Syntheses of the four stereoisomers of Phytophthora mating hormone α2 and a concise synthesis of mating hormone α1

Article abstract of DOI:10.1016/j.tet.2011.09.066

Four stereoisomers of Phytophthora mating hormone α2 were synthesized using both enantiomers of citronellol as starting materials. The absolute configuration of the natural product was determined to be 7S,11R,15R by oospore-inducing assays of the syntheti

Full text of DOI:10.1016/j.tet.2011.09.066

Tetrahedron 67 (2011) 8887e8894
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Syntheses of the four stereoisomers of Phytophthora mating hormone a2
and a concise synthesis of mating hormone a1
,
a
b
b
a
Arata Yajima a , Kou Toda , Shylaja D. Molli , Makoto Ojika , Tomoo Nukada
*
a Department of Fermentation Science, Faculty of Applied Biological Science, Tokyo University of Agriculture (NODAI), Sakuragaoka 1-1-1, Setagaya-ku, Tokyo 156-8502, Japan
b Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 August 2011
Received in revised form 14 September 2011
Accepted 15 September 2011
Available online 22 September 2011
Four stereoisomers of Phytophthora mating hormone a2 were synthesized using both enantiomers of
citronellol as starting materials. The absolute configuration of the natural product was determined to be
7S,11R,15R by oospore-inducing assays of the synthetic isomers. A concise synthetic procedure of 1 was
also established using a common synthetic intermediate of 2.
a
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Hormone
Hormone
Synthesis
a
a
2
1
Phytophthora
1. Introduction
whereas hormone a2 is secreted by A2 and induces oospores in the
A1 mating type. The oospores from Phytophthora have a doubly
thick-walled structure that allows them to survive for months or
years under harsh conditions, such as drying or freezing. Managing
phytopathogens with common fungicides is difficult. Furthermore,
sexual reproduction is thought to be the cause of the rapid spread
The fungus-like genus Phytophthora comprises approximately
80 pathogenic species that are responsible for the devastation of
hundreds of crops worldwide, including potato and tomato crops.1
Phytophthora, which means ‘plant destroyer,’ are some of the most
destructive pathogens in the world. In the mid-1840s, a massive
potato disease, late blight, destroyed the potato crops in Europe and
in the United States. This disease was caused by a member of the
genus, Phytophthora infestans. The late blight epidemic completely
destroyed Ireland’s staple potato crops, which led to the Great Irish
Famine of 1845 and 1846.2 Phytophthora ramorum has recently been
identified as an aggressive pathogen that induces extensive mor-
tality among the oak trees in California,3 known as sudden oak
death. In the 20th century, these diseases were effectively managed
with fungicides. Unfortunately, certain virulent and fungicide-
resistant strains have recently undergone extensive migration,
causing a worldwide resurgence of late blight in potatoes.2
of fungicide-resistant species. Chemical studies of hormones
a1
and 2 date back to 1929 when Ashby proposed that sexual re-
a
production in Phytophthora was regulated by hormone-like com-
pounds.4 Data that were later reported by Galloway5a and
Kouyears5b supported the hypothesis of chemical stimulation for
oospore formation. In 1978, Ko reported evidence for the hormonal
regulation of sexual reproduction, and the hormone-like com-
pounds were named hormones a1 and a2. Conflicting reports argue
that the compounds are more appropriately termed pheromones.6
Although extensive studies, including Ko’s partial characterization7
of
a
a1 and a2, have been conducted with the aim of isolating a1 and
2, their structures remained undetermined due to their scarcity.8
An important biological event in the lifecycle of Phytophthora is
sexual reproduction, which is conducted by two mating types, A1
and A2, in heterothallic species.1,2 Each individual is bisexual and
capable of producing both male (antheridia) and female (oogonia)
More than 70 years after the first proposal of the existence of
these hormone-like compounds, Ojika and co-workers succeeded
in isolating
a
1 from 1830 L of the A1 mating type culture broth of
Phytophthora nicotianae.9 The structure of
a1 was determined as 1
organs. Hormone
a
1 is secreted by the A1 mating type and induces
by spectral analyses (Fig. 1). The absolute configurations of C-3 and
the formation of sexual spores (oospores) in the A2 mating type,
C-15 were elucidated based on NMR studies of the corresponding
bis-MTPA ester of
and the four possible stereoisomers of
solute configuration of the natural product by direct comparison of
the biological activities of the synthetic samples with natural
1.11,12
a
1.10 We synthesized the stereoisomeric mixture
a
1. We determined the ab-
* Corresponding author. Tel./fax: þ81 3 5477 2264; e-mail address: ayaji@
a
nodai.ac.jp (A. Yajima).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.066

8888
A. Yajima et al. / Tetrahedron 67 (2011) 8887e8894
Fig. 1. Structures of Phytophthora mating hormones a1 and a2.
The importance of this compound has attracted the attention of
many synthetic organic chemists.13 The non-stereoselective14a and
stereoselective syntheses of natural14b and unnatural14c isomers of
a
1 have since been reported. Very recently, the final component of
the mating hormone of Phytophthora was isolated and character-
ized by Ojika and co-workers.15 The structure of
2, which is very
similar to that of 1, was determined as 2 after extensive MS and
a
a
Scheme 1. Retrosynthetic analysis of a2.
NMR studies and total synthesis (Fig. 1). Herein, we report details
regarding the total syntheses and biological activities of the four
stereoisomers of Phytophthora mating hormone
a concise synthesis of a biologically active form of
mon synthetic intermediate of a2.
a
2. We also report
1 using a com-
yield. Removal of the benzyl group in 10a under Birch conditions
(98%), followed by tosylation and successful iodination of the
resulting alcohol, yielded the corresponding iodide (64% in two
steps). The iodide was converted into corresponding sulfone 12a
with sodium sulfinate (92%). Further alkylation of the corre-
sponding dianion of 12a with known bromide 1316 at low tem-
perature (88%), followed by desulfonation, afforded 14a with the
a
2. Results and discussion
Our retrosynthetic analysis is summarized in Scheme 1. Because
the structure of 2 is similar to that of 1, we employed a similar
synthetic approach for 2 was con-
1.12 The carbon skeleton of
a
a
full carbon skeleton of
showed additional olefin proton signals, indicating contamination
by side reaction products such as -elimination of the sulfonyl
a
2. The 1H NMR analysis of the obtained 14a
a
a
structed by a coupling between the corresponding dianion of sul-
fone B with known bromide A.16 The hydroxyl group at C-11 was
introduced using a Sharpless asymmetric dihydroxylation (AD)17 of
C, followed by deoxygenation of the unnecessary resulting sec-
ondary hydroxyl group at C-10. The bond between C-12 and C-13 of
C was generated by the coupling of bromide D and known sulfone
E.18 Fragment D was prepared from the aldehyde F,19 which can be
b
group. Fortunately, the undesired side products were easily re-
moved by column chromatography with silver nitrate-impregnated
silica gel. The yield of pure 14a was 64%. Removal of the two TBS
groups in 14a with TBAF afforded (7S,11R,15R)-2a in an overall yield
of 5.8% from known aldehyde 4. Because both the enantiomers of
citronellol and the reagents for asymmetric dihydroxylation were
derived from citronellol. Although
centers at C-7, C-11, and C-15 that lead to eight possible stereo-
isomers of 2, we speculated that the absolute configuration of
C-15 could be determined by analogy to
1.12 The determined
a
2 possesses three stereogenic
readily available, the possible four stereoisomers of a2 were syn-
thesized using the above methodology to yield (7S,11S,15R)-2b,
(7R,11R,15R)-2c, and (7R,11S,15R)-2d.
a
a
NMR studies of the four synthetic stereoisomers of a2 (2aed)
stereogenic center, C-15, could be derived from a known compound
with distinct absolute configuration. The remaining stereogenic
were conducted for verification of the asymmetric carbon config-
urations. However, no significant differences between the 1H and
13C NMR spectra of the four synthetic stereoisomers and those of
the natural product were observed. Thus, determining the relative
center, C-11, could be derived using the appropriate AD-mix-
a or b.
Thus, to identify the absolute stereostructure of 2, the four pos-
a
sible stereoisomers with a fixed configuration of 15R were syn-
thesized. If the isomers showed weak activity, the other four
isomers with the 15S configuration could be synthesized.
and absolute configuration of natural
possible. The same observation applied to
a
2 by NMR analyses is im-
a
1.11,12
Next, the biological activities of the four stereoisomers of
a2
The stereoselective total synthesis of
a2 is shown in Scheme 2.
were measured using previously described methods.15 Fig. 2 shows
the dose-dependent increase in the oospore formation activities of
The optically active (97% ee) citronellol was converted into known
aldehyde 4.19 Wittig condensation of 4 with (carbethoxyethylidene)
triphenylphosphorane (98%), followed by reduction of the resulting
ester moiety, afforded alcohol 5 (90%). Alcohol 5 was converted to
the allylic bromide and then coupled to the bromide with the
known sulfone 6.18 Further desulfonation with sodium amalgam
afforded 7a. The stereoselective dihydroxylation17 of 7a with AD-
the natural and synthetic stereoisomers of a2 (2aed) against the A1
mating type of P. nicotianae. Only the (7S,11R,15R)-isomer (2a)
showed significant hormonal activity at dosages of 3 ng/disc, which
was comparable to that of the natural product. The other three
isomers were essentially inactive. The very weak activity observed
in the (7S,11S,15R)-isomer (2b) would reflect contamination by the
active (7S,11R,15R)-isomer from the asymmetric dihydroxylation
step. According to the findings of the unique bioactivity of the
mix-a produced diol 8a. For the synthesis of a1, the reaction pro-
ceeded in a 95:5 diastereomeric ratio (dr), as determined by HPLC
analysis.12 The diastereomeric ratio of 8a could not be determined
by chiral HPLC analysis. The biological properties of the final
products, however, supported the high stereoselectivity of the AD
(7S,11R,15R)-isomer (2a), the absolute configuration of natural
was determined to be 7S,11R,15R, which is consistent with
a2
a
1.
Surprisingly,
the A2 mating type and then converted to a
a
2 was found to be biosynthesized from phytol (15) in
1 by the A1 mating type
reactions as the synthesis of
a
1 (vide infra). Monomesylation of the
secondary hydroxyl group and demesylation with K2CO3 yielded
epoxide 9a. The regioselective reductive opening of the epoxy ring
with Super-HydrideÒ (LiEt3BH) yielded tertiary alcohol 10a in a 91%
to initiate sexual reproduction when both the mating types shared
the same habitat (Scheme 3).15 The absolute configurations of all
the stereogenic centers of a2 are consistent with a1.

A. Yajima et al. / Tetrahedron 67 (2011) 8887e8894
8889
Scheme 2. Asymmetric synthesis of
a
2. Reagents, conditions and yields: (a) Ph3P]C(Me)CO2Et, benzene, reflux, 98%; (b) DIBAL, CH2Cl2, hexane, ꢀ78 ꢁC, 90%; (c) n-BuLi, MsCl, THF,
ꢀ78 ꢁC, then LiBr, 86%; (d) 6, n-BuLi, THF, HMPA, ꢀ78 ꢁC, 82%; (e) Na/Hg, Na2HPO4, THF, MeOH, ꢀ15 ꢁC, 72%; (f) AD-mix-
a
, MeSO2NH2, t-BuOH, H2O, 0 ꢁC, 77%; (g) Ms2O, Et3N,
CH2Cl2, 0 ꢁC; (h) K2CO3, MeOH, 65% in two steps; (i) LiEt3BH, THF, 0 ꢁC, 91%; (j) Li, NH3, THF, ꢀ78 ꢁC, 98%; (k) TsCl, pyridine, 0 ꢁC; (l) NaI, acetone, reflux, 64% in two steps; (m)
PhSO2Na, DMF, 92%; (n) n-BuLi, 13, THF, HMPA, ꢀ78 ꢁC, 88%; (o) Na/Hg, Na2HPO4, THF, MeOH, ꢀ15 ꢁC, 64%; (p) TBAF, THF, 0 ꢁC, 87%.
Scheme 3. Biosynthetic pathway for a1 and a2.
(Scheme 4). The coupling of sulfone 12a with aldehyde 17, which
was prepared from 16, followed by oxidation and desulfonation,
afforded the protected
groups of 18 yielded (3RS,7R,11R,15R)-
a diastereomeric mixture at C3, we have reported that the stereo-
chemically pure (3R,7R,11R,15R)- 1 exhibited almost the same
biological activity with the natural product, which is a di-
astereomeric mixture at C3 (R/S¼ca. 3:2).12 This result indicates
that the synthetic (3RS)-1 will be as active as the natural product.
a
1 (18). Removal of the two silyl protecting
a
1. Although the product was
a
Fig. 2. The dose-dependent increase of oospore formation in the A1 mating type of
P. nicotianae, as induced by synthetic samples (ng/disc) in comparison with natural
at doses of 3e300 ng/disc. Values represent the mean of four replicates.
a2
The first stereoselective synthesis of
a1 was not satisfactory
based on the product yield. Namely, the yield of the coupling of
the C1eC5 fragment and the C6eC12 fragment was only 43%.12
Therefore, we examined the application of the synthetic
3. Conclusion
In summary, we achieved the first total synthesis of Phytoph-
intermediate of
a
2, sulfone 12a, for the total synthesis of
a
1
thora mating hormone a2. The biological activities of the four

8890
A. Yajima et al. / Tetrahedron 67 (2011) 8887e8894
74.96; H, 9.27%]; ½a D24
þ4.5 (c 1.2, CHCl3); nmax (liquid film) 2928,
ꢂ
2923, 2866, 1709, 1649, 1454, 1366, 1273, 1191, 1139, 1099, 1028,
736, 698 cmꢀ1
;
dH (400 MHz, CDCl3) 0.90 (d, J¼6.3 Hz, 3H),
1.27e1.33 (m, 4H), 1.45 (m, 2H) 1.65 (m, 2H), 1.82 (d, J¼1.0, 3H),
2.17 (m, 2H), 3.50 (m, 2H), 4.18 (m, 2H), 4.51 (d, J¼12.2 Hz, 1H),
6.73 (m, 1H), 7.24e7.36 (m, 5H); dC (100 MHz, CDCl3) 12.3, 14.3,
19.4, 26.2, 29.7, 35.7, 36.6, 60.3, 68.4, 72.9, 127.5, 127.58, 127.61,
128.3, 138.6, 142.3, 168.2.
4.1.2. (2E,6R)-2,6-Dimethyl-8-benzyloxy-2-octen-1-ol (5). To a stir-
red and cooled (ꢀ78 ꢁC) solution of the above compound (5.34 g,
17.4 mmol) in CH2Cl2 (40 ml) was added dropwise DIBAL (1.05 M
solution in hexane, 38.9 ml, 40.1 mmol) under Ar atmosphere. After
stirring for 30 min, MeOH and satd potassium sodium tartrate so-
lution were added carefully to the mixture. The mixture was
warmed to room temperature and stirred for 1 h. The aqueous layer
was extracted with AcOEt, and the combined organic layer was
washed with water and brine. The organic layer was dried over
MgSO4 and concentrated. The residue was purified by silica gel
column chromatography with AcOEt/hexane (1:20) to give 5
Scheme 4. Synthesis of
a
1. Reagents, conditions and yields: (a) TBDPSCl, imidazole,
ꢀ
DMF, 98%; (b) 9-BBN, THF then H2O2 NaOH aq, 95%; (c) PCC, MS4 A, CH2Cl2, 87%; (d)
n-BuLi, THF ꢀ78 ꢁC, then 17; (e) DesseMartin periodinane, NaHCO3, CH2Cl2, 81% in two
steps; (f) Al/Hg, THF, 62% (81% based on recovered starting material); (g) TBAF, THF,
quant.
(4.16 g, 90%) as a colorless oil. ½a D24
þ2.7 (c 1.1, CHCl3). [Found: C,
ꢂ
77.91; H, 9.91. C17H26O2 requires C, 77.82; H, 9.99%]; nmax (liquid
film) 3395, 2923, 2864, 1739, 1455, 1367, 1240, 1205, 1098, 1013,
synthetic stereoisomers were evaluated using an oospore-inducing
assay, and only the (7S,11R,15R)-isomer of
significantly active as the natural product. Based on the bioactivity,
the absolute configuration of the natural 2 was determined to be
7S,11R,15R. We also developed an alternative synthetic method for
1 using a common synthetic intermediate for 2 synthesis. No-
a2 was found to be as
846, 737, 698, 612 cmꢀ1
;
dH (400 MHz, CDCl3) 0.90 (d, J¼6.3 Hz, 3H),
1.27e1.33 (m, 2H), 1.45 (m, 2H) 1.65 (m, 2H), 1.82 (d, J¼1.0, 3H), 2.17
(m, 2H), 3.50 (m, 2H), 4.18 (m, 2H), 4.48 (d, J¼12.2 Hz, 1H), 4.51 (d,
J¼12.2 Hz,1H), 6.73 (m,1H), 7.24e7.36 (m, 5H); dC (100 MHz, CDCl3)
13.6, 14.2, 19.5, 25.0, 29.5, 36.6, 36.8, 68.6, 69.0, 72.9, 126.5, 127.5,
127.6, 128.3, 134.5, 138.6.
a
a
a
tably, both
a1 and a2 have been found to induce sexual re-
production in most of the heterothallic species.9,15 These results
demonstrate the interspecific universality of the Phytophthora
mating hormones. With a pair of the mating hormones, establish-
4.1.3. (2R,6E,10R)-12-Benzyloxy-1-tert-butyldimethylsilyloxy-2,6,10-
trimethyl-6-dodecen-4-yl phenyl sulfone. To a stirred and cooled
(ꢀ78 ꢁC) solution of 5 (1.59 g, 6.09 mmol) in THF (10 ml) was added
n-BuLi (1.65 M solution in hexane, 5.54 ml, 9.14 mmol) under Ar
atmosphere. After stirring for 20 min, methanesulfonyl chloride
(1.05 g, 9.14 mmol) was added to the mixture. After stirring for 1 h,
a solution of LiBr (794 mg, 9.14 mmol) in THF (6 ml) was added to
the mixture. The mixture was stirred for 1 h at the same temper-
ature and 1 h at room temperature, and then poured into satd
NaHCO3 solution. The aqueous layer was extracted with hexane,
and the combined organic layers were washed with water and
brine. The organic layer was dried over Na2SO4 and concentrated.
The residue was purified by silica gel column chromatography with
AcOEt/hexane (1:150) to give 1.70 g of the corresponding allylic
bromide as a colorless oil. This was immediately used for the next
reaction. To a stirred and cooled (ꢀ78 ꢁC) solution of 6 (1.29 g,
3.77 mmol) in THF (10 ml) and HMPA (1 ml) was added dropwise n-
BuLi (1.65 M solution in hexane, 2.74 ml, 4.52 mmol). After stirring
for 30 min, a solution of 1.35 g of the allylic bromide (4.15 mmol) in
THF (15 ml) was added. The mixture was stirred for 40 min, and
then quenched with water. The aqueous layer was extracted with
AcOEt, and the combined organic layer was washed with satd
Na2S2O3 solution, satd NaHCO3 solution, water and brine. The or-
ganic layer was dried over Na2SO4 and concentrated. The residue
was purified by flash chromatography with AcOEt/hexane (1:30) to
give the title compound (1.82 g, 70% for two steps) as a colorless oil.
ing the molecular mechanism of the hormones using synthetic
a1
or 2 as chemical probes is possible and would contribute to the
a
development of agricultural pest management methods for con-
trolling Phytophthora sexual reproduction. The complete stereo-
structures of the Phytophthora mating hormones have finally been
established since Ashby proposed the existence of hormone-like
compounds over 80 years ago.
4. Experimental
4.1. General
Optical rotations were measured on a Jasco P-2100. IR spectra
were measured on a Jasco IR-4100 spectrometer. 1H NMR spectra
were recorded on Jeol ECS400 (400 MHz) spectrometer using the
residual solvent peak at
internal standard. 13C NMR spectra were recorded on Jeol ECS400
(100 MHz) spectrometer using CDCl3 at ¼49.0
¼77.0 or CD3OD at
d¼7.26 (for CDCl3) or 3.30 (for CD3OD) as an
d
d
as an internal standard. Elemental compositions were analyzed on
a J-Science MICROCORDER JM10. High resolution ESI-TOF-MS data
were recorded on Mariner Biospectrometry Workstation (Applied
Biosystems), Bioapex II (Brucker), Jeol JMS-T100 and Jeol JMS-
HX110 spectrometers. Column chromatography was performed
with silica gel Wakogel-C200. Flush column chromatography was
performed with Kanto Silica Gel 60 (spherical).
½
a 2D4
ꢂ
ꢀ7.2 (c 1.1, CHCl3); [Found: C, 69.32; H, 9.32. C34H54O4SSi re-
quires C, 69.57; H, 9.27%]; nmax (liquid film) 2955, 2927, 2856, 1447,
4.1.1. (2E,6R)-Ethyl2,6-dimethyl-8-benzyloxy-2-octenoate. To a solu-
tion of (R)-4 (4.00 g, 16.8 mmol) in benzene (45 ml) was added[1-
(ethoxycarbonyl)ethylidene]triphenylphosphorane (9.13 g, 25.2
mmol), and the resulting mixture was refluxed for 4 h. After
cooling to room temperature, the solution was concentrated. The
residue was purified by silica gel column chromatography with
AcOEt/hexane (1:60) to give the title compound (5.34 g, 98%) as
a colorless oil. [Found: C, 74.85; H, 9.01. C19H28O3 requires C,
1387, 1362, 1304, 1252, 1145, 1086, 1027, 837, 777, 754, 734, 694,
606 cmꢀ1
; dH (400 MHz, CDCl3) 0.00e0.02 (m, 6H), 0.74e0.87 (m,
15H), 1.11 (m, 1H), 1.29 (m, 2H), 1.40 (m, 1H), 1.49e1.69 (m, 5H),
1.75e2.06 (m, 5H), 2.59, 2.62 (2ꢃbr s, 1H), 3.17e3.52 (m, 5H), 4.46
(d, J¼12.2 Hz, 1H), 4.49 (d, J¼12.2 Hz, 1H), 5.11 (m, 1H), 7.24e7.35
(m, 5H), 7.54 (m, 2H), 7.63 (m, 1H), 7.88 (m, 2H); dC (100 MHz,
CDCl3) ꢀ5.46, ꢀ5.42, 15.4, 16.4, 16.6, 18.3, 19.5, 25.47, 25.52, 25.91,
25.94, 29.6, 32.0, 33.3, 36.59, 36.62, 36.8, 40.1, 40.4, 60.2, 67.3, 68.3,

A. Yajima et al. / Tetrahedron 67 (2011) 8887e8894
8891
68.6, 72.9, 127.5, 127.6, 128.3, 128.94, 128.96, 129.03, 129.1, 129.3,
129.4, 129.8, 133.44, 133.45, 137.8, 137.9, 138.60, 138.62.
72.67; H, 10.89%]; nmax (liquid film) 2955, 2928, 2856, 1462, 1377,
1361, 1252, 1097, 836, 776, 734, 697 cmꢀ1
dH (400 MHz, CDCl3) 0.03
;
(s, 6H), 0.83 (d, J¼6.7 Hz, 3H), 0.84 (d, J¼6.7 Hz, 3H), 0.84 (s, 9H),
1.08 (m, 1H), 1.27 (s, 3H), 1.32e1.73 (m, 13H), 2.67 (t, J¼5.9 Hz, 1H),
3.36 (dd, J¼6.3, 9.9 Hz, 1H), 3.44 (dd, J¼5.9, 9.9 Hz, 1H) 3.51 (m, 2H),
4.48 (d, J¼12.2 Hz,1H), 4.51 (d, J¼12.6 Hz,1H), 7.25e7.63 (m, 5H); dC
(100 MHz, CDCl3) ꢀ5.3, 16.7, 18.3, 19.5, 22.3, 22.9, 25.9, 26.0, 29.8,
33.1, 33.5, 33.8, 35.7, 36.5, 61.0, 65.0, 68.2, 68.5, 72.9, 127.5, 127.6,
128.3, 138.6.
4.1.4. (2R,6E,10R)-tert-Butyldimethylsilyl 12-benzyloxy-2,6,10-
trimethyl-6-dodecenyl ether (7a). To a stirred and cooled (ꢀ15 ꢁC)
solution of the above compound (1.90 g, 3.24 mmol) in MeOH
(7 ml) and THF (14 ml) were added Na2HPO4 (1.37 g, 9.72 mmol)
and 5% Na/Hg (3.0 g). The mixture was stirred for 1 h at the same
temperature and for 30 min at room temperature, and then filtered
through a Celite pad. The filtrate was poured into water, and
aqueous layer was extracted with AcOEt. The combined organic
layer was washed with satd NH4Cl solution, satd NaHCO3 solution,
water and brine. The organic layer was dried over Na2SO4, and
concentrated. The residue was purified by flash column chroma-
tography with AcOEt/hexane (1:90) to give 7a (1.05 g, 72%) as
4.1.7. (2R,6R,10R)-12-Benzyloxy-1-tert-butyldimethylsilyloxy-2,6,10-
trimethyldodecan-6-ol (10a). To a stirred and cooled (0 ꢁC) solution
of 9a (315 mg, 680 m
mol) in THF (3 ml) was added Super-hydrideÒ
(1.0 M solution in THF, 2.72 ml, 2.72 mmol) under Ar atmosphere.
The mixture was warmed to room temperature and stirred for
5.5 h. The reaction was quenched with water (1 ml), and then 5%
NaOH solution (2 ml) and 30% H2O2 solution (2 ml) were succes-
sively added to the mixture. After stirring for 1.5 h, the mixture was
diluted with water. The aqueous layer was extracted with AcOEt,
and the combined organic layer was washed with water and brine.
The organic layer was dried over Na2SO4, and concentrated. The
residue was purified by flash column chromatography with AcOEt/
a colorless oil. ½a D25
ꢀ0.8 (c 1.2, CHCl3); [Found: C, 75.42; H, 11.22.
ꢂ
C28H50O2Si requires C, 75.27; H, 11.28%]; nmax (liquid film) 2954,
2928, 2856, 1461, 1362, 1254, 1097, 826, 775, 733, 697 cmꢀ1
; dH
(400 MHz, CDCl3) 0.03 (s, 6H), 0.83 (d, J¼6.7 Hz, 3H), 0.84 (d,
J¼6.7 Hz, 3H), 0.84 (s, 9H), 0.93e1.09 (m, 1H), 1.25 (m, 1H),
1.26e1.47 (m, 5H), 1.49e1.75 (m, 7H), 1.88e2.01 (m, 3H), 3.34 (dd,
J¼6.7, 9.5 Hz, 1H), 3.43 (dd, J¼5.9, 9.5 Hz, 1H), 3.50 (m, 2H), 4.48 (d,
J¼12.2 Hz, 1H), 4.51 (d, J¼12.2 Hz, 1H), 5.09 (dt, J¼1.1, 7.1 Hz, 1H),
7.25e7.36 (m, 5H); dC (100 MHz, CDCl3) ꢀ5.3, 15.8, 16.8, 18.4, 19.6,
25.4, 26.0, 29.6, 32.8, 35.7, 36.7, 37.2, 40.0, 68.4, 68.8, 72.9, 124.5,
127.5, 127.6, 128.3, 138.7.
hexane (1:20) to give 10a (291 mg, 91%) as a colorless oil. ½a D24
ꢀ0.1
ꢂ
(c 1.0, CHCl3); [Found: C, 72.27; H, 11.01. C28H52O3Si requires C,
72.35; H, 11.28%]; nmax (liquid film) 3459, 2953, 2932, 2903, 2856,
1470, 1462, 1362, 1254, 1097, 836, 776, 735, 697 cmꢀ1
; dH (400 MHz,
CDCl3) 0.03 (s, 6H), 0.83 (d, J¼6.7 Hz, 3H), 0.84 (d, J¼6.7 Hz, 3H),
0.84 (s, 9H), 1.02e1.16 (m, 2H), 1.15 (s, 3H), 1.25e1.46 (m, 12H),
1.56e1.71 (m, 3H), 3.36 (dd, J¼6.3, 9.9 Hz, 1H), 3.44 (dd, J¼5.9,
9.9 Hz, 1H) 3.51 (m, 2H), 4.48 (d, J¼11.8 Hz, 1H), 4.51 (d, J¼11.2 Hz,
1H), 7.25e7.63 (m, 5H); dC (100 MHz, CDCl3) -5.3, 16.7, 18.3, 19.6,
21.2, 21.3, 25.9, 27.0, 29.8, 33.7, 35.7, 36.8, 37.7, 42.1, 42.2, 68.3, 68.7,
72.8, 72.9, 127.5, 127.6, 128.3, 138.7.
4.1.5. (2R,6S,7S,10R)-12-Benzyloxy-1-tert-butyldimethylsilyloxy-
2,6,10-trimethyldodecane-6,7-diol (8a). To a stirred and cooled
(0 ꢁC) solution of 7a (651 mg, 1.45 mmol) in t-BuOH (9 ml) and
water (9 ml) were added AD-mix-aÒ (4.08 g) and meta-
nesulfonamide (415 mg, 3.36 mmol). After stirring for 24 h,
Na2S2O3 pentahydrate was added to the mixture, which was
allowed to warm to room temperature over 1 h. The mixture was
extracted with AcOEt, and the combined organic layer was washed
with brine. The organic layer was dried over MgSO4, and concen-
trated. The residue was purified by flash column chromatography
with AcOEt/hexane (1:10) to give 8a as a colorless oil (545 mg, 77%).
4.1.8. (3R,7R,11R)-12-tert-Butyldimethylsilyloxy-3,7,11-
trimethyldodecane-1,7-diol. Lithium (43.5 mg, 6.27 mmol) was
added to liquid NH3 (3 ml) at ꢀ78 ꢁC. After stirring for 30 min be-
low ꢀ40 ꢁC, a solution of 10a (291 mg, 620
mmol) in THF (3 ml) was
½
a 2D5
requires C, 69.95; H, 10.90%]; nmax (liquid film) 3435, 2952, 2929,
2856, 1461, 1362, 1254, 1096, 836, 776, 734, 776, 697 cmꢀ1
dH
ꢂ
ꢀ12.2 (c 0.97, CHCl3); [Found: C, 69.92; H, 10.62. C28H52O4Si
added dropwise. After stirring for 1 h, the reaction was quenched
with NH4Cl. Then NH3 was removed by gentle warming, and the
residue was diluted with water. The aqueous layer was extracted
with AcOEt, and the combined organic layer was washed with
water and brine. The organic layer was dried over MgSO4 and
concentrated. The residue was purified by silica gel column chro-
matography with AcOEt/hexane (1:5) to give the title compound
;
(400 MHz, CDCl3) 0.03 (s, 6H), 0.86 (d, J¼6.7 Hz, 3H), 0.88 (s, 9H),
0.90 (d, J¼6.3 Hz, 3H), 1.02e1.73 (m, 14H), 1.09 (s, 3H), 1.75 (br s,
2H), 3.37 (m, 2H), 3.43 (dd, J¼5.9, 9.5 Hz, 1H), 3.51 (m, 2H), 4.49 (d,
J¼12.2 Hz, 1H), 4.51 (d, J¼12.2 Hz, 1H), 7.25e7.36 (m, 5H); dC
(100 MHz, CDCl3) ꢀ5.3, 16.7, 18.4, 19.8, 20.6, 21.0, 26.0, 28.9, 30.1,
33.7, 34.3, 35.7, 36.5, 39.3, 68.4, 68.6, 72.9, 74.9, 77.7, 127.5, 127.7,
128.3, 138.6.
(231 mg, 98%) as a colorless oil. ½a D23
ꢀ0.5 (c 1.0, CHCl3); [Found: C,
ꢂ
67.12; H, 12.30. C21H46O3Si requires C, 67.32; H, 12.37%]; nmax (liquid
film) 3349, 2952, 2933, 2902, 2857, 1470, 1462, 1375, 1254, 1096,
1062, 836, 775 cmꢀ1
; dH (400 MHz, CDCl3) 0.03 (s, 6H), 0.86 (d,
4.1.6. (2R,6S,7R,10R)-12-Benzyloxy-1-tert-butyldimethylsilyloxy-6,7-
epoxy-2,6,10-trimethyldodecane (9a). To a stirred and cooled (0 ꢁC)
solution of 8a (545 mg, 1.13 mmol) in CH2Cl2 (5 ml) were added
J¼6.7 Hz, 3H), 0.88 (s, 9H), 0.90 (d, J¼6.3 Hz, 3H), 1.06 (m, 2H),
1.24e1.44 (m, 13H), 1.26 (s, 3H), 1.61 (m, 3H), 3.36 (dd, J¼6.3, 9.5 Hz,
1H), 3.43 (dd, J¼5.9, 9.5 Hz, 1H), 3.67 (m, 2H); dC (100 MHz, CDCl3)
ꢀ5.4, 16.7, 18.3, 19.6, 21.2, 21.3, 25.9, 27.0, 29.4, 33.7, 35.7, 37.6, 39.9,
42.0, 42.2, 61.1, 68.4, 72.8.
Et3N (631 ml, 4.54 mmol) and methanesulfonic anhydride (296 mg,
1.70 mmol). After stirring for 3.5 h, the mixture was poured into
water. The aqueous layer was extracted with AcOEt, and the com-
bined organic layer was washed with satd NaHCO3 solution, water
and brine. The organic layer was dried over Na2SO4, and concen-
trated to give a crude mesylate. This was dissolved in MeOH (5 ml),
and K2CO3 (235 mg, 1.70 mmol) was added to the resulting solution
at room temperature. After stirring for 40 min, the mixture was
poured into water. The aqueous layer was extracted with AcOEt,
and the combined organic layer was washed with water and brine.
The organic layer was dried over Na2SO4, and concentrated. The
residue was purified by flash column chromatography with AcOEt/
4.1.9. (2R,6R,10R)-1-tert-Butyldimethylsilyloxy-12-phenylsulfonyl-
2,6,10-trimethyldodecan-6-ol (12a). To a stirred and cooled (0 ꢁC)
solution of the above compound (217 mg, 580
mmol) in pyridine
(2.5 ml) was added p-toluenesulfonyl chloride (132 mg, 690
mmol).
After stirring for 4 h, the reaction was quenched with water. The
aqueous layer was extracted with ether, and the combined organic
layer was washed with satd CuSO4 solution, water, and brine. The
organic layer was dried over Na2SO4, and concentrated to give
crude tosylate. This was dissolved in acetone (2.5 ml), and then NaI
hexane (1:75) to give 9a (345 mg, 65%) as a colorless oil. ½a D24
ꢂ
þ5.1
(130 mg, 870
mmol) was added to the resulting solution at room
(c 1.1, CHCl3); [Found: C, 72.43; H, 10.81. C28H50O3Si requires C,
temperature. After stirring for 3.5 h under reflux condition, the

8892
A. Yajima et al. / Tetrahedron 67 (2011) 8887e8894
reaction mixture was poured into water. The aqueous layer was
extracted with ether, and the combined organic layer was washed
with satd NaHCO3 solution, water and brine. The organic layer was
dried over Na2SO4, and concentrated. The residue was purified by
silica gel column chromatography with AcOEt/hexane (1:50) to give
the corresponding iodide (180 mg). This was dissolved in DMF
(2 ml), and to the resulting solution was added benzensulfinic acid
sodium salt dihydrate (297 mg, 1.48 mmol). After stirring for 6 h,
the mixture was poured into water. The aqueous layer was
extracted with ether, and combined organic layer was washed with
water and brine. The organic layer was dried over Na2SO4, and
concentrated. The residue was purified by flash column chroma-
tography with AcOEt/hexane (1:10) to give 12a (171 mg, 59% for
1H), 1.60 (s, 3H), 1.96 (m, 2H), 3.36 (dd, J¼6.3, 9.7 Hz, 1H), 3.43 (dd,
J¼5.9, 9.7 Hz, 1H), 4.18 (d, J¼6.4 Hz, 2H), 5.28 (br t, J¼6.3 Hz, 1H); dC
(100 MHz, CDCl3) ꢀ5.4, ꢀ5.0, 16.3, 16.7, 18.35, 18.44, 19.6, 21.3, 21.4,
25.1, 25.96, 26.04, 27.0, 32.7, 33.8, 35.7, 36.7, 37.6, 39.8, 42.22, 42.24,
60.3, 68.4, 72.8, 124.2, 137.3; HRMS (ESI): MNaþ, found 579.4597.
C32H68O3Si2Na requires 579.4599.
4.1.12. (7S,11R,15R)-a
2 (2a). To a stirred and cooled (0 ꢁC) solution
of 14a (84 mg, 0.15 mmol) in THF (0.9 ml) was added TBAF (1.0 M
solution in THF, 0.60 ml, 0.60 mmol). After stirring for 7 h, the re-
action mixture was poured into water. The aqueous layer was
extracted with AcOEt, and the combined organic layer was washed
with brine. The organic layer was dried over MgSO4, and concen-
trated. The residue was purified by silica gel column chromatog-
three steps) as a colorless oil. ½a D24
ꢀ3.7 (c 1.0, CHCl3); [Found: C,
ꢂ
64.72; H, 9.90. C27H50O4SSi requires C, 65.01; H, 10.10%]; nmax (liq-
uid film) 3541, 2953, 2934, 2902, 2857, 1470, 1463, 1447, 1306, 1252,
raphy with AcOEt/hexane (1:1) to give (7S,11R,15R)-a2 (2a) (43 mg,
87%) as a colorless oil. ½a D24
ꢂ
ꢀ6.0 (c 1.0, CHCl3), lit.15; [
a
]
ꢀ5
D
1148, 1087, 837, 776, 742, 689 cmꢀ1
;
dH (400 MHz, CDCl3) 0.02 (s,
(CHCl3); nmax (liquid film) 3346 (br), 2935, 2868, 1742, 1725, 1669,
6H), 0.84 (d, J¼6.3 Hz, 3H), 0.86 (d, J¼6.3 Hz, 3H), 0.88 (s, 9H),
0.96e1.73 (m, 17H), 1.12 (s, 3H), 3.07 (m, 2H), 3.36 (dd, J¼6.5, 9.5 Hz,
1H), 3.42 (dd, J¼5.9, 9.5 Hz, 1H), 7.56 (m, 2H), 7.65 (m, 1H), 7.90 (d,
J¼1.1, 8.3 Hz, 2H); dC (100 MHz, CDCl3) ꢀ5.3, 16.7, 18.3, 19.1, 21.0,
21.3, 25.9, 26.9, 29.2, 31.9, 33.7, 35.7, 36.9, 41.9, 42.3, 54.4, 68.3, 72.6,
128.0, 129.2, 133.6, 139.2.
1462, 1375, 1242, 1042, 1012, 755 cmꢀ1
; dH (400 MHz, CDCl3) 0.84
(d, J¼6.3 Hz, 3H), 0.90 (d, J¼6.7 Hz, 3H), 1.01e1.13 (m, 3H), 1.14 (s,
3H), 1.21e1.45 (m, 14H), 1.58e1.62 (m, 1H), 1.64 (s, 3H), 1.80 (br s,
3H), 1.96 (t, J¼7.5 Hz, 2H), 3.40 (dd, J¼6.3, 10.5 Hz, 1H), 3.46 (dd,
J¼5.9, 10.5 Hz, 1H), 4.11 (d, J¼6.7 Hz, 2H), 5.37 (tq, J¼6.7, 1.1 Hz, 1H);
dC (100 MHz, CDCl3) 16.1, 16.6, 19.7, 21.15, 21.23, 24.9, 26.9, 32.4,
33.7, 35.6, 36.2, 37.4, 39.6, 41.9, 42.1, 59.2, 68.1, 72.8, 123.3, 139.7;
HRMS (ESI): MNaþ, found 351.2879. C20H40O3Na requires 351.2870.
The 1H and 13C NMR spectra were identical with those of the nat-
4.1.10. (2R,6R,10R,14E)-1,16-Bis-(tert-butyldimethylsilyloxy)-12-
phenylsulfonyl-2,6,10,14-tetramethyl-14-hexadecen-6-ol. To a stirred
and cooled (ꢀ78 ꢁC) solution of 12a (155 mg, 310
m
mol) in THF
ural
(7R,11S,15R)-
a
2. Diastereomers, (7R,11R,15R)-, (7S,11S,15R)-, and
2, were successively synthesized in a similar fashion.
(1.5 ml) and HMPA (0.15 ml) was added n-BuLi (1.65 M solution in
a
hexane, 430
30 min, a solution of 13 (112 mg, 400
m
l, 710
m
mol) under Ar atmosphere. After stirring for
mmol) in THF (1 ml) was
4.1.13. Properties of (7R,11R,15R)-
a
2 (2b). ½a 2D4
ꢀ5.2 (c 0.5, CHCl3);
ꢂ
added. After stirring for 2.5 h, the mixture was warmed to 0 ꢁC and
poured into water. The aqueous layer was extracted with AcOEt,
and the combined organic layer was washed with satd NaHCO3
solution, water and brine. The organic layer was dried over Na2SO4,
and concentrated. The residue was purified by flash column chro-
matography with AcOEt/hexane (1:15) to give the title compound
HRMS (ESI): MNaþ, found 351.2842. C20H40O3Na requires 351.2870.
The 1H and 13C NMR spectra, and IR spectrum were indistinguish-
able with those of (7S,11R,15R)-a2.
4.1.14. Properties of (7S,11S,15R)-
a
2 (2c). ½a 2D3
ꢀ5.0 (c 1.0, CHCl3);
ꢂ
HRMS (ESI): MNaþ, found 351.2851. C20H40O3Na requires 351.2870.
(191 mg, 88%) as a colorless oil. ½a D25
ꢀ6.3 (c 1.0, CHCl3); [Found: C,
ꢂ
The 1H and 13C NMR spectra, and IR spectrum were indistinguish-
65.69; H, 10.22. C38H72O5SSi requires C, 65.46; H, 10.41%]; nmax
(liquid film) 3532, 2931, 2856, 1470, 1462, 1385, 1360, 1304, 1254,
able with those of (7S,11R,15R)-a2.
1146, 1086, 1006, 836, 813, 776, 733, 691, 666, 605 cmꢀ1
;
dH
4.1.15. Properties of (7R,11S,15R)-
a
2 (2d). ½a 2D5
ꢀ4.3 (c 1.0, CHCl3);
ꢂ
(400 MHz, CDCl3) 0.03 (m, 12H), 0.75e0.89 (m, 24H), 0.95e2.11 (m,
24H), 2.61 (m, 1H), 3.14 (m, 1H), 3.34e3.39 (m, 1H), 3.41e3.46 (m,
1H), 4.10 (m, 2H), 5.31 (m, 1H), 7.56 (m, 2H), 7.64 (m, 1H), 7.87 (m,
2H); dC (100 MHz, CDCl3) ꢀ5.4, ꢀ5.2, 15.3, 15.8, 15.9, 16.7, 18.3, 18.4,
19.25 19.30, 21.0, 21.3, 25.9, 26.0, 26.9, 30.3, 30.5, 33.8, 35.5, 35.8,
36.0, 37.3, 37.5, 39.8, 40.2, 42.0, 42.1, 42.3, 59.9, 60.0, 60.2, 60.3, 65.8,
68.4, 72.7, 129.0, 129.1, 129.4, 131.2, 131.5, 133.55, 133.58, 137.9.
HRMS (ESI): MNaþ, found 351.2842. C20H40O3Na requires 351.2870.
The 1H and 13C NMR spectra, and IR spectrum were indistinguish-
able with those of (7S,11R,15R)-a2.
4.1.16. 4-tert-Butyldiphenylsilyloxy-2-methyl-1-butene. To a stirred
solution of 16 (200 mg, 2.33 mmol) in DMF (2 ml) were added
imidazole (317 mg, 4.66 mmol) and tert-butyldiphenylchlorosilane
(650 ml, 4.66 mmol). After stirring for 6 h, the mixture was poured
4.1.11. (2R,6R,10S,14E)-1,16-Bis-(tert-butyldimethylsilyloxy)-
into water. The aqueous layer was extracted with hexane, and the
combined organic layer was washed with water and brine, and
dried over MgSO4. After concentration in vacuo, the residue was
purified by column chromatography with hexane to give the title
compound (742 mg, 98%) as a colorless oil. [Found: C, 77.53; H, 8.07.
C21H28OSi requires C, 77.72; H, 8.70%]; nmax (liquid film) 3071, 2930,
2,6,10,14-tetramethyl-14-hexadecen-6-ol (14a). To
a stirred and
cooled (ꢀ15 ꢁC) solution of the above compound (168 mg,
240
mmol) in THF (1.2 ml) and MeOH (0.6 ml) were added Na2HPO4
(102 mg, 720
mmol) and 5% Na/Hg (350 mg). After stirring for 2.5 h,
the mixture was filtered through a Celite pad and poured into
water. The aqueous layer was extracted with AcOEt, and the com-
bined organic layers were washed with satd NaHCO3 solution,
water, and brine. The organic layer was dried over Na2SO4, and
concentrated. The residue was purified by flash chromatography
with AcOEt/hexane (1:30) to give the product (108 mg). This was
further purified with AgNO3-impregnated silica gel column chro-
matography with AcOEt/hexane (1:50) to give 14a (87 mg, 64%) as
1651, 1472, 1428, 1111 cmꢀ1
; dH (400 MHz, CDCl3) 1.04 (s, 9H), 1.68
(s, 3H), 2.28 (t, J¼6.9 Hz, 2H), 3.76 (t, J¼6.9 Hz, 2H), 4.68 (s, 1H), 4.74
(s, 1H), 7.36e7.44 (m, 6H), 7.66e7.73 (m, 4H); dC (100 MHz, CDCl3)
19.2, 22.7, 26.8, 40.9, 62.8, 111.7, 127.6, 129.5, 134.0, 135.6, 143.0.
4.1.17. 4-tert-Butyldiphenylsilyloxy-2-methylbutan-1-ol. To a stirred
and cooled (0 ꢁC) solution of the above compound (1.00 g,
3.09 mmol) in THF (8 ml) was added 9-BBN (0.5 M, in THF, 18.5 ml,
9.26 mmol) under Ar atmosphere. After stirring for 6 h at room
temperature, the mixture was cooled to 0 ꢁC, and 6 N NaOH
(8.18 ml) and 30% H2O2 (9.57 ml) were added to the mixture. After
stirring for 4 h at room temperature, the mixture was extracted
a colorless oil. ½a D27
ꢀ2.1 (c 1.0, CHCl3); nmax (liquid film) 3388, 2931,
ꢂ
2857, 1462, 1377, 1361, 1253, 1095, 1063, 938, 916, 835, 775,
666 cmꢀ1
; dH (400 MHz, CDCl3) 0.03 (s, 6H), 0.06 (s, 6H), 0.85 (d,
J¼6.3 Hz, 3H), 0.87 (d, J¼6.3 Hz, 3H), 0.89 (s, 9H), 0.90 (s, 9H),
1.04e1.12 (m, 3H), 1.15 (s, 3H), 1.20e1.48 (m, 15H), 1.54e1.63 (m,

A. Yajima et al. / Tetrahedron 67 (2011) 8887e8894
8893
with ether. The combined organic layer was washed with water and
brine, and dried over MgSO4. After concentration in vacuo, the
residue was purified by column chromatography with AcOEt/hex-
ane (1:20) to give the title compound (1.01 g, 95%) as a colorless oil.
[Found: C, 73.34; H, 8.66. C21H30O2Si requires C, 73.63; H, 8.83%];
nmax (liquid film) 3371 (br), 3071, 2928, 2858, 1472, 1428,1390, 1112,
CHCl3); nmax (liquid film) 3502, 3070, 2932, 2861, 1712, 1462, 1389,
1255, 1112, 837, 775, 703 cmꢀ1
dH (400 MHz, CDCl3) 0.03 (s, 6H),
;
0.86 (d, J¼6.3 Hz, 3H), 0.87 (d, J¼6.3 Hz, 3H), 0.89 (s, 9H), 1.05 (d,
J¼6.3 Hz, 3H), 1.06 (s, 9H), 1.15 (s, 3H), 1.20e1.48 (m, 14H), 1.54e1.63
(m, 4H), 1.96 (m, 1H), 2.44 (m, 2H), 2.81 (m, 1H), 3.37 (dd, J¼6.3,
9.9 Hz, 1H), 3.42 (dd, J¼5.9, 9.9 Hz, 1H), 3.65 (t, J¼6.2 Hz, 2H),
7.36e7.44 (m, 6H), 7.63e7.66 (m, 4H); dC (100 MHz, CDCl3) ꢀ5.4,
16.33,16.3516.7,18.3,19.2,19.32, 19.33 21.21, 21.23, 21.27, 25.9, 26.8,
26.9, 30.7, 32.5, 33.7, 35.4, 35.5, 35.7, 37.39, 37.43, 39.0, 39.1, 42.2,
42.54, 42.57, 61.6, 68.3, 72.7, 127.6, 129.6, 133.67, 133.72, 135.5,
214.79, 214.81; HRMS (ESI): MNaþ, found 719.48850.
C42H72O4Si2Na requires 719.48668.
703 cmꢀ1
;
dH (400 MHz, CDCl3) 0.90 (d, J¼6.9 Hz, 3H), 1.05 (s, 9H),
1.50 (m, 1H), 1.62 (m, 1H), 1.85 (sꢃt, J¼6.9 Hz, 1H), 3.48 (dd, J¼6.9,
11.0 Hz, 1H), 3.50 (m, 2H), 3.67e3.79 (m, 2H), 7.37e7.46 (m, 6H),
7.66e7.69 (m, 4H); dC (100 MHz, CDCl3) 17.1, 19.1, 26.8, 33.9, 36.8,
62.5, 68.3, 127.7, 129.7, 133.5, 133.6.
4.1.18. 4-tert-Butyldiphenylsilyloxy-2-methylbutanal (17). To a stir-
red solution of the above compound (1.03 g, 3.01 mmol) in CH2Cl2
(10 ml) were added powdered MS4 A (1.0 g) and PCC (1.30 g,
4.1.21. (3RS,7S,11R,15R)-
a1 (1). To a stirred solution of 18 (30 mg,
ꢀ
43 mol) in THF (0.5 ml) was added TBAF (1.0 M solution in THF,
m
6.02 mmol) at room temperature. After stirring for 3 h, the mixture
was diluted with ether. The mixture was filtered through a silica gel
pad, and the silica gel pad was rinsed with ether. After concentra-
tion in vacuo, the residue was purified by column chromatography
with AcOEt/hexane (1:20) to give 17 (873 mg, 87%) as a colorless oil.
[Found: C, 74.07; H, 8.18. C21H28O2Si requires C, 74.07; H, 8.29%];
0.17 ml, 0.17 mmol). After stirring for 3 h, the reaction mixture was
poured into water. The aqueous layer was extracted with AcOEt,
and the combined organic layer was washed with brine. The or-
ganic layer was dried over MgSO4, and concentrated. The residue
was purified by silica gel column chromatography with AcOEt/
hexane (3:1) to give (3RS,7S,11R,15R)-a1 (15 mg, quant.) as a color-
a 24
nmax (liquid film) 3071, 2930, 1708, 1472, 1428, 1112, 1048 cmꢀ1
;
dH
less oil. ½ ꢂD þ5.4 (c 0.3, MeOH); nmax (liquid film) 3375, 2936, 2870,
(400 MHz, CDCl3) 1.04 (s, 9H), 1.08 (d, J¼6.9 Hz, 3H), 1.62 (m, 1H),
2.01 (m, 1H), 2.58 (m, 1H), 3.66e3.77 (m, 2H), 7.36e7.45 (m, 6H),
7.63e7.67 (m, 4H), 9.68 (d, J¼1.4 Hz, 1H); dC (100 MHz, CDCl3) 13.1,
19.1, 26.8, 33.4, 43.5, 61.1, 127.7, 129.7, 133.5, 135.5, 204.9.
1704, 1462, 1406, 1377, 1152, 1052, 918, 736 cmꢀ1
; dH (400 MHz,
CD3OD) 0.89 (d, J¼6.4 Hz, 3H), 0.91 (d, J¼6.8 Hz, 3H), 1.07 (d,
J¼6.8 Hz, 3H), 1.10e1.65 (m, 15H), 1.12 (s, 3H), 1.89 (sꢃt, J¼6.8 Hz,
1H), 2.53 (m, 2H), 2.76 (sꢃt, J¼6.8 Hz, 1H), 3.33 (m, 1H), 3.41 (dd,
J¼6.6,10.7 Hz,1H), 3.52 (t, J¼6.6 Hz, 2H); dC (100 MHz, CD3OD) 16.9,
17.1, 19.88, 19.90, 22.3, 22.4, 26.9, 31.7, 33.6, 35.0, 36.71, 36.75, 36.9,
38.6, 40.0, 43.0, 44.0, 60.6, 68.4, 73.4, 217.48, 217.50; HRMS (ESI):
MNaþ, found 367.2827. C20H40O4Na requires 367.2824. The 1H and
4.1.19. (3RS,5RS,7R,11R,15R)-16-tert-Butyldimethylsilyloxy-1-tert-bu-
tyldiphenylsilyloxy-11-hydroxy-5-phenylsulfonyl-3,7,11,15-
tetramethyl-4-hexadecanone. To a stirred and cooled (ꢀ78 ꢁC) so-
lution of 12a (400 mg, 803
mmol) in THF (4 ml) was added n-BuLi
13C NMR spectra were in good accord with those of the natural 1.9
a
(1.63 M solution in hexane, 1.08 ml, 1.77 mmol) under Ar atmo-
sphere. After stirring for 30 min, a solution of 17 (328 mg,
964 mmol) in THF (3 ml) was added. The mixture was gradually
Acknowledgements
warmed to ꢀ20 ꢁC for 1.5 h and poured into water. The aqueous
layer was extracted with AcOEt, and the combined organic layer
was washed with water and brine. The organic layer was dried over
MgSO4, and concentrated. The residue was purified by column
chromatography with AcOEt/hexane (1:8) to give the coupled
product as a stereoisomeric mixture (658 mg). This was dissolved
in CH2Cl2 (10 ml), and to a stirred and cooled (0 ꢁC) solution were
added NaHCO3 (500 mg) and DesseMartin periodinane (511 mg,
1.20 mmol). After stirring for 30 min at the same temperature and
for 30 min at room temperature, the mixture was poured into
water. The aqueous layer was extracted with ether, and the com-
bined organic layer was washed with satd NaHCO3 solution. The
organic layer was dried over Na2SO4, and concentrated. The residue
was purified by column chromatography with AcOEt/hexane (1:5)
to give the titled product as a stereoisomeric mixture (541 mg, 81%
We are grateful to M. Takenaka (Takasago International Co.) for
his kind gift of citronellal. We thank Mr. S. Shibamoto and
M. Numayama for their assistance with the synthesis. This work
was supported by JSPS KAKENHI (No. 22248012 for M.O. and
21710239 for A.Y.) and the Naito Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.066.
References and notes
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ꢂ
þ6.3 (c 0.92, CHCl3); nmax (liquid film) 3565,
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