Total syntheses of rhodiolosides A and D and of sachalinols A-C

Article abstract of DOI:10.1002/ejoc.201001315

The glucosylated monoterpenoids (-)-rhodioloside A and (-)-rhodioloside D from the roseroot (Rhodiola rosea) have been synthesized for the first time. Glucosylation with tetrapivaloylglucosyl bromide proved superior to the use of tetraacetylglucosyl bromi

Full text of DOI:10.1002/ejoc.201001315

FULL PAPER
DOI: 10.1002/ejoc.201001315
Total Syntheses of Rhodiolosides A and D and of Sachalinols A–C
Kristina Simon,[a] Peter G. Jones,[a] and Thomas Lindel*[a]
Dedicated to Professor Henning Hopf on the occasion of his 70th birthday
Keywords: Glucosylation / Natural products / Rosiridol / Terpenoids / Oxygen heterocycles / Total synthesis
The glucosylated monoterpenoids (–)-rhodioloside A and (–)-
rhodioloside D from the roseroot (Rhodiola rosea) have been
synthesized for the first time. Glucosylation with tetra-
pivaloylglucosyl bromide proved superior to the use of tet-
raacetylglucosyl bromide or glucosyl iodides. Acid-catalyzed
cyclization of a homoglycidol-type geraniol derivative af-
forded the monoterpenoid tetrahydrofuran (+)-sachalinol C
from Rhodiola sachalinensis. The absolute configuration of
(+)-sachalinol C requires revision. (–)-Sachalinol A and (–)-
sachalinol B were also obtained.
Introduction
Secondary metabolites from the medicinal plant Rhodi-
ola rosea (Crassulaceae, roseroot) include hydroxylated and
glycosylated derivatives of the monoterpenoid (–)-rosiridol
(1, Figure 1, 4-hydroxygeraniol).[1–3] (–)-Rosiridol itself also
occurs in the leaves of Cunila spicata (Lamiaceae)[4] and in
the petals of the rose Rosa damascena.[5] (–)-Rosiridin (2) is
the β-glucosylated analogue of (–)-rosiridol (1)[6] and has
recently been identified as an inhibitor of monoamine ox-
idase B (MAO B), which is involved in neurodegenerative
diseases.[7] After contradictory assignments, the stereo-
chemistry of the monoterpenoid sections of (–)-rosiridol (1)
and (–)-rosiridin (2) was established as (4S) by total synthe-
sis[8,9] and by reinvestigation of the isolated natural prod-
ucts.[10,11]
In this paper we describe the first total syntheses of (–)-
rhodioloside A (4), (–)-rhodioloside D (5, Scheme 4, be-
low), (–)-sachalinol B (6, Scheme 5, below), and (+)-sachal-
inol C (7, Scheme 5, below). (–)-Rhodioloside A (4) from
Rhodiola sachalinensis is related to (–)-rosiridin (2) by ter-
minal hydroxylation at C-8. The tertiary alcohol (–)-rhodi-
oloside D (5) is the monoglucosylated form of (–)-sachal-
inol A (3, 4,7-dihydroxygeraniol).[12] Sachalinols B (6) and
C (7, vide infra) from Rhodiola sachalinensis each feature a
tetrahydrofuran ring and may arise by epoxidation of the
terminal double bond of (–)-rosiridol (1), followed by cycli-
zation.[6] The monoterpenoid tetrahydrofuran systems of
sachalinols B and C also occur in coumarin derivatives,
Figure 1. Sachalinols and rhodiolosides: oxygenated derivatives of
(–)-rosiridol (1) and (–)-rosiridin (2).
from Mutisia orbignyana (Asteraceae), for example.[13]
Closely related are the pantofuranoids D–F from the Ant-
arctic red alga Pantoneura plocamioides[14] and the further
oxidized geranylated coumarin derivative geiparvarin.
Results and Discussion
The starting material 8 (Scheme 1) was synthesized as
described earlier.[9] For the enantioselective reduction of 8,
we replaced DIP-Cl by the CBS reagent [(+)-(R)-2-methyl-
CBS-oxazaborolidine],[15] which provided the secondary
alcohol 9 in a higher yield (66% in comparison with 44%)
though with a slightly lower ee (90% in comparison with
94%). Mosher analysis[16] of 9 confirmed the stereochemi-
cal outcome of the CBS reduction, with the prenyl group
functioning as the smaller substituent.
[a] Institutes of Organic, Inorganic, and Analytical Chemistry,
Technische Universität Braunschweig,
Riley oxidation[17] of 10 with SeO2/TBHP afforded a
mixture of the (E)-allylic alcohol 11 (19–32% yield) and the
corresponding (E)-aldehyde (12, 6–32%), which was re-
duced back to the alcohol 11 with NaBH4/EtOH. Over two
Hagenring 30, 38106 Braunschweig, Germany
Fax: +49-531-391-7744
E-mail: th.lindel@tu-bs.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001315.
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FULL PAPER
(–)-Rhodioloside D (5) and (–)-sachalinol A (3) share
oxygenation at C-7. The epoxidized building block 17 was
therefore synthesized by mCPBA epoxidation of the ter-
minal double bond of 10 (Scheme 2).
Scheme 2. Synthesis of (–)-sachalinol A (3) through Super-Hy-
dride® reduction of the epoxide 17. Structure of the (–)-sachal-
inol A dihydrate in the crystal.
The epoxide 17 (88%, 1:1.3 mixture of diastereomers)
was reduced with LiBEt3H (5 equiv.) to afford the diol 18
in 77% yield. The reduction was accompanied by deacet-
ylation, which was faster than the subsequent regioselective
epoxide opening. Alternative use of NaBH4 (up to
30 equiv.) led to incomplete oxirane reduction (24%) and
afforded substantial amounts (70%) of the deacetylated ep-
oxide. Desilylation of 18 afforded the natural product (–)-
sachalinol A (3), exhibiting a negative optical rotation
{[α]2D4 = –12.8 (c = 1.0, MeOH)}, similar to that reported
Scheme 1. Synthesis of (–)-rhodioloside A (4) through CBS re-
duction of the ketone 8.
for the natural product {[α]D25
= –17.1 (c = 0.17,
MeOH)}.[3,6]
Originally, Kadota et al. proposed that (–)-sachalinol A
steps, the average yield of alcohol 11 ranged from 27 to was the (4R) enantiomer of structure 3.[6] Koike et al. reas-
45% with recovered starting material. signed the absolute configuration of (–)-sachalinol A (3) as
After protecting group manipulation, Koenigs–Knorr (4S).[11] Díez et al. reported the first total synthesis of 3 via
glucosylation of 13 (Scheme 1) with tetraacetylglucosyl an α,β-unsaturated nitrile intermediate.[18] X-ray analysis of
bromide (14) afforded pentaacetylrhodioloside A (15) in a crystal of our synthesized material obtained from chloro-
modest yield (36%, 45% based on recovered starting mate- form provided independent verification of the absolute con-
rial). Separation of the glucosylated product 15 and the pre- figuration of (–)-sachalinol A (3), based on the anomalous
cursor alcohol 13 by normal-phase chromatography proved scattering of the oxygen atoms. The compound crystallizes
to be tedious, but workup was facile at the level of the de- as a dihydrate. The atom sequence O2–C4–C5–C6–C7–C9
acetylated products (–)-rhodioloside A (4) and (–)-rhodi- displays an all-trans geometry. All hydrogen atoms of the
olol A (16), synthesized by methanolysis of a mixture of 15 water molecules and OH groups function as donors in clas-
and 13. The aglycon (–)-rhodiolol A (16) had originally sical hydrogen bonds, forming a layer structure parallel to
been obtained by Koike et al. by naringinase-catalyzed en- the bc plane with hydrophilic regions at z = 0, 1, etc.
zymatic hydrolysis of (–)-rhodioloside A (4).[12]
(Scheme 2).
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Total Syntheses of Rhodiolosides A and D and of Sachalinols A–C
Aiming at a more efficient synthesis of glucosylated
(–)-rhodioloside D (5), we compared glucosyl bromides and
iodides in the forms of their tetraacetylated and tetra-
pivaloylated derivatives. Glucosyl iodides can be superior
to the corresponding bromides.[19] We treated the model
compound geraniol (19) with peracetylated α-glucosyl
iodide (21, R = Ac, X = I)[20] in the presence of Ag2CO3 in
Et2O and obtained the β-glucoside 23 (R = Ac, Scheme 3)
in a yield of 53%, in comparison with 34% when the gluco-
syl bromide 14 was employed. Kunz et al. reported that
pivaloylated glucosyl bromides are superior to acetylated
building blocks, because orthoester formation is sup-
pressed.[21] For pivaloylated glucosyl donors we obtained
better yields with the glucosyl bromide 20 (67%) than with
the iodide 22 (48%). The new glucosyl iodide 22 (R = Piv,
X = I) was obtained by treatment of pentapivaloyl glucose
with I2/Me6Si2 in DCM.
Scheme 4. Synthesis of (–)-rhodioloside D (5) by use of the pivaloyl-
ated glucosyl donor 20.
chemistry. The 13C NMR spectroscopic data for 6 and 7
agree with those reported by Kadota et al. for sachalinols B
and C, respectively. In the NOESY spectrum of sachal-
inol C (7) we observe a correlation between 4-H and 6-H,
whereas this is not the case for its C-6 epimer 6. We can
thus confirm Kadota’s assignments of the relative stereo-
chemistry of sachalinols B and C, which were originally
based on pyridine-induced shifts of the NMR signals of the
protons cis to the hydroxy group on change of the solvent
from [D4]methanol to [D5]pyridine.[6]
Scheme 3. Study on the yields of geraniol β-glucosylation.
The diol 25 was prepared from 18 in two steps and was
then treated with tetrapivaloylglucosyl bromide (20) in the
presence of Ag2CO3 in Et2O (Scheme 4). Glucosylation
proceeded with 71% yield and complete β-diastereoselectiv-
ity, whereas with the tetraacetylglucosyl bromide (14),
yields of only 20–30% were reached. From a practical point
of view, monitoring of the glucosylation reaction by TLC
was easier in the case of the pivaloyl-protected glucosyl do-
nor 20. Deprotection of 26 with NaOMe/MeOH provided
the natural product 5.
For the synthesis of the tetrahydrofurans sachalinol B (6)
and C (7), the epoxide 17 was deacetylated by methanolysis
to afford the homoglycidol 27 as a mixture of diastereomers
(dr 1:1.3, Scheme 5). Treatment of 27 with CSA (0.4 equiv.)
in DCM led to epoxide opening and quantitative formation
of the tetrahydrofuran ring to afford the diastereomers 28
and 29, which were separated by semipreparative normal-
phase HPLC.[22] Desilylation of 28 and 29 by use of TBAF
liberated the target compounds 6 and 7 in 80% and 89%
yields, respectively. Nonstereoselective syntheses of 3-hy-
droxy-2,2-dimethyltetrahydrofurans have employed SeO2
oxidation of terminally epoxidized geraniol derivatives at C-
4 under acidic conditions.[23] Our pathway is stereoselective.
The availability of sachalinols B and C by total synthesis
Scheme 5. Cyclization to (–)-sachalinol B (6) and (+)-sachalinol C
allowed us to analyze their relative and absolute stereo- (7). Compounds 28 and 29 were separated by normal-phase HPLC.
Eur. J. Org. Chem. 2011, 1493–1503
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The picture is different with regard to the absolute
stereochemistry of sachalinols B and C. Synthetic (+)-sach-
alinol C exhibits a positive optical rotation {7, [α]2D9 = +47.0
(c = 0.06, MeOH)}, which is in agreement with the value
reported {[α]2D5 = +40.2 (c = 0.05, in MeOH)} for the natu-
ral product (+)-sachalinol C.[6] Because the configuration of
our synthetic product at C-4 is known, the absolute config-
uration of the natural product (+)-sachalinol C (7) must be
revised to (4S), as has already been necessary for (–)-sachal-
inol A (3, vide supra) and (–)-rosiridol (1).[9] However, the
sense of rotation of the synthesized (–)-sachalinol B {6,
[α]2D4 = –29.2 (c = 0.24, MeOH)} is the opposite of that of
the natural product (+)-sachalinol B {ent-6, [α]2D5 = +60.3 (c
= 0.07, in MeOH)} reported by Kadota.[6]
To verify that the synthesized compounds 6 and 7 are
epimeric only at C-6 and share the same configuration at
C-4, we converted the mixture of the TBDPS-protected pre-
cursors 28 and 29 into the corresponding mixtures of (R)-
and (S)-Mosher esters. In both cases, mixtures of only two
products were obtained, which confirms that the dia-
stereomers 28 and 29 are enantiomerically pure and that
no partial racemization had occurred on formation of the
Experimental Section
General: NMR spectra were taken with Bruker DRX 400, Bruker
AV III 400 (400.1 MHz for 1H, 100.6 MHz for 13C), and Bruker
AV II 600 (600.1 MHz for 1H; 150.9 MHz for 13C) instruments, ref-
erenced to the solvent signal or TMS. All measurements were car-
ried out at 300 K. Mass spectra were obtained with LTQ Orbitrap
Velos, Thermo Finnigan LTQ FT, Thermo Finnigan MAT95, and
Finnigan MAT 95 XLT spectrometers. IR spectra were recorded
with a Bruker Tensor 27 spectrometer. UV/Vis spectra were mea-
sured with a Varian Cary 100 Bio UV/Vis spectrometer. Optical ro-
tations were measured with a Dr. Kernchen Propol automatic pola-
rimeter. Melting points were measured with a Büchi 530 melting
point apparatus. Chemicals were purchased from commercial sup-
pliers and used without further purification. Silica gel 60 (40–
63 μm, Merck) was used for column chromatography. HPLC sepa-
rations were carried out with a Merck Hitachi L-6200 intelligent
pump system, fitted with a LiChrosorb Si-60 column (5 μm).
(2E)-1-(tert-Butyldiphenylsilanyloxy)-3,7-dimethylocta-2,6-dien-4-
one (8): IBX (2.06 g, 7.3 mmol, 1.5 equiv.) was dissolved in DMSO
(10 mL). After 15 min, a solution of rac-9 (2.00 g, 4.9 mmol,
1.0 equiv.) in DMSO (5 mL) was added, and the resulting solution
was stirred at room temp. for 15 h. The reaction mixture was di-
luted with water, and the resulting precipitate was filtered and
tetrahydrofuran ring. The Mosher esters exhibited positive washed with water and petroleum ether. The filtrate was extracted
with petroleum ether, and the combined organic layers were washed
with an aqueous solution of NaHCO3 and dried with MgSO4.
Evaporation of the solvent yielded the ketone 8 (1.80 g, 4.4 mmol,
(28) and negative (29) Δδ values (δ(S)-ester – δ(R)-ester) for the
methylene protons 5-Ha and 5-Hb, meaning that dia-
stereomers 28 and 29 are epimeric at C-6, but not at C-
4.[24] It can be assumed that desilylation does not lead to
epimerization of the stereogenic centers.
On the basis of the available data, the natural products
(+)-sachalinol B (ent-6) and (+)-sachalinol C (7) appear to
have opposite configurations at C-4. The deviation of the
absolute values of optical rotation might be a consequence
1
90%) as a yellow oil. Rf (petroleum ether/EtOAc, 20:1) = 0.40. H
NMR (300 MHz, CDCl3): δ = 7.69–7.67 (m, 4 H, Ph-o-H), 7.47–
7.37 (m, 6 H, Ph-m-H, Ph-p-H), 6.71–6.68 (m, 1 H, OCH2CH),
5.31–5.27 [m, 1 H, (CH3)2CCH], 4.44 (d, 3J = 5.3 Hz, 2 H,
OCH2CH), 3.34 (d, 3J = 7.0 Hz, 2 H, CH2CHO), 1.75 [s, 3 H,
(CH3)2C], 1.66 [s, 3 H, (CH3)2C], 1.56 (s, 3 H, CCH3), 1.08 [s, 9 H,
(CH3)3C] ppm. 13C NMR (75 MHz, CDCl3): δ = 200.0 (1 C, CO),
of the lower concentration chosen by Kadota on measure- 141.7 (1 C, OCH2CH), 135.6 [1 C, (CH3C)], 135.5 (4 C, o-CPh),
134.7 [1 C, (CH3)2C], 133.2 (2 C, ipso-CPh), 129.8 (2 C, p-CPh),
127.8 (4 C, m-CPh), 117.1 [1 C, (CH3)2CCH], 61.7 (1 C, OCH2CH),
37.3 (1 C, CH2CHO), 26.8 [3 C, (CH3)3C], 25.8 [1 C, (CH3)2C],
19.1 [1 C, (CH3)3C], 18.1 [1 C, (CH3)2C], 11.5 (1 C, CH3C) ppm.
ment.
With regard to the biosynthesis of (+)-sachalinol B (ent-
6), one could speculate that consumption of (–)-rosiridol (1)
by glucosylation to produce the by far major metabolite
(–)-rosiridin (2) would enrich a hitherto unidentified (+)-
rosiridol. Reagent-controlled diastereoselective epoxidation
of the terminal double bonds of (–)-rosiridol and (+)-rosir-
idol in the remaining mixture, followed by cyclization to the
tetrahydrofuran system, would generate (+)-sachalinol B
(ent-6) and (+)-sachalinol C (7), respectively, with opposite
configurations at C-4, but identical configurations at C-6.
IR (ATR): ν = 1674 (m), 1428 (m), 1106 (s), 1055 (s), 822 (m), 738
˜
(m), 700 (s), 612 (m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (4.46),
218 (4.33), 240 (3.89) nm. MS (FAB): m/z (%) = 407 (14), 405 (16),
349 (16), 291 (13), 239 (12), 199 (74), 135 (100). HRMS (FAB):
calcd. for C26H35O2Si [M + H]+ 407.2406; found 407.2370.
(2E,4S)-1-(tert-Butyldiphenylsilanyloxy)-3,7-dimethylocta-2,6-dien-
4-ol (9): Under Ar, the ketone 8 (300 mg, 0.73 mmol, 1.0 equiv.)
was dissolved in toluene (10 mL), and the solution was cooled to
–60 °C. (+)-(R)-2-Methyl-CBS-oxazaborolidine (1 m in toluene,
70 μL, 0.07 mmol, 0.1 equiv.) was added, followed by catecholbo-
rane (1 m in THF, 1.46 mL, 1.46 mmol, 2.0 equiv., by syringe pump
Conclusion
The oxygenated monoterpenoids (–)-rhodioloside A, (–)- over 12 h). After 24 h, the reaction was quenched by the addition
of MeOH (1 mL), and the mixture was allowed to warm to room
temp. and diluted with Et2O. The organic phase was washed with
NaOH solution (1 m) and saturated aqueous NaHCO3 solution un-
til the organic phase was colorless. The organic phase was then
washed with brine and dried with MgSO4, and the solvent was
evaporated. Chromatography (silica gel, petroleum ether/EtOAc,
10:1) yielded (S)-9 (260 mg, 0.64 mmol, 86%) as a colorless oil. Rf
(petroleum ether/EtOAc, 10:1) = 0.29. [α]2D5 = –4.3 (c = 2.8, ace-
tone). 1H NMR (400 MHz, CDCl3): δ = 7.71–7.76 (m, 4 H, Ph-
o-H), 7.44–7.35 (m, 6 H, Ph-m-H, Ph-p-H), 5.64–5.60 (m, 1 H,
rhodioloside D, and (+)-sachalinol C from the roseroot
Rhodiola sp. have been synthesized for the first time. In ad-
dition, (–)-sachalinol A and (–)-sachalinol B were obtained.
Key steps were the enantioselective CBS reduction of the
allyl homoallyl ketone 8, the optimized glucosylation of ge-
raniol derivatives by employing pivaloylated glucosyl bro-
mide, and the acid-catalyzed cyclization of homoglycidol 27
to the hydroxytetrahydrofuran system. The relative and ab-
solute stereochemistry of the natural products has been
clarified.
3
OCH2CH), 5.12–5.07 [m, 1 H, (CH3)2CCH], 4.27 (d, J = 6.1 Hz,
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Total Syntheses of Rhodiolosides A and D and of Sachalinols A–C
2 H, OCH2CH), 3.98–3.94 (m, 1 H, CHOH), 2.28–2.15 (m, 2 H,
CH2CHOH), 1.72 [d, 4J = 1.1 Hz, 3 H, (CH3)2C], 1.63 [s, 3 H,
Compound 11: [α]2D5 = –5.3 (c = 0.6, acetone). 1H NMR (400 MHz,
CDCl3): δ = 7.69–7.65 (m, 4 H, Ph-m-H), 7.44–7.35 (m, 6 H, Ph-
o-H, Ph-p-H), 5.66–5.63 (m, 1 H, OCH2CH), 5.35–5.30 (m, 1 H,
4
(CH3)2C], 1.49 (br., 1 H, OH), 1.45 (d, J = 1.1 Hz, 3 H, CCH3),
1.05 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = CHCCH2OH), 5.13 (t, 3J = 6.8 Hz, 1 H, CHO), 4.25–4.24 (m, 2
138.1 (1 C, CHCCH3), 135.6 (4 C, o-CPh), 134.8 [1 C, (CH3)2C],
H, OCH2CH), 3.97 (s, 2 H, CH2OH), 2.44–2.26 (m, 2 H,
133.9 (1 C, ipso-CPh), 133.9 (1 C, ipso-CPh), 129.6 (2 C, p-CPh), CH2CHO), 2.03 (s, 3 H, CH3COO), 1.67 [d, 4J = 1.0 Hz, 3 H,
4
127.6 (4 C, m-CPh), 125.5 (1 C, OCH2CH), 119.9 [1 C, (CH3)2- (CH3CCH2OH)], 1.44 (d, J = 1.1 Hz, 3 H, CH3C), 1.04 [s, 9 H,
CCH], 76.6 (1 C, CHOH), 60.8 (1 C, OCH2CH), 33.9 (1 C,
CH2CHOH), 26.8 [3 C, (CH3)3C], 25.9 [1 C, (CH3)2C], 19.1 [1 C, CH3COO), 137.2 (1 C, CCH2OH), 135.2 (4 C, m-CPh), 133.7 (1 C,
(CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9 (1 C,
(CH3)3C], 18.0 [1 C, (CH3)2C], 12.0 (1 C, CH3C) ppm. IR (ATR):
CHCCH3), 133.5 (1 C, ipso-CPh), 133.4 (1 C, ipso-CPh), 129.3 (2
C, p-CPh), 127.3 (4 C, o-CPh), 127.1 (1 C, OCH2CH), 120.2 (1 C,
CHCCH2OH), 77.4 (1 C, CHO), 68.3 (1 C, CH2OH), 60.3 (1 C,
OCH2CH), 30.8 (1 C, CH2CHO), 26.4 [3 C, (CH3)3C], 20.9 (1 C,
ν = 3401 (br., w), 1109 (m), 1066 (m), 822 (m), 740 (m), 701 (s),
˜
609 (m) cm–1. UV/Vis (MeOH): λmax (lgε) = 205 (4.34) nm. MS
(EI, 70 eV): m/z (%) = 408 (1), 333 (3), 267 (7), 201 (6), 200 (17),
199 (100), 181 (11), 135 (18), 77 (18). HRMS (EI): calcd. for CH3COO), 18.8 [1 C, (CH3)3C], 13.5 (1 C, CH3CCH2OH), 12.3 (1
C26H34OSi [M – H2O]+ 390.2379; found 390.2392.
C, CH C) ppm. IR (ATR): ν = 3432 (w, br.), 2931 (m), 2857 (m),
˜
3
1737 (m), 1428 (m), 1370 (m), 1235 (m), 1109 (m), 1043 (m), 1017
(m), 823 (m), 740 (m), 702 (s), 611 (m) cm–1. UV/Vis (MeOH): λmax
(lgε) = 203 (4.53), 217 (4.29) nm. MS (ESI): m/z (%) = 489 (100),
490 (30), 491 (9). HRMS (ESI): calcd. for C28H42O4N1Si [M +
NH4]+ 484.2878 found 484.2884.
(2E,4S)-1-(tert-Butyldiphenylsilyloxy)-3,7-dimethylocta-2,6-dien-4-
yl Acetate (10): DMAP (14.9 mg, 0.12 mmol, 0.1 equiv.), anhy-
drous NEt3 (0.85 mL, 6.10 mmol, 5.0 equiv.), and Ac2O (1.14 mL,
12.2 mmol, 10 equiv.) were added to a solution of (S)-9 (500 mg,
1.22 mmol, 1.0 equiv.) in anhydrous DCM (10 mL). After 17 h, the
reaction was quenched by the addition of an aqueous NH4Cl solu-
tion, and the aqueous phase was extracted with DCM. The organic
phase was dried with MgSO4, and the solvent was evaporated. Af-
ter chromatography (silica gel, petroleum ether/EtOAc, 40:1), the
acetate 10 (470 mg, 1.04 mmol, 85%) was obtained as a colorless
oil. Rf (petroleum ether/EtOAc, 40:1) = 0.14. [α]2D5 = –9.6 (c = 4.8,
acetone). 1H NMR (400 MHz, CDCl3): δ = 7.70–7.66 (m, 4 H, Ph-
o-H), 7.44–7.35 (m, 6 H, Ph-m-H, Ph-p-H), 5.66–5.62 (m, 1 H,
Compound 12: Rf (petroleum ether/EtOAc, 10:1) = 0.51. [α]2D5 = –3.7
(c = 0.43, acetone). 1H NMR (400 MHz, CDCl3): δ = 9.37 (s, 1 H,
COH), 7.68–7.65 (m, 4 H, m-Ph-H), 7.45–7.35 (m, 6 H, Ph-o-H,
Ph-p-H), 6.40–6.35 (m, 1 H, CHCCHO), 5.70–5.66 (m, 1 H,
3
3
OCH2CH), 5.27 (t, J = 6.6 Hz, 1 H, CHO), 4.25 (d, J = 6.0 Hz,
2 H, OCH2CH), 2.70 (m, 1 H, CH2CHO), 2.63–2.56 (m, 1 H,
CH2CHO), 2.05 (s, 3 H, CH3COO), 1.75 [d, 4J = 1.2 Hz, 3 H,
(CH3CCHOH)], 1.46 (d, 4J = 1.0 Hz, 3 H, CH3C), 1.04 [s, 9 H,
(CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 194.8 (1 C,
OCH2CH), 5.09 (t, 3J = 6.9 Hz, 1 H, CHO), 5.04–4.99 [m, 1 H,
3
(CH3)2CCH], 4.24 (d, J = 5.9 Hz, 2 H, OCH2CH), 2.37–2.20 (m, CHO), 169.9 (1 C, CH3COO), 148.2 (1 C, CHCCHO), 141.1 (1 C,
2 H, CH2CHOH), 2.03 (s, 3 H, CH3CO), 1.68 [d, 4J = 1.1 Hz, 3 CCHO), 135.5 (4 C, m-CPh), 133.6 (2 C, ipso-CPh), 133.1 (1 C,
H, (CH3)2C], 1.61 [d, 4J = 0.6 Hz, 3 H, (CH3)2C], 1.43 (d, 4J = CHCCH3), 129.6 (2 C, p-CPh), 128.1 (1 C, OCH2CH), 127.6 (4 C,
1.1 Hz, 3 H, CCH3), 1.04 [s, 9 H, (CH3)3C] ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.2 (1 C, CH3COO), 135.6 (4 C, o-CPh),
o-CPh), 76.2 (1 C, CHO), 60.5 (1 C, OCH2CH), 32.2 (1 C,
CH2CHO), 26.7 [3 C, (CH3)3C], 21.1 (1 C, CH3COO), 19.1 [1 C,
134.2 (1 C, CHCCH3), 134.2 [1 C, (CH3)2C], 133.8 (2 C, ipso-CPh), (CH3)3C], 12.6 (1 C, CH3C), 9.4 (1 C, CH3CCOH) ppm. IR (ATR):
129.6 (2 C, p-CPh), 127.6 (4 C, m-CPh), 127.3 (1 C, OCH2CH), 119.0 ν = 2931 (m), 2857 (m), 1739 (m), 1689 (s), 1428 (m), 1370 (m),
˜
[1 C, (CH3)2CCH], 78.1 (1 C, CHO), 60.7 (1 C, OCH2CH), 31.6 (1 1232 (s), 1110 (s), 1045 (m), 1021 (m), 823 (m), 741 (m), 704 (s),
C, CH2CHOH), 26.8 [3 C, (CH3)3C], 25.8 [1 C, (CH3)2C], 21.2 (1 612 (m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (4.54) nm. MS
C, CH3COO), 19.1 [1 C, (CH3)3C], 17.9 [1 C, (CH3)2C], 12.6 (1 C,
(EI, 70 eV): m/z (%) = 407 (2), 347 (9), 267 (11), 242 (19), 241 (89),
CH C) ppm. IR (ATR): ν = 1737 (m), 1237 (s), 1110 (m), 1067
199 (100), 181 (15). HRMS (EI): calcd. for C24H27O4Si [M –
˜
3
(m), 1046 (m), 1019 (m), 823 (m), 740 (m), 703 (s), 611 (m) cm–1. tBu]+ 407.1679; found 407.1662.
UV/Vis (MeOH): λmax (lgε) = 203 (4.54), 217 (4.27) nm. MS (ESI):
(2E,5S,6E)-8-[(tert-Butyldiphenylsilanyl)oxy]-2,6-dimethylocta-2,6-
diene-1,5-diyl Diacetate (30): DMAP (3 mg, 0.03 mmol, 0.1 equiv.),
anhydrous NEt3 (180 μL, 1.25 mmol, 5.0 equiv.), and Ac2O
m/z (%) = 473 (100), 474 (35), 475 (8). HRMS (ESI): calcd. for
C28H38O3SiNa [M + Na]+ 473.2488; found 473.2495.
(2E,4S,6E)-1-(tert-Butyldiphenylsilanyloxy)-8-hydroxy-3,7-dimeth- (235 μL, 2.50 mmol, 10.0 equiv.) were added to a solution of the
ylocta-2,6-dien-4-yl Acetate (11) and (2E,4S,6E)-1-[(tert-Butyldi-
alcohol 11 (116 mg, 0.25 mmol, 1.0 equiv.) in DCM (4 mL). After
phenylsilanyl)oxy]-3,7-dimethyl-8-oxoocta-2,6-dien-4-yl Acetate
16 h, the reaction was quenched by the addition of an aqueous
(12): SeO2 (4.3 mg, 0.04 mmol, 0.05 equiv.) and salicylic acid NH4Cl solution, and the aqueous phase was extracted with DCM.
(10.6 mg, 0.08 mmol, 0.10 equiv.) were suspended in DCM (2 mL). The organic phase was dried with MgSO4, and the solvent was
tert-Butyl hydroperoxide (500 μL, 4.00 equiv. 70% aqueous solu-
tion) was added in one portion at 0 °C. A solution of 10 (345 mg,
0.77 mmol, 1.00 equiv.) in DCM (2 mL) was added slowly at 0 °C.
The solution was stirred at room temp. for 5 d and then poured
into an aqueous solution of FeSO4 (0.5 m, 20 mL) at 0 °C. Stirring
was continued at 0 °C for 30 min. After separation of the phases,
the aqueous layer was extracted with DCM, and the combined or-
ganic layers were washed with aqueous NaOH (1 m), H2O, and
brine. The organic layers were dried with MgSO4, and the solvent
was evaporated. Chromatography (silica gel, petroleum ether/
EtOAc, 20:1 Ǟ 10:1 Ǟ 5:1 Ǟ 3:1) yielded the alcohol 11 (116 mg,
0.25 mmol, 32 %) as a colorless oil along with the aldehyde 12
(22 mg, 0.05 mmol, 6%) as a colorless oil and the starting material
10 (116 mg, 0.26 mmol, 43%).
evaporated. After chromatography (silica gel, petroleum ether/
EtOAc, 10:1), the diacetylated product (121 mg, 0.24 mmol, 96%)
was obtained as a colorless oil. Rf (petroleum ether/EtOAc, 40:1)
= 0.37. [α]2D2 = –12.8 (c = 1.72, acetone). 1H NMR (400 MHz,
CDCl3): δ = 7.68–7.65 (m, 4 H, Ph-o-H), 7.44–7.35 (m, 6 H, Ph-
m-H, Ph-p-H), 5.66–5.63 (m, 1 H, OCH2CH), 5.38–5.34 (m, 1 H,
CH2CCH), 5.13 (t, 3J = 6.8 Hz, 1 H, CHOAc), 4.43 (s, 2 H,
3
CH2OAc), 4.24 (d, J = 6.0 Hz, 2 H, OCH2CH), 2.41 (td, J = 7.5,
J = 14.9 Hz, 1 H, CH2CHOAc), 2.30 (td, J = 7.5, J = 14.9 Hz, 1
H, CH2CHOAc), 2.05 (s, 3 H, CH3COOCH2), 2.03 (s, 3 H,
CH3COOHCH), 1.66 (d, J = 0.9 Hz, 3 H, CH3CCH2), 1.43 (d, J
= 1.0 Hz, 3 H, CCH3), 1.04 [s, 9 H, (CH3)3C] ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.9 (1 C, CH3COOCH2), 170.1 (1 C,
CH3COOCH), 135.6 (4 C, o-CPh), 133.9 (1 C, CHCCH3), 133.8 (2
Eur. J. Org. Chem. 2011, 1493–1503
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1497

K. Simon, P. G. Jones, T. Lindel
FULL PAPER
C, ipso-CPh), 132.8 [1 C, (CH3CCH2)], 129.6 (2 C, p-CPh), 127.6 (4 C, OCH2CH), 62.0 (1 C, C6-H), 31.3 (1 C, CH2CHOAc), 21.1 (1
C, m-CPh), 127.5 (1 C, OCH2CH), 124.0 [1 C, (CH2CCH)], 77.4 (1 C, CH3COO-CH), 20.9 (1 C, CH3COO-C6), 20.7 (1 C, CH3COO-
C, CHOOAc), 69.8 (1 C, CH2OAc), 60.7 (1 C, OCH2CH), 31.3 (1
C, CH2CHOAc), 26.8 [3 C, (CH3)3C], 21.2 (1 C, CH3COOCH2), C, CH3COO-C4), 14.1 (1 C, CH2CCH3), 12.4 (1 C, CH3C) ppm.
20.9 (1 C, CH3COOCH), 19.1 [1 C, (CH3)3C], 14.2 (1 C, IR (ATR): ν = 1730 (s), 1429 (m), 1367 (m), 1209 (s), 1166 (m),
C2), 20.7 (1 C, CH3COOCH2), 20.6 (1 C, CH3COO-C3), 20.6 (1
˜
CH CCH ), 12.6 (1 C, CH C) ppm. IR (ATR): ν = 2932 (m), 2858 1149 (m), 1033 (s), 954 (m), 928 (m), 904 (m), 854 (m), 832 (m),
˜
3
2
3
(m), 1737 (m), 1428 (m), 1370 (m), 1229 (s), 1110 (m), 1046 (m), 602 (m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (3.98) nm. MS
1020 (m), 823 (m), 741 (m), 703 (s), 611 (m) cm–1. UV/Vis (MeOH): (ESI): m/z (%) = 623 (100), 324 (29), 493 (7). HRMS (ESI): calcd.
λmax (lgε) = 203 (4.55), 265 (3.32) nm. MS (ESI): m/z (%) = 531 for C28H40O14Na [M + Na]+ 623.2310; found 623.2316.
(100), 532 (34), 533 (10). HRMS (ESI): calcd. for C30H40O5SiNa
(–)-Rhodioloside A (4) and (–)-Rhodiolol A (16): NaOMe
[M + Na]+ 531.2543; found 531.2543.
(0.26 mmol, 30% in MeOH, 48 μL, 1.3 equiv.) was added to a solu-
tion of 15 (118 mg, 0.20 mmol, 1.0 equiv.) in MeOH (14 mL). After
(2E,5S,6E)-8-Hydroxy-2,6-dimethylocta-2,6-diene-1,5-diyl Diacet-
1.5 h at room temp., the solvent was evaporated, and the crude
ate (13): TBAF·3H2O (1 m solution in THF, 0.8 mL, 0.8 mmol,
product was purified by flash chromatography (silica gel, CHCl3/
1.5 equiv.) was added to a solution of 30 (265 mg, 0.5 mmol,
MeOH, 5:1). Rhodioloside A (4, 49 mg, 0.14 mmol, 70%) was ob-
1.0 equiv.) in THF (8 mL). After 1.5 h at room temp. and evapora-
tained as a colorless viscous oil along with rhodiol A (16, 7 mg,
tion of the solvent, chromatography (silica gel, petroleum ether/
0.04 mmol, 19%).
EtOAc, 2:1) yielded 13 (101 mg, 0.3 mmol, 72%) as a colorless oil.
Rf (petroleum ether/EtOAc, 2:1) = 0.22. [α]2D2 = –11.3 (c = 2.68,
Compound 4: Rf (CHCl3/MeOH, 5:1) = 0.12. [α]2D4 = –34.3 (c =
1.26, MeOH). H NMR (400 MHz, CD3OD): δ = 5.60–5.57 (m, 1
acetone). 1H NMR (400 MHz, CDCl3): δ = 5.65–5.60 (m, 1 H,
1
3
OCH2CH), 5.35 (m, 1 H, CHCH2CHOAc), 5.15 (t, J = 6.9 Hz, 1 H, OCH2CH), 5.42–5.38 (m, 1 H, CHCH2CHOH), 4.39–4.28 (m,
H, CHOAc), 4.45 (s, 2 H, CH2OAc), 4.18 (d, 3J = 6.6 Hz, 2 H, 2 H, OCH2CH), 4.29 (d, J = 7.8 Hz, 1 H, C1-H), 4.02 (t, J =
HOCH2CH), 2.49–2.45 (m, 1 H, CH2CHOAc), 2.39–2.32 (m, 1 H,
6.7 Hz, 1 H, CHOH), 3.92 (s, 2 H, CH2OH), 3.87 (dd, J = 2.0,
CH2 CHOAc), 2.07 (s, 3 H, CH3 COOCH2 ), 2.05 (s, 3 H, 11.9 Hz, 1 H, C6-H2), 3.66 (dd, J = 5.5, 11.9 Hz, 1 H, C6-H2),
CH3COOCH), 1.66 [s, 3 H, (CH3)CCH2], 1.66 [s, 3 H, (CH3)2C]
p p m . 1 3 C N M R ( 1 0 0 M H z , C D C l 3 ) : δ = 1 7 1 . 0 ( 1 C ,
3.32–3.22 (m, 3 H, C3-H, C4-H, C5-H), 3.17 (dd, J = 7.8, 9.0 Hz,
1 H, C2-H), 2.30 (t, J = 6.9 Hz, 2 H, CH2CHOH), 1.67 (s, 3 H,
CH3COOCH2), 170.2 (1 C, CH3COOCH), 135.6 (1 C, CHCCH3), CH3CCH), 1.65 (s, 3 H, CH3CCH2) ppm. 13C NMR (100 MHz,
132.8 (1 C, CH3CCH2), 127.0 (1 C, HOCH2CH), 123.6 (1 C,
CD3OD): δ = 142.9 (1 C, CHCCH3), 137.7 (1 C, CH3CCH2), 123.0
CH2CCH), 77.5 (1 C, CHOAc), 69.7 (1 C, CH2OAc), 58.9 (1 C, (1 C, OCH2CH), 122.7 (1 C, CH2CCH), 102.8 (1 C, C1-H), 78.1
HOCH2CH), 31.0 (1 C, CH2CHOAc), 21.6 (1 C, CH3COOCH), (1 C, C-H)*, 78.0 (1 C, C-H)*, 77.6 (1 C, CCHOH), 75.1 (1 C, C2-
20.9 (1 C, CH3COOCH2), 14.1 (1 C, CH3CCH2), 12.4 (1 C, CH3C)
H), 71.7 (1 C, C-H)*, 68.9 (1 C, CH2CCH3), 66.0 (1 C, OCH2CH),
ppm. IR (ATR): ν = 3449 (w, br.), 1732 (m), 1437 (m), 1371 (m), 62.8 (1 C, C6-H), 34.4 (1 C, CH2CHOH), 14.0 (1 C, CH2CCH3),
˜
1226 (s), 1017 (m), 956 (m), 852 (m) cm–1. UV/Vis (MeOH): λmax 12.1 (1 C, CH3C) ppm; * no differentiation between C3, C4 and
(lg ε) = 202 nm (4.00), 313 (2.39) nm. HRMS (ESI): calcd. for
C5 possible. IR (ATR): ν = 3316 (m, br.), 2919 (m), 2863 (m), 1430
˜
C14H22O5 [M + Na]+ 293.13594; found 293.13688.
(m), 1374 (m), 1072 (m), 1012 (s) cm–1. UV/Vis (MeOH): λmax (lgε)
= 202 (3.94) nm. MS (ESI): m/z (%) = 371 (100), 372 (23), 373 (4).
HRMS (ESI): calcd. for C16H28O8Na [M + Na]+ 371.1682; found
317.1682.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-{[(2E,4S,6E)-4,8-diacetoxy-
3,7-dimethylocta-2,6-dien-1-yl]oxy}tetrahydro-2H-pyran-3,4,5-triyl
Triacetate (15): 2,3,4,6-Tetra-O-acetyl-α-d-glucopyranosyl bromide
(14, 337 mg, 0.82 mmol, 2.0 equiv.) and Ag2CO3 (282 mg,
1.02 mmol 2.5 equiv.) were added under Ar to a solution of 13
(110 mg, 0.41 mmol, 1.0 equiv.) in anhydrous Et2O (8 mL). The
mixture was stirred at room temp. in the dark for 22 h. The solution
was filtered, and the solvent was evaporated. After chromatography
(silica gel, petroleum ether/EtOAc, 2:1), 15 (90 mg, 0.15 mmol,
37%) was obtained as a colorless oil. Rf (petroleum ether/EtOAc,
Compound 16: Rf (CHCl3/MeOH, 5:1) = 0.43. [α]2D4 = –1.6 (c =
0.25, MeOH). 1H NMR (400 MHz, CDCl3): δ = 5.68–5.63 (m, 1
H, OCH2CH), 5.45–5.40 (m, 1 H, CHCH2CHOH), 4.22 (d, J =
6.7 Hz, 2 H, CHCH2OH), 4.09 (t, J = 6.5 Hz, 1 H, CH2CHOH),
4.02 (s, 2 H, CCH2OH), 2.35–2.31 (m, 2 H, CHCH2CHOH), 1.69
(s, 6 H, CH3CCH2, CH3CCH), 1.60 (br. s, 3 H, CCH2OH,
CHCH2OH, CHOH) ppm. 13C NMR (100 MHz, CDCl3): δ =
140.2 (1 C, CHCCH3), 137.9 (1 C, CH3CCH2), 124.7 (1 C,
OCH2CH), 121.2 (1 C, CH2CCH), 76.3 (1 C, CHOH), 68.6 (1 C,
CH2CCH3), 59.1 (1 C, OCH2CH), 33.4 (1 C, CH2CHOH), 14.0 (1
1
2:1) = 0.24. [α]2D2 = –22.7 (c = 2.2, acetone). H NMR (400 MHz,
CDCl3): δ = 5.55–5.51 (m, 1 H, OCH2CH), 5.38–5.34 (m, 1 H,
CHCH2CHOAc), 5.21 (t, J = 9.5 Hz, 1 H, C3-H), 5.15 (t, J =
6.8 Hz, 1 H, CHOAc), 5.09 (t, J = 9.7 Hz, 1 H, C4-H), 4.99 (dd, J
= 9.6, 8.0 Hz, 1 H, C2-H), 4.53 (d, J = 8.0 Hz, 1 H, C1-H), 4.45
(s, 2 H, CH2OAc), 4.35–4.13 (m, 4 H, OCH2CH, C6-H2), 3.68 (ddd,
J = 2.5, 4.7, 9.9 Hz, 1 H, C5-H), 2.45 (td, J = 7.5, 14.9 Hz, 1 H,
C, CH CCH ), 12.1 (1 C, CH C) ppm. IR (ATR): ν = 3299 (m,
˜
2
3
3
br.), 2916 (m), 2862 (m), 1432 (m), 1385 (m), 995 (s), 603 (m) cm–1.
UV/Vis (MeOH): λmax (lgε) = 205 (3.78) nm. HRMS (ESI): calcd.
for C10H18O3Na [M + Na]+ 209.11482; found 209.11475.
CHCH2CHOAc), 2.37–2.30 (m, 1 H, CHCH2CHOAc), 2.09 (s, 3 (2S,3E)-5-[(tert-Butyldiphenylsilanyl)oxy]-1-(3,3-dimethyloxiran-2-
H, CH3COOCH2), 2.07 (s, 3 H, CH3COO-C6), 2.06 (s, 3 H, yl)-3-methylpent-3-en-2-yl Acetate (17, Mixture of Diastereomers):
CH3COOCH), 2.05 (s, 3 H, CH3COO-C2), 2.03 (s, 3 H, CH3COO- mCPBA (70% with H2O, 200 mg, 0.81 mmol, 1.1 equiv.) was added
C4), 2.00 (s, 3 H, CH3COO-C3), 1.67 (s, 3 H, CH3CCH2), 1.66 (s,
in small portions at 0 °C to a solution of 10 (335 mg, 0.74 mmol,
3 H, CH3CCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.8 (1 1.0 equiv.) in DCM (10 mL), and the solution was stirred at 0 °C
C, CH3COOCH2), 170.6 (1 C, CH3COO-C6), 170.3 (1 C, for 3 h. The reaction was quenched by the addition of aqueous
CH3COO-C3), 170.1 (1 C, CH3COO-CH), 169.4 (1 C, CH3COO- NaOH (1 m) and extracted with DCM. The organic phase was
C4), 169.3 (1 C, CH3COO-C1), 138.0 (1 C, CHCCH3), 133.1 (1 C,
CH3CCH2), 123.5 (1 C, CH2CCH), 122.8 (1 C, OCH2CH), 99.2 (1
washed with saturated aqueous NaHCO3 and brine and dried with
MgSO4, followed by evaporation of the solvent. Chromatography
C, C1-H), 78.4 (1 C, CHOAc), 72.9 (1 C, C3-H), 71.8 (1 C, C5-H), (silica gel, petroleum ether/EtOAc, 10:1) yielded a mixture of dia-
71.3 (1 C, C2-H), 69.6 (1 C, CH2CCH3), 68.4 (1 C, C4-H), 64.9 (1 stereomers as a colorless oil (283 mg, 0.61 mmol, 82%). Rf (petro-
1498
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1493–1503

Total Syntheses of Rhodiolosides A and D and of Sachalinols A–C
leum ether/EtOAc, 10:1) = 0.32. [α]2D4 = –13.1 (c = 1.23, acetone).
obtained from CHCl3. M.p. 35 °C. Rf (CHCl3/MeOH, 10:1) = 0.26.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.66 (m, 8 H, Ph-o-H), [α]2D4 = –12.8 (c = 1.0, MeOH). 1H NMR (400 MHz, CD3OD): δ =
7.44–7.35 (m, 12 H, Ph-m-H, Ph-p-H), 5.71–5.67 (m, 2 H, 5.55 (t, 3J = 6.5 Hz, 1 H, OCH2CH), 4.13 (d, 3J = 6.5 Hz, 2 H,
OCH2CH), 5.33–5.25 (m, 2 H, CHOAc), 4.26–4.24 (m, 4 H,
OCH2CH), 2.74 [t, J = 6.2 Hz, 1 H, (CH3)2CCH], 2.72 [t, J =
6.0 Hz, 1 H, (CH3)2CCH], 2.07 (s, 3 H, CH3COOHCH), 2.06 (s, 3
OCH2CH), 3.91 (t, J = 6.5 Hz, 1 H, CHOH), 1.63 (s, 3 H,
CH3CCHO), 1.61–1.49 (m, 3 H, CH2CH2COH), 1.41–1.32 (m, 1
H, CH2CH2COH), 1.18 [s, 3 H, (CH3)2COH], 1.17 [s, 3 H,
H, CH3COOHCH), 1.94–1.75 (m, 4 H, CH2CHOAc), 1.46–1.45 (CH3)2COH] ppm. 13C NMR (100 MHz, CD3OD): δ = 140.9 (1 C,
(m, 6 H, CH3C), 1.29 [s, 3 H, (CH3)2C], 1.29 [s, 3 H, (CH3)2C],
CHCCH3), 126.2 (1 C, OCH2CH), 78.6 (1 C, CHOH), 71.1 [1 C,
1.27 [s, 3 H, (CH3)2C], 1.25 [s, 3 H, (CH3)2C], 1.04 [s, 18 H, (CH3)2COH], 59.2 (1 C, OCH2CH), 40.8 (1 C, CH2CH2COH), 30.6
(CH3)3C] ppm. 13C NMR (100 MHz, CDCl3): δ = 170.0 (1 C, (1 C, CH2CH2COH), 29.3 [1 C, (CH3)2COH], 29.2 [1 C,
CH3COOCH), 169.9 (1 C, CH3COOCH), 135.5 (8 C, o-CPh), 133.9 (CH ) COH], 11.6 (1 C, CH C) ppm. IR (ATR): ν = 3315 (s, br.),
˜
3 2
3
(1 C, CHCCH3), 133.8 (1 C, CHCCH3), 133.7 (2 C, ipso-CPh), 2968 (m), 2946 (m), 2872 (m), 1467 (m), 1444 (m), 1379 (m), 1365
133.7 (1 C, ipso-CPh), 133.7 (1 C, ipso-CPh), 129.6 (4 C, p-CPh), (m), 1212 (m), 1152 (m), 1058 (m), 998 (s), 950 (m), 906 (m), 731
127.6 (8 C, m-CPh), 127.4 (1 C, OCH2CH), 127.3 (1 C, OCH2CH), (m), 618 (m), 571 (m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202
76.0 (1 C, CHOOAc), 75.8 (1 C, CHOOAc), 60.9 [1 C,
(3.68) nm. HRMS (ESI): calcd. for C10H20O3Na [M + Na]+
(CH3)2CCH], 60.9 [1 C, (CH3)2CCH], 60.6 (1 C, OCH2CH), 60.6 211.13101; found 211.13106.
(1 C, OCH2CH), 58.2 [1 C, (CH3)2C], 57.8 [1 C, (CH3)2C], 32.6 (1
(2E,4S)-1-[(tert-Butyldiphenylsilanyl)oxy]-7-hydroxy-3,7-dimeth-
C, CH2CHOAc), 32.6 (1 C, CH2CHOAc), 26.8 [6 C, (CH3)3C], 24.7
[1 C, (CH3)2C], 24.6 [1 C, (CH3)2C], 21.2 (1 C, CH3COOCH), 21.1
(1 C, CH3COOCH), 19.1 [2 C, (CH3)3C], 18.9 [1 C, (CH3)2C], 18.9
yloct-2-en-4-yl Acetate (31): Ac2O (210 μL, 2.3 mmol, 10 equiv.),
Et3N (155 μL, 1.1 mmol, 5.0 equiv.), and DMAP (2.7 mg,
0.02 mmol, 0.1 equiv.) were added to a solution of diol 18 (98 mg,
0.23 mmol, 1.0 equiv.) in DCM (10 mL). The solution was stirred
at room temp. for 15 h and the reaction quenched by the addition
of a saturated aqueous NH4Cl solution. The aqueous phase was
extracted with DCM, and the combined organic phases were
washed with a saturated aqueous NaHCO3 solution and dried with
MgSO4. After evaporation of the solvent, rapid column chromatog-
raphy (silica, petroleum ether/EtOAc, 5:1) yielded 31 (95 mg,
0.20 mmol, 88 %) as a colorless oil, accompanied by the diace-
tylated product 32 (11 mg, 0.02 mmol, 9%).
[1 C, (CH ) C], 12.9 (2 C, CH C) ppm. IR (ATR): ν = 2959 (m),
˜
3 2
3
2931 (m), 2858 (m), 1739 (m), 1428 (m), 1373 (m), 1234 (s), 1109
(m), 1047 (m), 1020 (m), 823 (m), 780 (m), 740 (m), 702 (s), 611
(m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (4.51), 265 (2.85) nm.
MS (ESI): m/z (%) = 489 (100), 490 (30). HRMS (ESI): calcd. for
C28H38O4SiNa [M + Na]+ 489.2432; found 489.2437.
(5S,6E)-8-[(tert-Butyldiphenylsilanyl)oxy]-2,6-dimethyloct-6-ene-
2,5-diol (18): Under Ar, the epoxide 17 (570 mg, 1.22 mmol,
1.0 equiv.) was dissolved in dry THF (35 mL), and the mixture was
cooled to 0 °C. LiBEt3H (1 m in THF, 6.1 mL, 6.1 mmol, 5.0 equiv.)
was added dropwise, and the solution was heated at reflux. After
2 h, the solution was allowed to cool to room temp. and the reac-
tion quenched by the addition of aqueous NaOH (2 m). The aque-
ous phase was extracted with Et2O. The organic phase was dried
with MgSO4, and the solvent was evaporated. Column chromatog-
raphy (silica gel, petroleum ether/EtOAc, 2:1) afforded 18 (401 mg,
0.94 mmol, 77%) as a colorless solid. M.p. 95 °C. Rf (petroleum
ether/EtOAc, 2:1) = 0.15. [α]2D6 = –2.4 (c = 1.18, MeOH). 1H NMR
(400 MHz, CDCl3): δ = 7.70–7.67 (m, 4 H, Ph-o-H), 7.45–7.36 (m,
6 H, Ph-m-H, Ph-p-H), 5.61–5.58 (m, 1 H, OCH2CH), 4.31–4.23
(m, 2 H, OCH2CH), 3.98–3.93 (m, 1 H, CHOH), 1.84 (br. s, 2 H,
COH, CHOH), 1.64–1.51 (m, 3 H, CH2CH2COH), 1.43 (d, J =
1.1 Hz, 3 H, CHCCH3), 1.22 [s, 3 H, (CH3)2COH], 1.21 [s, 3 H,
(CH3)2COH], 1.04 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.5 (1 C, CHCCH3), 135.6 (2 C, o-CPh), 133.9 (1 C,
ipso-CPh), 133.9 (1 C, ipso-CPh), 129.6 (2 C, p-CPh), 127.6 (4 C, m-
CPh), 125.7 (1 C, OCH2CH), 77.5 (1 C, CHOH), 70.5 [1 C,
(CH3)2COH], 60.8 (1 C, OCH2CH), 39.8 (1 C, CH2CH2COH), 29.6
[1 C, (CH3)2COH], 29.4 (1 C, CH2 CH2COH), 29.2 [1 C,
(CH3)2COH], 26.8 [3 C, (CH3)3C], 19.1 [1 C, (CH3)3C], 11.8 (1 C,
Monoacetylated Compound 31: Rf (petroleum ether/EtOAc, 5:1) =
0.23. [α]2D2 = –10.4 (c = 1.78, acetone). 1H NMR (400 MHz,
CDCl3): δ = 7.69–7.66 (m, 4 H, Ph-o-H), 7.44–7.35 (m, 6 H, Ph-
m-H, Ph-p-H), 5.66–5.63 (m, 1 H, OCH2CH), 5.10 (t, J = 6.8 Hz,
1 H, CHOAc), 4.25 (d, J = 5.9 Hz, 2 H, OCH2CH), 2.04 (s, 3 H,
CH3COOCH), 1.75–1.60 (m, 2 H, CH2CH2COAc), 1.48–1.31 (m,
2 H, CH2CH2COAc), 1.43 (d, 3 H, CHCCH3), 1.21 [s, 6 H,
(CH3)2COH], 1.04 [s, 9 H, (CH3)3C] ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.2 (1 C, CH3COOCH), 135.6 (4 C, o-CPh), 134.1
(1 C, CHCCH3), 133.8 (1 C, ipso-CPh), 133.8 (1 C, ipso-CPh), 129.6
(2 C, p-CPh), 127.6 (1 C, OCH2CH), 127.6 (4 C, m-CPh), 78.7 (1 C,
CHOAc), 70.5 [1 C, (CH3)2COH], 60.6 (1 C, OCH2CH), 39.2 (1 C,
CH2CH2COAc), 29.3 [1 C, (CH3)2COH], 29.2 [1 C, (CH3)2COH],
27.3 (1 C, CH2CH2COAc), 26.8 [3 C, (CH3)3C], 21.2 (1 C,
CH3COOCH), 19.1 [1 C, (CH3)3C], 12.3 (1 C, CH3C) ppm. IR
(ATR): ν = 3349 (w, br.), 2962 (m), 2932 (m), 2858 (m), 1735 (m),
˜
1428 (m), 1370 (m), 1237 (m), 1108 (m), 1045 (m), 1022 (m), 940
(m), 823 (m), 786 (m), 740 (m), 702 (s), 611 (m) cm–1. UV/Vis
(MeOH): λmax (lgε) = 202 (4.45), 217 (4.20) nm. MS (ESI): m/z (%)
= 491 (100), 492 (30), 493 (10). HRMS (ESI): calcd. for C28H40O4-
SiNa [M + Na]+ 491.2588; found 491.2593.
CH C) ppm. IR (ATR): ν = 3346 (m), 3251 (m), 2956 (m), 2932
˜
3
(m), 2886 (m), 2858 (m), 1470 (m), 1426 (m), 1321 (m), 1158 (m),
1108 (m), 1050 (m), 1017 (m), 953 (m), 938 (m), 918 (m), 907 (m),
860 (m), 824 (m), 796 (m), 775 (m), 744 (m), 702 (s), 684 (m), 618
(m) cm–1. UV/Vis (MeOH): λmax (lgε) = 203 (4.50), 216 (4.25) nm.
MS (ESI): m/z (%) = 449 (100), 450 (29), 451 (8). HRMS (ESI):
calcd. for C26H38O3SiNa [M + Na]+ 449.2482; found 449.2488.
Diacetylated Analogue 32: Rf (petroleum ether/EtOAc, 5:1) = 0.51.
1
[α]2D6 = –8.6 (c = 1.33, acetone). H NMR (400 MHz, CDCl3): δ =
7.68–7.66 (m, 4 H, Ph-o-H), 7.44–7.35 (m, 6 H, Ph-m-H, Ph-p-H),
5.66–5.63 (m, 1 H, OCH2CH), 5.08 (t, J = 5.8 Hz, 1 H, CHOAc),
4.25 (d, J = 6.0 Hz, 2 H, OCH2CH), 2.05 (s, 3 H, CH3COOCH),
1.96 (s, 3 H, CH3COOCH), 1.68–1.60 (m, 4 H, CH2CH2COAc),
1.43–1.42 [m, 9 H, CHCCH3, (CH3)2COH], 1.04 [s, 9 H, (CH3)3C]
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.3 (1 C, CH3COOC),
170.2 (1 C, CH3COOCH), 135.6 (4 C, o-CPh), 133.9 (1 C,
CHCCH3), 133.8 (1 C, ipso-CPh), 133.8 (1 C, ipso-CPh), 129.6 (2 C,
p-CPh), 127.8 (1 C, OCH2CH), 127.6 (4 C, m-CPh), 81.6 [1 C,
(CH3)2COAc], 78.4 (1 C, CHOAc), 60.6 (1 C, OCH2CH), 36.6 (1
(–)-Sachalinol A (3): TBAF·3H2O (0.28 mmol, 280 μL, 1.5 equiv.)
was added to a solution of 18 (80 mg, 0.19 mmol, 1.0 equiv.) in
THF (5 mL). After the mixture had been stirred at room temp. for
3 h, the solvent was evaporated, and the crude product was sub-
jected to column chromatography (silica, CHCl3/MeOH, 10:1) to
yield 3 (28 mg, 0.15 mmol, 78%) as a colorless oil. Crystals were
Eur. J. Org. Chem. 2011, 1493–1503
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1499

K. Simon, P. G. Jones, T. Lindel
FULL PAPER
C, CH2CH2COAc), 26.8 (1 C, CH2CH2COAc), 26.8 [3 C,
(CH3)3CCOO-C5], 38.6 [1 C, (CH3)3CCOO-C4], 38.6 [1 C,
(CH3)3C], 26.0 [1 C, (CH3)2COAc], 25.9 [1 C, (CH3)2COAc], 22.4 (CH3)3CCOO-C3], 29.2 [1 C, (CH3)2C], 29.1 [1 C, (CH3)2C], 27.2
(1 C, CH3COOC), 21.3 (1 C, CH3COOCH), 19.2 [1 C, (CH3)3C], ( 1 C, C H2 CH2 C H OA c ) , 2 7 . 0 [ 6 C, (CH3 )3 CCOO-C3,
12.2 (1 C, CH C) ppm. IR (ATR): ν = 2932 (m), 2858 (m), 1733 (CH3)3CCOO-C6], 26.9 [3 C, (CH3)3CCOO-C4], 26.9 [3 C,
˜
3
(s), 1428 (m), 1367 (m), 1235 (s), 1212 (m), 1109 (m), 1047 (m), (CH3)3CCOO-C2], 21.1 (1 C, CH3COO-CH), 12.4 (1 C, CH3C)
1017 (m), 940 (m), 823 (m), 784 (m), 740 (m), 702 (s), 610 (m) cm–1. ppm. IR (ATR): ν = 3541 (w, br.), 2970 (m), 1736 (s), 1480 (m),
˜
UV/Vis (MeOH): λmax (lgε) = 203 (4.45), 216 (4.24) nm. MS (ESI):
m/z (%) = 533 (100), 534 (38), 535 (10). HRMS (ESI): calcd. for
C30H42O5SiNa [M + Na]+ 533.2694; found 533.3063.
1368 (m), 1279 (m), 1237 (m), 1134 (s), 1037 (m), 941 (m), 761 (m)
cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (3.63) nm. HRMS (ESI):
calcd. for C38H64O13Na [M + Na]+ 751.42446; found 751.42385.
(4S,2E)-1,7-Dihydroxy-3,7-dimethyloct-2-en-4-yl Acetate (25):
TBAF·3H2O (1 m in THF, 300 μL, 0.3 mmol, 1.5 equiv.) was added
to a solution of 31 (95 mg, 0.2 mmol, 1 equiv.) in THF (3 mL).
After stirring at room temp. for 1.5 h, the solvent was evaporated,
and the crude product was subjected to column chromatography
(silica, petroleum ether/EtOAc, 2:1) to yield 25 (38 mg, 0.1 mmol,
54%) as a colorless oil. Rf (petroleum ether/EtOAc, 2:1) = 0.21.
(–)-Rhodioloside D (5): NaOMe (30% in MeOH, 0.05 mmol, 9 μL)
was added to a solution of 26 (20 mg, 0.04 mmol, 1.0 equiv.) in
MeOH (4 mL). After 5 h at room temp., the solvent was evapo-
rated, and the crude product was purified by flash chromatography
(silica, CHCl3/MeOH, 5:1). The product 5 (7 mg, 0.02 mmol, 58%)
was obtained as a colorless viscous oil. Rf (CHCl3/MeOH, 5:1) =
0.08. [α]2D6 = –24.8 (c = 0.73, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 5.60–5.57 (m, 1 H, OCH2CH), 4.41–4.28 (m, 2 H,
[α]2D6 = –11.2 (c = 1.30, acetone). H NMR (400 MHz, CDCl3): δ
1
= 5.66–5.62 (m, 1 H, OCH2CH), 5.10 (t, J = 6.8 Hz, 1 H, CHOAc), OCH2CH), 4.30 (d, J = 7.8 Hz, 1 H, C1-H), 3.94 (t, J = 6.4 Hz, 1
4.18 (d, J = 6.6 Hz, 2 H, OCH2CH), 2.06 (s, 3 H, CH3COOCH), H, CHOH), 3.87 (dd, J = 2.0, 11.9 Hz, 1 H, C6-H2), 3.66 (dd, J =
1.77–1.68 (m, 2 H, CH2CH2COAc), 1.66–1.66 (m, 3 H, CHCCH3),
1.56–1.33 (m, 2 H, CH2CH2COH), 1.21 [s, 3 H, (CH3)2COH], 1.21 H), 3.27–3.23 (m, 1 H, C4-H), 3.17 (dd, J = 7.8, 9.0 Hz, 1 H, C2-
[s, 3 H, (CH3)2COH] ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5
H), 1.66 (d, J = 0.6 Hz, 3 H, CCH3), 1.64–1.54 (m, 2 H,
(1 C, CH3COOCH), 136.0 (1 C, CHCCH3), 126.9 (1 C, OCH2CH), CH2CH2COAc), 1.54–1.48 (m, 1 H, CH2CH2COAc), 1.38–1.31 (m,
5.5, 11.9 Hz, 1 H, C6-H2), 3.36–3.30 (m, 1 H, C3-H), (m, 1 H, C5-
78.8 (1 C, CHOAc), 70.5 [1 C, (CH3)2COH], 58.8 (1 C, OCH2CH),
1 H, CH2CH2COAc), 1.18 [s, 3 H, (CH3)2COH], 1.17 [s, 3 H,
38.1 (1 C, CH2CH2COAc), 29.3 [1 C, (CH3)2COH], 29.1 [1 C, (CH3)2COH] ppm. 13C NMR (100 MHz, CD3OD): δ = 143.1 (1 C,
(CH3)2COH], 27.3 (1 C, CH2CH2COAc), 21.2 (1 C, CH3COOCH), CHCCH3), 123.0 (1 C, OCH2CH), 103.0 (1 C, C1-H), 78.5 (1 C,
12.2 (1 C, CH C) ppm. IR (ATR): ν = 3365 (m, br.), 2968 (m),
CHOH), 78.2 (1 C, C3-H), 78.1 (1 C, C4-H), 75.1 (1 C, C2-H),
˜
3
2930 (m), 1717 (m), 1370 (m), 1235 (s), 1156 (m), 1017 (m), 945 71.8 (1 C, C5-H), 71.2 [1 C, (CH3)2COH], 66.2 (1 C, OCH2CH),
(m), 600 (m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (3.64) nm. 62.8 (1 C, C6-H), 40.8 (1 C, CH2CH2CHOH), 30.6 (1 C,
HRMS (ESI): calcd. for C12H22O4Na [M + Na]+ 253.14103; found
253.14079.
CH2CH2CHOH), 29.3 [1 C, (CH3)2COH], 29.2 [1 C, (CH3)2COH],
11.8 (1 C, CH C) ppm. IR (ATR): ν = 3332 (m, br.), 2965 (m),
˜
3
2923 (m), 2873 (m), 1369 (m), 1072 (s), 1016 (s), 903 (m) cm–1. UV/
Vis (MeOH): λmax (lgε) = 202 (3.60) nm. MS (ESI): m/z (%) = 373
(100), 374 (18). HRMS (ESI): calcd. for C16H30O8Na [M + Na]+
373.1833; found 373.1838.
(2R,3R,4S,5R,6R)-2-{[(2E,4S)-4-Acetoxy-7-hydroxy-3,7-dimeth-
yloct-2-en-1-yl]oxy}-6-[(pivaloyloxy)methyl]tetrahydro-2H-pyran-
3,4,5-triyl Tris(2,2-dimethylpropanoate) (26): 2,3,4,6-Tetra-O-piva-
loyl-α-d-glucopyranosyl bromide (20, 452 mg, 0.78 mmol,
1.5 equiv.) and Ag2CO3 (359 mg, 1.3 mmol, 2.5 equiv.) were added
under Ar to a solution of 25 (120 mg, 0.52 mmol, 1.0 equiv.) in
anhydrous Et2O (6 mL). The mixture was stirred at room temp. in
the dark for 15 h. A second portion of 2,3,4,6-tetra-O-pivaloyl-α-
d-glucopyranosyl bromide (20, 150 mg, 0.26 mmol, 0.5 equiv.) was
added, and the mixture was stirred for 24 h. The solution was then
filtered, and the solvent was evaporated. After chromatography (sil-
ica gel, petroleum ether/EtOAc, 5:1 Ǟ 3:1), 26 (268 mg, 0.37 mmol,
71%) was obtained as a colorless oil. Rf (petroleum ether/EtOAc,
(2S,3E)-5-[(tert-Butyldiphenylsilanyl)oxy]-1-(3,3-dimethyloxiran-2-
yl)-3-methylpent-3-en-2-ol (27): NaOMe solution (30% in MeOH,
0.96 mmol, 177 μL, 1.3 equiv.) was added to a solution of 17
(300 mg, 0.64 mmol, 1 equiv.) in MeOH (35 mL). After the mixture
had been kept at room temp. for 4 h, the solvent was evaporated,
and the crude product was purified by flash chromatography (silica
gel, petroleum ether/EtOAc, 4:1). Compound 27 (249 mg,
0.59 mmol, 92%) was obtained as a colorless viscous oil. Rf (petro-
1
leum ether/EtOAc, 4:1) = 0.28. [α]2D4 = –2.8 (c = 1.36, acetone). H
1
3:1) = 0.29. [α]2D2 = –8.1 (c = 1.90, acetone). H NMR (600 MHz,
NMR (400 MHz, CDCl3): δ = 7.70–7.67 (m, 8 H, Ph-o-H), 7.45–
7.36 (m, 12 H, Ph-m-H, Ph-p-H), 5.69–5.64 (m, 2 H, OCH2CH),
4.28–4.27 (m, 4 H, OCH2CH), 4.25–4.15 (m, 2 H, CHOAc), 2.88
CDCl3): δ = 5.50 (t, J = 6.6 Hz, 1 H, OCH2CH), 5.32 (t, J = 9.6 Hz,
1 H, C3-H), 5.13–5.09 (m, 2 H, CHOAc, C4-H), 5.02 (dd, J = 9.7,
8.1 Hz, 1 H, C2-H), 4.53 (d, J = 8.1 Hz, 1 H, C1-H), 4.33 (dd, J = [dd, J = 4.7, 7.3 Hz, 1 H, (CH3)2CCH], 2.84 [dd, J = 4.8, 7.7 Hz,
6.2, 12.4 Hz, 1 H, OCH2CH), 4.24–4.22 (m, 1 H, C6-H2), 4.16 (dd, 1 H, (CH3)2CCH], 1.99 (d, J = 2.7 Hz, 1 H, CHOH), 1.83–1.76
J = 7.3, 12.4 Hz, 1 H, OCH2CH), 4.07 (dd, J = 5.7, 12.3 Hz, 1 H, (m, 2 H, CH2CHOAc), 1.69–1.57 (m, 2 H, CH2CHOAc), 1.46 (d,
C6-H2), 3.73 (ddd, J = 10.1, 5.7, 1.9 Hz, 1 H, C5-H), 2.06 (s, 3 H,
J = 1.0 Hz, 3 H, CH3C), 1.45 (d, J = 1.0 Hz, 3 H, CH3C), 1.31 [s,
CH3COOCH), 1.73–1.68 (m, 2 H, CH2CH2COAc), 1.64 (s, 3 H, 3 H, (CH3)2C], 1.31 [s, 3 H, (CH3)2C], 1.28 [s, 3 H, (CH3)2C], 1.27
CCH3), 1.49–1.42 (m, 1 H, CH2CH2COAc), 1.39–1.33 (m, 1 H, [s, 3 H, (CH3)2C], 1.04 [s, 18 H, (CH3)3C] ppm. 13C NMR
CH2CH2COAc), 1.23 [s, 9 H, (CH3)3CCOO-C6], 1.21 [s, 6 H, (100 MHz, CDCl3): δ = 138.3 (1 C, CHCCH3), 137.7 (1 C,
(CH3)2COH], 1.15 [s, 18 H, (CH3)3CCOO-C2, (CH3)3CCOO-C4], CHCCH3), 135.6 (8 C, o-CPh), 133.9 (2 C, ipso-CPh), 133.9 (2 C,
1.11 [s, 9 H, (CH3)3CCOO-C3] ppm. 13C NMR (100 MHz, CDCl3):
ipso-CPh), 129.6 (4 C, p-CPh), 127.6 (8 C, m-CPh), 125.9 (1 C,
δ = 178.0 [1 C, (CH3)3CCOO-C6], 177.1 [1 C, (CH3)3CCOO-C3], OCH2CH), 125.6 (1 C, OCH2CH), 75.6 (1 C, CHOOH), 74.7 (1 C,
176.4 [1 C, (CH3)3CCOO-C2], 176.3 [1 C, (CH3)3CCOO-C4], 170.1
(1 C, CH3 COO-CH), 138.0 (1 C, CHCCH3), 122.6 (1 C,
CHOOH), 62.2 [1 C, (CH3)2CCH], 61.4 [1 C, (CH3)2CCH], 60.8 (2
C, OCH2CH), 58.3 [1 C, (CH3)2C], 57.8 [1 C, (CH3)2C], 34.1 (1 C,
OCH2CH), 99.5 (1 C, C1-H), 78.3 (1 C, CHOAc), 72.1 (1 C, C5- CH2CHOAc), 34.1 (1 C, CH2CHOAc), 26.8 [6 C, (CH3)3C], 24.8
H), 72.0 (1 C, C3-H), 70.8 (1 C, C2-H), 70.2 [1 C, (CH3)2C], 67.9 [1 C, (CH3)2C], 24.7 [1 C, (CH3)2C], 19.1 [2 C, (CH3)3C], 19.0 [1
(1 C, C4-H), 64.7 (1 C, OCH2CH), 61.9 (1 C, C6-H), 39.0 (1 C, C, (CH3)2C], 19.0 [1 C, (CH3)2C], 12.1 (1 C, CH3C), 11.9 (1 C,
CH2CH2CHOAc), 38.7 [1 C, (CH3)3CCOO-C6], 38.6 [1 C, CH C) ppm. IR (ATR): ν = 3439 (w, br.), 2959 (m), 2857 (m), 1428
˜
3
1500
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1493–1503

Total Syntheses of Rhodiolosides A and D and of Sachalinols A–C
(m), 1380 (m), 1109 (s), 1049 (m), 823 (m), 740 (m), 702 (s), 611 THF (3 mL). After 3 h at room temp., the solvent was evaporated,
(m) cm–1. UV/Vis (MeOH): λmax (lgε) = 204 (4.47) nm. MS (EI):
and the crude product was subjected to column chromatography
m/z (%) = 367 (2), 289 (9), 199 (100), 139 (21), 43 (21). HRMS (silica, CHCl3/MeOH, 10:1) to yield 6 (7 mg, 0.04 mmol, 80%) as
(EI): calcd. for C22H27O3Si [M – tBu]+ 367.1729; found 367.1723.
a colorless oil. Rf (CHCl3/MeOH, 8:1) = 0.38. [α]2D4 = –29.2 (c =
0.24, MeOH). H NMR (400 MHz, CD3OD): δ = 5.66–5.63 (m, 1
1
(3R,5S)-5-{(2E)-4-[(tert-Butyldiphenylsilanyl)oxy]but-2-en-2-yl}-
2,2-dimethyltetrahydrofuran-3-ol (28) and (3S,5S)-5-{(2E)-4-[(tert-
Butyldiphenylsilanyl)oxy]but-2-en-2-yl}-2,2-dimethyltetrahydro-
furan-3-ol (29): The epoxide 27 (1.06 g, 2.5 mmol, 1.0 equiv.) was
dissolved in DCM (250 mL). Camphorsulfonic acid (145 mg,
0.62 mmol, 0.25 equiv.) was added at 0 °C, and the solution was
stirred at room temp. for 16 h. The reaction was quenched with a
saturated aqueous NaHCO3 solution, extracted with DCM, and
washed with brine, and the solvent was evaporated. A mixture of
the diastereomers 28 and 29 (1.04 mg, 2.4 mmol, 98%) was ob-
tained after quick column chromatography (silica, petroleum ether/
EtOAc, 4:1). A portion (70 mg) was separated by semipreparative
HPLC (LiChrospher Si-60, 5 μm, n-hexane/ethyl acetate, 77:23) to
yield 28 (19 mg) and 29 (10 mg), together with a mixture of 28 and
29 (35 mg).
H, OCH2CH), 4.51 (t, J = 6.5 Hz, OCHCCH), 4.12 (d, J = 6.5 Hz,
2 H, OCH2CH), 3.93 [dd, J = 3.9, 6.0 Hz, 1 H, HOCHC(CH3)2],
2.08 (ddd, J = 6.1, 8.7, 13.1 Hz, 1 H, CH2CHO), 1.97 (ddd, J =
3.9, 6.9, 13.0 Hz, 1 H, CH2CHO), 1.62 (s, 3 H, CH3C), 1.22 [s, 3
H, (CH3)2C], 1.22 [s, 3 H, (CH3)2C] ppm. 13C NMR (100 MHz,
CD3OD): δ = 139.0 (1 C, CHCCH3), 125.9 (1 C, OCH2CH), 84.8
[1 C, (CH3)2C], 82.3 (1 C, OCHCCH), 78.5 [1 C, HOCHC(CH3)2],
59.2 (1 C, OCH2CH), 39.8 (1 C, CH2CHO), 28.1 [1 C, (CH3)2C],
22.0 [1 C, (CH ) C], 12.0 (1 C, CH C) ppm. IR (ATR): ν = 3352
˜
3 2
3
(m, br.), 2972 (m), 2933 (m), 2879 (m), 1677 (m), 1460 (m), 1370
(m), 1180 (m), 1134 (m), 1092 (m), 989 (s), 801 (m), 593 (m), 538
(m) cm–1. UV/Vis (MeOH): λmax (lgε) = 202 (3.63) nm. HRMS
(ESI): calcd. for C10H18O3Na [M + Na]+ 209.11482; found
209.11478.
(+)-Sachalinol C (7): TBAF·3H2O (1 m in THF, 180 μL, 1.5 equiv.)
was added to a solution of 29 (46 mg, 0.12 mmol, 1.0 equiv.) in
THF (12 mL). After 3 h at room temp., the solvent was evaporated,
and the crude product was subjected to column chromatography
(silica, CHCl3/MeOH, 10:1) to yield 7 (18 mg, 0.04 mmol, 89%) as
a colorless oil. Rf (CHCl3/MeOH, 8:1) = 0.39. [α]2D9 = +47.0 (c =
Compound 28: Rf (petroleum ether/EtOAc, 4:1) = 0.27. [α]2D4 = –14.6
(c = 1.92, MeOH). 1H NMR (600 MHz, CDCl3): δ = 7.69–7.67 (m,
4 H, Ph-o-H), 7.43–7.36 (m, 6 H, Ph-m-H, Ph-p-H), 5.73–5.70 (m,
1 H, OCH2CH), 4.52 (dd, J = 6.9, 8.7 Hz, OCHCCH), 4.26 (d, J
= 6.1 Hz, 2 H, OCH2CH), 3.98 [dd, J = 3.5, 5.7 Hz, 1 H,
HOCHC(CH3)2], 2.03 (ddd, J = 5.8, 9.0, 13.2 Hz, 1 H, CH2CHO),
1.95 (ddd, J = 3.4, 6.7, 13.2 Hz, 1 H, CH2CHO), 1.40 (d, J =
1.0 Hz, 3 H, CH3C), 1.27 [s, 3 H, (CH3)2C], 1.22 [s, 3 H, (CH3)2C],
1.03 [s, 9 H, (CH3)3C] ppm. 13C NMR (125 MHz, CDCl3): δ =
136.0 (1 C, CHCCH3), 135.6 (2 C, o-CPh), 133.9 (1 C, ipso-CPh),
133.8 (1 C, ipso-CPh), 129.5 (2 C, p-CPh), 129.5 (2 C, p-CPh), 127.6
(2 C, m-CPh), 127.6 (2 C, m-CPh), 125.6 (1 C, OCH2CH), 83.0 [1
C, (CH3)2C], 80.9 (1 C, OCHCCH), 78.3 [1 C, HOCHC(CH3)2],
60.8 (1 C, OCH2CH), 38.9 (1 C, CH2CHO), 27.8 [1 C, (CH3)2C],
26.8 [3 C, (CH3)3C], 21.5 [1 C, (CH3)2C], 19.1 [1 C, (CH3)3C], 11.9
1
0.06, MeOH). H NMR (600 MHz, CD3OD): δ = 5.66–5.63 (m, 1
H, OCH2CH), 4.31 (dd, J = 6.7, 9.3 Hz, OCHCCH), 4.12 (dd, J =
6.6, 3.8 Hz, 2 H, OC H2 CH), 4. 01 [t, J = 6.7 Hz, 1 H,
HOCHC(CH3)2], 2.35 (ddd, J = 6.7, 6.7, 12.8 Hz, 1 H, CH2CHO),
1.76 (ddd, J = 7.3, 9.4, 12.7 Hz, 1 H, CH2CHO), 1.65 (d, J =
1.0 Hz, 3 H, CH3C), 1.22 [s, 3 H, (CH3)2C], 1.18 [s, 3 H, (CH3)2C]
ppm. 13C NMR (125 MHz, CD3OD): δ = 138.8 (1 C, CHCCH3),
126.0 (1 C, OCH2CH), 83.7 [1 C, (CH3)2C], 80.8 (1 C, OCHCCH),
78.7 [1 C, HOCHC(CH3)2], 59.2 (1 C, OCH2CH), 39.9 (1 C,
CH2CHO), 26.7 [1 C, (CH3)2C], 23.3 [1 C, (CH3)2C], 12.0 (1 C,
(1 C, CH C) ppm. IR (ATR): ν = 3425 (w, br.), 2964 (m), 2932
˜
3
CH C) ppm. IR (ATR): ν = 3351 (m, br.), 2969 (m), 2929 (m),
˜
3
(m), 2891 (m), 2857 (m), 1467 (m), 1428 (m), 1380 (m), 1364 (m),
1109 (m), 1085 (m), 1054 (m), 1024 (m), 1009 (m), 857 (m), 822
(m), 788 (m), 740 (m), 702 (s), 612 (m) cm–1. UV/Vis (MeOH): λmax
(lgε) = 265 (2.82), 259 (2.82), 204 (4.45) nm. HRMS (ESI): calcd.
for C26H36O3SiNa [M + Na]+ 447.23259; found 447.23261.
2873 (m), 1677 (m), 1453 (m), 1368 (m), 1259 (m), 1203 (m), 1142
(m), 1073 (m), 1003 (s), 836 (m), 799 (m) cm–1. UV/Vis (MeOH):
λmax (lgε) = 203 (3.48) nm. MS (EI): m/z (%) = 168 (2), 155 (100),
150 (3), 137 (9), 110 (11), 81 (59), 69 (71). HRMS (ESI): calcd. for
C10H18O3Na [M + Na]+ 209.11482; found 209.11479.
Compound 29: Rf (petroleum ether/EtOAc, 4:1) = 0.28. [α]2D9 = +3.7
(c = 0.51, MeOH). 1H NMR (400 MHz, CDCl3): δ = 7.69–7.67 (m,
4 H, Ph-o-H), 7.44–7.35 (m, 6 H, Ph-m-H, Ph-p-H), 5.78–5.74 (m,
1 H, OCH2CH), 4.31 (t, J = 7.5 Hz, OCHCCH), 4.26 (d, J =
6.1 Hz, 2 H, OCH2CH), 3.98–3.94 [m, 1 H, HOCHC(CH3)2], 2.46–
2.39 (m, 1 H, CH2CHO), 1.73 (ddd, J = 4.5, 7.1, 13.4 Hz, 1 H,
CH2CHO), 1.45 (d, J = 0.8 Hz, 3 H, CH3C), 1.28 [s, 3 H,
(CH3)2C], 1.21 [s, 3 H, (CH3)2C], 1.03 [s, 9 H, (CH3)3C] ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.0 (1 C, CHCCH3), 135.6 (2 C,
o-CPh), 133.9 (1 C, ipso-CPh), 133.9 (1 C, ipso-CPh), 129.5 (2 C, p-
CPh), 127.6 (2 C, m-CPh), 127.6 (2 C, m-CPh), 124.8 (1 C,
OCH2CH), 82.9 [1 C, (CH3)2C], 79.3 (1 C, OCHCCH), 78.3 [1 C,
HOCHC(CH3)2], 60.8 (1 C, OCH2CH), 39.4 (1 C, CH2CHO), 26.8
[3 C, (CH3)3C], 25.8 [1 C, (CH3)2C], 22.4 [1 C, (CH3)2C], 19.1 [1
2,3,4,6-Tetra-O-pivaloyl-α-D-glucopyranosyl Iodide (22): Hexa-
methyldisilane (165 μL, 0.8 mmol, 0.6 equiv.) and iodine (203 mg,
0.8 mmol, 0.6 equiv.) were added to a solution of pentapivaloylglu-
cose (760 mg, 1.3 mmol, 1.0 equiv.) in DCM (3 mL). The brown
solution was stirred at room temp. for 3.5 h. The reaction mixture
was quenched with saturated aqueous Na2S2O3 solution and stirred
until the solution was colorless. The aqueous phase was extracted
with DCM, and the organic phases were washed with aqueous
NaHCO3 solution and brine and dried with MgSO4. The crude
product was subjected to flash chromatography with petroleum
ether/EtOAc to yield 22 (650 mg, 1.04 mmol, 80%) as a colorless
solid. M.p. 140–142 °C. Rf (petroleum ether/EtOAc, 20:1) = 0.29.
1
[α]3D1 = +168.0 (c = 1.25, CHCl3). H NMR (400 MHz, CDCl3): δ
= 6.99 (d, J = 4.4 Hz, 1 H, C1-H), 5.54 (t, J = 9.6 Hz, 1 H, C3-
H), 5.26–5.21 (m, 1 H, C4-H), 4.22 (dd, J = 4.4, 9.8 Hz, 1 H, C2-
H), 4.18 (d, J = 3.4 Hz, 2 H, C6-H2), 4.08 (td, J = 3.3, 10.8 Hz, 1 H,
C5-H), 1.22 [s, 9 H, C6-OOC(CH3)3], 1.20 [s, 9 H, C2-OOC(CH3)3],
1.19 [s, 9 H, C4-OOC(CH3)3], 1.13 [s, 9 H, C3-OOC(CH3)3] ppm.
13C NMR (100 MHz, CDCl3): δ = 177.9 [1 C, C6-OOCC(CH3)3],
177.1 [1 C, C2-OOCC(CH3)3], 176.7 [1 C, C3-OOCC(CH3)3], 176.4
[1 C, C4-OOCC(CH3)3], 75.4 (1 C, C5-H), 73.4 (1 C, C1-H), 71.1
(1 C, C3-H), 70.4 (1 C, C2-H), 66.3 (1 C, C4-H), 60.8 (1 C, C6-
C, (CH ) C],12.3 (1 C, CH C) ppm. IR (ATR): ν = 3429 (w, br.),
˜
3 3
3
2960 (m), 2890 (m), 2858 (m), 1469 (m), 1428 (m), 1109 (m), 1001
(m), 854 (m), 821 (m), 740 (m), 701 (s), 609 (m) cm–1. UV/Vis
(MeOH): λmax (lgε) = 259 (3.10), 218 (4.24), 203 (4.40) nm. HRMS
(ESI): calcd. for C26H36O3SiNa [M + Na]+ 447.23259; found
447.23266.
(–)-Sachalinol B (6): TBAF·3H2O (1 m in THF, 70 μL, 1.5 equiv.)
was added to a solution of 28 (19 mg, 0.05 mmol, 1.0 equiv.) in
Eur. J. Org. Chem. 2011, 1493–1503
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1501

K. Simon, P. G. Jones, T. Lindel
FULL PAPER
H2), 38.9 [1 C, C6-OOCC(CH3)3], 38.8 [1 C, C4-OOCC(CH3)3],
38.7 [1 C, C3-OOCC(CH3)3], 38.6 [1 C, C2-OOCC(CH3)3], 27.1 [2
C, C2-OOCC(CH3 )3 ; C2-OOCC(CH3 )3 ], 27.1 [1 C, C6-
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Li597/4-1). Henning Kuhz is thanked for laboratory assistance. We
also thank Merck KGaA (Darmstadt, Germany) for a generous
gift of chromatography materials. BASF AG (Ludwigshafen, Ger-
many) and Honeywell Specialty Chemicals Seelze GmbH (Seelze,
Germany) are thanked for the donation of solvents.
OOCC(CH ) ], 27.0 [1 C, C4-OOCC(CH ) ] ppm. IR (ATR): ν =
˜
3 3
3 3
2972 (m), 1733 (s), 1480 (m), 1278 (m), 1123 (s), 1084 (m), 1035
(m), 987 (m), 763 (m), 563 (m) cm–1. UV/Vis (MeOH): λmax (lgε)
= 263 nm (3.02), 203 (4.00). HRMS (ESI): calcd. for C26H43O9INa
[M + Na]+ 649.18440; found 649.18189.
(2R,3R,4S,5R,6R)-2-{[(2E)-3,7-Dimethylocta-2,6-dien-1-yl]oxy}-
6-[(pivaloyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyl Tris(2,2-di-
methylpropanoate) (24): Geraniol (19, 100 mg, 0.64 mmol,
1.0 equiv.) was dissolved in anhydrous Et2O (6 mL) under Ar.
2,3,4,6-Tetra-O-pivaloyl-α-d-glucopyranosyl bromide (20, 556 mg,
0.96 mmol, 1.5 equiv.) and Ag2CO3 (442 mg, 1.6 mmol, 2.5 equiv.)
were added to the resulting solution, and the mixture was stirred
at room temp. in the dark for 22 h. The solution was then filtered,
and the solvent was evaporated. After chromatography (silica gel,
petroleum ether/EtOAc, 20:1) 24 (282 mg, 0.43 mmol, 67%) was
obtained as a colorless oil. Rf (petroleum ether/EtOAc, 20:1) =
0.29. [α]3D1 = 1.25 (c = 2.87, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 5.31 (t, J = 9.5 Hz, 1 H C3-H), 5.26–5.22 (m, 1 H, OCH2CH),
5.13–5.06 [m, 2 H, C4-H, (CH3)2CCH], 5.04–5.00 (m, 1 H, C2-H),
4.53 (d, J = 8.1 Hz, 1 H, C1-H), 4.27–4.18 (m, 3 H, OCH2CH, C6-
H2), 4.07 (dd, J = 5.8, 12.2 Hz, 1 H, C6-H2), 3.70 (ddd, J = 1.7,
5.7, 10.1 Hz, 1 H, C5-H), 2.11–2.02 (m, 4 H, CCH2CH2), 1.70 [s,
3 H, C(CH3)2], 1.65 [s, 3 H, C(CH3)2], 1.61 (s, 3 H, CCH3), 1.23–
1.23 [m, 9 H, C(CH3)3], 1.60–1.54 [m, 18 H, 2ϫ C(CH3)3], 1.11 [m,
9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 177.9 [1 C,
OCC(CH3)3], 177.1 [1 C, OCC(CH3)3], 176.3 [2 C, 2 ϫ OCC-
(CH3)3], 141.6 (1 C, CCH3), 131.7 [1 C, C(CH3)2], 123.6 [1 C,
(CH3)2CCH], 119.3 (1 C, OCH2CH), 98.8 (1 C, C1-H), 72.2 (2 C,
C3-H, C5-H), 71.0 (1 C, C2-H), 68.1 (1 C, C4-H), 64.8 (1 C,
OCH2CH), 62.1 (1 C, C6-H2), 39.4 (1 C, CCH2CH2), 38.7 [1 C,
OCC(CH3)3], 38.6 [1 C, OCC(CH3)3], 38.6 [2 C, 2ϫ OCC(CH3)3],
27.0 [3 C, OCC(CH3)3], 27.0 [3 C, OCC(CH3)3], 26.9 [3 C,
OCC(CH3)3], 26.9 [3 C, OCC(CH3)3], 26.2 (1 C, CCH2CH2), 25.6
[1 C, C(CH3)2], 17.6 (1 C, CCH3), 16.3 [1 C, C(CH3)2] ppm. IR
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X-ray Structure Analysis of (–)-3·2H2O: Crystal data: C10H24O5,
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Supporting Information (see footnote on the first page of this
article): NMR spectra of compounds 3, 15–18, 22, 24–32; packing
of 3 in the crystal; Mosher analysis of compounds 28 and 29.
1502
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1493–1503

Total Syntheses of Rhodiolosides A and D and of Sachalinols A–C
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Received: September 21, 2010
[25]
Published Online: February 2, 2011
Eur. J. Org. Chem. 2011, 1493–1503
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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