Total Syntheses of (R)-Strongylodiols C and D

Article abstract of DOI:10.1021/acs.jnatprod.5b00713

The first total syntheses of two marine natural products, (R)-strongylodiols C and D, with 99% ee were achieved. The key steps of the strategy include the zipper reaction of an alkyne, the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed with Trost's ProPhenol ligand, and the Cadiot-Chodkiewicz cross-coupling reaction of a chiral propargylic alcohol with a bromoalkyne.

Full text of DOI:10.1021/acs.jnatprod.5b00713

Note
pubs.acs.org/jnp
Total Syntheses of (R)‑Strongylodiols C and D
Feipeng Liu, Jiangchun Zhong, Shuoning Li, Minyan Li, Lin Wu, Qian Wang, Jianyou Mao, Shikuo Liu,
Bing Zheng, Min Wang, and Qinghua Bian*
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, People’s Republic of
China
S
* Supporting Information
ABSTRACT: The first total syntheses of two marine natural products, (R)-
strongylodiols C and D, with 99% ee were achieved. The key steps of the strategy
include the zipper reaction of an alkyne, the asymmetric alkynylation of an
unsaturated aliphatic aldehyde catalyzed with Trost’s ProPhenol ligand, and the
Cadiot−Chodkiewicz cross-coupling reaction of a chiral propargylic alcohol with a
bromoalkyne.
ong-chain acetylenic alcohols are important marine natural
products,1 which have been found to show many biological
enantioselectivity. Therefore, it remains a challenge to search
for more efficient and convenient asymmetric syntheses of
these acetylenic alcohols. The enantioselective addition of
commercial terminal alkynes to aldehydes is the most
convenient protocol to obtain chiral propargyl alcohols.9a,b
Furthermore, no examples of the syntheses of strongylodiols C
and D have been reported. Herein, we disclose the first total
syntheses of (R)-strongylodiols C (1) and D (2) with 99% ee
and demonstrate that the asymmetric enantioselective addition
of terminal alkynes to aldehydes can construct the chiral
propargylic alcohol unit of long-chain acetylenic alcohols.
The retrosynthetic analysis of (R)-strongylodiol C (1) is
outlined in Figure 1. The target long-chain acetylenic alcohol 1
can be formed via the Cadiot−Chodkiewicz cross-coupling
reaction of chiral propargylic alcohol 19 with 3-bromoprop-2-
yn-1-ol. The enantioselective addition of trimethylsilylacetylene
to olefinic aldehyde 16 was envisioned to yield the key chiral
intermediate 19. Olefinic aldehyde 16 can be obtained by
partial reduction and oxidation of acetylenic alcohol 14, which
would be achieved via the coupling of terminal alkyne 12 with
alkyl iodide 9. Terminal alkyne 12 would be derived from the
zipper reaction of alkynol 11. Due to the structural similarity
with (R)-strongylodiol C (1), (R)-strongylodiol D (2) can be
prepared through a similar approach.
L
activities such as antibacterial,2 antitumor,3 and neuritogenic
effects.4 Strongylodiols C and D were both isolated from an
Okinawan marine sponge of the genus Strongylophora, and their
structures were elucidated based on spectroscopic analysis.3,5
They were found to exist as enantiomeric mixtures (R/S ratio
84:16 for strongylodiol C and 95:5 for strongylodiol D)
through application of the modified Mosher’s method.3,5
Recently Ojika and co-workers reported that these compounds
induced nerve growth factor (NGF)-like neuronal differ-
entiation of PC12 cells6 and showed an inhibitory effect on
platelet-derived growth factor (PDGF)-induced DNA syn-
thesis.7 In addition, strongylodiol C was found to exhibit
cytotoxic activity against human T lymphocyte leukemia
(MOLT-4) tumor cells.3
Our synthesis began with the preparation of alkyl iodide 9
(Scheme 1), which served as the key building block for both
(R)-strongylodiols C and D. Simply heating α,ω-diol 3 and
concentrated hydrobromic acid in toluene at reflux gave
monobromo alcohol 4 in 86% yield. 7-Bromoheptanoic acid
5 was obtained smoothly via the oxidation of 4 with
concentrated HNO3. Subsequent esterification of 5 with
MeOH furnished ω-bromo ester 6 in 91% yield. 8-Bromo-2-
methyloctan-2-ol (7) was formed from the addition of
CH3MgBr to the ester 6 in 92% yield. After dehydration with
Strongylodiols A and B, two analogues of strongylodiols C
and D, were also isolated from an Okinawan marine sponge of
the genus Strongylophora.3 A number of enantioselective
syntheses of these two acetylenic alcohols have been reported,
and the main asymmetric synthetic methods involved the
addition of 1,3-diynes to aldehydes by Trost,8 Carreira,8b and
our group8c or the reduction of ynones.8d However, these
strategies tended to use lengthy sequences or 1,3-diynes that
required prior preparation or gave the target product with low
Received: August 11, 2015
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.5b00713
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
Scheme 2. Synthesis of Alkynol 14
Scheme 3. Synthesis of (R)-Strongylodiol C (1)
Figure 1. Retrosynthetic analysis of (R)-strongylodiol C (1).
Scheme 1. Synthesis of Alkyl Iodide 9
reduction of alkynol 14 was achieved and afforded (Z)-19-
methylicos-11-en-1-ol (15) as a single product in 98% yield
with Brown’s P2−Ni catalyst, followed by the oxidation to
olefinic aldehyde 16 almost quantitatively (98% yield) with
iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO).12 Initial studies showed that aldehyde 16 was a
good substrate in the enantioseletive addition with trimethylsi-
lylacetylene using 20 mol % of the (S,S)-ProPhenol ligand and
Me2Zn, which provided (R,Z)-21-methyl-1-(trimethylsilyl)-
docos-13-en-1-yn-3-ol (17) in 74% yield and 84% ee.13 The
enantiomeric purity of enynic alcohol 17 was determined by
HPLC analysis of its 3,5-dinitrobenzoate 18. Furthermore, slow
recrystallization of 18 from n-hexane−diethyl ether (5:1) could
improve the optical purity to 99% ee.14 The final in situ
desilylation and methanolysis of 18 with potassium carbonate
and MeOH afforded enynic alcohol 19 in 98% yield, which was
engaged in a Cadiot−Chodkiewicz cross-coupling reaction with
3-bromoprop-2-yn-1-ol to give the target (R)-strongylodiol C
(1) in 93% yield and 99% ee.15 The optical purity of 1 was also
measured on chiral-phase HPLC analysis of its bis(4-
bromobenzoate).16 The NMR spectroscopic data and specific
p-toluenesulfonic acid and reduction with H2 over Pd/C, the ω-
bromo alcohol 7 was converted to 1-bromo-7-methyloctane (8)
in 86% yield over the two steps. Finally, alkyl bromide 8 was
subjected to NaI in acetone to afford 1-iodo-7-methyloctane
(9) in 98% yield via a Finkelstein reaction.10
With the main intermediate 9 in hand, we next focused on
the synthesis of another important fragment, alkynol 14
(Scheme 2). The alkylation of propargyl alcohol 10 with 1-
bromononane in the presence of n-BuLi and HMPA gave
dodec-2-yn-1-ol (11) in 94% yield. The zipper reaction of
alkynol 11 with NaH11 and the protection of the resulting
alcohol with dihydropyran proceeded efficiently to furnish the
desired terminal alkyne 12 in 84% yield. The alkylation of
terminal alkyne 12 with alkyl iodide 9 generated the THP ether
13 in 91% yield. The final deprotection with p-toluenesulfonic
acid afforded the corresponding alkynol 14 in 98% yield.
Having accessed building block 14, the asymmetric synthesis
of (R)-strongylodiol C (1) was studied (Scheme 3). The partial
B
DOI: 10.1021/acs.jnatprod.5b00713
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
rotation of synthetic chiral acetylenic alcohol 1 ([α]20D −7.3 (c
1.0, CHCl3)) were consistent with those of the natural (R)-
strongylodiol C ([α]22D −7.5 (c 0.093, CHCl3)).3 To search for
a more concise synthesis, we tried the asymmetric addition of
methyl propiolate to olefinic aldehyde 16 with the (S,S)-
ProPhenol ligand and Me2Zn.17 Fortunately, 99% ee enynic
ester 17′ was obtained. Decarboxylation involving saponifica-
tion with LiOH and treatment with CuCl gave enynic alcohol
19 in 73% yield. The final Cadiot−Chodkiewicz cross-coupling
with 3-bromoprop-2-yn-1-ol also afforded almost optically pure
(R)-strongylodiol C (94% yield, 99% ee).15
In summary, we have accomplished the total syntheses of
marine natural products (R)-strongylodiols C (1) and D (2)
with high optical purity (99% ee) for the first time. Central to
our approach were a zipper reaction of an alkyne to prepare the
terminal alkyne, the asymmetric alkynylation of an aliphatic
aldehyde catalyzed with Trost’s ProPhenol ligand to construct
the chiral propargylic alcohol, and the Cadiot−Chodkiewicz
cross-coupling reaction of a chiral propargylic alcohol with a
bromoalkyne to obtain the long-chain acetylenic alcohols.
These enantioselective syntheses further confirmed the
structures of these two natural products.
As depicted in Scheme 4, the synthesis of (R)-strongylodiol
D commenced with alkynol 14, which was oxidized to
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were
obtained on a Stuart-SMP3Melt-Temp apparatus without correction.
Optical rotations were measured on a Perkin Elmer 341 polarimeter.
NMR spectra were collected on a Bruker DP-X300 MHz
spectrometer. Chemical shifts were reported in ppm relative to
Scheme 4. Synthesis of (R)-Strongylodiol D (2)
1
internal tetramethylsilane (TMS) for H NMR (TMS δ = 0.00 ppm)
and to CDCl3 for 13C NMR (CDCl3 δ = 77.00 ppm). High-resolution
mass spectra (HRMS) were recorded on an Agilent instrument using
the TOF MS technique. Enantiomeric excesses (ee) were determined
on an Agilent 1200 HPLC system using an R&C OD chiral-phase
column and elution with n-hexane and 2-propanol. All reactions were
carried out under a dry argon atmosphere. Solvents were dried
according to standard procedures and distilled before use. Unless
otherwise stated, all chemicals were commercially available and used
without further purification.
Synthesis of (R,Z)-24-Methylpentacosa-16-en-2,4-diyne-1,6-
diol ((R)-Strongylodiol C, 1) (CAS 320717-32-6). To a stirred
solution of n-BuNH2 (0.5 mL) and distilled H2O (1 mL) was added
copper(I) chloride (10 mg, 0.10 mml, 0.2 equiv) at 0 °C under argon,
which resulted in a deep blue solution. A few crystals of NH2OH·HCl
were added to discharge the blue color, and a solution of enynic
alcohol 19 (167 mg, 0.50 mmol) in CH2Cl2 (2 mL) was added via
syringe at the same temperature. Then 3-bromoprop-2-yn-1-ol (74
mg, 0.55 mmol, 1.1 equiv) was added slowly. The reaction mixture was
warmed to room temperature and stirred for 30 min. A few crystals of
NH2OH·HCl were added occasionally to prevent the solution from
turning green or blue throughout the reaction. Upon completion, the
reaction solution was extracted with CH2Cl2 (2 × 10 mL). The
combined organic phases were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (n-hexane−ethyl acetate, 5:1) to furnish
(R)-strongylodiol C (1) (180 mg, 93% yield, 99% ee, measured on
chiral-phase HPLC analysis of its bis(4-bromobenzoate)) as a colorless
oil: [α]20D −7.3 (c 1.0, CHCl3), lit.3 [α]22D −7.5 (c 0.093, CHCl3); 1H
NMR (300 MHz, CDCl3) δH 5.37−5.33 (m, 2H), 4.46−4.40 (dd, J =
12.1, 6.2 Hz, 1H), 4.35 (d, J = 5.6 Hz, 2H), 2.11 (d, J = 5.2 Hz, 1H)
2.02−1.98 (m, 5H), 1.76−1.68 (m, 2H), 1.56−1.39 (m, 3H), 1.28−
1.14 (m, 22H), 0.86 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δC 129.88, 129.81, 80.5, 77.6, 69.7, 68.8, 62.7, 51.2, 39.0, 37.4, 29.77,
29.73, 29.72, 29.51, 29.50, 29.48, 29.29, 29.27, 29.2, 27.9, 27.3, 27.2,
25.0, 22.6; HRMS (APCI-TOF) m/z 371.3326 [MH+ − H2O]+ (calcd
for C26H43O, 371.3314).
acetylenic aldehyde 20 in 98% yield with iodobenzene diacetate
and TEMPO.12 An initial attempt was the Zn-(S,S)-ProPhenol
asymmetric addition of trimethylsilylacetylene to aldehyde 20,
which delivered (R)-21-methyl-1-(trimethylsilyl)docosa-1,13-
diyn-3-ol (21) in 78% yield and 85% ee.13 The optical purity
of 21 was measured and improved to 99% ee via its 3,5-
dinitrobenzoate 22.14 Removal of the trimethylsilyl and 3,5-
dinitrobenzoyl groups from 22 proceeded smoothly with
potassium carbonate and MeOH to obtain chiral propargylic
alcohol 23. Final Cadiot−Chodkiewicz cross-coupling of 23
with 3-bromoprop-2-yn-1-ol gave almost optically pure (99%
ee) (R)-strongylodiol D (2) in 93% yield.15,16 Furthermore, the
Synthesis of (R)-24-Methylpentacosa-2,4,16-triyne-1,6-diol
((R)-Strongylodiol D, 2) (CAS 334973-93-2). According to a
similar procedure to that described above for (R)-strongylodiol C (1),
the cross-coupling of chiral propargyl alcohol 23 (166 mg, 0.50 mmol)
with 3-bromoprop-2-yn-1-ol (74 mg, 0.55 mmol) afforded (R)-
strongylodiol D (2) (179 mg, 93% yield, 99% ee, measured on chiral-
phase HPLC analysis of its bis(4-bromobenzoate)) as a white solid:
mp 43−44 °C; [α]20 −7.0 (c 1.3, CHCl3), lit.5 [α]25 −8.0 (c 0.56,
specific rotation measured for 2 ([α]20 −7.0 (c 1.3, CHCl3))
D
was in agreement with the value of natural (R)-strongylodiol D
([α]25 −8.0 (c 0.56, CHCl3, R/S ratio 95:5)).5 The synthetic
D
route to (R)-strongylodiol D (2) was optimized as for the
synthesis of (R)-strongylodiol C (1). Acetylenic ester 21′ was
obtained in 97% ee via Zn-(S,S)-ProPhenol asymmetric
addition of methyl propiolate to aldehyde 20.17 Subsequent
decarboxylation furnished chiral propargylic alcohol 23 in 73%
yield, which was coupled with 3-bromoprop-2-yn-1-ol to give
(R)-strongylodiol D (92% yield, 97% ee).15
D
D
CHCl3, R/S ratio 95:5); 1H NMR (300 MHz, CDCl3) δH 4.43 (dd, J =
12.3, 6.5 Hz, 1H), 4.35 (d, J = 6.0 Hz, 2H), 2.16−2.10 (m, 5H), 2.05−
1.99 (m, 1H), 1.76−1.68 (m, 2H), 1.54−1.24 (m, 23H), 1.19−1.15
(m, 2H), 0.86 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δC
80.5, 80.3, 80.2, 77.5, 69.8, 68.8, 62.8, 51.4, 39.0, 37.4, 29.4, 29.2, 29.1,
C
DOI: 10.1021/acs.jnatprod.5b00713
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
28.9, 28.8, 27.9, 27.3, 25.0, 22.6, 18.7; HRMS (APCI-TOF) m/z
369.3174 [MH+ − H2O]+ (calcd for C26H41O, 369.3157).
(16) The bis-bromobenzoates of 1 and 2 were prepared for the
determination of the enantiomeric excess, as the ester derivatives are
more readily separable by chiral-phase HPLC.
(17) Trost, B. M.; Quintard, A. Org. Lett. 2012, 14, 4698−4700.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.5b00713.
■
S
Experimental procedures and characterization data for
the bis-bromobenzoates of 1 and 2, 4−9, and 11−23;
1
copies of H and 13C NMR spectra of compounds 1, 2,
and the bis-bromobenzoates of 1 and 2, 4−9, and 11−
23; HPLC chromatography of the bis-bromobenzoates of
1 and 2, 17′, 18, 21′, and 22 (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: bianqinghua@cau.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank New Century Excellent Talents in University
(NCET-12-0528) and the National Key Technology Research
and Development Program (No. 2015BAK45B01) for the
financial support.
REFERENCES
■
(1) Zhou, Z.-F.; Menna, M.; Cai, Y.-S.; Guo, Y.-W. Chem. Rev. 2015,
115, 1543−1596.
(2) Ankisetty, S.; Slattery, M. Mar. Drugs 2012, 10, 1037−1043.
(3) 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.
(4) Aoki, S.; Matsui, K.; Wei, H.; Murakami, N.; Kobayashi, M.
Tetrahedron 2002, 58, 5417−5422.
(5) Watanabe, K.; Tsuda, Y.; Hamada, M.; Omori, M.; Mori, G.;
Iguchi, K.; Naoki, H.; Fujita, T.; Van Soest, R. W. M. J. Nat. Prod.
2005, 68, 1001−1005.
(6) Horikawa, K.; Yagyu, T.; Yoshioka, Y.; Fujiwara, T.; Kanamoto,
A.; Okamoto, T.; Ojika, M. Tetrahedron 2013, 69, 101−106.
(7) Choi, B.-K.; Cha, B.-Y.; Yagyu, T.; Woo, J.-T.; Ojika, M. Bioorg.
Med. Chem. 2013, 21, 1804−1810.
(8) Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010,
132, 5186−5192. (b) Reber, S.; Knopfel, T. F.; Carreira, E. M.
̈
Tetrahedron 2003, 59, 6813−6817. (c) 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. (d) Kirkham, J. E. D.; Courtney,
T. D. L.; Lee, V.; Baldwin, J. E. Tetrahedron Lett. 2004, 45, 5645−
5647.
(9) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
̈
2000, 122, 1806−1807. (b) Trost, B. M.; Bartlett, M. J. Acc. Chem. Res.
2015, 48, 688−701.
(10) Finkelstein, H. Ber. Dtsch. Chem. Ges. 1910, 43, 1528−1532.
(11) Santandrea, J.; Bed
3892−3895.
́
ard, A.-C.; Collins, S. K. Org. Lett. 2014, 16,
(12) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974−6977.
(13) Trost, B. M.; Quintard, A. Angew. Chem., Int. Ed. 2012, 51,
6704−6708.
(14) Yang, Y.-Q.; Li, S.-N.; Zhong, J.-C.; Zhou, Y.; Zeng, H.-Z.;
Duan, H.-J.; Bian, Q.-H.; Wang, M. Tetrahedron: Asymmetry 2015, 26,
361−366.
(15) Chodkiewicz, W.; Cadiot, P. Compt. Rend. 1955, 241, 1055−
1057.
D
DOI: 10.1021/acs.jnatprod.5b00713
J. Nat. Prod. XXXX, XXX, XXX−XXX