Total synthesis of (-)-fasicularin and (-)-lepadiformine a based on zn-mediated allylation of chiral N-tert-butanesulfinyl ketimine

Article abstract of DOI:10.1002/ejoc.200901422

The stereoselective total synthesis of fasicularin (1) and lepadiformine A (2) is described, which features the utilization of a Zn-mediated allylation of a chiral, aliphatic, N-tertbutariesulfinyl ketimlne to construct the amino-substituted quaternary carbon center in good yield and with excellent diastereoselectivity. The azaspirocyclic scaffold was installed sequentially by a Sharpless dihydroxylation and an internal epoxide-opening reaction, and this scaffold was further converted into common intermediate S. Removing the tosyl (Ts) protecting group of 5 and reductively animating using Luche's reagent completed the synthesis of (-)-fasicularin (1), while reducing S using L-selectride, deprotecting the Ts group, and finishing with an intramolecular amino alcohol cyclocondensation completed the total synthesis of (-)lepadiformine A (2).

Full text of DOI:10.1002/ejoc.200901422

FULL PAPER
DOI: 10.1002/ejoc.200901422
Total Synthesis of (–)-Fasicularin and (–)-Lepadiformine A Based on
Zn-Mediated Allylation of Chiral N-tert-Butanesulfinyl Ketimine
San-Lin Mei[a] and Gang Zhao*[a]
Keywords: Total synthesis / Alkaloids / Fasicularin / Lepadiformine A / Zinc / Allylation
The stereoselective total synthesis of fasicularin (1) and
lepadiformine A (2) is described, which features the utiliza-
tion of a Zn-mediated allylation of a chiral, aliphatic, N-tert-
butanesulfinyl ketimine to construct the amino-substituted
quaternary carbon center in good yield and with excellent
diastereoselectivity. The azaspirocyclic scaffold was installed
sequentially by a Sharpless dihydroxylation and an internal
epoxide-opening reaction, and this scaffold was further con-
verted into common intermediate 5. Removing the tosyl (Ts)
protecting group of 5 and reductively aminating using
Luche’s reagent completed the synthesis of (–)-fasicularin (1),
while reducing 5 using
L-selectride, deprotecting the Ts
group, and finishing with an intramolecular amino alcohol
cyclocondensation completed the total synthesis of (–)-
lepadiformine A (2).
Chiral N-tert-butanesulfinamide is a versatile reagent in
asymmetric synthesis, especially as an excellent chiral auxil-
iary for asymmetric induction in the preparation of all
kinds of synthetically useful chiral amines.[5] However, ap-
plications of this useful chiral auxiliary in the total synthe-
sis of complex natural products are rare. With our contin-
ued interest in the total synthesis of natural alkaloids
bearing an azaspirotricyclic skeleton with a sterically con-
gested, quaternary carbon center,[6] we hypothesized that
chiral N-tert-butanesulfinamides should be highly useful for
the synthesis of such alkaloids. Herein, we report the utili-
zation of a Zn-mediated, allylation reaction of a chiral N-
tert-butanesulfinyl ketimine as the key step in the synthesis
of (–)-fasicularin and (–)-lepadiformine A (1 and 2, respec-
tively, Figure 1).
Introduction
Lepadiformines A–C and fasicularin, separately isolated by
Biad et al. from Clavelina lepadiformis off the coast of Tuni-
sia and later from Clavelina moluccensis[1a–1c] and by Patil
et al. from Nephteis fasicularis collected in Pompeii,[1d] be-
long to a series of tricyclic, marine alkaloids bearing a com-
mon pyrrolo-/pyrido[1,2-j]quinoline framework including a
trans-1-azadecalin, A–B ring system. In addition to their
peculiar structures, these compounds also have some biolo-
gically interesting activities such as moderate in vitro cyto-
toxicity against several tumor cell lines, various cardiovas-
cular effects in vitro and in vivo and antiarrythmia proper-
ties.[1a,1c,2] Therefore, these complex structures have been
the focus of many synthetic efforts.[3,4]
Figure 1. Structures of lepadiformines A–C and fasicularin.
Results and Discussion
[a] Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences,
Retrosynthetic Analysis
345 Lingling Road, Shanghai 20032, P. R. of China
Fax: +86-21-64166128
We envisioned that both 1 and 2 could be obtained by
different cyclization processes from a common intermediate
5, which, in turn, could be derived from azaspirobicyclic
E-mail: Zhaog@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901422.
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Total Synthesis of (–)-Fasicularin and (–)-Lepadiformine A
Scheme 1. Retrosynthetic analysis.
alcohol 6 (Scheme 1). The synthesis of 6 could be achieved of our knowledge, there has been little study on the nucleo-
by an intramolecular Sharpless dihydroxylation sequence philic addition of organometallic reagents with chiral N-
from sulfonamide 7 with an amino-substituted, quaternary, tert-butanesulfinyl imines derived from aliphatic cyclic
carbon center. In view of the recent studies on the synthesis ketones, notwithstanding the great usefulness of the re-
of chiral homoallylic amines by the Zn-mediated allylation sulting chiral amine products.[5b,5c] At first, we attempted
of chiral N-tert-butanesulfinyl imines by Lin and cowork- to synthesize 7 directly by the addition of homoallylic metal
ers,[5b,5c] we envisaged that the allylation of the correspond- reagents. However, both the corresponding organolithium
ing, chiral, N-tert-butanesulfinyl ketimine 9 would produce and Grignard reagents provided the desired product in very
sulfinamide 8 with the desired chiral quaternary carbon low yield.[9] We then turned to the known, Zn-mediated,
center, which could be further converted to 7.
allylation system, because organozinc reagents are generally
less basic. To our delight, treating ketimine 9 with preacti-
vated Zn powder and allylic bromide in THF produced the
desired sulfinamide 8 in 89% yield and with a dr of up to
12:1 in the absence of a Lewis acid. Notably, in the case of
Construction of the Quaternary, Amino-Substituted Carbon
Center
Our synthetic route to the key sulfonamide intermediate the ketimines derived from simple aromatic ketones, stoi-
7 is outlined in Scheme 2. The condensation of chiral chiometric In(OTf)3 was required as an additive for the re-
ketone 10[7] (94% ee), and (R)-tert-butanesulfinamide with action to proceed.[5a] The stereochemical result of this
a known procedure[8] using Ti(OEt)4 as both the Lewis-acid transformation was tentatively explained by a chelated,
promoter and water scavenger afforded desired ketimine 9 chair-like, transition state model I (Scheme 2), in which the
in 72% combined yield and with a dr of 9:1; these isomers allyl-Zn could coordinate to the sulfinyl oxygen.[5a] We note
could be separated by chromatography on a multigram that the chiral sulfinyl group prevailed over chiral induction
scale. Next, efforts were directed to the construction of the by the substrate in the stereochemical outcome; when the
amino-substituted, quaternary, carbon center. To the best diastereomer of 9 with an (S) configuration at the tert-
Scheme 2. Synthesis of sulfonamide 7 with the quaternary carbon center.
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S.-L. Mei, G. Zhao
FULL PAPER
butanesulfinyl group underwent the same reaction, the pre- verted to mesylate 18. Treating 18 with excess potassium
dominant configuration of the newly created quaternary cyanide gave nitrile 19, which was treated with n-hexylmag-
center was (R). The subsequent removal of the tert-butane- nesium bromide to generate desired ketone 5 in excellent
sulfinyl group generated primary amine 11. After the pro- yield.
tection by the tosyl (Ts) group and hydroboration-oxidation
of 11,[10] the resulting primary alcohol 12 was converted
Completion of the Total Synthesis of (–)-Fasicularin
into the corresponding lactam 13 by TPAP oxidation.[11,12]
Having the ring-closure precursor for the third cycle of
the tricyclic alkaloids in hand, we first investigated its trans-
formation to (–)-fasicularin (1). The removal of the Ts
group of 5 with Na/naphthalene[16] generated a cyclized in-
termediate enamine in situ, which was directly reduced in
the next step without further purification because of its in-
stability (Scheme 4). After performing some experimenta-
tion, the Luche reduction[6,17] of the enamine was identified
as the optimum method, affording the desired tricyclic terti-
ary amine 20 as a single isomer. The subsequent removal of
the TBDPS group followed by Kibayashi’s procedure (see
the Experimental Section for details) completed the total
synthesis of (–)-fasicularin (1), whose spectroscopic data
were identical with those of reported values.[4g]
Reduction with DIBAL-H followed by a Wittig reaction
successfully gave desired sulfonamide 7. The structure of 13
was confirmed by the X-ray analysis of its ester, which was
obtained by replacing the benzyl group with a 4-nitrobenz-
oyl group (see the Supporting Information for details).
Preparation of Azaspirobicyclic Ketone 5
With sulfonamide 7 in hand, our designed strategy sub-
sequently called for the construction of the azaspirobicyclic
core. Disappointingly, the direct, intramolecular amino-
hydroxylation of 7 using m-CPBA[13] as the oxygen source
unselectively afforded spirocyclic alcohol 6 in 98% yield
with a 6/13-epi-6 diastereoselectivity of 1:1; these isomers
could not be separated by flash chromatography
(Scheme 3). Attempts to improve the diastereoselectivity by
an asymmetric epoxidation and ring-opening sequence
Completion of the Total Synthesis of (–)-Lepadiformin
To synthesize (–)-lepadiformine A, ketone 5 was first re-
using Shi’s epoxidation[14a] and Jacobsen’s epoxidation[14b] duced to the corresponding alcohol 22 (Scheme 5). Among
also failed. Finally, Sharpless dihydroxylation[15a,15b] fol- the various conditions screened for this transformation, the
lowed by selective protection[15c] gave isomers 14 and 15 reduction with -Selectride[4o] gave the desired product with
(14/15 = 2.8:1), which could be separated by column the best dr of 6:1 in 99% yield. After removing the Ts group
chromatography. Treating 14 with NaH gave 6 with the de- of 22, an intramolecular, Mitsunobu-type reaction gener-
sired configuration, which was confirmed by the X-ray crys- ated tricyclic 23 in excellent yield. We note that no desired
tallographic analysis of the corresponding diester 16 (see product was found without the addition of a catalytic
the Supporting Information for details). Having established amount of DMAP to the standard reaction conditions of
the azaspirobicyclic structure, the synthesis of ring-closure Ph3P, CBr4 and Et3N.[4g] Finally, the removal of the TBDPS
precursor 5 could be achieved by several routine steps. group led to the total synthesis of (–)-lepadiformine A (2),
TBDPS protection of 6 followed by the removal of the ben- whose spectroscopic data were identical with reported val-
zyl group led to primary alcohol 17, which was further con- ues.[4h]
Scheme 3. Synthesis of the azaspirobicyclic ketone 5.
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Total Synthesis of (–)-Fasicularin and (–)-Lepadiformine A
Scheme 4. Completion of the total synthesis of (–)-fasicularin (1).
Scheme 5. Completion of the total synthesis of (–)-lepadiformine A (2).
morpholine oxide, PCC: pyridinium chlorochromate, TPAP: tetra-
n-propylammonium perruthenate, TBDPS: tert-butyldiphenylsilyl.
Conclusions
In summary, we have successfully developed a Zn-medi-
ated allylation of a chiral, aliphatic, cyclic, N-tert-butane-
sulfinyl ketimine for the stereoselective total synthesis of
lepadiformine A and fasicularin. This flexible strategy
could also provide an amenable approach to the synthesis
of other analogues of the azaspirotricyclic alkaloids of this
family.
Ketimine 9: To chiral ketone 10 (2.0 g, 8.61 mmol) in distilled THF
(20 mL), were added (R)-tert-butanesulfinamide (1.46 g,
12.07 mmol) and Ti(OEt)4 (3.6 mL, 17.17 mmol) at room tempera-
ture, and the reaction mixture was refluxed overnight. After the
mixture was cooled to room temperature, the reaction was
quenched with anhydrous MeOH (8 mL) and saturated aqueous
NaHCO3 (0.2 mL) and stirred for 2 h. After the mixture was fil-
tered and concentrated, the reaction mixture was diluted with ethyl
acetate (EA) and dried with anhydrous MgSO4. After the mixture
was filtered and concentrated, it was purified by flash chromatog-
raphy [petroleum ether (PE)/EA, 5:1) to give ketimine 9 as a color-
less oil (2.0 g) and 5-epi-9 (200 mg) in a combined yield of 76%. Rf
Experimental Section
Explanation of Acronyms: CBS: Corey–Bakshi–Shibata reagent, m-
CPBA: m-chloroperbenzoic acid, (DHQD)2PHAL: 1,4-bis(9-O-di- = 0.42 (PE/EA = 3:1). [α]2D2 = –42.6 (c = 0.96, CHCl3). IR (neat):
1
hydroquinine)phthalazine, DIBAL-H: diisobutyaluminum hydride,
DMP: Dess–Martin periodinane, DMAP: 4-(dimethylamino)pyr-
idine, NaHMDS: sodium hexamethyldisilazane, NMO: N-methyl-
ν = 1625 cm–1. H NMR (300 MHz, CDCl ): δ = 7.33–7.26 (m, 5
˜
3
H), 4.45 (s, 2 H), 3.52 (t, J = 6.5 Hz, 2 H), 3.45 (d, J = 12.9 Hz, 1
H), 2.56–2.44 (m, 1 H), 2.20–1.99 (m, 4 H), 1.73–1.48 (m, 5 H),
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S.-L. Mei, G. Zhao
1.21 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 190.0, 138.3, were separated, and the aqueous layer was extracted with EA
FULL PAPER
128.2, 127.5, 127.4, 72.7, 67.8, 56.0, 45.8, 35.2, 34.5, 30.7, 28.6,
25.0, 22.0 ppm. ESI-MS: calcd. for C19H29NO2S 335.2; found m/z
[M + Na]+ 358.2. HRMS (MALDI): m/z 358.1811. [M + Na]+;
calcd. for C19H29NO2SNa 358.1817.
(10 mLϫ3). The combined organic phases were washed with brine
and dried with anhydrous Na2SO4. After the mixture was filtered
and concentrated, the mixture was purified by flash chromatog-
raphy (PE/EA, 25:1 to 3:1) to afford the protected amine product
(3.6 g) in quantitative yield.
5-epi-9: Rf = 0.35 (PE/EA = 3:1). [α]2D2 = –112.6 (c = 0.24, CHCl3).
1
IR (neat): ν = 1618 cm–1. H NMR (300 MHz, CDCl ): δ = 7.37–
To the protected amine product (3.6 g, 7.83 mmol) in distilled THF
(30 mL) was added 9-BBN (3.8 g, 31.15 mmol). After the mixture
was stirred for 24 h, saturated aqueous NaHCO3 (60 mL) and
H2O2 (30 mL) were added, and the mixture was stirred for 3 h. The
mixture was extracted with EA (20 mLϫ3). The combined organic
phases were washed with brine and dried with anhydrous Na2SO4.
After the mixture was filtered and concentrated, the mixture was
purified by flash chromatography (PE/EA, 3:1) to afford primary
alcohol 12 as a colorless oil (3.0 g) in 86% yield.
˜
3
7.27 (m, 5 H), 4.48 (AB, J = 12.6, 15.8 Hz, 2 H), 3.55–3.51 (m, 2
H), 3.33 (d, J = 13.5 Hz, 1 H), 2.58–2.49 (m, 1 H), 2.41–2.31 (m,
1 H), 2.27–2.16 (m, 1 H), 2.10–2.05 (m, 1 H), 1.94 (br., 1 H), 1.78
(br., 1 H), 1.65–1.51 (m, 3 H), 1.43–1.29 (m, 1 H), 1.22 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 190.3, 138.1, 128.0, 127.3,
127.2, 72.6, 67.8, 55.6, 45.6, 34.5, 34.0, 30.6, 27.7, 24.4, 21.9 ppm.
ESI-MS: calcd. for C19H29NO2S 335.2; found m/z [M + Na]+ 358.1.
HRMS (MALDI): m/z 358.1811, m/z [M + Na]+; calcd. for
C19H29NO2SNa 358.1817.
Rf = 0.46 (PE/EA, 1:1). [α]2D4 = –33.0 (c = 1.17, CHCl3). IR (neat):
1
ν = 3288, 1599, 1495, 1455 cm–1. H NMR (300 MHz, CDCl ): δ
˜
3
Sulfinamide 8: To ketimine 9 (620 mg, 1.85 mmol) in distilled THF
(10 mL) were added activated Zn powder (482 mg, 7.41 mmol) and
a solution of allyl bromide (0.64 mL, 7.41 mmol) in THF (5 mL),
and the mixture was stirred for 1 h at room temperature. The reac-
tion mixture was quenched with brine (15 mL) and saturated aque-
ous NaHCO3 (2 mL). After the mixture was stirred for 1 h, the
mixture was filtered through celite, and the filtrate was separated
and extracted with EA. The combined organic phases were washed
with brine and dried with anhydrous Na2SO4. After the mixture
was filtered and concentrated, the mixture was purified by flash
chromatography (PE/EA, 5:1) to afford 8 as a colorless oil (622 mg)
in 89% yield. Rf = 0.35 (PE/EA, 3:1). [α]2D5 = –45.4 (c = 0.81,
= 7.77 (d, J = 7.5 Hz, 2 H), 7.36–7.21 (m, 7 H), 5.70 (s, 1 H), 4.54–
4.45 (m, 2 H), 3.62–3.35 (m, 4 H), 2.39 (s, 3 H), 2.05–1.94 (m, 3 H),
1.75–1.11 (m, 11 H), 0.91–0.84 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 142.5, 141.1, 138.4, 129.4, 128.3, 127.8, 127.5, 126.8,
72.9, 69.5, 62.7, 42.5, 32.1, 29.6, 28.6, 28.1, 25.4, 24.4, 22.1, 21.4
ppm. ESI-MS: calcd. for C25H35NO4S 445.2; found m/z [M +
Na]+ 468.3. HRMS (ESI): m/z 446.2360, m/z [M + H]+ calcd. for
C25H36NO4S 446.2365.
Lactam 13: To alcohol 12 (2.5 g, 5.62 mmol) in CH2Cl2 (50 mL)
were added 4 Å molecular sieves (2.5 g) and NMO (1.58 g,
13.49 mmol). After the mixture was stirred for 15 min, TPAP
(631 mg, 1.80 mmol) was added, and the mixture was stirred for an
additional 15 min. After the mixture was filtered and concentrated,
the mixture was purified by flash chromatography (PE/EA, 3:1) to
afford lactam 13 as a white solid (1.98 g) in 80% yield. Rf = 0.41
CHCl ). IR (neat): ν = 3290, 1631, 1453, 1261, 1068 cm–1. 1H
˜
3
NMR (500 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H), 5.94–5.79 (m, 1
H), 5.24–5.14 (m, 2 H), 4.49 (AB, J = 12.0, 28.4 Hz, 2 H), 3.55–
3.88 (m, 3 H), 2.57 (dd, J = 6.9, 14.4 Hz, 1 H), 2.08–1.93 (m, 8 H),
1.39–1.25 (m, 4 H), 1.19 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 138.5, 133.1, 128.3, 127.6, 127.5, 120.2, 73.0, 69.2, 59.6, 56.2,
40.8, 37.2, 36.6, 29.1, 28.1, 24.8, 22.9 ppm. ESI-MS: calcd. for
C22H35NO2S 377.2; found m/z [M + Na]+ 400.3. HRMS (MALDI):
m/z 400.2281, m/z [M + Na]+ calcd. for C22H35NO2SNa 400.2286.
(PE/EA, 3:1); m.p. 121–123 °C [α]1D9 = +17.8 (c = 1.00, CHCl3). IR
1
(KBr): ν = 1728 cm–1. H NMR (300 MHz, CDCl ): δ = 8.00 (d,
˜
3
J = 8.3 Hz, 2 H), 7.37–7.23 (m, 7 H), 4.54 (AB, J = 11.8, 16.2 Hz,
2 H), 3.61 (t, J = 6.8 Hz, 2 H), 2.78–2.67 (m, 2 H), 2.40–2.30 (m,
5 H), 2.15–2.06 (m, 1 H), 1.90–1.68 (m, 6 H), 1.40–1.27 (m, 3 H),
1.13–1.04 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.8,
144.5, 138.5, 136.4, 129.2, 129.0, 128.3, 127.7, 127.5, 75.2, 72.9,
68.6, 40.7, 37.8, 30.0, 29.8, 28.9, 25.1, 23.3, 21.6 ppm. ESI-MS:
calcd. for C25H31NO4S 441.2; found m/z [M + Na]+ 464.3. HRMS
(MALDI): m/z 464.1866, m/z [M + Na]+ calcd. for C25H31NO4SNa
464.1871.
Primary Amine 11: To 8 (3.45 g, 9.15 mmol) in distilled MeOH
(69 mL) was added HCl (4  in dioxane, 23 mL). After the mixture
was stirred for 10 min, saturated aqueous K2CO3 (23 mL) was
added, and the mixture was stirred for 10 min. After the mixture
was concentrated, distilled water (50 mL) was added, and the mix-
ture was extracted with EA (15 mLϫ3). The combined organic
phases were washed with brine and dried with anhydrous Na2SO4.
After the mixture was filtered and concentrated, the mixture was
purified by flash chromatography (PE/EA, 5:1) to afford primary
amine 11 as a colorless oil (2.3 g) in 92% yield. Rf = 0.47 (CH2Cl2/
Sulfonamide 7: To lactam 13 (1.73 g, 3.92 mmol) in CH2Cl2 (40 mL)
was added DIBAL-H (9.8 mL, 1.0  in cyclohexane, 9.8 mmol) at
–78 °C, and the mixture was stirred for another 2 h. The reaction
was warmed to –40 °C, quenched with MeOH (1.0 mL) and satu-
rated aqueous Rochelle‘s salt (100 mL) was added. The mixture
was stirred for 1 h at room temperature, the layers were separated,
and the aqueous layer was extracted with EA. The combined or-
ganic phases were washed with brine and dried with anhydrous
Na2SO4. After the mixture was filtered and concentrated, the mix-
ture was used directly in the next step without further purification.
EtOH, 9:1). [α]2D7 = –32.6 (c = 1.77, CHCl ). IR (neat): ν = 1637
˜
3
cm–1. H NMR (300 MHz, CDCl3): δ = 7.35–7.24 (m, 5 H), 5.91–
1
5.77 (m, 1 H), 5.12–5.05 (m, 2 H), 4.51 (AB, J = 11.2, 15.9 Hz, 2
H), 3.58–3.43 (m, 2 H), 2.32 (dd, J = 7.5, 13.5 Hz, 1 H), 2.06–1.89
(m, 2 H), 1.74–1.38 (m, 6 H), 1.26–1.03 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 134.1, 128.3, 127.5, 127.4, 118.0, 72.81, 69.4,
53.3, 45.1, 38.3, 37.4, 29.2, 28.0, 25.3, 22.6 ppm. ESI-MS: calcd.
To PPh3CH3Br (5.6 g, 15.68 mmol) in THF (20 mL) was slowly
added NaHMDS (7.65 mL, 2.0  in THF, 15.3 mmol) at 0 °C, and
stirring was continued for 0.5 h. After the mixture was cooled to
–78 °C, a solution of the reduced lactam, prepared above, in THF
(20 mL) was added, and stirring was continued at this temperature
for 20 min. The reaction mixture was allowed to stir at 0 °C and
then slowly warmed to room temperature and stirred for 2 h. The
reaction was quenched with saturated aqueous NH4Cl and ex-
tracted with EA. The combined organic phases were washed with
for C18H27NO 273.2; found m/z [M
+
H]+ 274.2. HRMS
(MALDI): m/z 274.2165, m/z [M + H]+ calcd. for C18H28NO
274.2171.
Alcohol 12: To primary amine 11 (2.3 g, 8.42 mmol) in distilled
CH2Cl2 (50 mL) were added Et3N (4.65 mL, 33.70 mmol), DMAP
(103 mg, 0.84 mmol) and TsCl (3.21 g, 16.84 mmol) at room tem-
perature. After the mixture was stirred overnight, the reaction was
quenched by the addition of distilled water (25 mL). The layers
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Total Synthesis of (–)-Fasicularin and (–)-Lepadiformine A
brine and dried with anhydrous Na2SO4. After the mixture was
filtered and concentrated, the mixture was purified by flash
chromatography (PE/EA, 9:1) to afford 7 as a colorless oil (1.6 g)
in 92% yield over two steps. Rf = 0.45 (PE/EA, 5:1). [α]2D4 = –22.7
Azaspirocyclic 6: To 14 (866 mg, 1.38 mmol) in THF (17 mL) was
added NaH (133 mg, 3.33 mmol) at 0 °C, and the mixture was
stirred for 12 h. The reaction was quenched with saturated aqueous
NH4Cl (5.0 mL) and extracted with EA (3ϫ10 mL). The combined
organic phases were washed with brine and dried with MgSO4.
After the mixture was filtered and concentrated, the mixture was
purified by flash chromatography (PE/EA, 5:3) to afford 6 (560 mg)
(c = 1.29, CHCl ). IR (neat): ν = 3284, 1094 cm–1. 1H NMR
˜
3
(300 MHz, CDCl3): δ = 7.74 (d, J = 8.2 Hz, 2 H), 7.36–7.26 (m, 5
H), 7.23 (d, J = 7.9 Hz, 2 H), 5.75–5.62 (m, 1 H), 5.22 (s, 1 H),
4.96–4.90 (m, 2 H), 4.52 (AB, J = 11.8, 19.4 Hz, 2 H), 3.56–3.42 in 89% yield. Rf = 0.56 (PE/EA, 5:4); m.p. 120–122 °C. [α]2D4
=
(m, 2 H), 2.39 (s, 3 H), 2.07–1.07 (m, 15 H) ppm. 13C NMR +41.1 (c = 0.98, CHCl ). IR (KBr): ν = 3480, 1153, 1095 cm–1. 1H
˜
3
(75 MHz, CDCl3): δ = 142.6, 141.0, 138.30, 138.26, 129.4, 128.3, NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 7.9 Hz, 2 H), 7.37–7.31
127.7, 127.5, 126.9, 114.8, 72.9, 69.4, 62.7, 42.8, 31.7, 31.4, 29.8,
28.7, 26.8, 24.4, 22.0, 21.4 ppm. ESI-MS: calcd. for C26H35NO3S
(m, 5 H), 7.22 (d, J = 8.2 Hz, 2 H), 4.43 (s, 2 H), 3.80–3.62 (m, 3
H), 3.47–3.39 (m, 1 H), 3.22–3.14 (m, 1 H), 2.87 (s, 1 H), 2.59 (td,
441.2; found m/z [M + Na]+ 464.1. HRMS (MALDI): m/z J = 3.2, 12.9 Hz, 1 H), 2.42–2.37 (m, 1 H), 2.10 (s, 1 H), 2.07–1.60
464.2220, m/z [M + Na]+ calcd. for C26H35NO3SNa 464.2235.
(m, 9 H), 1.25–0.96 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 143.1, 138.5, 138.4, 129.5, 128.4, 127.65, 127.56, 127.3, 75.7, 73.1,
69.2, 65.9, 63.2, 42.4, 39.7, 32.2, 31.1, 30.4, 28.0, 25.2, 24.6, 21.5
ppm. ESI-MS: calcd. for C26H35NO4S 457.2; found m/z [M +
Na]+ 480.1. HRMS (MALDI): m/z 480.2179, m/z [M + Na]+ calcd.
for C26H35NO4SNa 480.2184.
14 and 15: To K3Fe(CN)6 (3.22 g, 9.8 mmol), NaHCO3 (821 mg,
9.7 mmol), K2CO3 (1.35 g, 9.8 mmol), (DHQD)2PHAL (102 mg,
0.13 mmol), OsO4 (9 mg, 0.035 mmol) and MeSO2NH2 (310 mg,
3.3 mmol) in tBuOH/H2O (15:18, 33 mL), which was stirred at
room temperature for 20 min, was added 7 (1.44 g, 3.26 mmol) in
tBuOH (5 mL) at 0 °C, and stirring was continued overnight. The
reaction was then quenched with Na2SO3 (6.0 g), and distilled
water (10 mL) was added to dissolve the solid. The mixture was
extracted with EA (3ϫ10 mL), and the combined organic phases
were washed with brine and dried with anhydrous MgSO4. After
the mixture was filtered and concentrated, the mixture was purified
by flash chromatography (CH2Cl2/EtOH, 20:1) to afford the diol
(1.54 g) in 99% yield, and the crude product was directly used in
the next step.
Primary Alcohol 17: To 6 (400 mg, 1.38 mmol) in DMF (1.0 mL)
was added imidazole (239 mg, 3.51 mmol) and DMAP (11 mg,
0.09 mmol) at 0 °C, and the mixture was stirred overnight at room
temperature. The reaction was quenched with distilled water
(5.0 mL) and extracted with EA (3ϫ5 mL). The combined organic
phases were washed with brine and dried with MgSO4. After the
mixture was filtered and concentrated, the mixture was directly
used in the next step without further purification. To the crude
material, dissolved in MeOH (12 mL), was added Pd(OH)2/C un-
der an atmosphere of H2, and the mixture was stirred overnight.
After the mixture was filtered and concentrated, the mixture was
purified by flash chromatography (PE/EA, 10:1 to 2:1 to 1:4) to
afford 17 (500 mg) in 94% yield over two steps. Rf = 0.69 (PE/EA,
To the diol (1.7 g, 3.57 mmol) in CH2Cl2 (40 mL) were added
Bu2SnO (889 mg, 3.57 mmol), Et3N (0.59 mL, 4.28 mmol) and
TsCl (715 mg, 3.75 mmol), and the mixture was stirred overnight.
EA (40 mL) was added to dilute the mixture. After the mixture
was filtered and concentrated, the mixture was purified by flash
chromatography (PE/EA, 3:2) to afford 14 (1.49 g) and 15 (532 mg)
in a combined yield of 89%.
2:1); m.p. 140–142 °C. [α]2D4 = –24.6 (c = 1.10, CHCl3). IR (KBr):
1
ν = 3523 cm–1. H NMR (300 MHz, CDCl ): δ = 7.62–7.58 (m, 6
˜
3
H), 7.44–7.38 (m, 6 H), 7.14 (d, J = 7.6 Hz, 2 H), 4.03–3.96 (m, 1
H), 3.71 (d, J = 9.6 Hz, 1 H), 3.63 (br., 1 H), 3.45–3.36 (m, 2 H),
2.47–2.29 (m, 5 H), 2.08–1.04 (m, 11 H), 1.00 (s, 9 H), 0.96–0.82
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.7, 140.0,
135.63, 135.61, 133.44, 133.40, 129.73, 129.69, 129.3, 127.67,
127.65, 127.2, 75.0, 64.4, 62.5, 61.2, 42.2, 39.8, 34.1, 31.8, 30.3,
26.9, 26.1, 25.3, 24.5, 21.4, 19.2 ppm. ESI-MS: calcd. for
C35H47NO4SSi 605.3; found m/z [M + Na]+ 628.2. HRMS
(MALDI): m/z 628.2887, m/z [M + Na]+ calcd. for C35H47NO4S-
SiNa 628.2894.
14: Rf = 0.42 (PE/EA, 1:1). [α]1D9 = –15.2 (c = 0.91, CHCl3). IR
(neat): ν = 3524, 3305 cm–1. 1H NMR (300 MHz, CDCl ): δ = 7.80
˜
3
(d, J = 8.2 Hz, 2 H), 7.73 (d, J = 7.9 Hz, 2 H), 7.37–7.27 (m, 7 H),
7.22 (d, J = 8.2 Hz, 2 H), 5.63 (s, 1 H), 4.52–4.44 (m, 2 H), 3.91
(dd, J = 9.9, 3.2 Hz, 1 H), 3.80 (dd, J = 6.5, 10.0 Hz, 1 H), 3.62 (s,
1 H), 3.49–3.42 (m, 1 H), 3.40–3.35 (m, 1 H), 2.64 (d, J = 4.1 Hz,
1 H), 2.45 (s, 3 H), 2.39 (s, 3 H), 1.89–1.10 (m, 15 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 145.1, 142.6, 140.9, 138.2, 132.5,
130.0, 129.4, 128.4, 127.9, 127.8, 127.6, 126.8, 73.7, 72.9, 69.5, 69.3,
62.4, 42.4, 32.0, 29.5, 28.3, 27.5, 25.5, 24.1, 22.0, 21.6, 21.5 ppm.
ESI-MS: calcd. for C33H43NO7S2 629.2; found m/z [M + Na]+
652.1. HRMS (MALDI): m/z 652.2373, m/z [M + Na]+ calcd. for
C33H43NO7S2Na 652.2379.
Mesylate 18: To 17 (467 mg, 0.77 mmol) in CH2Cl2 (12 mL) were
added Et3N (0.32 mL, 2.32 mmol), DMAP (11 mg, 0.09 mmol) and
MsCl (0.12 mL, 1.55 mmol) at 0 °C, and the mixture was stirred
for 1 h. The reaction was quenched with distilled water (5 mL) and
extracted with EA (3ϫ5.0 mL). The combined organic phases were
washed with brine and dried with MgSO4. After the mixture was
15: Rf = 0.5 (PE/EA, 1:1). [α]1D9 = –13.7 (c = 1.30, CHCl3). IR
(neat): ν = 3524, 3299 cm–1. 1H NMR (300 MHz, CDCl ): δ = 7.81 filtered and concentrated, the mixture was directly used in the next
˜
3
(d, J = 7.9 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.38–7.27 (m, 7 H),
7.22 (d, J = 8.2 Hz, 2 H), 5.58 (s, 1 H), 4.55 (AB, J = 11.7, 14.7 Hz,
2 H), 3.91 (dd, J = 9.6, 3.2 Hz, 1 H), 3.82 (dd, J = 6.7, 10.0 Hz, 1
step without further purification. Rf = 0.44 (PE/EA, 3:1). [α]2D4
=
–18.7 (c = 0.70, CHCl ). IR (neat): ν = 1094 cm–1. 1H NMR
˜
3
(300 MHz, CDCl3): δ = 7.60–7.38 (12 H), 7.15 (d, J = 8.2 Hz, 2
H), 3.69 (s, 1 H), 3.52–3.42 (m, 1 H), 3.40–3.35 (m, 1 H), 2.45 (s, H), 4.24–4.13 (m, 1 H), 4.04–3.92 (m, 2 H), 3.68 (dd, J = 3.7,
4 H), 2.39 (s, 3 H), 1.82–1.11 (m, 15 H) ppm. 13C NMR (100 MHz, 10.1 Hz, 1 H), 3.35 (t, J = 9.6 Hz, 1 H), 3.00 (s, 3 H), 2.51–2.42
CDCl3): δ = 145.1, 142.7, 140.8, 138.2, 132.5, 130.0, 128.58, 128.4,
127.9, 127.8, 127.6, 126.8, 73.6, 72.9, 69.4, 69.3, 62.4, 42.8, 31.9,
29.8, 28.69, 27.4, 25.6, 24.3, 21.9, 21.6, 21.4 ppm. ESI-MS: calcd.
for C33H43NO7S2 629.2; found m/z [M + Na]+ 652.1. HRMS
(m, 2 H), 2.37 (s, 3 H), 2.05–1.83 (m, 2 H), 1.69–1.60 (m, 8 H),
1.25–1.02 (m, 2 H), 0.90 (s, 9 H), 0.88–0.81 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 143.0, 135.6, 133.4, 129.8, 129.7,
129.5, 127.69, 127.66, 127.03, 74.6, 68.5, 64.1, 62.2, 42.1, 39.9, 37.4,
31.8, 30.4, 30.2, 29.7, 26.9, 26.3, 25.1, 24.4, 21.5, 19.2 ppm. ESI-
MS: calcd. for C36H49NO6S2Si 683.3; found m/z [M + Na]+ 706.1.
(MALDI): m/z 652.2373, m/z [M
+
Na]+ calcd. for
C33H43NO7S2Na 652.2379.
Eur. J. Org. Chem. 2010, 1660–1668
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1665

S.-L. Mei, G. Zhao
FULL PAPER
HRMS (MALDI): m/z 706.2663, m/z [M + Na]+ calcd. for
C36H49NO6S2SiNa 706.2668.
bined organic phases were washed with brine and dried with anhy-
drous MgSO4. After the mixture was filtered and concentrated, the
mixture was purified by flash chromatography (PE/EA, 5:1) to af-
ford the desired tertiary amine 20 (6 mg) in 89% yield. Rf = 0.46
Nitrile 19: To 18 (the mixture described above) in DMSO (15 mL)
was added KCN (301 mg, 4.63 mmol), and the mixture was heated
at 60–70 °C for 5 h. After the mixture was cooled to room tempera-
ture, the reaction was quenched with distilled water (15 mL) and
extracted with EA (3ϫ10 mL). The combined organic phases were
washed with brine and dried with MgSO4. After the mixture was
filtered and concentrated, the mixture was purified by flash
chromatography (PE/EA, 4:1) to afford 19 (430 mg) in 91% yield
(PE/EA, 2:1). [α]2D8 = –3.7 (c = 0.80, CHCl ). IR (neat): ν = 3070,
˜
3
2928, 2857, 1462, 1428 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.67 (d, J = 6.9 Hz, 2 H), 7.42–7.33 (m, 6 H), 3.82 (dd, J = 5.9,
10.0 Hz, 1 H), 3.53 (dd, J = 9.6, 10.1 Hz, 1 H), 3.03–2.98 (m, 1 H),
2.38–2.23 (m, 1 H), 2.11–2.04 (m, 3 H), 1.80–1.06 (m, 26 H), 1.05 (s,
9 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 135.6, 129.5, 127.55, 127.52, 70.1, 67.6, 67.2, 62.6, 43.6, 38.6,
37.1, 32.0, 31.4, 30.8, 29.7, 27.0, 26.62, 26.55, 26.5, 26.3, 26.0, 24.7,
23.6, 22.6, 19.3, 14.1 ppm. ESI-MS: calcd. for C35H53NOSi 531.4;
found m/z [M + H]+ 532.4. HRMS (MALDI): m/z 532.3969, m/z
[M + H]+ calcd. for C35H54NOSi 532.3975.
over two steps. Rf = 0.5 (PE/EA = 4:1); m.p. 137–139 °C. [α]2D4
=
–40.4 (c = 0.84, CHCl ). IR (KBr): ν = 2235 cm–1. 1H NMR
˜
3
(300 MHz, CDCl3): δ = 7.65–7.56 (m, 6 H), 7.47–7.41 (m, 6 H),
7.20 (d, J = 7.6 Hz, 2 H), 4.03–3.95 (br., 1 H), 3.87 (dd, J = 3.0,
10.0 Hz, 1 H), 3.45 (dd, J = 9.3, 10.2 Hz, 1 H), 2.45–2.37 (m, 4 H),
2.22–2.12 (m, 2 H), 2.02–1.88 (m, 2 H), 1.78–1.71 (m, 6 H), 1.61–
1.11 (m, 3 H), 1.05 (s, 9 H), 1.00–0.88 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 143.3, 139.8, 135.7, 135.6, 133.4, 129.8,
129.7, 129.6, 127.71, 127.67, 126.7, 119.7, 74.2, 64.7, 62.6, 42.4,
42.3, 31.8, 29.2, 27.3, 26.9, 26.1, 25.0, 24.3, 21.5, 19.2, 15.0 ppm.
ESI-MS: calcd. for C36H46NO3SSi 614.3; found m/z [M + H]+
615.3. HRMS (ESI): m/z 615.3071, m/z [M + Na]+ calcd. for
C36H47NO3SSi 615.3077.
Amino Alcohol 21: To 20 (19 mg, 0.036 mmol) in THF (1.0 mL)
was added TBAF (0.18 mg, 0.18 mmol) at 0 °C, and the mixture
was stirred for 48 h at room temperature. The reaction was
quenched with iced water (1 mL) and extracted with EA
(3ϫ2.0 mL). The combined organic phases were washed with brine
and dried with anhydrous K2CO3. After the mixture was filtered
and concentrated, the mixture was purified by flash chromatog-
raphy (Et2O/MeOH, 20:1) to afford 21 (9 mg) in 85% yield. Rf =
0.44 (EA/MeOH, 5:1). [α]2D5 = +11.2 (c = 0.50, MeOH). IR (neat):
Ketone 5: To 19 (420 mg, 0.684 mmol) in Et2O (15 mL) was added
n-C6H13MgBr (5.5 mL, 1.0  in Et2O, 5.5 mmol), and the mixture
was refluxed for 5 h. After the mixture was cooled to room tem-
perature, the reaction was quenched with saturated aqueous NH4Cl
(10 mL) and extracted with EA (3ϫ5.0 mL). The combined or-
ganic phases were washed with brine and dried with MgSO4. After
the mixture was filtered and concentrated, the mixture was purified
by flash chromatography (PE/EA, 20:1) to afford 5 (432 mg) in
ν = 3346 cm–1. 1H NMR (400 MHz, CDCl ): δ = 3.53 (dd, J = 6.0,
˜
3
10.5 Hz, 1 H), 3.38–3.32 (m, 1 H), 3.16–3.10 (m, 1 H), 2.84 (br., 1
H), 2.24 (br., 1 H), 1.97–1.88 (m, 2 H), 1.78–1.52 (m, 7 H), 1.44–
1.08 (m, 18 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 67.2, 66.6, 64.9, 60.6, 41.8, 39.0, 37.6, 31.9, 31.2, 29.5,
27.8, 27.0, 26.3, 25.8, 25.7, 24.5, 23.8, 22.6, 14.1 ppm. ESI-MS:
calcd. for C19H35NO 293.2; found m/z [M + H]+ 294.2. HRMS
(MALDI): m/z 294.2791, m/z [M + H]+ calcd. for C19H36NO
294.2797.
90% yield. Rf = 0.5 (PE/EA, 9:1). [α]2D4 = –40.4 (c = 0.84, CHCl3).
1
IR (neat): ν = 2235 cm–1. H NMR (300 MHz, CDCl ): δ = 7.62–
˜
3
7.61 (m, 4 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.42–7.36 (m, 6 H), 7.12
(d, J = 8.2 Hz, 2 H), 3.96–3.91 (m, 1 H), 3.86 (dd, J = 3.3, 9.5 Hz,
1 H), 3.44 (t, J = 9.3 Hz, 1 H), 2.48–2.38 (m, 1 H), 2.34 (s, 1 H),
2.28–2.22 (m, 3 H), 2.13–1.67 (m, 24 H), 1.04 (s, 9 H), 0.95–0.86
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 210.9, 142.4,
140.1, 135.64, 135.62, 133.5, 129.7, 129.6, 129.3, 127.64, 127.61,
127.0, 75.0, 64.7, 62.6, 42.6, 42.5, 42.2, 40.7, 31.8, 31.6, 29.8, 28.9,
26.9, 26.2, 25.3, 24.8, 24.5, 23.7, 22.5, 21.4, 19.2, 14.0 ppm. ESI-
MS: calcd. for C42H59NO4SSi 701.4; found m/z [M + Na]+ 724.2.
Fasicularin (1):[4g] To PPh3 (49 mg, 0.187 mmol), NH4SCN (17 mg,
0.223 mmol) and DEAD (30 µL, 0.190 mmol) was added dropwise
21 (9 mg, 0.031 mmol) in CH2Cl2 (1.0 mL) at room temperature,
and the mixture was stirred overnight at room temperature. The
reaction was quenched with saturated aqueous NaHCO3 (5 mL)
and extracted with EA (3ϫ2.0 mL). The combined organic phases
were washed with brine and dried with anhydrous K2CO3. After
the mixture was filtered and concentrated, the mixture was purified
by flash chromatography (PE/EA, 100:1 to 10:1 to 3:1) to afford
fasicularin (1, 4 mg) and a more polar isomer (4 mg) which was
stirred in CH3CN (1 mL) for 24 h to obtain fasicularin (1, 3.5 mg).
HRMS (ESI): m/z 724.3826, m/z [M
C42H59NO4SSiNa 724.3832.
+
Na]+ calcd. for
Rf = 0.55. [α]2D6 = –4.4 (c = 0.34, MeOH). IR (neat): ν = 2152 cm–1.
˜
Tertiary Amine 20: To 5 (12 mg, 17.1 µmol) in DME (1.0 mL) was
added Na/naphthalene [which was prepared by stirring fresh so-
dium and naphthalene (13.2 mg, 103.1 µmol) in DME (1.0 mL) for
30 min at room temperature] at –68 °C, and the mixture was stirred
for 10 min at this temperature. The reaction was quenched with
saturated aqueous NH4Cl (2.0 mL) and stirred at room tempera-
ture for awhile. The layers were separated, and the aqueous layer
was extracted with EA (3ϫ3.0 mL). The combined organic phases
were washed with brine and dried with anhydrous K2CO3. After
the mixture was filtered and concentrated, the mixture was purified
by flash chromatography (PE/EA, 9:1) to afford the desired en-
amine (7 mg) in 77% yield.
1H NMR (400 MHz, [D5]-Py): δ = 3.63–3.54 (m, 1 H), 3.42 (dd, J
= 14.2, 11.9 Hz, 1 H), 3.31 (dd, J = 4.1, 13.2 Hz, 1 H), 2.98–2.90
(m, 1 H), 2.57 (d, J = 13.3 Hz, 1 H), 1.98–1.96 (m, 1 H), 1.91–1.74
(m, 1 H), 1.61–1.06 (m, 24 H), 0.86 (t, J = 6.8 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 111.6, 56.3, 52.3, 46.5, 46.1, 40.2,
34.3, 34.1, 32.3, 32.1, 30.3, 29.5, 27.7, 27.2, 26.3, 24.0, 22.9, 22.7,
19.3, 14.3 ppm. ESI-MS: calcd. for C20H34N2S 334.2; found m/z
[M + H]+ 335.1. HRMS (MALDI): m/z 335.2516, m/z [M + H]+
calcd. for C20H35N2S 335.2521.
Amino Alcohol 22: To 5 (108 mg, 0.154 mmol) in THF (5.0 mL)
was added -Selectride (1.6 mL, 1  in THF, 1.6 mmol) at –78 °C,
and the mixture was stirred at this temperature for 5 h. The reac-
tion was quenched with MeOH (1.0 mL) and stirred at room tem-
perature for 0.5 h. After the mixture was concentrated, the mixture
was purified by flash chromatography (PE/EA, 10:1 to 3:1) to af-
ford 22 (91 mg) and the epimer of 22 (16 mg) in a combined yield
of 99%. Rf = 0.56 (PE/EA, 6:1). [α]2D5 = –42.2 (c = 1.00, CHCl3).
To the enamine (7 mg, 12.66 µmol) in THF/MeOH (1:2.5, 1.4 mL)
was added CeCl3·7H2O (29 mg, 76.6 µmol), and the mixture was
stirred until the CeCl3·7H2O dissolved. To the mixture was added
NaBH4 (3 mg, 78.9 µmol) at –78 °C, and the mixture was stirred at
this temperature for 15 min. The reaction was quenched with dis-
tilled water (1.0 mL) and extracted with EA (3ϫ2.0 mL). The com-
1666
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1660–1668

Total Synthesis of (–)-Fasicularin and (–)-Lepadiformine A
1
IR (neat): ν = 3548 cm–1. H NMR (300 MHz, CDCl ): δ = 7.60
in 95% yield. Rf = 0.35 (EA/MeOH, 4:1). [α]2D8 = –14.7 (c = 0.25,
˜
3
1
(d, J = 7.9 Hz, 6 H), 7.45–7.35 (m, 6 H), 7.15 (d, J = 7.9 Hz, 2 H),
3.97–3.90 (m, 1 H), 3.78 (dd, J = 4.1, 9.9 Hz, 1 H), 3.38 (dd, J =
9.7, 9.4 Hz, 1 H), 3.27–3.19 (br., 1 H), 2.48–2.40 (m, 1 H), 2.36 (s,
MeOH). IR (neat): ν = 3331 cm–1. H NMR (500 MHz, CDCl ):
˜
3
δ = 3.42–3.30 (m, 2 H), 3.23 (d, J = 8.7 Hz, 1 H), 3.16–3.10 (m, 1
H), 1.78–1.07 (m, 27 H), 1.02–0.94 (m, 1 H), 0.87 (t, J = 6.8 Hz, 3
3 H), 2.23–2.15 (m, 1 H), 2.04–1.76 (m, 3 H), 1.59–1.26 (m, 10 H), H) ppm. 13C NMR (100 MHz, CDCl3): δ = 67.6, 62.2, 58.5, 53.4,
1.03–0.96 (13 H), 0.96 (s, 9 H), 0.89 (t, J = 5.9 Hz, 3 H) ppm. 13C 39.8, 38.1, 33.9, 31.8, 30.5, 29.5, 28.0, 27.6, 27.5, 26.2, 24.2, 23.2,
NMR (100 MHz, CDCl3): δ = 142.5, 140.2, 135.64, 135.62, 133.53,
22.5, 22.4, 14.0 ppm. ESI-MS: calcd. for C19H35NO 293.2; found
133.49, 129.68, 129.66, 129.3, 127.7, 127.6, 127.3, 75.6, 72.4, 64.5,
m/z [M + H]+ 294.1. HRMS (MALDI): m/z 294.2791, m/z [M +
62.4, 42.9, 42.5, 37.4, 35.2, 31.84, 31.76, 30.1, 29.7, 29.3, 27.3, 26.9, H]+ calcd. for C19H36NO 294.2797.
26.3, 25.4, 24.6, 22.6, 21.4, 19.2, 14.1 ppm. ESI-MS: calcd. for
Supporting Information (see also the footnote on the first page of
C42H61NO4SSi 703.4; found m/z [M + Na]+ 726.3. HRMS (ESI):
this article): Procedures for the synthesis of 6, 16 and 24, HPLC
analysis of 10, X-ray crystal structure of 16 and 24 and copies of
m/z 726.3983, m/z [M
+
Na]+ calcd. for C42H61NO4SSiNa
726.3988.
1
of the H and 13C NMR spectra of the prepared compounds.
Minor Epimer of 22: Rf = 0.36 (PE/EA, 6:1). [α]2D2 = –42.2 (c =
2.18, CHCl ). IR (neat): ν = 3545 cm–1. 1H NMR (300 MHz,
˜
3
Acknowledgments
CDCl3): δ = 7.59–7.56 (m, 6 H), 7.45–7.26 (m, 6 H), 7.09 (d, J =
8.2 Hz, 2 H), 3.99–3.92 (m, 1 H), 3.61 (dd, J = 3.7, 9.6 Hz, 1 H),
3.34–3.27 (m, 2 H), 2.48–2.40 (m, 1 H), 2.34 (s, 3 H), 2.28–2.25 (m,
1 H), 2.05–1.17 (m, 24 H), 1.02 (s, 9 H), 1.02–0.95 (m, 1 H), 0.89
(t, J = 6.9 Hz, 3 H), 0.87–0.81 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 142.4, 140.1, 135.6, 135.57, 133.5, 133.4, 129.7, 129.6,
129.3, 127.63, 127.60, 127.1, 75.9, 70.9, 64.3, 62.3, 42.3, 42.2, 37.9,
34.6, 31.9, 31.8, 29.8, 29.4, 26.9, 26.8, 26.4, 25.9, 25.4, 24.7, 22.6,
21.4, 19.1, 14.1 ppm. ESI-MS: calcd. for C42H61NO4SSi 703.4;
found m/z [M + Na]+ 726.2. HRMS (ESI): m/z 726.3983, m/z
[M + Na]+ calcd. for C42H61NO4SSiNa 726.3988.
Research support from the National Natural Science Foundation
of China (no. 20172064, 203900502 and 20532040), the Basic Re-
search Program (973 Program) of China (no. 2010CB833204), and
Excellent Young Scholars Foundation of National Natural Science
Foundation of China (no. 20525208) is acknowledged.
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˜
3
(500 MHz, CDCl3): δ = 7.71–7.64 (m, 4 H), 7.41–7.34 (m, 6 H),
3.75 (dd, J = 3.7, 8.2 Hz, 1 H), 3.26 (dd, J = 9.6, 8.7 Hz, 1 H),
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Eur. J. Org. Chem. 2010, 1660–1668
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1667

S.-L. Mei, G. Zhao
FULL PAPER
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Received: December 7, 2009
Published Online: February 9, 2010
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