.8 Hz, 1H), 5.08 (t, J=7.8 Hz, 1H), 3.73 (dd, J=11.5,
5.1 Hz, 1H), 2.93 (dd, J=16.8, 5.0 Hz, 1H), 2.65 (dd, J=16.9, 6.8 Hz, 1H), 2.12–1.89 (m,
2H), 1.66–1.62 (m, 1H), 1.61 (s, 3H), 1.52 (s, 3H), 1.50–1.46 (m, 1H), 1.23 (s, 3H). 13C NMR
(150 MHz, DMSO-d6) δ (ppm): 167.5, 155.3, 130.7, 129.8, 126.8, 125.8, 124.4, 120.0, 116.0,

JouRnaL of aSian natuRaL PRoduCtS ReSeaRCH
11
79.1, 67.2, 33.0, 30.6, 25.4, 22.0, 21.3, 17.4. HR-ESI-MS: m/z 290.1740 [M+H]+ (calcd for
C17H24O3 N, 290.1751).
3.17. (2R,3R)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxamide (21)
21 (26 mg, 96%) was prepared from 17 (40 mg, 0.092 mmol) following the procedure
described for 20.
Compound 21: m. p. 158–160 °C. [ꢀ]20 +19.81 (c 0.369, MeOH); 1H NMR (600 MHz,
DMSO-d6) δ (ppm): 7.74 (s, 1H), 7.63 (d,DJ=2.2 Hz, 1H), 7.60 (dd, J=8.5, 2.2 Hz, 1H), 7.09
(s, 1H), 6.74 (d, J=8.5 Hz, 1H), 5.13 (d, J=4.8 Hz, 1H), 5.09 (t, J=7.1 Hz, 1H), 3.74 (dt,
J=6.7, 5.1 Hz,1H), 2.95 (dd, J=16.9, 5.1 Hz, 1H), 2.66 (dd, J=16.9, 6.8 Hz, 1H), 2.08–2.00
(m, 2H), 1.69–1.64 (m, 1H), 1.62 (s, 3H), 1.51 (s, 3H), 1.52–1.47 (m, 1H), 1.24 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) δ (ppm): 167.6, 155.3, 130.7, 129.8, 126.8, 125.8, 124.4, 120.0,
116.0, 79.1, 67.2, 33.1, 30.6, 25.4, 22.0, 21.3, 17.4. HR-ESI-MS: m/z 290.1741 [M+H]+ (calcd
for C17H24O3 N, 290.1751).
3.18. (2S,3R)-3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxamide (22)
22 (15 mg, 91%) was prepared from 18 (25 mg, 0.057 mmol) following the procedure
described for 20.
Compound 22: m. p. 117–119 °C. [ꢀ]2D0 −11.18 (c 0.93, MeOH); H NMR (600 MHz,
1
DMSO-d6) δ (ppm): 7.73 (s, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.60 (dd, J=8.5, 2.2 Hz, 1H), 7.09
(s, 1H), 6.74 (d, J=8.5 Hz, 1H), 5.18 (d, J=5.0 Hz, 1H), 5.11 (t, J=7.1 Hz, 1H), 3.75 (dt,
J=7.8, 5.2 Hz, 1H), 2.93 (dd, J=16.6, 5.2 Hz, 1H), 2.67 (dd, J=16.6, 7.8 Hz, 1H), 2.12–2.08
(m, 2H), 1.64 (s, 3H), 1.60–1.58 (m, 2H), 1.56 (s, 3H), 1.16 (s, 3H). 13C NMR (150 MHz,
DMSO-d6) δ (ppm): 167.5, 155.5, 130.8, 129.7, 126.9, 125.8, 124.3, 119.9, 116.0, 79.2, 65.8,
37.5, 30.8, 25.4, 21.1, 18.3, 17.4. HR-ESI-MS: m/z 290.1739 [M+H]+ (calcd for C17H24O3 N,
290.1751).
3.19. (2R,3S)-3-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)chroman-6-
carboxamide (23)
23 (10 mg, 92%) was prepared from 19 (16 mg, 0.036 mmol) following the procedure
described for 20.
Compound 23: m. p. 47–49 °C. [ꢀ]20 +10.43 (c 0.23, MeOH); H NMR (400 MHz,
1
DMSO-d6) δ (ppm): 7.72 (s, 1H), 7.63 (dD, J=2.0 Hz, 1H), 7.58 (dd, J=8.5, 2.2 Hz, 1H), 7.07
(s, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.17–5.15 (m, 1H), 5.09 (t, J=7.1 Hz, 1H), 3.73 (dt, J=7.7,
5.4 Hz,1H), 2.92 (dd, J=16.6, 5.2 Hz, 1H), 2.65 (dd, J=16.6, 7.8 Hz, 1H), 2.12–2.04 (m, 2H),
1.62 (s, 3H), 1.60–1.58 (m, 2H), 1.55 (s, 3H), 1.15 (s, 3H). 13C NMR (150 MHz, DMSO-d6)
δ (ppm): 167.5, 155.5, 130.9, 129.8, 126.9, 125.7, 124.3, 119.9, 116.0, 79.3, 65.8, 37.5, 30.8,
25.5, 21.2, 18.4, 17.5. HR-ESI-MS: m/z 290.1738 [M+H]+ (calcd for C17H24O3 N, 290.1751).

12
Y.-Y. Yao et aL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
We are grateful to the National Natural Science Foundation of China [grant number 81102321] for
financial support.
References
[1] Z.Y. You, Y.H. Wang, Z.G. Zhang, M.J. Xu, S.J. Xie, T.S. Han, L. Feng, X.G. Li, and J. Xu, Mar.
Drugs. 11, 4035 (2013).
[2] C.B. Nanthakumar, R.J. Hatley, S. Lemma, J. Gauldie, R.P. Marshall, and S.J. Macdonald, Drug
disc. 14, 693 (2015).
[3] X.J. Liu, M.J. Xu, S.T. Fan, Z. Wu, J. Li, X.M. Yang, Y.H. Wang, J. Xu, and Z.G. Zhang, Invest.
Dermatol. 133, 1351 (2013).
[4] M.J. Xu, X.J. Liu, Y.L. Zhao, D. Liu, Z.H. Xu, X.M. Lang, P. Ao, W.H. Lin, S.L. Yang, Z.G. Zhang,
and J. Xu, Mar. Drugs. 10, 639 (2012).
[5] X.Z. Jiao, Y.Y. Yao, B.B. Yang, X.Y. Liu, X.Y. Li, H.G. Yang, L. Li, J. Xu, M.J. Xu, and P. Xie, Org.
Biomol. Chem. 14, 1805 (2016).
[6] C.C. Bian, R. Yan, and X.Y. Yu, Tetrahedron. 70, 2982 (2014).
[7] S. Zhu and D.W.C. MacMillan, J. Am. Chem. Soc. 134, 10815 (2012).
[8] A. Lattanzi and A. Scettri, Synlett. 6, 942 (2002).
[9] P. Zhang, I.A. Roundtree, and J.P. Morken, Org. Lett. 14, 1416 (2012).
[10] D.O. Gerbino, S.D. Mandolesi, and H.G. Schmalz, Eur. J. Org. Chem. 23, 3964 (2009).
[11] Z. Li, W. Zhang, and H. Yamamoto, Angew. Chem. Int. Ed. 47, 7520 (2008).
[12] M. Jacolot, M. Jean, N. Tumma, A. Bondon, S. Chandrasekhar, and P. Weghe, J. Org. Chem.
78, 7169 (2013).
[13] A.O. Chong and K.B. Sharpless, J. Org. Chem. 42, 1587 (1977).
[14] E.D. Mihelich, K. Daniels, and D.J. Eickhoff, J. Am. Chem. Soc. 103, 7690 (1981).
[15] S. Inoue, M. Asami, K. Honda, K.S. Shrestha, M. Takahashi, and T. Yoshino, Synlett. 7, 679
(1988).
[16] N. Argade and M. Singh, Synthesis. 44, 3797 (2012).
[17] B.M. Trost, R.C. Bunt, and S.R. Pullay, J. Org. Chem. 59, 4202 (1994).
[18] L. Li and Y.K. Si, Chirality. 24, 987 (2012).
[19] N. Berova, L.D. Bari, and G. Pescitelli, Chem. Soc. Rev. 36, 914 (2007).