Synthesis of the A,G-spiroimine of pinnatoxins by a microwave-assisted tandem Claisen-Mislow-Evans rearrangement

Article abstract of DOI:10.1016/j.tetlet.2006.08.083

The synthesis of the characteristic A,G-spiromine of pinnatoxins and pteriatoxins employing a microwave-assisted tandem Claisen-Mislow-Evans rearrangement is described. The study also features a highly efficient Suzuki-Miyaura cross-coupling reaction form

Full text of DOI:10.1016/j.tetlet.2006.08.083

Tetrahedron Letters 47 (2006) 7519–7523
Synthesis of the A,G-spiroimine of pinnatoxins by a
microwave-assisted tandem Claisen–Mislow–Evans rearrangement
Matthew J. Pelc and Armen Zakarian*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, United States
Received 1 August 2006; revised 21 August 2006; accepted 22 August 2006
Abstract—The synthesis of the characteristic A,G-spiromine of pinnatoxins and pteriatoxins employing a microwave-assisted tan-
dem Claisen–Mislow–Evans rearrangement is described. The study also features a highly efficient Suzuki–Miyaura cross-coupling
reaction forming a tetrasubstituted vinyl ether as a part of the dihydropyran ring and a brief study of the hydrolytic stability of the
spirocyclic imine.
ꢀ 2006 Published by Elsevier Ltd.
Pinnatoxins belong to an expanding group of marine
natural products characterized by the presence of
unusual spirocyclic imines in their structure (Fig. 1).1
Presently, this group also includes gymnodimine,2 pte-
riatoxins,1d,3 prorocentrolides,4 and spirolides.5 The
structure of pinnatoxin A was established first by Uem-
ura et al. in 1995.1b One of the particularly striking
features of the natural products is the stability of the
cyclic imine functional group toward hydrolysis.
relies on a cascade sigmatropic process that integrates
the Claisen and Mislow–Evans rearrangements to build
the quaternary chiral center at the core of the A,G-spi-
roimine. Under the original conditions, the key cascade
rearrangement requires heating the reaction mixture for
15 h at 150 ꢁC (Scheme 1). In this letter, we describe an
improved version of our original route. The most signif-
icant modifications include (a) a microwave-assisted
tandem sigmatropic process that dramatically reduces
the reaction time, and (b) an improved cross-coupling
reaction en route to the substrate for the rearrangement
(1). In addition, we report our observations regarding
the hydrolytic stability of the A,G-spirocyclic imine
fragment of pinnatoxins.
A combination of intriguing molecular architecture and
potent bioactivity makes these natural products compel-
ling targets for total synthesis.6 Recently, we developed
the synthesis of the spirocyclic imine ring system com-
mon to pinnatoxins and pteriatoxins.7 Our approach
Vinylic sulfoxide 1 has been prepared via triflate 3 de-
rived from known ketone 4 in five straightforward steps
(Scheme 2).7 Perhaps the most challenging transforma-
tion in the synthetic sequence was the cross-coupling
reaction with 3 resulting in a three-carbon chain exten-
sion. In our original approach, we employed the Negishi
1
A
A
N
5
N
G
31
E
10
R
H
O
F
O
O
O
O
F
O
HO
O
B
O
B
OH
E
C
C
O
O
HO
HO
D
D
13
PvO
PvO
(EtO) P, s-collidine
3
Pinnatoxin A: R = CO2H
Pteriatoxin A: R =
Me(OCH CH ) OH
2
2 2
13-desmethylspirolideC
O
+
o
NH3
150 C, 15 h
S
-
OH
O
OH
CO2
PMBO
R
O
S
PMBO
O
O
O
Figure 1.
O
2
1
R = p-Tolyl
*
Corresponding author. Tel.: +1 850 645 2235; fax: +1 850 644
8281; e-mail: zakarian@chem.fsu.edu
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.08.083

7520
M. J. Pelc, A. Zakarian / Tetrahedron Letters 47 (2006) 7519–7523
The Suzuki–Miyaura cross-coupling was investigated
next.11 The requisite reagent, borane 9, could be expedi-
ently accessed in situ from allyl p-methoxybenzyl ether
and 9-borabicyclo[3.3.1]nonane. Intriguingly, while
Pd[PPh3]4 proved to be an excellent catalyst in the
cross-coupling reaction, Pd(dppf)Cl2 was ineffective.
As expected, sodium hydroxide was superior to potas-
sium phosphate as the base additive in ethereal solvents
(Table 1, entry 5). The use of excess sodium hydroxide
was detrimental and resulted in a rapid decomposition
of the starting material (Table 1, entry 6). With excess
borane 9 with respect to sodium hydroxide, the cross-
coupling reaction occurred smoothly to give the desired
product. Thus, under optimized conditions, the reaction
of triflate 4 with 4 equiv of alkylborane 9 in the presence
of sodium hydroxide (3 equiv) and Pd[Ph3P]4
(0.05 equiv) at 60 ꢁC for 3 h afforded the coupling prod-
uct 5 in 91% yield (Table 1, entry 8).12,13 Importantly,
the reaction was highly reproducible even with commer-
cial Pd[Ph3P]4 (Aldrich).
PvO
PvO
2
see Table 1
PMBO
TfO
O
O
O
O
TIPSO
O
RO
O
5a: R = TIPS
5b: R = H
4
5 steps
ref. 7
5 steps
ref. 7
O
PCy2
OPr-i
1
i-PrO
O
O
TIPSO
3
10
2.2 eq.
ZnCl2, THF, -78 oC to rt
t
-BuLi, Et2O, -78 oC;
PMBO
I
PMBO
ZnX
6
8
7
9-BBN, THF, 25 oC, 5 h
PMBO
B
PMBO
9
Having found an efficient cross-coupling procedure, a
substantial amount of key vinylsulfoxide 1 for further
study was expediently prepared. Previously, the next
step involved a thermal cascade sigmatropic rearrange-
ment of 1 to 2 (Scheme 1).
Scheme 2.
protocol to obtain dihydropyran 5. Subsequently, com-
pound 5 was advanced to sulfoxide 1 by a short series of
reactions (Scheme 2).
The benefits of microwave synthesis, most important of
which are cleaner reactions and significantly reduced
reaction times, for slower reactions with high activation
energy are well recognized.14 We were attracted by the
possibility of the application of microwave technology
for the cascade sigmatropic rearrangement of 1. After
a series of preliminary optimization experiments, we
found that the tandem rearrangement can indeed be car-
ried out using microwave conditions at 50 W, 172 ꢁC, in
20 min and in only a slightly diminished yield (Scheme
3). As before, the presence of s-collidine as a buffer
was advantageous and ensured more consistent re-
sults.15 The microwave-assisted reaction allows for an
improved material throughput as several runs can be
performed in the course of a few hours delivering gram
quantities of the rearrangement product.
In the course of our experiments it became apparent that
dihydropyranyl triflate 4 is a challenging substrate for
palladium-catalyzed cross-coupling reactions. Thus, a
reaction of 4 with alkylzinc reagent 7, generated in situ
from iodide 6, in the presence of 7 mol % of Pd(dppf)Cl2
in THF/NMP at 50 ꢁC for 15 h yielded only 14% of cou-
pling product 5 along with 72% of recovered starting
material (Table 1, entry 1). Because cross-coupling reac-
tions with similar substrates lacking a substituent at the
C2 position are well-documented,8 and because our
model cross-coupling reactions with 4-iodotoluene were
very facile, we postulated that the reason for poor reac-
tivity of 4 is due to steric shielding provided by the alkyl
group at C2, which impedes either the oxidative addi-
tion or, less likely, the reductive elimination step in the
catalytic cycle. As an alternative, we turned to a more
electron-rich Pd[t-Bu3P]2 catalyst.9 This resulted in a
dramatically faster reaction, giving the expected product
in 75–80% yield after 30 min at 30 ꢁC (Table 1, entry 2).
However, a significant disadvantage of the reaction was
its poor reproducibility. In many instances, the reaction
halted at 25–30% conversion requiring resubmission of
the mixture of products to the cross-coupling protocol.
In this manner, the reaction could be driven to comple-
tion after several cycles. High cost of the palladium cat-
alyst coupled with its extremely low stability made this
procedure quite exasperating and compelled us to con-
tinue the search for a more practical alternative. At-
tempted generation of the catalyst in situ from
Pd2dba3 (0.05 equiv, dba = dibenzylideneacetone) and
t-Bu3P (0.2 equiv) resulted in no reaction (Table 1, entry
3). The palladium complex generated from Buchwald’s
ligand 10 also failed to promote the cross-coupling reac-
tion (Table 1, entry 4).10
With cylcohexenol 2 in hand, we set out to prepare the
A,G-spiroimine ring system of pinnatoxins. Removal
of the pivaloate with sodium methoxide, tosylation of
the primary alcohol, displacement of the tosylate with
azide, and acetylation of the tertiary allylic alcohol
delivered azide 11 in good overall yield.7 The azepine
ring closure was achieved by Staudinger reduction of
the azide and aza-Wittig cyclization of the intermediate
iminophosphorane affording cyclic imine 12 in quantita-
tive yield.7
The stability of the cyclic imine is one of the most
intriguing attributes of pinnatoxins and related natural
products. The precise structural features imparting this
resistance to acidic or basic hydrolysis are not estab-
lished. It has been proposed that the proximity of a qua-
ternary carbon center at the core of the spiroimine ring
system at least partially contributes to the imine stabil-
ity.16 In spirolides, the relationship between the ring A

M. J. Pelc, A. Zakarian / Tetrahedron Letters 47 (2006) 7519–7523
Table 1. Reaction conditions for conversion of 4 to 5 shown in Scheme 2
7521
Entry
Reagent (equiv)
Catalyst (mol %)
Reaction conditions
Yield (%)
1
2
3
4
5
6
7
8
9
7 (3)
7 (3)
7 (3)
7 (3)
9 (3)
9 (3)
9 (2)
9 (4)
9 (4)
Pd(dppf)Cl2 (7)
Pd[t-Bu3P]2 (5)
Pd2dba3 (5), t-Bu3P (20)
Pd2dba3 (2.5), 10 (10)
Pd[Ph3P]4 (5)
Pd[Ph3P]4 (5)
Pd[Ph3P]4 (5)
Pd[Ph3P]4 (5)
Pd(dppf)Cl2 (5)
THF, NMP, 0 ꢁC, 10 min, 50 ꢁC, 15 h
THF, NMP, 0 ꢁC, 10 min, 30 ꢁC, 30 min
THF, NMP, 0 ꢁC, 10 min, 30 ꢁC, 3 h
THF, NMP, 0 ꢁC, 10 min, 65 ꢁC, 3 h
K3PO4 (3 equiv), dioxane, 60 ꢁC, 24 h
NaOH (10 equiv), dioxane, 25 ꢁC, 24 h
NaOH (3 equiv), dioxane, 25 ꢁC, 24 h
NaOH (3 equiv), dioxane, 60 ꢁC, 3 h
NaOH (3 equiv), dioxane, 60 ꢁC, 3 h
14
75b
0 (starting material recovered)
0 (starting material recovered)
<5 (starting material recovered)
0a
30
91c
0 (starting material recovered)
a Decomposition.
b Low reproducibility.
c Overall after two steps involving the cross-coupling and removal of the primary TIPS protecting group.12,13
key tandem Claisen–Mislow–Evans rearrangement was
developed and was found to be a viable alternative sig-
nificantly reducing reaction times. Finally, the hydro-
lytic stability of the A,G-spiroimine fragment of
pinnatoxins and pteriatoxins was explored. The results
indicate that the imine stability in the natural products
is due to a combination of structural features, rather
than to one single structural element imparting the sta-
bility to the pharmacophore.
(EtO)3P, s-collidine
Me(OCH2CH2)2OH
PvO
PvO
μν, 50W, 170 oC, 20 min
O
OH
O
PMBO
R
82%
S
O
PMBO
O
O
O
O
2
1
R = p-Tolyl
1. MeONa, MeOH
PMe3, rt, 8h;
then 110 oC,
12 h
2. Ts2O, Et3N
3. NaN3, DMF
4. Ac2O, DMAP
N3
N
O
Acknowledgements
OAc
OAc
75%
We thank the ACS Petroleum Research Fund (43838-
G1) and the Department of Chemistry and Biochemis-
try, Florida State University for financial support of this
work. Dr. Joseph Vaughn and Dr. Umesh Goli are
thanked for assistance with the NMR and high-resolu-
tion mass spectrometry, respectively.
PMBO
PMBO
O
O
O
O
12
11
Scheme 3.
stability and bioactivity has been demonstrated.5a It has
been shown that spirolides that contain the vicinal di-
methyl group in the imine ring are stable to aqueous
hydrolysis, while those that do not are readily hydro-
lyzed. Because of this unusual behavior of the imine
group and to gain further insight into properties of the
marine natural products we investigated the hydrolytic
stability of imine 12.
References and notes
1. (a) Kuramoto, M.; Arimoto, H.; Uemura, D. Mar. Drugs
2004, 2, 39–54; (b) Uemura, D.; Chuo, T.; Haino, T.;
Nagatsu, A.; Fukuzawa, S.; Zheng, S.; Chen, H. J. Am.
Chem. Soc. 1995, 117, 1155–1156; (c) Takada, N.;
Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.;
Haino, T.; Yamada, K.; Uemura, D. Tetrahedron Lett.
2001, 42, 3491–3494; Pteriatoxins: (d) Takada, N.; Ume-
mura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.; Haino, T.;
Yamada, K.; Uemura, D. Tetrahedron Lett. 2001, 42,
3495–3498.
2. (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.;
Yasumoto, T. Tetrahedron Lett. 1995, 36, 7093–7096; (b)
Stewart, M.; Blunt, J. W.; Munro, M. H. G.; Robinson,
W. T.; Hannah, D. T. Tetrahedron Lett. 1997, 38, 4889–
4890.
3. (a) Matsuura, F.; Peters, R.; Anada, M.; Harried, S. S.;
Hao, J.; Kishi, Y. J. Am. Chem. Soc. 2006, 128, 7463–
7465; (b) Hao, J.; Matsuura, F.; Kishi, Y.; Kita, M.;
Uemura, D.; Asai, N.; Iwashita, T. J. Am. Chem. Soc.
2006, 128, 7742–7743.
4. Hu, T.; deFreitas, A. S. W.; Curtis, J. M.; Oshima, Y.;
Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 1996, 59,
1010–1014.
We found that imine 12 is stable in solution in anhy-
drous toluene or deuterochloroform, but decomposes
rapidly upon exposure to water. Rather than clean
hydrolytic cleavage to the amino ketone, we observed
a complex, intractable mixture of products (500 MHz
NMR). Our results indicate that the presence of a qua-
ternary chiral center at the core of the spiroimine ring
system and the vicinal dimethyl group are not sufficient
for the hydrolytic stability of pinnatoxins and, probably,
spirolides. It is likely that the correct position of the
double bond in the cyclohexene ring and a side-chain
at C31 are at least the minimum requirements. Further
studies in that direction are underway in our laboratory.
In conclusion, we achieved a significant improvement in
the cross-coupling reaction of hindered dihydropyranyl
triflate 4 using the Suzuki–Miyaura protocol affording
5 in high yield. The microwave-assisted version of the
5. (a) Hu, T.; Burton, I. W.; Cembella, A. D.; Curtis, J. M.;
Quilliam, M. A.; Walter, J. A.; Wright, J. L. C. J. Nat.
Prod. 2001, 64, 308–312; (b) Hu, T.; Curtis, J. M.; Walter,

7522
M. J. Pelc, A. Zakarian / Tetrahedron Letters 47 (2006) 7519–7523
J. A.; Wright, J. L. C. Tetrahedron Lett. 1996, 37, 7671–
7674.
2924, 2874, 1614, 1514, 1462, 1380, 1372, 1248, 1210, 1174,
1154, 1070, 1036, 1014. 1H NMR (500 MHz, C6D6); d
(ppm): 7.26 (d, J = 8.5 Hz, 2H); 6.83 (d, J = 8.5 Hz, 2H);
4.62 (dd, J1 = J2 = 7.5 Hz, 1H); 4.37 (s, 2H); 4.26 (dd,
J1 = J2 = 8.5 Hz, 1H); 4.12 (dd, J1 = 8.0 Hz, J2 = 7.0 Hz,
1H); 4.03 (dd, J1 = 11.0 Hz, J2 = 7.0 Hz, 1H); 3.97 (dd,
J1 = 11.0 Hz, J2 = 6.5 Hz, 1H); 3.83 (d, J = 10.5 Hz, 1H);
3.76 (d, J = 10.5 Hz, 1H); 3.45 (t, J = 6.0 Hz, 2H); 3.33 (s,
3H); 2.45 (ddd, J1 = 16.0 Hz, J2 = J3 = 8.0 Hz, 1H); 4.37
(ddd, J1 = 16.0 Hz, J2 = J3 = 8.0 Hz, 1H); 2.11 (dd,
J1 = 13.0 Hz, J2 = 6.5 Hz, 1H); 2.04–1.94 (m, 4H); 1.91–
1.87 (m, 1H); 1.84–1.76 (m, 4H); 1.50 (s, 3H); 1.38 (s, 3H);
1.21 (s, 9H); 1.12–1.09 (m, 21H); 0.76–0.75 (m, 6H). 13C
NMR (75 MHz, C6D6); d (ppm): 177.6, 159.6, 147.4,
131.5, 129.2, 114.0, 109.0, 103.9, 77.7, 76.5, 72.7, 69.7,67.9,
65.0, 64.1, 54.7, 38.8, 37.5, 35.7, 32.4, 28.5, 27.6, 27.4, 26.7,
25.4, 23.7, 22.2, 18.2, 14.6, 12.3, 11.6. HRMS (ESI) calcd
for C42H72O8SiNa [M+Na] 755.48941, found 755.49282.
13. Tetra-n-butylammonium fluoride trihydrate (3.57 g,
11.3 mmol) was added to a solution of the crude 5a in
THF (50 mL) and the mixture was stirred at room
temperature for 0.5 h. Saturated aqueous ammonium
chloride was added, and the mixture was extracted with
EtOAc, washed with water and brine, dried with anhy-
drous sodium sulfate, and concentrated under reduced
pressure. The resultant oil was purified by column
chromatography (silica, 40% ethyl acetate–hexanes con-
taining 1.5% triethylamine) to give 1.97 g (3.41 mmol,
6. For the synthetic work on pinnatoxins, see: Hirama group:
(a) Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada,
K.; Ishii, K.; Noda, T.; Inoue, M.; Hirama, M. Angew.
Chem., Int. Ed. 2004, 43, 6505; (b) Wang, J.; Sakamoto, S.;
Kamada, K.; Nitta, A.; Noda, T.; Oguri, H.; Hirama, M.
Synlett 2003, 891; (c) Ishiwata, A.; Sakamoto, S.; Noda,
T.; Hirama, M. Synlett 1999, 692; (d) Nitta, A.; Ishiwata,
A.; Noda, T.; Hirama, M. Synlett 1999, 695; (e) Noda, T.;
Ishiwata, A.; Uemura, S.; Sakamoto, S.; Hirama, M.
Synlett 1998, 298; Hashimoto group: (f) Nakamura, S.;
Inagaki, J.; Kudo, M.; Sugimoto, T.; Obara, K.; Nakaj-
ima, M.; Hashimoto, S. Tetrahedron 2002, 58, 10353; (g)
Nakamura, S.; Inagaki, J.; Sugimoto, T.; Ura, Y.;
Hashimoto, S. Tetrahedron 2002, 58, 10375; (h) Nakam-
ura, S.; Inagaki, J.; Sugimoto, T.; Kudo, M.; Nakajima,
M.; Hashimoto, S. Org. Lett. 2001, 3, 4075; Kishi group:
(i) McCauley, J. A.; Nagasawa, K.; Lander, P. A.;
Mischke, S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem.
Soc. 1998, 120, 7647, and Ref. 3; Murai group: (j)
Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.; Murai, A.
Synlett 2002, 403; (k) Ishihara, J.; Tojo, S.; Kamikawa, A.;
Murai, A. Chem. Commun. 2001, 1392; (l) Sugimoto, T.;
Ishihara, J.; Murai, A. Synlett 1999, 541; (m) Ishihara, J.;
Sugimoto, T.; Murai, A. Synlett 1998, 603; (n) Sugimoto,
T.; Ishihara, J.; Murai, A. Tetrahedron Lett. 1997, 38,
7379; Kitching group: (o) Suthers, B. D.; Jacobs, M. F.;
Kitching, W. Tetrahedron Lett. 1998, 39, 2621.
20
91%) of primary alcohol 5b. ½aꢀD +13.6 (c 1.0 CH2Cl2). IR
7. Pelc, M. J.; Zakarian, A. Org. Lett. 2005, 7, 1629–1631.
8. For recent applications in organic synthesis, see: Negishi
protocol: (a) Kadota, I.; Takamura, H.; Sato, K.;
Yamamoto, Y. J. Org. Chem. 2002, 67, 3494–3498; (b)
Kadota, I.; Kadowaki, C.; Park, C.-H.; Takamura, H.;
Sato, K.; Chan, P. W. H.; Thorand, S.; Yamamoto, Y.
Tetrahedron 2002, 58, 1799–1816; Cuprate coupling: (c)
Fujiwara, K.; Sato, D.; Watanabe, M.; Morishita, H.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004,
45, 5243–5246.
(film, cmꢁ1): 3444, 2960, 2934, 1728, 1680, 1614, 1514,
1480, 1396, 1284, 1098, 1038. 1H NMR (300 MHz, C6D6);
d (ppm): 7.24 (d, J = 8.4 Hz, 2H); 6.82 (d, J = 8.4 Hz, 2H);
4.41 (t, J = 6.6 Hz, 1H); 4.32 (s, 2H); 4.10–3.85 (m, 4H);
3.70–3.60 (br m, 2H); 3.33 (s, 3H); 3.39–3.29 (m, 2H); 2.45
(br s, 1H); 2.28 (t, J = 7.2 Hz, 2H); 2.00–1.68 (m, 10H);
1.41 (s, 3H); 1.27 (s, 3H); 1.20 (s, 9H); 0.73 (d, J = 6.6 Hz,
3H); 0.69 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, C6D6);
d (ppm): 177.9, 159.7, 146.9, 131.1, 129.5, 114.2, 114.0,
109.2, 104.4, 78.7, 76.2, 72.8, 69.7, 68.1, 65.0, 63.2, 54.8,
38.9, 37.3, 35.8, 32.4, 28.2, 27.7, 27.4, 26.4, 25.1, 22.5, 21.8,
14.7, 11.8.
9. Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719–
2724.
10. Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028–13032, The cuprate reagent generated from 6, t-
butyllithium, and CuBrMe2S was also tested and delivered
only a trace amount of 5.
11. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–
2483; (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4544–4568.
14. Hayes, B. L. Microwave Synthesis; CEM Publishing:
Matthews, NC, 2002.
15. To a flame dried 10 mL microwave reactor vial were added
vinylsulfoxide 1 (77 mg, 0.108 mmol), (EtO)3P (74 lL,
0.433 mmol), s-collidine (57 lL, 0.433 mmol), and
MeOCH2CH2OCH2CH2OH (1.2 mL). The vial was sealed
with a septum and purged with argon for 10 min. The
septum was removed and replaced by a reusable cap
(CEM part # 908140) and the vial placed in a microwave
reactor (CEM Discover). The reaction was carried out
with the following parameters: temperature 172 ꢁC; max-
imum pressure 15 psi; max power 50 W; ramp time 5 min;
reaction time 20 min. After a brief cool down period, the
solution was diluted with EtOAc and washed with
saturated aqueous ammonium chloride, with water three
times, and the combined aqueous layers were extracted
with ethyl acetate. The combined organic layers were
washed with brine, dried with anhydrous sodium sulfate
and concentrated. The residue was subjected to column
chromatography (silica, 40% ethyl acetate–hexanes) to
12. A solution of 9-BBN (0.5 M in THF, 30 mL, 15.0 mmol)
was added dropwise to a solution of p-methoxybenzyl allyl
ether (2.67 g, 15.0 mmol) in dry THF (7.0 mL) under
argon at room temperature. The solution was stirred for
5 h at rt. The solvent was removed under vacuum at 0 ꢁC
and was replaced with dry 1,4-dioxane (35 mL). In a
separate flask was placed triflate 4 (2.64 g, 3.76 mmol),
Pd(PPh3)4 (Aldrich, 0.22 g, 0.19 mmol), and NaOH
(0.45 g, 11.3 mmol) under argon followed by dioxane
(20 mL). This solution was stirred for <1 min at 0 ꢁC, and
then the borane was transferred via cannula. This solution
was then stirred at 60 ꢁC for 3 h, cooled to rt and the
reaction mixture quenched with saturated aqueous ammo-
nium chloride. The organic phase was washed with water
(3 · 30 mL), the combined aqueous layers were extracted
with EtOAc and the combined organic layers washed with
brine, dried with anhydrous sodium sulfate, and concen-
trated under reduced pressure and dried under vacuum.
The crude product was then submitted to the next step
without further purification. Data for purified a sample:
20
yield 52 mg (0.087 mmol, 81%) of 2. ½aꢀD ꢁ25.4 (c 0.5
CH2Cl2). IR (film, cmꢁ1): 2928, 2934, 1726, 1706, 1612,
1514, 1458, 1370, 1284, 1068, 672. 1H NMR (500 MHz,
C6D6); d (ppm): 7.23 (d, J = 8.5 Hz, 2H); 6.83 (d,
J = 8.5 Hz, 2H); 5.93 (d, J = 10.0 Hz, 1H); 5.54 (d,
J = 10.0 Hz, 1H); 4.30 (s, 2H); 3.97–3.92 (m, 2H); 3.88
(dd, J1 = J2 = 8.0 Hz, 1H); 3.84 (dd, J1 = 11.5 Hz,
J2 = 6.5 Hz, 1H); 3.79 (dd, J1 = 8.0 Hz, J2 = 7.0 Hz,
20
½aꢀD ꢁ8.9 (c 1.0 CH2Cl2). IR (film, cmꢁ1): 3442, 2956,

M. J. Pelc, A. Zakarian / Tetrahedron Letters 47 (2006) 7519–7523
7523
1H); 3.36–3.29 (m, 2H); 3.32 (s, 3H); 2.61 (ddd,
J1 = 18.5 Hz, J2 = J3 = 7.0 Hz, 1H); 2.48 (ddd, J1 =
18.5 Hz, J2 = J3 = 7.0 Hz, 1H); 2.26 (ddd, J1 = 13.5 Hz,
J2 = 9.5 Hz, J3 = 4.0 Hz, 1H); 2.04 (br s, 1H); 1.97–1.92
(m, 2H); 1.78–1.62 (m, 5H); 1.40–1.35 (m, 1H); 1.35 (s,
3H); 1.29 (dd, J1 = 14.0 Hz, J2 = 7.0 Hz, 1H); 1.27 (s, 3H);
1.21 (s, 9H); 0.68 (d, J = 7.0 Hz, 3H); 0.65 (d, J = 6.5 Hz,
3H). 13C NMR (75 MHz, C6D6); d (ppm): 210.7, 177.7,
159.7, 135.0, 131.2, 130.1, 129.4, 114.0, 109.4, 80.7, 72.6,
69.3, 69.0, 67.4, 65.2, 54.7, 52.8, 42.7, 38.8, 37.6, 35.6, 30.4,
29.9, 27.4, 26.4, 25.3, 24.5, 15.9, 11.2. HRMS (ESI) calcd
for C34H52O8SNa [M+Na] 611.3559, found 611.3531.
16. Ahn, Y.; Cardenas, J. Y.; Yang, J.; Romo, D. Org. Lett.
2001, 3, 751–754.