Toward the synthesis of tulearin C: Stereoselective synthesis of the C1-C18 macrolactone core

Article abstract of DOI:10.1016/j.tetlet.2013.02.052

The asymmetric and convergent synthesis of fully functionalized macrocyclic core of tulearin C is described. Sharpless asymmetric epoxidation, Gillman's reaction, olefin cross metathesis, α aminoxylation, and ring closing metathesis reactions are the key

Full text of DOI:10.1016/j.tetlet.2013.02.052

Tetrahedron Letters 54 (2013) 2336–2339
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Tetrahedron Letters
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Toward the synthesis of tulearin C: stereoselective synthesis of the C1–C18
macrolactone core
⇑
J. S. Yadav , M. Venkatesh, N. Swapnil, A. R. Prasad
Centre for SemioChemicals, CSIR – Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric and convergent synthesis of fully functionalized macrocyclic core of tulearin C is
Received 1 November 2012
Revised 15 February 2013
Accepted 19 February 2013
Available online 13 March 2013
described. Sharpless asymmetric epoxidation, Gillman’s reaction, olefin cross metathesis,
tion, and ring closing metathesis reactions are the key steps utilized in the synthesis of macrolactone.
a aminoxyla-
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tulearin C
Sharpless asymmetric epoxidation
Gillman reaction
Olefin cross metathesis
a-Aminoxylation
Recently, Kashman and co-workers, isolated the cytotoxic com-
and 7 which can be coupled by olefin cross metathesis. Fragment
7 in turn can be obtained by regioselective opening of epoxide
13 which in turn can be derived from 9 through Sharpless asym-
metric epoxidation.
pounds salarins and tulearins, from the Madagascan sponge Fasca-
plysinopsis sp. They were found to inhibit cell proliferation and
modulate the cycle of cultured cell lines from both mouse and
human origins. However, the preliminary data showed that the
sister compound tulearin A 2 was endowed with a carbamate at
the C8-OH group, exhibited strong and differential antiproliferative
effects against human leukemia cell lines.1 The structure of
these macrolides was elucidated by spectrometric means. Their
relative and absolute configurations were determined by X-ray
diffraction analysis and modified Mosher’s method.2 These
macrolides differ in their structure at C-3 and C-8, of which tulea-
rin C 1 (Fig. 1) was determined to be the hydroxy precursor of 2.
Owing to the structural complexity, incomplete biological evalua-
tion, tulearins have generated a wide interest on their synthesis.
Consequently, several approaches have been reported by various
research groups.3 In continuation of our efforts in the synthesis
of complex natural products, herein an approach to the fully func-
tionalized macrolactone core segment 3 of tulearin C is disclosed.
From a retro synthetic perspective as shown in Figure 2, it is
planned that the side chain installation onto macrolactone core 3
would be the late stage reaction. The macrolactone 3 in turn can
achieve from two fragments, 4 and 5 via esterification followed
by a ring-closing metathesis reaction. The synthesis of fragment
The synthesis of fragment 7, the core intermediate is outlined in
Scheme 1. This is initiated from the known alcohol 9 using a
two-step sequence.4 The hydroxyl group in 9 was tosylated (TEA,
p-TsCl) and then transformed to terminal alkyne 10 in 69% yield
over two steps (using Li acetylideethylenediamine complex).5
The acetylenic compound is homologated using paraformaldehyde
to yield propargylic alcohol 11 in 90% yield which was then
reduced with LAH to produce allylic alcohol 12 in 90% yield. The
requisite chiral epoxide is introduced at this stage via a Sharpless
asymmetric epoxidation reaction6 using (ꢀ) diisopropylethyl
tartarate to yield epoxy alcohol 13 (with dr ratio 94.7). Regioselec-
tively 13 is opened with Gillman cuprate7 generated from MeLi and
CuI at ꢀ23 °C and upon reacting with NaIO4, obtained the pure
1,3-diol 14 albeit in moderate yields. A three-step protection–
deprotection sequence involving chemoselective protection of the
C5H11
C5H11
O
O
O
O
OH HO
OH HO
5 is envisioned from the known aldehyde 8, using a-aminoxylation
as the key step. Further, analysis of 4 can reveal two sub units 6
OCONH2
Tulearin A (2)
Figure 1. Structures of tulearin A and C.
OH
Tulearin C (1)
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.052

J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 2336–2339
2337
aminoxylation
18
1
C5H11
HO
O
13
O
ring closing
metathesis
O
O
OP
O
OH HO
3
Gilmann's
reaction
O
8
OH
cross
metathesis
3
P = MOM
Tulearin C (1)
O
O
+
TBDPSO
HO2C
MOMO
4
OH
5
OBn
TBDPSO
OH
+
O
O
O
6
8
MOMO
7
S-Citronellol
HO
D Xylose
OBn
O
13
OBn
HO
9
Figure 2. Retrosynthetic analysis of tulearin C.
metathesis conditions,10 using second generation Grubb’s catalyst
to obtain the desired alkene 18 in 71% yield. Hydrogenation of 18
has provided the reduced product 19 in 95% yield. Compound 19
is then oxidized and subjected to one carbon Wittig methylenation
to obtain olefin 20 in 68% yield over two steps. By removing the si-
lyl group using TBAF in THF alcohol 21 is afforded. The ensuing pri-
mary alcohol is then subjected to a two- step oxidation sequence
(IBX followed by Pinnick oxidation)11 to afford acid 4 in 89% over
two-steps.
HO
b
a
OBn
HO
c
OBn
OBn
11
10
9
d
e
HO
HO
OBn
OBn
O
12
13
f, g
HO
TBDPSO
h
OBn
OBn
OH
14
OR
The synthesis of fragment 5 commenced from the known alde-
hyde 8 (Scheme 3), derived from commercially available S-citronel-
15, R = H
16, R = MOM
i
lol.12 The aldehyde 8 is subjected to the crucial -aminoxylation13
a
TBDPSO
7
OH
using nitrosobenzene and 25 mol % of D-proline in DMSO, followed
MOMO
17
by a rapid reduction with sodium borohydride to furnish the unsta-
ble anilinoxy compound. It is further treated with 30 mol % of
CuSO4 in methanol at room temperature to cleave the O–N bond
providing the diol 22 in 65% yield with good diastereoselectivity
(de 94.4 observed from 1H NMR spectrum). The camphorsulfonic
acid catalyzed acetalization of 1,2-diol of 22 has furnished 23
(95% yield) which is then reduced to alcohol 24 via catalytic hydro-
genation. Oxidation of 24 followed by Wittig methylenation of the
resulting aldehyde has afforded the alkene 25 in 69% yield. The
deacetalization of 25 is carried out using catalytic p-TSA to afford
diol 26 (87% yield) in which the primary hydroxyl group is
chemoselectively protected as tert-butyldiphenylsilyl ether to suc-
cessfully accomplish the desired fragment 5 in 91% yield.
Having both the desired fragments 4 and 5 in hand, by following
the route described in Scheme 4 the targeted macrolide 3 is
achieved. The esterification of carboxylic acid 4 with alcohol 5 is
carried out under Steglich esterification (DCC-DMAP) conditions14
to obtain ester 27 in 75% yield which has paved way for the mac-
rocyclization by ring-closing metathesis.15 Reaction of 27 with sec-
ond-generation Grubbs catalyst in refluxing dichloromethane has
provided the desired E-macrocyclic lactone 28 in 68% yield. Finally
Scheme 1. Reagents and conditions: (a) (1) p-TsCl, DMAP, CH2Cl2, 0 °C–rt. (2)
HC„CLiꢁEDA, DMSO, rt, 1 h, 69% over two-steps. (b) nBuLi, (CH2O)n, THF, ꢀ78 °C–rt,
3 h, 90%. (c) LAH, THF, 0 °C–rt, 90%. (d) (ꢀ) DIPT, Ti(OiPr)4, TBHP, MS 4oA, CH2Cl2,
ꢀ20 °C, 12 h, 88%. (e) (1) MeLi, CuI, Et2O, ꢀ23 °C, 3 h. (2) NaIO4, THF/H2O (4:1), rt,
2 h, 65% over two-steps. (f) TBDPSCl, imidazole, CH2Cl2, 0 °C–rt, 92%. (g) MOMCl,
DIPEA, CH2Cl2, 0 °C–rt, 90%. (h) Li, Naphthalene, THF, ꢀ20 °C, 30 min. 90%. (i) (1)
IBX, DMSO, CH2Cl2, rt, 2 h. (2) Ph3PCH3+Iꢀ, KHMDS, THF, ꢀ78 °C–rt, 2 h, 65% over
two-steps.
primary hydroxyl group in 14 as tert-butyldiphenylsilyl (TBDPS)
ether (imidazole, TBDPSCl), secondary hydroxyl as methoxy
methyl (MOM) ether (DIPEA, MOMCl), and the cleavage of the ben-
zyl ether with lithium-naphthalene8 has produced alcohol 17 in
75% yield over three steps. The primary hydroxyl functionality in
17 is oxidized and subjected to one carbon Wittig methylenation
to provide olefin 7 in 65% yield over two-steps.
The compound 7 is transformed to the desired key fragment 4
as shown in Scheme 2. As proposed, compound 7 is coupled with
the known fragment 69 (obtained from D xylose) under olefin cross

2338
J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 2336–2339
O
O
O
O
a
b
TBDPSO
OH
6 + 7
TBDPSO
OH
d
MOMO
MOMO
19
18
O
O
O
O
c
e
4
HO
TBDPSO
MOMO
MOMO
21
20
Scheme 2. Reagents and conditions: (a) G-II cat. (4 mol %), CH2Cl2, reflux, 12 h, 71%. (b) Pd/C, H2, EtOAc, 5 h, 95%. (c) (1) IBX, DMSO, CH2Cl2, rt, 2 h. (2) Ph3PCH3+Iꢀ, KHMDS,
THF, ꢀ78 °C–rt, 68% over two-steps. (d) TBAF, THF, 0 °C–rt, 6 h, 90%. (e) (1) IBX, DMSO, CH2Cl2, rt, 2 h. (2) NaClO2, NaH2PO4, 2-Methyl-2-butene, tBuOH, H2O, rt, 3 h, 89%.
OBn
OBn
a
References and notes
OBn
OH
f
b
HO
O
OH
O
1. Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.; Kashman, Y. Org.
Lett. 2008, 10, 153.
2. Bishara, A.; Rudi, A.; Goldberg, I.; Aknin, M.; Kashman, Y. Tetrahedron Lett. 2009,
50, 3820.
3. (a) Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B.; Fürstner, A. Angew. Chem., Int. Ed.
2011, 50, 11373; (b) Alexander, L. M.; Bellosta, V.; Curran, D. P.; Cossy, J. Org.
Lett. 2009, 11, 3282.
4. (a) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985,
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29, 4139; (b) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
5. (a) Yadav, J. S.; Ather, H.; Rao, N. V.; Reddy, M. S.; Prasad, A. R. Synlett 2010,
1205; (b) Toshima, K.; Jyojima, T.; Miyamoto, N.; Katohno, M.; Nakata, M.;
Matsumura, S. J. Org. Chem. 2001, 66, 1708; (c) Moune, S.; Niel, G.; Busquet, M.;
Eggleston, I.; Jouin, P. J. Org. Chem. 1997, 62, 3332; (d) Andrew, T.; Philip, K.
Tetrahedron 1990, 46, 4503.
6. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974; (b) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765.
8
22
24
c
d
O
O
O
O
23
25
e
5
HO
O
OH
26
Scheme 3. Reagents and conditions: (a) (1) Nitrosobenzene, D-Proline, DMSO then
NaBH4, MeOH. (2) CuSO4ꢁ5H2O, MeOH, 65% for two-steps. (b) 2,2-DMP, cat. CSA,
CH2Cl2, 0 °C, 1 h, 95%. (c) Pd/C, H2, EtOAc, 8 h, 96%. (d) (1) IBX, DMSO, CH2Cl2, rt, 2 h.
(2) Ph3PCH3+Iꢀ, KHMDS, THF, ꢀ78 °C–rt, 2 h, 69% over two-steps. (e) p-TSA, MeOH,
rt, 30 min, 87%. (f) TBDPSCl, imidazole, CH2Cl2, 0 °C–rt, 91%.
7. (a) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873; (b) Yadav, J. S.; Sathaiah,
K.; Srinivas, R. Tetrahedron 2009, 65, 3545; (c) Komatsu, K.; Tanino, K.;
Miyashita, M. Angew. Chem. 2004, 116, 4441.
8. (a) Yadav, J. S.; Reddy, Ch. S. Org. Lett. 2009, 11, 1705; (b) Liu, H.-J.; Yip, J.; Shia,
K.-S. Tetrahedron Lett. 1997, 13, 2253.
TBDPSO
O
TBDPSO
O
O
O
c
b
a
3
9. (a) Yadav, J. S.; Barma, D. K. Tetrahedron 1996, 52, 4457; (b) Shing, T. K. M.;
Wong, W. F.; Ikeno, T.; Yamada, T. Chem. Eur. J. 2009, 15, 2693.
10. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953; (b)
Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783; (c) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
11. (a) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091; (b)
Yadav, J. S.; Pratap, T. V.; Rajender, V. J. Org. Chem. 2007, 72, 5882.
12. Yadav, J. S.; Venkatesh, M.; Thrimurtulu, N.; Prasad, A. R. Synlett 2010, 1255.
13. (a) Mangion, I. K.; Macmillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696; (b)
Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9, 1461; (c) Brown, S. P.; Brochu, M.
P.; Sinz, C. J.; Macmillan, D. W. C .J. Am. Chem. Soc. 2003, 125, 10808; (d) For
other reports on proline-catalyzed oxidation of aldehydes see: (i) Zhong, G.
Angew. Chem., Int. Ed. 2003, 42, 4247; (ii) Hayashi, Y.; Yamaguchi, J.; Hibino, K.;
Shoji, M. Tetrahedron Lett. 2003, 44, 8293.; (e) Reddy, B. P.; Pandurangam, P.;
Yadav, J. S.; Reddy, B. V. S. Tetrahedron Lett. 2012, 53, 5749; (f) Yadav, J. S.;
Lakshmi, K. A.; Reddy, N. M.; Swapnil, N.; Prasad, A. R. Tetrahedron: Asymmetry
2012, 23, 1155.
14. (a) Yadav, J. S.; Thrimurtulu, N.; Venkatesh, M.; Rao, K. V. R.; Prasad, A. R.;
Reddy, B. V. S. Synthesis 2010, 73; (b) Chakraborty, T. K.; Ghosh, S.; Laxman, P.;
Dutta, S.; Samanta, R. Tetrahedron Lett. 2005, 46, 5447; (c) Fürstner, A.;
Bouchez, L. C.; Funel, J. A.; Liepins, V.; Poree, F. H.; Gilmour, R.; Beaufils, F.;
Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265; (d) Ghosh, A. K.;
Liu, C. Org. Lett. 2001, 3, 635.
15. (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543; (b)
Fürstner, A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;
Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001, 7, 3236; (c) Fürstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012; (d) Fürstner, A.; Nevado, C.; Waser, M.; Trembley, M.;
Chevrier, C.; Teply, F.; Assa, C.; Moulin, E.; Muller, O. J. Am. Chem. Soc. 2007, 129,
9150.
4 + 5
O
OP
OP
O
O
O
28, P = MOM
27,
P = MOM
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 12 h, 75%. (b) G-II
cat. (5 mol %), CH2Cl2, reflux, 12 h, 68%. (c) TBAF, THF, 0 °C–rt, 3 h, 86%.
the lactone 28 is subjected to desilylation under TBAF conditions to
yield the macrocyclic core 3 in 86% yield. The structure of macro-
lactone 3 is fully characterized by 1H NMR, 13C NMR, and mass
spectral data.16 Thus, a highly convergent stereoselective approach
to complete the synthesis of the C1–C18 segment 3 of tulearin C is
herewith illustrated.
By utilizing high-yielding chemical transformations, a highly
convergent and stereoselective synthesis of the macrolactone core
segment of tulearin C, a potent cytotoxic macrolide is accom-
plished. Sharpless asymmetric epoxidation, regioselective epoxide
opening using Gillman’s reaction, olefin cross metathesis reaction,
and a-aminoxylation reactions are efficiently used for the prepara-
tion of key intermediates. The salient features of the approach in-
clude an efficient and scalable synthesis of two fragments 4 and 5
in a stereoselective manner and the use of ring-closing metathesis
for macrocyclization.
16. Spectral
data
for ((2R,3R)-3-((R)-3-(benzyloxy)-2-methylpropyl)oxiran-2-
ꢂ
yl)methanol (13): ½a D25
+11.51 (c 1.2, CHCl3); IR (KBr) mmax 3434,2926, 2854,
1642, 670 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.35–7.20 (m, 5H), 4.47 (s, 2H),
;
3.82 (dd, J = 12.4, 2.6 Hz, 1H), 3.58 (dd, J = 12.4, 2.6 Hz, 1H), 3.36–3.25 (m, 2H),
3.0–2.93 (m, 1H), 2.85–2.81 (m, 1H), 2.08–1.94 (m, 1H), 1.76–1.63 (m, 1H),
1.47–1.36 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 138.4,
128.3, 127.5, 75.3, 72.9, 61.6, 58.7, 54.4, 35.8, 31.5, 17.0; MS
(ESI) m/z 259 [M+Na]+; HRMS calcd for C14H20O3Na [M+Na]+ 259.1310, found
259.1299.
Acknowledgements
M.V. and N.S. thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, India, for financial assistance in the form
of research fellowships.
(2S,3R,5R)-6-(Benzyloxy)-2,5-dimethylhexan-1,3-diol (14):
½ ꢂ +22.01 (c 1.25, CHCl3); IR (KBr) m ,
a 2D5 max 3338, 2925, 1457, 1075, 736 cmꢀ1 1H

J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 2336–2339
2339
NMR (500 MHz, CDCl3) d 7.36–7.23 (m, 5H), 4.52 (s, 2H), 3.67 (dd, J = 10.8,
3.9 Hz, 1H), 3.59–3.49 (m, 2H), 3.41 (dd, J = 8.9, 3.9 Hz, 1H), 3.24 (t, J = 8.9 Hz,
1H), 1.99–1.89 (m, 1H), 1.66–1.52 (m, 2H), 1.51–1.43 (m, 1H), 0.93(d, J = 6.9 Hz,
3H), 0.88 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 137.5, 128.4, 127.7,
76.6, 76.5, 73.2, 67.6, 41.9, 40.6, 31.9, 18.1, 14.2; MS (ESI) m/z 253 [M+H]+;
HRMS calcd for C15H24O3Na [M+Na]+ 275.1623, found 275.1629.
7.22 (m, 5H), 4.48 (s, 2H), 3.76 (br s, 1H), 3.66–3.44 (m, 4H), 3.43–3.28 (m, 1H),
1.94–1.75 (m, 1H), 1.71–1.41 (m, 2H), 1.23–1.07 (m, 1H), 0.93(d, J = 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 138.2, 128.3, 127.7, 127.5, 72.9, 68.2, 37.0,
26.5, 19.5; MS (ESI) m/z 261 [M+Na]+; HRMS calcd for C14H22O3Na [M+Na]+
261.1466, found 261.1460.
(R)-4-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methylbutan-1-ol (24): ½a D25
ꢂ
+3.64
(2R,4R,5S)-6-(tert-Butyldiphenylsilyloxy)-4-(methoxymethoxy)-2,5-
(c 1.25, CHCl3); IR (KBr) mmax 3421, 2926, 2855, 1217, 1058 cmꢀ1 1H NMR
;
dimethylhexan-1-ol (17): ½a D25
ꢂ
+18.75 (c 0.9, CHCl3); IR (KBr) mmax 3421, 2929,
;
1H NMR (300 MHz, CDCl3) d 7.67–7.58 (m, 4H),
(300 MHz, CDCl3) d 4.22–3.95 (m, 2H), 3.78–3.57 (m, 2H), 3.46 (t, J = 7.5 Hz,
1H), 1.87–1.72 (m, 1H), 1.72–1.55 (m, 2H), 1.55–1.41 (m, 1H), 1.39 (s, 3H), 1.34
(s, 3H), 1.32–1.21 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
108.6, 74.4, 69.8, 60.5, 40.6, 40.0, 26.9, 25.7, 19.7; MS (EI) m/z 188.
2859, 1106, 1037, 703 cmꢀ1
7.44–7.31 (m, 6H), 4.67–4.52 (m, 2H), 3.89–3.80 (m, 1H), 3.55–3.44 (m, 3H),
3.43–3.37 (m, 1H), 3.35 (s, 3H), 2.15–2.04 (m, 1H), 1.86–1.68 (m, 1H), 1.58–
1.44 (m, 1H), 1.20–1.10 (m, 1H), 1.05 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.83 (d,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 135.5, 133.8, 129.5, 127.5, 93.6,
76.8, 72.1, 65.4, 60.3, 40.9, 39.9, 34.5, 26.8, 19.2, 17.3, 13.6; MS (ESI) m/z 467
[M+Na]+; HRMS calcd for C26H40O4SiNa [M+Na]+ 467.2593, found 467.2583.
(5R,6S)-6,10,10-Trimethyl-5-((R)-2-methylbut-3-enyl)-9,9-diphenyl-2,4,8-trioxa-
(2S,4R)-1-(tert-Butyldiphenylsilyloxy)-4-methylhept-6-en-2-ol (5): ½a D25
ꢂ
ꢀ4.07 (c
2.25, CHCl3); IR (KBr) mmax 3459, 2860, 1429, 1110, 704, 614 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 7.80–7.65 (m, 4H), 7.52–7.35 (m, 6H), 5.86–5.69 (m, 1H),
5.06–4.95 (m, 2H), 3.90–3.79 (m, 1H), 3.70–3.62 (m, 1H), 3.55–3.45 (m, 1H),
2.12–1.88 (m, 2H), 1.87–1.73 (m, 1H), 1.58–1.44 (m, 1H), 1.38–1.24 (m, 1H),
1.10 (s, 9H), 0.91(d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 137.1, 135.5,
134.7, 129.7, 129.5, 127.7, 127.6, 115.8, 69.7, 68.5, 41.9, 39.3, 28.9, 26.8, 26.5,
19.0; MS (ESI) m/z 405 [M+Na]+; HRMS Calcd for C24H34O2SiNa [M+Na]+
405.2225, found 405.2211.
9-silaundecane (7): ½a D25
+11.74 (c 1.0, CHCl3); IR (KBr) mmax 2924, 2856, 1103,
ꢂ
1038, 700 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.66–7.59 (m, 4H), 7.43–7.31 (m,
;
6H), 5.78–5.64 (m, 1H), 4.98–4.83 (m, 2H), 4.61–4.50 (m, 2H), 3.78–3.70 (m,
1H), 3.56–3.45 (m, 2H), 3.32 (s, 3H), 2.32–2.20 (m, 1H), 2.08–1.96 (m, 1H),
1.54–1.41 (m, 1H), 1.30–1.17 (m, 1H), 1.05 (s, 9H), 0.98 (d, J = 6.6 Hz, 3H), 0.86
(d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 145.0, 135.6, 133.7, 129.5,
127.5, 112.0, 96.1, 77.1, 65.7, 55.6, 38.8, 37.0, 33.8, 26.8, 19.2, 11.9; MS (ESI) m/
(2R,3R,5S)-((2S,4R)-1-(tert-Butyldiphenylsilyloxy)-4-methylhept-6-en-2-yl)-7-
((4S,5R)-5-(but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methoxymethoxy)-
2,5-dimethylheptanoate (27): ½a D25
ꢂ
ꢀ7.61 (c 0.85, CHCl3); IR (KBr) mmax 2930,
z
463 [M+Na]+; HRMS Calcd for C27H40O3SiNa [M+Na]+ 463.2644, found
2858, 1731, 1109, 1036, 704 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.75–7.60 (m,
;
463.2654.
4H), 7.48–7.33 (m, 6H), 5.92–5.63 (m, 2H), 5.21–5.10 (m, 1H), 5.10–4.92 (m,
4H), 4.72–4.56 (m, 2H), 4.03–3.94 (m, 1H), 3.76–3.51 (m, 4H), 3.37 (s, 3H),
2.90–2.77 (m, 1H), 2.34–2.08 (m, 2H), 2.08–1.82 (m, 2H), 1.77–1.45 (m, 9H),
1.37 (s, 6H), 1.45–1.20 (m, 3H), 1.12 (d, J = 6.9 Hz, 3H), 1.04 (s, 9H), 0.89 (d,
J = 6.6 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.7, 138.0,
136.6, 135.5, 129.6, 127.6, 116.1, 114.8, 96.2, 81.0, 80.2, 76.5, 72.3, 65.6, 55.8,
43.5, 41.7, 37.9, 37.4, 34.2, 32.1, 30.4, 30.2, 29.0, 28.8, 27.2, 26.7, 19.0, 18.8,
10.6; MS (ESI) m/z 737 [M+H]+; HRMS calcd for C44H68O7SiNa [M+Na]+
759.4632, found 759.4599.
3-((4S,5S)-5-((3R,5R,6S,E)-7-(tert-Butyldiphenylsilyloxy)-5-(methoxymethoxy)-
3,6-dimethylhept-1-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol (18): ½a D26
ꢂ
+8.70 (c 1.2, CHCl3); IR (KBr) mmax 3414, 2926, 2859, 1037, 700 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 7.67–7.60(m, 4H), 7.44–7.31 (m, 6H), 5.68–5.58 (m, 1H),
5.37–5.27(m, 1H), 4.54 (q, J = 6.7 Hz, 2H), 3.9 (t, J = 8.3 Hz, 1H), 3.71–3.45 (m,
6H), 3.32 (s, 3H), 2.34–2.19 (m, 1H), 2.04–1.91 (m, 1H), 1.78–1.58 (m, 3H),
1.57–1.41 (m, 2H), 1.39 (s, 3H), 1.38 (s, 3H), 1.34–1.23 (m, 1H), 1.05 (s, 9H),
0.99 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
143.3, 142.8, 135.5, 133.6, 129.8, 129.5, 127.7, 127.5, 124.7, 108.3, 95.7, 82.7,
80.5, 76.8, 65.4, 62.5, 55.6, 38.4, 37.1, 32.7, 29.4, 28.3, 27.1, 26.9, 26.7, 19.3,
19.1, 12.2; MS (ESI) m/z 621 [M+Na]+; HRMS calcd for C35H54O6SiNa [M+Na]+
621.3587, found 621.3580.
(2R,3R,5S)-(2S,4R)-1-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-6-en-2-yl
7-
((4S,5S)-5-(but-3-en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methoxymethoxy)-
2,5-dimethylheptanoate (28): ½a D24
ꢂ
ꢀ7.18 (c 0.9, CHCl3); IR (KBr) mmax 2930,
2859, 1732, 1107, 1039, 702 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 7.71–7.59 (m,
(5R,6S)-5-((S)-4-((4S,5S)-5-(But-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-
methylbutyl)-6,10,10-trimethyl-9,9-diphenyl-2,4,8-trioxa-9-silaundecane(20):
4H), 7.48–7.33 (m, 6H), 5.47 (dt, J = 15.8, 6.8 Hz, 1H), 5.40–5.24 (m, 2H), 4.72–
4.61 (m, 2H), 4.13–4.04 (m, 1H), 3.80–3.69 (m, 1H), 3.69–3.55 (m, 3H), 3.39 (s,
3H), 2.93–2.82 (m, 1H), 2.29–2.06 (m, 3H), 2.02–1.88 (m, 1H), 1.88–1.44 (m,
9H), 1.37 (s, 6H), 1.35–1.20 (m, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.03 (s, 9H), 0.92(d,
J = 6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 173.3, 135.5, 135.4, 133.3, 133.2,
130.6, 129.7, 127.6, 107.7, 96.3, 80.8, 78.5, 75.5, 71.9, 66.1, 55.9, 43.3, 41.3,
38.2, 37.4, 33.0, 31.8, 29.9, 28.8, 28.5, 28.3, 27.2, 26.6, 19.1, 18.0, 17.8, 10.4; MS
(ESI) m/z 709 [M+H]+; HRMS calcd for C42H64O7SiNa [M+Na]+ 731.4319, found
731.7306.
½ ꢂ +2.02 (c 1.15, CHCl3); IR (KBr) m ;
a 2D5 max 2927, 2857, 1104, 1037, 701 cmꢀ1 1H
NMR (300 MHz, CDCl3) d 7.66–7.58 (m, 4H), 7.43–7.30 (m, 6H), 5.88–5.72 (m,
1H), 5.07–4.91 (m, 2H), 4.64–4.48 (m, 2H), 3.85–3.77 (m, 1H), 3.61–3.43 (m,
4H), 3.31 (s, 3H), 2.33–1.95 (m, 4H), 1.67–1.40 (m, 5H), 1.40–1.35 (m, 2H), 1.34
(s, 6H), 1.05 (s, 9H), 0.90 (d, J = 6.6 Hz, 3H), 0.83(d, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 138.0, 135.5, 133.7, 129.5, 127.5, 114.8, 107.8, 96.0, 81.1,
80.3, 65.9, 55.6, 39.0, 37.2, 34.4, 32.2, 30.5, 30.2, 29.2, 27.3, 26.8, 19.2, 18.9,
11.4; MS (ESI) m/z 619 [M+Na]+; HRMS calcd for C36H56O5SiNa [M+Na]+
619.3794, found 619.3785.
(3aS,6S,8R,9R,12S,14R,19aR,E)-12-(Hydroxymethyl)-8-(methoxymethoxy)-
2,2,6,9,14-pentamethyl-4,5,6,7,8,9,12,13,14,15,19,19a-dodecahydro-3aH-
(2R,3R,5S)-7-((4S,5S)-5-(But-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
[1,3]dioxolo[4,5-i][1]oxacyclooctadecin-10(18H)-one (3):
½
a 2D5
ꢂ
ꢀ5.06(c 0.7,
1H NMR
(methoxymethoxy)-2,5-dimethylheptanoic acid (4): ½a D25
ꢂ
ꢀ7.32 (c 1.5, CHCl3); IR
CHCl3); IR (KBr) mmax 3454, 2925, 2854, 1713, 1172, 1038 cmꢀ1
;
(KBr) mmax 3448, 2925, 2854, 1711, 1036 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d
(300 MHz, CDCl3): d 5.49 (dt, J = 15.8, 6.8 Hz, 1H), 5.37 (dt, J = 15.1, 6.0 Hz, 1H),
5.24–5.14(m, 1H), 4.71 (d, J = 6.7 Hz, 1H), 4.65 (d, J = 6.7 Hz, 1H), 4.07–3.98 (m,
1H), 3.79–3.69 (m, 1H), 3.68–3.64 (m, 1H), 3.64–3.52 (m, 2H), 3.39(s, 3H),
3.14(br s,1H), 2.96–2.86 (m, 1H), 2.23–2.09 (m, 2H), 2.06–1.88 (m, 2H), 1.88–
1.41 (m, 10H), 1.37(s, 3H), 1.36 (s, 3H), 1.35–1.29 (m, 2H), 1.19 (d, J = 7.5 Hz,
3H), 0.93 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
174.2, 130.7, 129.6, 107.7, 96.4, 80.7, 78.5, 75.9, 73.0, 65.7, 56.0, 43.7, 41.0,
38.0, 32.9, 31.8, 30.0, 29.0, 28.6, 28.4, 27.2, 18.0, 11.1; MS (ESI) m/z 493
[M+Na]+; HRMS calcd for C26H46O7Na [M+Na]+ 493.3141, found 493.3144.
5.88–5.70 (m, 1H), 5.08–4.92 (m, 2H), 4.69–4.57 (m, 2H), 4.00–3.91 (m, 1H),
3.60–3.48 (m, 2H), 3.36 (s, 3H), 2.91-2.81 (m, 1H), 2.33–2.00 (m, 3H), 1.97–1.77
(m, 1H), 1.71–1.44 (m, 4H), 1.43–1.36 (m, 1H), 1.34 (s, 6H), 1.16(d, J = 7.1 Hz, 3
H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 179.6, 138.0, 114.8,
107.9, 96.3, 80.9, 80.2, 76.8, 55.8, 43.5, 38.4, 34.0, 32.1, 30.3, 30.1, 29.0, 27.2,
18.9, 10.9; MS (ESI) m/z 395 [M+Na]+; HRMS calcd for C20H36O6Na [M+Na]+
395.2409, found 395.2392.
(2S,4R)-6-(Benzyloxy)-4-methylhexan-1,2-diol (22): ½a D26
ꢀ3.7 (c 0.75, CHCl3); IR
ꢂ
(KBr) m ;
max 3432, 2929, 1094, 738, 699 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.39–