Towards stereoselective synthesis of the C(31)-C(39) and C(20)-C(27) fragments of phorboxazole A

Article abstract of DOI:10.1002/hlca.201400279

The stereoselective synthesis of the C(31)-C(39) and C(20)-C(27) fragments of phorboxazole A (1) was achieved from commercially available and inexpensive D-mannitol. Crimmins aldol reaction and a decarboxylative Claisen-type reaction are the key steps for

Full text of DOI:10.1002/hlca.201400279

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Towards Stereoselective Synthesis of the C(31) – C(39) and C(20) – C(27)
Fragments of Phorboxazole A
by Kammari Bal Raju, Bejjanki Naveen Kumar, Bandari Sampath Kumar, and Kommu Nagaiah*
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad
500076, India (phone: þ 91-40-27191659; fax: þ 91-40-27193275; e-mail: nagaiah@iict.res.in)
The stereoselective synthesis of the C(31) – C(39) and C(20) – C(27) fragments of phorboxazole A
(1) was achieved from commercially available and inexpensive d-mannitol. Crimmins aldol reaction and
a decarboxylative Claisen-type reaction are the key steps for the C(31) – C(39) fragment, and l-proline-
catalyzed aldol reaction, Sharpless asymmetric epoxidation, and epoxide ring opening reaction with
Gilmanꢀs reagent are the key steps for the C(20) – C(27) fragment of phorboxazole.
Introduction. – The most potent cytostatic natural product, phorboxazole A
(Scheme 1), a ꢁ21-membered C(1) – C(26) macrolideꢀ, was isolated from a marine
Indian Ocean sponge Phorbas sp. by Searl and Molinski [1]. Phorboxazole exerted
incredible cytotoxic activity (GI50 of 1.58 · 10ꢀ9 m) against the entire panel of 60 human
tumor cell lines at the National Cancer Institute (NCI) [2]. In addition to this cytotoxic
activity, phorboxazole A exhibits anticancer activity and in vitro antifungal activity
against Candida albicans and Saccharomyces carlsbergensis, respectively. Phorboxazole
A induces cell cycle arrest in the S phase Burkitt lymphoma cells. In the light of its
intriguing biological activities and unique structure, the total synthesis of this
compound has attracted high interest [3]. Several groups have reported different
routes for the synthesis of the C(31) – C(39) and C(20) – C(27) fragments [4].
Previously, we published the stereoselective approach to the C(31) – C(39) fragment
from m-anisaldehyde as starting material [5]. It was reported that most aldol reactions
require pregeneration of enolates or enolate-like species for generation of b-hydroxy-
a-methyl-substituted aldehydes with chiral catalysts [6]. However, in recent years,
asymmetric aldol reactions with proline as catalyst have attracted organic chemists,
since these reactions allow the direct coupling of aldehyde substrates without requiring
the pregeneration of enolates [7]. Accordingly, we hoped that this methodology would
be helpful in the installation of the stereogenic centers C(25) and C(26) of the C(20) –
C(27) fragment of phorboxazole.
In continuation of our work on the construction of biologically active natural
products [8], herein we describe a short and convenient route to the synthesis of these
fragments from the sugar building block d-mannitol.
Results and Discussion. – Synthesis of the C(31) – C(39) Fragment. Our retro-
synthetic analysis for the C(31) – C(39) fragment (of 1) is presented in Scheme 1. The
pyran ring could be synthesized with the requisite configurations by displacement of the
auxiliary of aldol product 2, followed by the cyclization of the b-oxo ester. Product 2
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 98 (2015)
Scheme 1. Retrosynthetic Route
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would be obtained from mercuration/reductive demercuration of enol ether 3 and
subsequent stereoselective acetate aldol reaction by using Crimminsꢀ protocol. Finally,
enol ether 3 could be prepared from diol 4 by oxidative cleavage, followed by
(methoxymethylidene)triphenylphosphine (Ph3P¼CHOMe) Wittig reaction. For the
preparation of 4, d-mannitol with the requisite configurations at C(4) and C(5)
matching with those of C(37) and C(38), respectively, of phorboxazole A (Scheme 1)
was selected as the chiral precursor.
Thus, our synthesis commenced from the known diol 5, which was prepared from d-
mannitol as described in [9] (Scheme 2). Compound 5 was treated with NaIO4, and
immediate reduction of the resulting aldehyde with NaBH4 in MeOH at 08 furnished
arabinitol 6 [10]. The primary OH group of 6 was protected with BnBr using NaH and
a catalytic amount of Bu4NI (TBAI) to afford monobenzyl ether 7 [11] in 86% yield.
Selective deprotection of 7 was achieved with 50% aqueous AcOH [11], affording diol
4 in 80% yield (based on the recovery of starting material). Oxidative cleavage of 4
with NaIO4 gave the corresponding aldehyde 8 [12], and the subsequent Wittig
homologation [13] of crude 8 under conventional conditions with Ph3PþCH2OMe Clꢀ
t
and BuOK at ꢀ 788 afforded the corresponding methyl enol ether 3 as inseparable
(E)/(Z) mixture in 78% yield over the two steps. Initially, we attempted to hydrolyze
the methyl enol ether group of 3 with 2n HCl in MeOH to give the aldehyde, which
rendered poor yield of aldehyde and acetals as side-products with complete
consumption of starting material. Thus, we chose a mercuration/reductive demercura-
tion [14] reaction, i.e., 3 was treated with (AcO)2Hg in THF/H2O 1:4 at 08, followed by
treatment with NaBH4 at the same temperature, leading to aldehyde 9 in 85% yield.
Addition of aldehyde 9 to a solution of the tetrachlorotitanium enolate of 1-[(4R)-
4-benzyl-2-thioxo-1,3-thiazolidin-3-yl]ethanone (10) (for the synthesis of N-acetyl-
thiazolidinethione complex, see [15]), generated with TiCl4 and EtN(iPr)2 at ꢀ 788 in
CH2Cl2, afforded the easily separable diastereoisomers mixture 11a/11b of the b-
hydroxy amide in a ratio of 82 :18 (syn/anti) (for procedures for aldol reactions, see
1
[16]). The ratio was determined by H-NMR spectroscopy of the crude aldol product
and by HPLC. After flash column chromatography on SiO2, the major diastereoisomer
11a was isolated in 62% yield. The syn- and anti-isomers were well characterized by
their coupling constants in the 1H-NMR spectra (in CDCl3). The syn-aldol product 11a
showed characteristic signals for the Ha-atoms at d(H) 3.55 (dd, J ¼ 17.9, 2.2, 1 H) for
the less-shielded H-atom, and at 3.26 (dd, J ¼ 17.7, 8.6, 1 H) for the more-shielded one,
along with other signals in their respective positions, whereas the less-polar minor anti-
1
aldol product 11b showed H-NMR signals for the corresponding Ha-atoms at d(H)
3.55 (dd, J ¼ 10.2, 4.6, 1 H) and 3.38 (dd, J ¼ 11.5, 7.3, 1 H), while, in the 13C-NMR
spectra, the C¼S and C¼O groups appeared at d(C) 201.3 and 172.5, respectively.
After determining the configuration at C(35) in 11a, several methylation methods
such as MeI/Ag2O and CH2N2 procedures were performed to protect the free OH
group for the synthesis of 2, which were unsuccessful. Finally, with Meerweinꢀs salt
(Me3OBF4) [17] and N,N,N’,N’-tetramethylnaphthalene-1,8-diamine (Proton Sponge)
in the presence of CH2Cl2 at 08 for 24 h gave the desired compound 2 in moderate yield
of 60%. Our next concern was the formation of the b-oxo ester 12. Therefore, we
adopted a decarboxylative Claisen-type reaction [16b][18]. Thus, the thioxothiazoli-
dinyl moiety of 2 was replaced by treatment with the potassium monoethyl malonate

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Scheme 2. Synthesis of the C(31) – C(39) Fragment

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(EtOC(O)CH2COOK) and MgCl2 in the presence of 1H-imidazole in THF at room
temperature for 12 h to afford 12 in excellent yield of 85%, and (4R)-4-benzyl-1,3-
thiazolidine-2-thione was recovered. Deprotection of the acetonide of 12 and in situ
cyclization of the dihydroxy b-oxo ester intermediate, in the presence of pyridinium p-
toluenesulfonate (PPTS) in MeOH/CH2Cl2 [4h][5] at 08 to room temperature for 3 h,
resulted in the formation of the desired C(31) – C(39) fragment (in 1) in 75% yield. The
spectroscopic and analytical data of 1 were in good agreement with those reported in
1
[4]. For example, in the H-NMR spectrum, the anomeric HOꢀC(33) resonated at
d(H) 3.62, HꢀC(35) at 2.80, and HꢀC(37) and HꢀC(38) at 3.68 – 3.82, and the signals
of C(33), C(35), C(37), and C(38) appeared at d(C) 99.4, 69.3, 72.3, and 73.5 in the
13C-NMR spectrum, respectively.
Synthesis of the C(20) – C(27) Fragment. The retrosynthetic approach for the
synthesis of the C(20) – C(27) fragment (in 13) of phorboxazole A is also depicted in
Scheme 1. Accordingly, we envisaged that the substituted pyran ring could be accessed
from the d-hydroxy a,b-unsaturated ester 14 by an oxa-Michael reaction. Compound
14 was prepared with the requisite configurations at C(23) and C(24) from the b-
hydroxy a-methyl aldehyde 15 by applying Gillmanꢀs reaction and Sharpless
asymmetric epoxidation. For the synthesis of 15 with the required configurations at
C(25) and C(26), the l-proline-catalyzed aldol reaction between (R)-2,3-O-isopropyl-
idene glyceraldehyde ((4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde; 16; synthe-
sized from d-mannitol [19]) and EtCHO was identified as the principal CꢀC coupling
strategy.
The synthesis of the C(20) – C(27) fragment (in 13) was commenced from (R)-16 as
outlined in Scheme 3. To create the required configurations at C(25) and C(26) via l-
proline-catalyzed aldol reaction, 16 was treated with EtCHO in DMF at 48 in the
presence of l-proline as catalyst for 36 h to give a mixture of diastereoisomers of b-
1
hydroxy aldehyde 15 in a ratio of 90 :10 (syn/anti; H-NMR) [20]. Interestingly, we
were also able to show that by changing l- to d-proline (10 mol-%), under otherwise
identical conditions, aldol 15b was received in a slightly lower yield with the same
diastereoselectivity, indicating that there is a negligible matched or mismatched effect
on the diastereoselectivity of 15a [21] and 15b. Furthermore, the reagent played a
decisive role on the anti-aldol diastereoselectivity, which was also consistent with
similar proline-catalyzed reactions [20]. The mixture was homologated with the Wittig
reagent Ph3P¼CHCOOEt in benzene at 808 for 12 h to afford 17 in 76% yield. The
structure of 17 was confirmed by its 1H-NMR spectrum, which revealed characteristic
signals for olefinic H-atoms at d(H) 5.77 (d, J ¼ 15.6, 1 H) and 6.97 (dd, J ¼ 15.8, 8.3,
1 H). The geometry of the C¼C bond was confirmed as (E) by the large coupling
constant of 15.8. Compound 17 was treated with tBuMe2SiOSO2CF3 (TBSOTf) in the
presence of 2,6-lutidine (2,6-dimethylpyridine) in dry CH2Cl2 at 08 for 1 h, to furnish
the silyl-protected a,b-unsaturated ester 18 [22] in 92% yield. Selective reduction of the
ester group of 18 with DIBAL-H at ꢀ 788 to room temperature in dry CH2Cl2 for 4 h
gave allyl alcohol 19 [22] in quantitative yield of 89%. Epoxidation of this allyl alcohol
by using Sharpless asymmetric epoxidation protocol [23], (ꢀ)-diisopropyltartarate
t
((ꢀ)-DIPT), (iPrO)4Ti, and BuOOH (TBHP) or cumene hydroperoxide (2-phenyl-
propan-2-yl hydroperoxide) in dry CH2Cl2 at ꢀ 208 for 10 h afforded the epoxy
compound 20 in 85% yield (Scheme 3). Next, regioselective epoxide ring opening [24]

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Scheme 3. Synthesis of the C(20) – C(27) Fragment
of 20 with MeLi in the presence of CuI in dry Et2O at ꢀ 208 for 6 h furnished diol 21 in
62% yield. Selective oxidation of the primary alcohol [25] was carried out with 2,2,6,6-
tetramethylpiperidinyloxyl (TEMPO) and bis(acetoxy)iodobenzene (BAIB) in dry
CH2Cl2 at room temperature for 1 h gives 22. Further treatment with the Wittig reagent
Ph3P¼CHCOOEt in benzene at 808 for 12 h, without purification, afforded the
unsaturated ester 14 in 70% yield. In the 1H-NMR spectrum of 14, the olefinic H-atoms
resonated at d(H) 6.94 (dd, J ¼ 15.9, 8.9, 1 H) and 5.74 (d, J ¼ 15.3, 1 H); the geometry
of the C¼C bond was confirmed as (E) by the large coupling constant of 15.9, and the

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signals of two Me groups at d(H) 1.07 (d, J ¼ 6.9) and 0.72 (d, J ¼ 7.1). In the 13C-NMR
spectrum, the signals of the C-atoms of the C(23) – C(26) fragment appeared at d(C)
39.8, 76.9, 39.3, and 75.4, respectively. By adopting a general procedure described in
[26], deprotection of the (tert-butyl)(dimethyl)silyl (TBS) group in 14, followed by
cyclization by an oxa-Michael reaction in the presence of Bu4NF (TBAF) in dry THF
for 24 h, resulted in the formation of the desired substituted pyran ring as the C(20) –
C(27) fragment (in 13).
Conclusions. – We accomplished a new synthesis of the C(31) – C(39) and C(20) –
C(27) fragments of phorboxazole A. The main highlights of our synthetic strategy
involve stereocontrolled Crimminsꢀ aldol reaction and decarboxylative Claisen-type
reaction, l-proline-catalyzed aldol reaction, Sharpless asymmetric epoxidation, and
epoxide ring opening by Gilmanꢀs reagent. This approach offers high stereoselectivity,
readily available, inexpensive starting material, and simple experimental conditions,
rendering it a useful and attractive process for the synthesis of furher natural-product
fragments.
K. B. R. thanks CSIR, New Delhi, for financial support, and the Director of the Indian Institute of
Chemical Technology (IICT) for his encouragement.
Experimental Part
General. Moisture- and air-sensitive reactions were carried out under N2. All solvents and reagents
were purified by standard techniques. TLC: Merck Kieselgel 60 F254 plates (layer thickness 0.25 mm).
Column chromatography (CC): silica gel (SiO2; 60 – 120 and 100 – 200 mesh). Optical rotations: JASCO
P-2000 digital polarimeter. IR Spectra: Perkin-Elmer RX-1 FT-IR system; ˜n in cmꢀ1. 1H- and 13C-NMR
spectra: Varian Gemini-200, Bruker Avance-300, and Inova-500 spectrometers; d in ppm rel. to Me4Si
as internal standard, J in Hz. ESI- and HR-MS: Q STAR mass spectrometer (Applied Biosystems, USA);
in m/z.
(4S,4’R,5R)-5-[(Benzyloxy)methyl]-2,2,2’,2’-tetramethyl-4,4’-bis[1,3-dioxolane] (7) [11]. To a stirred
soln. of NaH (0.6 g, 25.7 mmol) in THF (30 ml), 6 (5 g, 21.4 mmol) [10] in THF (30 ml) was added
dropwise at 08 under N2. After 30 min, BnBr was added slowly via syringe, and the mixture was stirred for
12 h at r.t., the reaction was quenched with sat. aq. NH4Cl at 08, and the mixture was extracted with
AcOEt (3 ꢁ 50 ml). The combined org. layers were washed with brine (30 ml), dried (Na2SO4),
concentrated under reduced pressure, and separated by CC (SiO2; hexane/AcOEt 19 :1) to afford 7 (6 g,
86%). [a]2D5 ¼ þ20.0 (c ¼ 0.3, CHCl3). IR (neat): 3450, 2986, 2933, 2877, 1630, 1454, 1374, 1249, 1215,
1153, 1080, 913, 845, 739, 698, 512. 1H-NMR (300 MHz, CDCl3): 7.22 – 7.35 (m, 5 H); 4.64 – 4.48 (m, 2 H);
4.06 (dd, J ¼ 13.9, 6.1, 2 H); 4.01 – 3.94 (m, 1 H); 3.89 (dd, J ¼ 7.9, 4.5, 1 H); 3.75 – 3.66 (m, 2 H); 3.54 (dd,
J ¼ 10.6, 5.6, 1 H); 1.39 (s, 3 H); 1.36 (s, 3 H); 1.31 (s, 3 H); 1.29 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
138.1; 128.3; 127.6; 127.5; 109.7; 109.5; 79.7; 77.6; 77.1; 73.4; 70.6; 67.5; 27.0 (2 C); 26.6; 25.2. ESI-MS: 323
([M þ H]þ), 345 ([M þ Na]þ). HR-MS: 345.1685 ([M þ Na]þ, C18H26NaOþ5 ; calc. 345.1672).
1-O-Benzyl-2,3-O-(1-methylethylidene)-d-arabinitol (4) [11]. Compound 7 (5 g, 15.4 mmol) was
stirred at r.t. in 50% AcOH (38 ml). After stirring overnight at the same temp., the mixture was
neutralized with aq. NaHCO3 and extracted with AcOEt (2 ꢁ 100 ml). The combined org. extracts were
washed with brine (30 ml), dried (Na2SO4), concentrated under reduced pressure, and separated by CC
(SiO2; hexane/AcOEt 5 :5) to afford 4 (3.5 g, 80% based on recovery of starting material). [a]2D5 ¼ þ5.9
(c ¼ 0.25, CHCl3). IR (neat): 3420, 3031, 2930, 2874, 1637, 1453, 1374, 1249, 1213, 1165, 910, 857, 806, 741,
698, 607, 511. 1H-NMR (300 MHz, CDCl3): 7.39 – 7.20 (m, 5 H); 4.64 – 4.50 (m, 2 H); 4.15 – 4.04 (ddd, J ¼
11.9, 7.9, 4.5, 2 H); 3.79 – 3.66 (m, 3 H); 3.58 (ddd, J ¼ 16.2, 10.8, 6.5, 4 H); 1.41 – 1.28 (s, 6 H). 13C-NMR

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(75 MHz, CDCl3): 136.9; 128.6; 128.1; 128.0; 109.4; 80.1; 78.1; 73.9; 72.4; 70.7; 63.8; 26.8. ESI-MS: 283
([M þ H]þ), 305 ([M þ Na]þ). HR-MS: 305.1355 ([M þ Na]þ, C15H22NaOþ5 ; calc. 305.1359).
(4E)-1-O-Benzyl-4-deoxy-5-O-methyl-2,3-O-(1-methylethylidene)-d-threo-pent-4-enitol (¼(4R,
5R)-4-(Benzyloxymethyl)-5-(2-methoxyvinyl)-2,2-dimethyl-1,3-dioxolane; 3; (E)/(Z) isomers). To a
soln. of 4 (5 g, 33.0 mmol) in dry CH2Cl2 (60 ml), NaIO4, adsorbed on SiO2, and sat. aq. NaHCO3 soln.
(4.6 g, 42.88 mmol) were added portionwise at 08 under N2. After stirring for 4 h at r.t., the mixture was
filtered and the filtrate concentrated under reduced pressure to give aldehyde 8, which was used in the
next step without any purification.
To a suspension of Ph3PþCH2OMe Clꢀ (8.2 g, 24 mmol) in THF (80 ml) under N2 at ꢀ 788, tBuOK
(96.8 ml, 1m in THF) was added portionwise, and the mixture was stirred at this temperature for 2 h. A
soln. of 8 (2 g, 8 mmol) in THF (20 ml) was then slowly added via syringe, and the mixture was stirred for
additional 2 h at ꢀ 788. The mixture was then warmed to r.t. and stirred for 30 – 45 min until completion
of the reaction. The reaction was then quenched with a sat. aq. NaHCO3 soln., and the mixture was
extracted with Et2O and washed with brine. The org. layer was then dried (Na2SO4), filtered,
concentrated in vacuo, and separated by CC (SiO2; hexane/AcOEt 9 :1) to afford 3 (1.7 g, 78%, (E)/(Z)
isomers). [a]2D5 ¼ þ6.3 (c ¼ 0.3, CHCl3). IR (neat): 3450, 2985, 2931, 2865, 1726, 1660, 1454, 1373, 1241,
1214, 1167, 1089, 1024, 937, 861, 741, 699, 600, 511. 1H-NMR (300 MHz, CDCl3): 7.38 – 7.23 (m, 5 H); 6.53
(d, J ¼ 12.6, 1 H); 6.06 (d, J ¼ 6.2, 1 H); 4.76 – 4.54 (m, 2 H); 4.46 – 4.41 (dd, J ¼ 8.7, 6.3, 1 H); 4.24 – 4.10
(t, J ¼ 8.7, 1 H); 3.81 (ddd, J ¼ 8.6, 5.6, 3.1, 1 H); 3.62 – 3.59 (s, 3 H); 3.59 – 3.56 (m, 1 H); 1.43 (s, 6 H).
13C-NMR (75 MHz, CDCl3): 152.4; 138.2; 128.4; 128.3; 127.7; 127.5; 108.7; 103.0; 99.3; 80.6; 73.5; 70.0;
69.2; 56.1; 27.2; 27.0. ESI-MS: 279 ([M þ H]þ), 301 ([M þ Na]þ). HR-MS: 301.1405 ([M þ Na]þ,
C16H22NaOþ4 ; calc. 301.1410).
5-O-Benzyl-2-deoxy-3,4-O-(1-methylethylidene)-d-threo-pentose (2-{(4R,5R)-5-[(Benzyloxy)-
methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}acetaldehyde; 9) [14]. A soln. of 3 (1.5 g, 5.3 mmol) in THF
(15 ml) was cooled to 08 and treated with (AcO)2Hg (2.7 g, 10.8 mmol, dissolved in 4 ml H2O). After
complete conversion of the substrate (TLC; generally 30 min), the mixture was diluted with 56 ml of
H2O reaching a 1:4 THF/H2O solvent ratio. Then, NaBH4 (1.19 g, 32.3 mmol) was added at 08, and after
1 min the mixture was treated with bubbling CO2 until pH 7. The suspension was extracted twice with
AcOEt (2 ꢁ 50 ml).The combined extracts were washed with brine, dried (Na2SO4), concentrated under
reduced pressure, and the residue was separated by CC (SiO2; hexane/AcOEt 4 :1) to yield 9 (1.2 g,
85%). 1H-NMR (300 MHz, CDCl3): 9.75 (s, 1 H); 7.22 – 7.33 (m, 5 H); 4.52 (s, 2 H); 4.23 – 4.30 (m, 1 H);
3.76 – 3.85 (m, 1 H); 3.67 (dd, J ¼ 9.8, 4.7, 1 H); 3.54 (dd, J ¼ 9.8, 5.9, 1 H); 2.61 – 2.67 (m, 2 H); 1.32 – 1.41
(s, 6 H). 13C-NMR (75 MHz, CDCl3): 199.9; 137.7; 128.4; 127.8; 127.7; 109.7; 79.2; 73.8; 73.7; 70.0; 46.8;
27.1; 26.9.
(3R)-4-{(4R,5R)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-1-[(4R)-4-benzyl-2-thio-
xo-1,3-thiazolidin-3-yl]-3-hydroxybutan-1-one (11a). A soln. of 1-[(4R)-4-benzyl-2-thioxo-1,3-thiazoli-
din-3-yl]ethanone (10; 1 g, 3.98 mmol) in freshly dist. CH2Cl2 (25 ml) at 08 was treated dropwise with a
soln. of TiCl4 (4 ml, 1m in CH2Cl2, 3.98 mmol) under N2, and the soln. was stirred for 10 min at the same
temp. To this mixture, EtN(iPr)2 (0.72 ml, 4.98 mmol) was added, and the soln. was stirred for 15 min at
08. The mixture was cooled to ꢀ 788, and stirring was continued for 15 min. A soln. of 9 (1.1 g,
3.98 mmol) in CH2Cl2 (10 ml) was transferred via cannula to the mixture, which was then stirred for 1 h at
ꢀ 788. The reaction was quenched with sat. NH4Cl (30 ml), and the layers were separated. The org. layer
was dried (Na2SO4), and the solvent was removed in vacuo to afford the aldol product as a mixture of
diastereoisomers 11a/11b (82 :18). Purification by CC (SiO2; hexane/AcOEt 9 :1) afforded 11a (1.3 g,
62%). Yellow semisolid. [a]2D5 ¼ ꢀ17.22 (c ¼ 0.2, CHCl3). IR (neat): 3457, 3028, 2923, 2855, 1695, 1493,
1452, 1370, 1341, 1259, 1203, 1163, 1083, 1044, 894, 742, 700, 513. 1H-NMR (500 MHz, CDCl3): 7.40 – 7.20
(m, 10 H); 5.44 – 5.30 (m, 1 H); 4.61 – 4.53 (m, 2 H); 4.40 (s, 1 H); 4.07 (m, 1 H); 3.93 – 3.86 (m, 1 H);
3.66 – 3.59 (m, 2 H); 3.55 (dd, J ¼ 17.7, 2.2, 1 H); 3.38 (dd, J ¼ 11.5, 7.3, 1 H); 3.26 (dd, 17.7, 8.6, 1 H); 3.20
(dd, J ¼ 13.2, 3.7, 1 H); 3.30 – 3.12 (m, 1 H); 3.02 (dd, J ¼ 13.1, 10.6, 1 H); 2.88 (d, J ¼ 11.6, 1 H); 1.92 – 1.67
(m, 2 H); 1.38 (d, J ¼ 7.2, 6 H).13C-NMR (75 MHz, CDCl3): 201.3; 172.6; 136.4; 129.4; 128.9; 128.4; 127.7;
127.2; 109.1; 79.7; 75.7; 73.6; 70.3; 68.3; 65.5; 46.0; 39.4; 36.8; 32.0; 29.7; 27.3; 26.9. ESI-MS: 516 ([M þ
H]þ), 538 ([M þ Na]þ). HR-MS: 538.1440 ([M þ Na]þ, C27H33NNaO5Sþ2 ; calc. 538.1692).

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(3R)-4-{(4R,5R)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-1-[(4R)-4-benzyl-2-thio-
xo-1,3-thiazolidin-3-yl]-3-methoxybutan-1-one (2). To a soln. of 11a (1.2 g, 0.123 mmol) in dry CH2Cl2
(10 ml) at 08 Proton Sponge (5.2 g, 1.23 mmol) was added, followed by Meerweinꢀs salt (Me3OBF4; 3.6 g,
1.23 mmol), and the mixture was stirred for 24 h at 08. The reaction was quenched by addition of iPrOH
(5 ml), and the mixture was allowed to warm to ambient temp. prior to addition of sat. NaHCO3 (20 ml).
Separation of the layers was followed by extraction of the aq. phase with CH2Cl2 (2 ꢁ 30 ml). The
combined org. layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification via CC
(SiO2; hexane/AcOEt 19 :1) afforded 2 (0.75 g, 60%). [a]2D5 ¼ ꢀ19.34 (c ¼ 0.2, CHCl3). IR (neat): 3457,
3028, 2923, 2855, 2830, 1695, 1493, 1452, 1370, 1341, 1259, 1203, 1163, 1083, 1044, 894, 742, 700, 513.
1H-NMR (300 MHz, CDCl3): 7.40 – 7.23 (m, 10 H); 5.38 (m, 1 H); 4.60 (s, 2 H); 4.28 (s, 1 H); 4.15 – 4.03
(m, 1 H); 3.90 – 3.79 (m, 1 H); 3.75 – 3.50 (m, 2 H); 3.42 (m, 1 H); 3.26 (dd, J ¼ 17.3, 9.4, 1 H); 3.20 (dd,
J ¼ 12.5, 3.6, 1 H); 3.14 (s, 3 H); 3.06 (dd, J ¼ 13.1, 10.6, 1 H); 2.92 (d, J ¼ 11.5, 1 H); 1.95 – 1.82 (m, 1 H);
1.77 – 1.61 (m, 2 H); 1.38 (d, J ¼ 13.6, 6 H). 13C-NMR (75 MHz, CDCl3): 201.2; 172.5; 136.3; 129.4;
128.9; 128.4; 127.7; 127.3; 109.1; 79.8; 75.7; 73.6; 70.3; 68.3; 65.5; 58.2; 46.1; 39.4; 36.8; 32.0; 29.7; 27.3;
26.9. ESI-MS: 530 ([M þ H]þ), 552 ([M þ Na]þ). HR-MS: 552.1640 ([M þ Na]þ, C28H35NNaO5Sþ2 ; calc.
552.1849).
Ethyl (5R)-6-{(4R,5R)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-5-methoxy-3-oxo-
hexanoate (12). A round-bottomed flask was charged with a soln. of thiazolidinethione aldol adduct 2
(0.5 g, 1.94 mmol) in THF (10 ml), EtOC(O)CH2COOK (0.7 g, 3.88 mmol,) was added, followed by
MgCl2 (0.184 g, 1.94 mmol). The flask was flushed with N2, and the suspension was stirred rapidly at r.t.
After 30 min, 1H-imidazole (0.130 g, 0.194 mmol) was added in one portion, and the suspension was
stirred rapidly at r.t. for 12 h. During this time, the bright-yellow color slowly faded to a very light yellow.
The mixture was diluted with AcOEt (10 ml), washed with 0.5m HCl (5 ml), and the aq. layer was back-
extracted with AcOEt (3 ꢁ 2 ml). The combined org. layers were then washed with 0.5m NaHCO3 (5 ml)
and back-extracted with AcOEt (3 ꢁ 2 ml). Finally, the combined org. layers were dried (Na2SO4),
filtered, and concentrated in vacuo to give light-yellow oil containing the desired product contaminated
with free thiazolidinethione auxiliary. Purification by CC (SiO2; hexane/AcOEt 19 :1) afforded 12
(0.32 g, 85%). [a]2D5 ¼ ꢀ22.13 (c ¼ 0.5, CHCl3). IR (neat): 3516, 2985, 2926, 2858, 2825, 1741, 1713, 1453,
1410, 1373, 1312, 1247, 1164, 1086, 1029, 842, 742, 699, 515. 1H-NMR (300 MHz, CDCl3): 7.43 – 7.30 (m,
5 H); 4.59 (s, 2 H); 4.37 – 4.28 (m, 1 H); 4.21 (q, J ¼ 7.1, 2 H); 4.02 (td, J ¼ 8.9, 3.4, 1 H); 3.95 – 3.83 (m,
1 H); 3.60 (m, 4 H); 3.31 (s, 3 H); 2.87 – 2.64 (m, 2 H); 1.87 – 1.80 (m, 2 H); 1.89 – 1.58 (m, 3 H); 1.42 (s,
6 H). 13C-NMR (75 MHz, CDCl3): 203.4; 170.3; 137.7; 128.4; 127.7; 108.9; 79.6; 75.6; 73.6; 70.3; 65.2; 61.5;
59.9; 49.8; 49.6; 39.4; 29.6; 27.2; 26.9; 14.1. ESI-MS: 409 ([M þ H]þ), 431 ([M þ Na]þ). HR-MS: 417.1788
([M þ Na]þ, C22H32NaOþ7 ; calc. 431.2040).
Ethyl {(2S,4R,6R)-6-[(1R)-2-(Benzyloxy)-1-hydroxyethyl]tetrahydro-2-hydroxy-4-methoxy-2H-pyr-
an-2-yl}acetate (1). To a stirred soln. of 12 (0.25 g, 33.0 mmol) in dry MeOH/CH2Cl2 (5 ml), a cat. amount
of PPTS was added portionwise at 08 under N2. After stirring for 3 h at 08 to r.t., the mixture was treated
with NaHCO3 soln., and extracted with AcOEt, dried (Na2SO4), filtered, concentrated under reduced
pressure, and separated by CC (SiO2; hexane/AcOEt 7:3) to give 1 (0.18 g, 75%). [a]2D5 ¼ ꢀ26.33 (c ¼
0.3, CHCl3). IR (neat): 3416, 2924, 1729, 1451, 1372, 1315, 1233, 1097, 1030, 879, 746, 699, 613.
1H-NMR (300 MHz, CDCl3): 7.43 – 7.25 (m, 5 H); 4.56 (s, 2 H); 4.23 – 4.05 (m, 3 H); 3.82 – 3.68 (m, 2 H);
3.65 – 3.54 (m, 2 H); 3.22 (s, 3 H); 2.89 – 2.58 (m, 2 H); 2.27 – 2.34 (m, 2 H); 1.94 – 1.83 (m, 2 H); 1.60 –
1.36 (m, 2 H); 1.22 – 1.30 (t, 3 H). 13C-NMR (75 MHz, CDCl3): 169.1; 137.8; 128.4; 127.8; 99.5; 73.5;
72.3; 70.6; 69.3; 64.3; 60.7; 48.0; 42.5; 41.9; 35.7; 29.5; 14.2. ESI-MS: 369 ([M þ H]þ), 391 ([M þ Na]þ).
HR-MS: 391.1731 ([M þ Na]þ, C19H28NaO7þ ; calc. 391.1727).
2-Deoxy-2-methyl-4,5-O-(1-methylethylidene)-d-lyxose (¼(2S,3R)-3-[(R)-2,2-Dimethyl-1,3-dioxo-
lan-4-yl]-3-hydroxy-2-methylpropanal; 15a) [21]. A DMF soln. (25 ml) of EtCHO (1.78 g, 30.8 mmol;
freshly dist.) was added slowly during 24 h to a stirred precooled (48) DMF (25 ml) suspension of 16 (2 g,
15.4 mmol) and l-proline (177 mg, 1.54 mmol). After 12 h stirring at the same temp., the mixture was
diluted with Et2O (1 ꢁ 75 ml), and washed successively with H2O (2 ꢁ 75 ml) and brine (2 ꢁ 75 ml). The
combined aq. layers were extracted with AcOEt (5 ꢁ 150 ml). The combined org. layers were dried
1
(Na2SO4) and concentrated in vacuo to give 15a. [a]2D5 ¼ ꢀ1.25 (c ¼ 1.3, CHCl3). H-NMR (300 MHz,
CDCl3): 9.74 (dd, J ¼ 16.0, 5.6, 1 H); 4.25 – 4.07 (m, 2 H); 4.06 – 3.71 (m, 3 H), 2.49 (ddd, J ¼ 20.6, 10.3,

Helvetica Chimica Acta – Vol. 98 (2015)
395
4.4, 1 H); 1.41 (d, J ¼ 5.9, 3 H); 1.35 (s, 3 H); 1.18 (d, J ¼ 7.0, 3 H). ESI-MS: 189 ([M þ H]þ), 211 ([M þ
Na]þ). HR-MS: 211.0862 ([M þ Na]þ, C9H16NaOþ4 ; calc. 211.0941).
1,2-Dideoxy-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4,5-O-(1-methylethylidene)-d-xylitol (¼ Ethyl
(4R,5R,E)-5-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5-hydroxy-4-methylpent-2-enoate; 17). To a soln. of
15 (2 g, 10.6 mmol) in dry benzene (20 ml) Ph3P¼CHCOOEt (4.4 g, 12.8 mmol) was added, and the
mixture was stirred at 808 for 12 h and then concentrated in vacuo, and the residue was separated by CC
(SiO2; hexane/AcOEt 8 :2) to afford 17 (3 g, 76%). Yellow oil. [a]2D5 ¼ þ15.0 (c ¼ 1.3, CHCl3). IR (neat):
1
3019, 1711, 1647, 1530, 1372, 1214, 1038, 929, 850, 746, 667, 626. H-NMR (300 MHz, CDCl3): 6.97 (dd,
J ¼ 15.8, 8.3, 1 H); 5.77 (d, J ¼ 15.8, 1 H); 4.16 (q, J ¼ 7.1, 2 H); 4.05 – 3.91 (m, 2 H); 3.75 – 3.64 (m, 2 H);
3.43 (dd, J ¼ 9.5, 4.6, 1 H); 2.39 (qt, J ¼ 19.2, 9.5, 1 H); 1.39 (s, 3 H); 1.32 (s, 3 H); 1.30 – 1.23 (m, 3 H); 1.15
(d, J ¼ 6.9, 3 H). 13C-NMR (75 MHz, CDCl3): 166.4; 149.6; 121.9; 109.5; 76.6; 74.8; 66.1; 60.3; 40.1; 26.5;
25.3; 16.3; 14.2. ESI-MS: 259 ([M þ H]þ), 276 ([M þ NH4]þ). HR-MS: 281.1369 ([M þ Na]þ,
C13H22NaOþ5 ; calc. 281.1359).
3-O-[(tert-Butyl)(dimethyl)silyl]-1,2-dideoxy-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4,5-O-(1-
methylethylidene)-d-xylitol (¼ Ethyl (4R,5R,E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-5-[(R)-2,2-dimethyl-
1,3-dioxolan-4-yl]-4-methylpent-2-enoate; 18) [22]. To a cold (08), stirred soln. of 17 (430 mg, 1.7 mmol),
2,6-lutidine (0.724 ml, 4.17 mmol) in dry CH2Cl2 (20 ml) and TBSOTf (0.602 ml, 3.33 mmol) were added.
After 1 h, the reaction was quenched with sat. NH4Cl, and the mixture was extracted with CH2Cl2, dried
(Na2SO4), concentrated under reduced pressure, and separated by CC (SiO2; hexane/AcOEt 9 :1) to
furnish 18 (576 mg, 92%). Colorless oil. [a]2D5 ¼ þ7.0 (c ¼ 1.3, CHCl3). IR (neat): 2932, 1718, 1550, 1489,
1370, 1219, 1183, 1153, 1073, 1037, 836, 772, 639, 574. 1H-NMR (300 MHz, CDCl3): 6.98 (ddd, J ¼ 15.7, 8.2,
5.1, 1 H); 5.75 (d, J ¼ 15.8, 1 H); 4.20 (dt, J ¼ 7.1, 6.2, 2 H); 4.00 – 3.85 (m, 2 H); 3.70 – 3.43 (m, 2 H);
2.35 – 2.19 (m, 1 H); 1.40 (s, 3 H); 1.36 – 1.30 (m, 6 H); 1.16 (d, J ¼ 6.9, 3 H); 0.94 (s, 9 H); 0.10 (dd, J ¼
10.6, 6.4, 6 H). 13C-NMR (75 MHz, CDCl3): 166.4; 149.7; 121.5; 109.0; 78.6; 77.5; 65.6; 60.2; 40.2; 29.7;
26.6; 26.5; 26.0; 25.9; 25.5; 17.9; 14.2; ꢀ 3.92; ꢀ 4.8. ESI-MS: 373 ([M þ H]þ), 395 ([M þ Na]þ). HR-
MS: 390.26748 ([M þ NH4]þ, C19H40NO5Siþ; calc. 390.26703).
3-O-[(tert-Butyl)(dimethyl)silyl]-1,2-dideoxy-2-[(1E)-3-hydroxyprop-1-en-1-yl]-4,5-O-(1-methyl-
ethylidene)-d-xylitol (¼(4R,5R,E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-5-[(R)-2,2-dimethyl-1,3-dioxolan-
4-yl]-4-methylpent-2-en-1-ol; 19) [22]. A soln. of DIBAL-H (4.5 ml, 1m in hexane, 4.5 mmol) was added
dropwise over 5 min to a stirred soln. of 18 (0.5 g, 1.51 mmol) in CH2Cl2 (15 ml) at ꢀ 788 under N2
atmosphere. The mixture was stirred at ꢀ 788 for 2 h, then allowed to warm to r.t. and stirred for further
2 h. The reaction was quenched by dropwise addition of MeOH (1.5 ml), and then the mixture was
poured into an aq. soln. of sat. potassium sodium tartrate (30 ml), diluted with CH2Cl2 (100 ml), and
stirred vigorously for 2 h. The separated aq. layer was extracted with AcOEt (3 ꢁ 50 ml), and the
combined org. layers were then dried (Na2SO4), evaporated in vacuo, and separated by CC (SiO2;
hexane/AcOEt 8 :2) to give 19 (0.394 g, 89%). Colorless oil. [a]2D5 ¼ þ7.5 (c ¼ 1.3, CHCl3). IR (neat):
2930, 1679, 1550, 1468, 1375, 1253, 1219, 1038, 975, 834, 772, 670. 1H-NMR (300 MHz, CDCl3): 5.73 – 5.43
(m, 2 H); 4.01 (d, J ¼ 5.7, 2 H); 3.97 – 3.81 (m, 2 H); 3.52 – 3.41 (m, 2 H); 2.50 (br. s, 1 H); 2.13 – 1.94 (m,
1 H); 1.31 (s, 3 H); 1.24 (d, J ¼ 4.8, 3 H); 0.92 (d, J ¼ 6.8, 3 H); 0.81 (m, 9 H); ꢀ 0.01 (dd, J ¼ 9.8, 7.0,
6 H). 13C-NMR (126 MHz, CDCl3): 134.0; 127.9; 109.1; 78.7; 74.5; 69.7; 62.7; 37.4; 30.9; 25.2; 25.1; 25.0;
24.9; 24.8; 17.1; ꢀ 4.9; ꢀ 5.1. ESI-MS: 348 ([M þ NH4]þ), 353 ([M þ Na]þ). HR-MS: 353.21226 ([M þ
Na]þ, C17H34NaO4Siþ; calc. 353.21186).
3-O-[(tert-Butyl)(dimethyl)silyl]-1,2-dideoxy-2-[(2R,3R)-3-(hydroxymethyl)oxiran-2-yl]-4,5-O-(1-
methylethylidene)-d-xylitol (¼ [(2R,3R)-3-((1R,2R)-1-{[(tert-Butyl)dimethylsilyl]oxy})-1-[(R)-2,2-di-
methyl-1,3-dioxolan-4-yl]propan-2-yl)oxiran-2-yl]methanol; 20). To a soln. of Ti(OiPr)4 (0.1 ml,
0.3 mmol) and 4-ꢄ molecular sieves (1 g) in CH2Cl2 (10 ml), (ꢀ)-DIPT (0.6 ml, 0.3 mmol) was added
at ꢀ 208. After 15 min at this temp., a soln. of 19 (0.35 g, 1.11 mmol) in dry CH2Cl2 (2 ml) was added
dropwise, followed by the addition (after additional 30 min) of TBHP (0.7 ml, 4m soln. in toluene;
2.8 mmol) at ꢀ 208. The mixture was stirred for 10 h at this temp., then filtered, and the filtrate was
diluted with AcOEt (5 ml) and washed with a sat. aq. soln. of Na2SO4. After decantation, the aq. phase
was extracted with AcOEt (3 ꢁ 5 ml), and the combined org. layers were dried (Na2SO4), filtered,
concentrated, and separated by CC (SiO2; hexane/AcOEt 8 :2) to give 20 (0.312 g, 85%). Colorless
oil. [a]2D5 ¼ þ22.5 (c ¼ 1.3, CHCl3). IR (neat): 3395, 2925, 1740, 1514, 1417, 1268, 1219, 1103, 901, 772,

396
Helvetica Chimica Acta – Vol. 98 (2015)
686. 1H-NMR (500 MHz, CDCl3): 4.01 (q, J ¼ 7.2, 2 H); 3.87 – 3.78 (m, 1 H); 3.77 – 3.72 (m, 1 H); 3.56 –
3.49 (m, 2 H); 3.41 (dd, J ¼ 10.8, 5.7, 1 H); 2.96 – 2.84 (m, 1 H); 2.11 – 2.01 (m, 2 H); 1.31 – 1.27 (m, 3 H);
1.25 – 1.22 (m, 3 H); 1.06 – 1.02 (m, 3 H); 0.81 – 0.78 (m, 9 H); (ꢀ0.04) – (ꢀ0.03) (m, 6 H). 13C-NMR
(75 MHz, CDCl3): 109.2; 78.2; 74.1; 65.8; 61.9; 58.7; 57.2; 39.2; 29.6; 26.5; 26.4; 26.0; 25.6; 25.1; 15.5; ꢀ
3.9; ꢀ 4.8. ESI-MS: 347 ([M þ H]þ), 369 ([M þ Na]þ). HR-MS: 347.20724 ([M þ H]þ, C17H35O5Siþ; calc.
347.22483).
(1R)-1-O-[(tert-Butyl)(dimethyl)silyl]-2,4-dideoxy-1-C-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,4-
dimethyl-l-arabinitol (21). To a suspension of CuI (250 mg, 4.33 mmol) in dry Et2O (5 ml), MeLi (1.7 ml,
4m in Et2O) was added dropwise at 08. Then, a soln. of 20 (250 mg, 0.7 mmol) in dry Et2O (3 ml) at ꢀ 208
was added dropwise to the resulting light blue-colored soln. of Me2CuLi. The mixture was stirred for 6 h
at this temp., and the reaction was quenched by careful addition of sat. aq. NH4Cl soln., followed by
dilution with Et2O (10 ml). The aq. phase was extracted with Et2O (2 ꢁ 10 ml), and the combined org.
layers were sequentially washed with a sat. aq. soln. of NH4Cl, H2O, and brine, and dried (Na2SO4). The
solvent was removed under reduced pressure, and the residue was separated by CC (SiO2; hexane/
AcOEt 8 :2) to afford 21 (0.162 g, 62%). Colorless oil. [a]2D5 ¼ þ11.6 (c ¼ 1.3, CHCl3). IR (neat): 2924,
1
1550, 1465, 1382, 1219, 836, 772, 672. H-NMR (500 MHz, CDCl3): 4.16 – 4.04 (m, 2 H); 4.02 – 3.95 (m,
2 H); 3.87 – 3.82 (m, 1 H); 3.73 – 3.68 (m, 1 H); 3.66 – 3.58 (m, 1 H); 3.49 (dd, J ¼ 11.0, 5.4, 1 H); 3.40 (dt,
J ¼ 16.5, 7.3, 1 H); 2.23 – 2.02 (m, 2 H); 1.29 – 1.25 (m, 6 H); 0.87 (d, J ¼ 7.0, 3 H); 0.80 (d, J ¼ 7.1, 3 H ) ;
0.75 (s, 9 H); 0.04 – (ꢀ0.11) (m, 6 H). 13C-NMR (75 MHz, CDCl3): 109.4; 80.2; 77.4; 75.4; 66.1; 65.7; 38.2;
36.2; 31.9; 26.5; 25.9; 25.7; 14.8; 12.1; ꢀ 3.9; ꢀ 4.6. ESI-MS: 363 ([M þ H]þ), 385 ([M þ Na]þ). HR-MS:
391.23896 ([M þ Na]þ, C18H38NaO5Siþ; calc. 385.23807).
(5R)-5-O-[(tert-Butyl)(dimethyl)silyl]-2,4-dideoxy-5-C-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,4-
dimethyl-l-lyxose (¼(2R,3R,4R,5R)-5-{[(tert-Butyl)dimethylsilyl]oxy}-5-[(R)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-3-hydroxy-2,4-dimethylpentanal (22). To a stirred soln. of 21 (0.1 g, 0.27 mmol) in dry CH2Cl2
(10 ml), TEMPO (0.008 g, 0.05 mmol) and BAIB (0.177 g, 0.55 mmol) were added at r.t. The mixture was
stirred for 1 h at r.t. The reaction was quenched with an aq. soln. of Na2S2O3 (15 ml), and the mixture was
extracted with CH2Cl2 (4 ꢁ 30 ml). The combined org. layers were washed with a sat. NaHCO3 soln.,
dried (Na2SO4), and concentrated under reduced pressure, and the residue was used in the next step
without any purification.
3-O-[(tert-Butyl)(dimethyl)silyl]-1,2-dideoxy-2-[(1S,2S,3E)-5-ethoxy-1-hydroxy-2-methyl-5-oxo-
pent-3-en-1-yl]-4,5-O-(1-methylethylidene)-d-xylitol (¼ Ethyl (4S,5S,6R,7R,E)-7-{[(tert-Butyl)dimethyl-
silyl]oxy}-7-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-hydroxy-4,6-dimethylhept-2-enoate; 14). To a soln. of
22 in dry benzene (10 ml) Ph3P¼CHCOOEt (0.190 g, 0.55 mmol) was added at 808, and the mixture was
stirred for 12 h. The mixture was concentrated in vacuo and separated by CC (SiO2; hexane/AcOEt 7:3)
to give 14 (0.083 g, 70%. Colorless oil. [a]2D5 ¼ þ14.3 (c ¼ 1.3, CHCl3). IR (neat): 2955, 1729, 1693, 1550,
1465, 1382, 1219, 836, 772, 672. 1H-NMR (300 MHz, CDCl3): 6.94 (dd, J ¼ 15.9, 8.9, 1 H); 5.74 (d, J ¼ 15.3,
1 H); 4.17 – 4.01 (m, 2 H); 3.85 (dd, J ¼ 7.9, 6.3, 1 H); 3.77 (dd, J ¼ 5.8, 2.5, 1 H); 3.51 – 3.44 (m, 1 H);
2.49 – 2.29 (m, 1 H); 1.56 – 1.40 (m, 1 H); 1.31 (s, 3 H); 1.24 (d, J ¼ 5.2, 3 H); 1.16 (d, J ¼ 3.0, 6 H); 1.07 (d,
J ¼ 6.9, 3 H); 0.79 (d, J ¼ 1.9, 9 H); 0.72 (d, J ¼ 7.1, 3 H); 0.60 (s, 6 H). 13C-NMR (126 MHz, CDCl3):
166.4; 149.5; 122.2; 109.2; 78.6; 76.9; 75.5; 66.2; 60.2; 39.9; 39.4; 31.9; 26.7; 26.5; 26.1; 25.9; 25.7; 17.5; 14.3;
12.1; ꢀ 4.3; ꢀ 4.7. ESI-MS: 431 ([M þ H]þ), 448 ([M þ NH4]þ). HR-MS: 453.22268 ([M þ Na]þ,
C22H42NaO6Siþ; calc. 453.26429).
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Received August 28, 2014