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
J. Nat. Prod. XXXX, XXX, XXX−XXX