Investigation of an organomagnesium-based [3 + 3] annelation to pyrans and its application in the synthesis of rhopaloic acid A

Article abstract of DOI:10.1021/jo702620e

(Chemical Equation Presented) A stepwise [3 + 3] annelation reaction has been developed that allows access to pyrans from epoxides. This process involves the addition of an allylmagnesium reagent, itself readily prepared from methallyl alcohol, and a Pd-c

Full text of DOI:10.1021/jo702620e

Investigation of an Organomagnesium-Based [3 + 3] Annelation to
Pyrans and Its Application in the Synthesis of Rhopaloic Acid A
Julien C. R. Brioche,† Katharine M. Goodenough,† David J. Whatrup,‡ and
Joseph P. A. Harrity*,†
Department of Chemistry, UniVersity of Sheffield, Sheffield, S3 7HF, United Kingdom, and
GlaxoSmithKline Research and DeVelopment, Tonbridge, Kent, TN11 9AN, United Kingdom
j.harrity@sheffield.ac.uk
ReceiVed December 8, 2007
A stepwise [3 + 3] annelation reaction has been developed that allows access to pyrans from epoxides.
This process involves the addition of an allylmagnesium reagent, itself readily prepared from methallyl
alcohol, and a Pd-catalyzed cyclodehydration reaction. The potential of this process to be employed in
natural product synthesis has been exemplified by its use in the preparation of rhopaloic acid A.
SCHEME 1
Introduction
Recent studies within our laboratories have focused on the
development of [3 + 3] annelation processes to functionalized
piperidines.1 As outlined in Scheme 1, our key strategy was to
exploit aziridines, readily prepared in enantiomerically enriched
form, as three-atom components in an annelation process with
an appropriate conjunctive reagent. To date, we have employed
Trost’s Pd-TMM reagent,2 the Bu¨chi Grignard,3 and an allyl-
magnesium reagent derived from the double deprotonation of
methallyl alcohol.4
In an effort to broaden the scope of this strategy, we turned
our attention to the synthesis of functionalized pyrans via the
[3 + 3] annelation of epoxides. Pyrans are a common motif to
many natural products, in particular those of a marine source.5
Not surprisingly therefore, a significant number of methods have
been developed for the synthesis of these compounds. Assembly
of the six-membered ring by [4 + 2] approaches has received
widespread attention;6 in contrast however, the employment of
a formal [3 + 3] strategy has been much less generally explored.
Nonetheless, techniques based on addition of 4-hydroxy-2-
pyrones to enals and Sakurai-Prins sequences have been
reported.7 Moreover, we were intrigued by a report from Klumpp
and co-workers that demonstrated that Grignard reagent 2
reacted with epoxides to produce pyrans after in situ Pd-
catalyzed cyclization.8 This reagent is closely related to the
organomagnesium reagent 4 that we had employed in the
synthesis of piperidines (Scheme 2). In the context of the
preparation of these organomagnesium reagents, 2 is prepared
in two steps9 while 4 can be accessed in one pot by double
(6) Tietze, L. F.; Kettschau, G.; Gewert, J. A.; Schuffenhauer, A. Curr.
Org. Chem. 1998, 2, 19.
† University of Sheffield.
‡ GlaxoSmithKline Research and Development.
(7) (a) Hua, D. H.; Chen, Y.; Sin, H.-S.; Maroto, M. J.; Robinson, P.
D.; Newell, S. W.; Perchellet, E. M.; Ladesich, J. B.; Freeman, J. A.;
Perchellet, J.-P.; Chiang, P. K. J. Org. Chem. 1997, 62, 6888. (b) Hsung,
R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; degen, S. J.; Yao, L. J.
J. Org. Chem. 1999, 64, 690. (c) Shen, H. C.; Wang, J.; Cole, K. P.;
McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.; Hsung, R. P.; Coverdale,
H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Wei, L.-L.; Sklenicka, H. M.;
Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68, 1729. (d) Epstein,
O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480.
(1) For reviews of [3 + 3] approaches to heterocycle systems see: (a)
Harrity, J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 1349. (b) Hsung,
R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(2) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596. (b) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286.
(3) Pattenden, L. C.; Wybrow, R. A. J.; Smith, S. A.; Harrity, J. P. A.
Org. Lett. 2006, 8, 3089.
(4) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2005, 7,
2993.
(5) (a) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7. (b) Norcross, R. D.;
Paterson, I. Chem. ReV. 1995, 95, 2041.
(8) van der Louw, J.; van der Baan, J. L.; Out, G. J. J.; de Kanter, F. J.
J.; Bickelhaupt, F.; Klumpp, G. W. Tetrahedron 1992, 48, 9901.
(9) van der Louw, J.; van der Baan, J. L.; de Kanter, F. J. J.; Bickelhaupt,
F.; Klumpp, G. W. Tetrahedron 1992, 48, 6087.
10.1021/jo702620e CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/07/2008
1946
J. Org. Chem. 2008, 73, 1946-1953

Organomagnesium-Based [3 + 3] Annelation to Pyrans
SCHEME 2
SCHEME 4
TABLE 1. Addition of Grignard 4 to Epoxides
SCHEME 3
deprotonation of methallyl alcohol and transmetalation with
magnesium bromide (Scheme 2). We set out to investigate the
suitability of Grignard reagent 4 for the formation of pyrans
and report herein the scope and limitations of this technique.10
Furthermore, we demonstrate the employment of this methodol-
ogy in the total synthesis of rhopaloic acid A.
Results and Discussion
In our preliminary studies, we opted to prepare pyrans from
epoxides using conditions that had been developed for the
analogous transformation of aziridines to piperidines.4 Accord-
ingly, as outlined in Scheme 3, treatment of methallyl alcohol
3 with an excess of BuLi in the presence of TMEDA followed
by addition of MgBr2 provided a Grignard reagent that
underwent addition to 2-benzyloxirane 5 to provide the corre-
sponding diol 6 in 78% yield. Furthermore, we were delighted
to find that cyclocondensation could be achieved directly,
without prior activation of the allylic alcohol,11 by Pd-catalysis
to provide pyran 7 in high yield.
While we were pleased that the potential of the annelation
reaction with in situ generated Grignard reagent 4 had been
verified, a significant limitation was the requirement for 5 equiv
of this Grignard reagent. A similar requirement was observed
in our earlier studies on the addition of 4 to aziridines. It was
apparent to us that one reason for the requirement of excess
Grignard was an overestimation of the concentration of 4 during
titration of this reagent. Specifically, the use of 3.0 equiv of
BuLi meant that a full equivalent of butylmagnesium species
remained after transmetalation and that this would account for
some of the active Grignard reagent as assessed by titration.
We were aware that Trost’s procedure for the double deproto-
nation of 3 required 2.6 equiv of BuLi12 and wondered if this
could be further reduced without a significant deleterious effect
on the deprotonation process. Accordingly, as outlined in
Scheme 4, the employment of 2.1 equiv each of 10 M BuLi
and TMEDA resulted in formation of a red gum after stirring
at room temperature for 24 h. Removal of the ethereal solution
by cannula and addition of fresh ether and freshly prepared
MgBr2 resulted in the formation of a white precipitate that was
a Conditions: 1.5 equiv of Grignard added to a THF solution of epoxide.
b 2.5 equiv of Grignard used in this case.
removed from the Grignard reagent by cannula filtration.
Titration of the resulting solution generally provided a concen-
tration of active reagent of around 0.1-0.2 M, providing an
estimated yield for formation of 4 of 20-40%, over two steps.
With the Grignard reagent in hand, we turned our attention
to the study of its addition to epoxides. As outlined in Table 1,
we were delighted to find that the organomagnesium reagent
underwent smooth addition to a range of epoxides. MoreoVer,
only 1.5 equiV of reagent was generally required to achieVe
complete conVersion of each epoxide substrate. As outlined in
entries 1-3, 2-alkyl epoxides underwent smooth addition to
provide the corresponding diols in high yield. Moreover, we
demonstrated that 2,2-disubstituted epoxides could be trans-
formed to the corresponding diols under these conditions (entries
4 and 5).
(10) For a preliminary report of this work see: Brioche, J. C. R.;
Goodenough, K. M.; Whatrup, D. J.; Harrity, J. P. A. Org. Lett. 2007, 9,
3941.
(11) Yang, S.-C.; Hung, C.-W. J. Org. Chem. 1999, 64, 5000.
(12) Trost, B. M.; Chan, D. M. T.; Nanninga, T. N. Org. Synth. 1984,
62, 58.
We had assumed in our studies that the organomagnesium
reagent had the formula 4; however, it occurred to us that the
J. Org. Chem, Vol. 73, No. 5, 2008 1947

Brioche et al.
TABLE 2. Pd-Catalyzed Cyclization
SCHEME 5
reactive reagent could well be the cyclic organomagnesium
alkoxide 16 formed by the Schlenk equilibrium as outlined in
Scheme 5.13 In an effort to further clarify this issue, we opted
to drive the equilibrium toward the cyclic organomagnesium
reagent 16. Accordingly, treatment of the Grignard reagent with
dioxane resulted in precipitation of the MgBr2‚dioxane adduct.
The organomagnesium reagent was removed by cannula filtra-
tion and added to epoxide 5. A complex mixture of products
resulted from which the diol 6 could not be isolated. In contrast,
however, addition of freshly prepared MgBr2 to this organo-
magnesium reagent followed by addition of epoxide 5 provided
the corresponding diol 6 in 40% yield. These experiments
suggest that MgBr2 is essential for successful addition of the
doubly deprotonated methallyl alcohol to epoxides; however,
it is not clear whether the reaction involves Grignard reagent
4, or is the result of a MgBr2-promoted addition of cyclic
magnesium alkoxide 16.
We next turned our attention to the Pd-catalyzed cyclization
reaction and our results are summarized in Table 2. We were
delighted to find that the Pd/Ti-catalyzed cyclodehydration
proceeded efficiently for a range of diols to provide the
corresponding pyrans in high yield (entries 1-3). Tertiary
alcohol substrates proved to be a disappointing exception as
these provided the corresponding pyrans in low yield (entries
4-6). In these cases, dimerization via allylic alcohol dehydration
proceeded in favor of the cyclization, presumably because of
steric hindrance surrounding the tertiary-alcohol moiety.
The Ti-promoted cyclodehydration process was first reported
for the coupling of allylic alcohols and anilines11 and so we
were intrigued by the applicability of this process for ether
formation, in particular with regard to the role of Ti(OPri)4. As
outlined in Table 3, preliminary control experiments indicated
that the inclusion of the Ti-Lewis acid significantly promotes
this cyclization (entry 1), and poor conversions of 9 to 17 were
observed in its absence, even after prolonged reaction times
(∼20% after 24 h). We therefore assumed that the Lewis acid
was simply assisting the removal of the hydroxyl group; to our
surprise, however, the corresponding acetate14 also failed to
undergo cyclization in the absence of Ti(OPri)4 (entry 2). In
contrast, cyclization of 22 proceeded smoothly within 2 h in
the presence of 25 mol % of Lewis acid. Therefore, while it is
likely that Ti(OPri)4 does assist removal of OH in the cyclo-
dehydration, we believe that it has a significant role in addition
of the alcohol moiety to the putative intermediate Pd π-allyl
complex, presumably via formation of a soft Ti-alkoxide
nucleophile.15
The studies outlined in Table 3 also provided a solution to
the low-yielding cyclization of compounds 13 and 15a,b.
Specifically, the competing dimerization reaction was readily
obviated in each case by acetylation of the allylic alcohol as
outlined in Scheme 6.
(13) For a recent example of the preparation and use of cyclic magnesium
alkoxides see: Fleming, F. F.; Gudipati, S.; Vu, V. A.; Mycka, R. J.;
Knochel, P. Org. Lett. 2007, 9, 4507.
To assess the applicability of this methodology in the
stereoselective synthesis of target compounds, we opted to
(14) Compound 22 was prepared from 9 in 76% yield (Ac2O, Et3N, cat.
DMAP), see the Experimental Section for details.
(15) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2931.
1948 J. Org. Chem., Vol. 73, No. 5, 2008

Organomagnesium-Based [3 + 3] Annelation to Pyrans
TABLE 3. Role of Ti(OPri)4 in the Cyclodehydration
SCHEME 7a
Ti(OPri)4 loading
yield
(%)
entry
X
(mol %)
1
2
3
OH; 9
OAc; 22
OAc; 22
<5
<5
86
25
SCHEME 6a
a Reagents and conditions: (a) 4, THF, 79%; (b) 5% Pd(OAc)2, 20%
PPh3, 25% Ti(OPri)4, toluene, reflux, 86%; (c) I2, imid., PPh3, THF, rt,
92%; (d) 30, LDA, DMPU, THF, -78 °C; (e) 10% PdCl2(DPPF), LiEt3BH,
THF, rt, 70% over two steps; (f) TBAF, THF, rt, 98%; (g) Swern; (h)
CH2NMe2I, Et3N, CH2Cl2, rt, 66% over two steps; (i) NaH2PO4, NaO2Cl,
t
2-methyl-2-butene, BuOH/H2O, rt, 80%.
compounds exhibit potent inhibition of the gastrulation of
starfish embryos, in vitro cytotoxicity toward human myeloid
K-562 cells, human MOLT-4 leukemia cells, and murine L1210
cells, and RCE protease inhibitory activity. The interesting
biological activity of these compounds coupled with the paucity
of material available from their natural sources has inspired some
significant synthetic effort toward these molecules. Specifically,
Snider developed a short synthesis of racemic rhopaloic acid A
that also provided minor quantities of rhopaloic acid B methyl
ester.18 Additionally, enantioselective syntheses of rhopaloic acid
A have been reported by Ogasawara19 and Ohkata.20 The former
requiredsome30stepsfromanenantiomericallypuredioxabicyclo-
[3.2.1]octane while the latter, shorter synthesis featured an
inefficient pyran-forming cyclization (30-40% yield). We
hoped to develop a new approach to the rhopaloic acids that
would deliver short, stereoselective routes to this family of
compounds21 and turned our attention to the synthesis of
rhopaloic acid A.
a Reagents and conditions: (a) Ac2O, Et3N, cat. DMAP; (b) 5%
Pd(OAc)2, 20% PPh3, 25% Ti(OPri)4.
As shown in Scheme 7, addition of the Grignard 4 to epoxide
26 and subsequent cyclization proceeded without incident to
provide pyran 27 in good overall yield. Functionalization of
the exomethylene group in 27 would set the stage for elaboration
of this intermediate to each member of the rhopaloic acids.
Therefore, we opted to investigate the diastereoselectivity of
various hydroboration protocols at this stage and our results
are highlighted in Table 4. Preliminary studies were discouraging
and poor selectivity was observed when bulky monoalkylboranes
were employed (entries 1 and 2). Employment of Evans’ Rh-
FIGURE 1. Rhopaloic acids.
exploit the [3 + 3] annelation in the synthesis of the rhopaloic
acids. The rhopaloic acids (Figure 1) are a class of novel
norsesterterpenes that were first isolated from the marine sponge
Rhopaloeides sp. by Ohta and Ikegami,16 and subsequently also
from Hippospongia sp. by Andersen and co-workers.17 These
(18) Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453.
(19) Kadota, K.; Ogasawara, K. Heterocycles 2003, 59, 485.
(20) (a) Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. Chem. Commun.
1997, 1887. (b) Takagi, R.; Sasaoka, A.; Nishitani, H.; Kojima, S.; Hiraga,
Y.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 925.
(21) For a recent enantioselective synthesis of related hippospongic acid
A and lead references see: Trost, B. M.; Machacek, M. R.; Tsui, H. C. J.
Am. Chem. Soc. 2005, 127, 7014.
(16) (a) Ohta, S.; Uno, M.; Yoshimura, M.; Hiraga, Y.; Ikegami, S.
Tetrahedron Lett. 1996, 37, 2265. (b) Yanai, M.; Ohta, S.; Ohta, E.; Ikegami,
S. Tetrahedron 1998, 54, 15607.
(17) Craig, K. S.; Williams, D. E.; Hollander, I.; Frommer, E.; Mallon,
R.; Collins, K.; Wojciechowicz, D.; Tahir, A.; Van Soest, R.; Andersen, R.
J. Tetrahedron Lett. 2002, 43, 4801.
J. Org. Chem, Vol. 73, No. 5, 2008 1949

Brioche et al.
TABLE 4. Diastereoselective Hydroboration
Experimental Section
Experimental procedures and characterization data for compounds
6, 7, 9, 11, 17, 18, 26, 27, 29, and 30 have been described
previously.10
Procedure for the Synthesis of Grignard Reagent 4. To n-BuLi
(15 mL, 10 M, 2.1 equiv) at 0 °C were added anhydrous ether
(114 mL) and TMEDA (22.6 mL, 2.1 equiv). After the solution
was cooled at -78 °C, methallyl alcohol 3 was added dropwise
(6.40 mL, 1 equiv) and the reaction was stirred at -78 °C for 1 h.
The bath was then removed and the resulting mixture was
vigorously stirred for 24 h. After this time, stirring was stopped
for 30 min and the solvent was removed via cannula filtration.
Anhydrous ether (100 mL) was added to the remaining orange solid
and the suspension was cooled to 0 °C. At this point, a solution of
freshly prepared MgBr2 [prepared from magnesium (3.9 g, 2.1
equiv) and dibromoethane (13.8 mL, 2.1 equiv) in ether (58 mL)]
was transferred quickly via cannula to the suspension. After
addition, the bath was removed and the suspension was vigorously
stirred for 30-45 min. At this stage, the stirring was stopped and
the Grignard solution was separated from colorless solid via cannula.
The Grignard solution was stored at 0 °C under argon.
yield (%)
(trans:cis)
entrya
borane
1
2
3
4
ThexylBH2
92 (1:2)
93 (1:1)
88 (1:3)
96 (3:1)
ButPriCHBH2
HBC at 5% RhCl(PPh3)3
9-BBN
SCHEME 8
Representative Procedure for the Addition of 4 to Epoxides:
6-(tert-Butyldiphenylsilyloxy)-5-methyl-2-methylenehexane-1,5-
diol (13). To a solution of Grignard 4 (17.0 mL, 0.11 M, 1.87 mmol)
was added a solution of epoxide 12 (244 mg, 0.75 mmol) in THF
(7.5 mL) via cannula at rt and the reaction was stirred for 2 h. The
crude residue was purified by flash chromatography (60:40;
petroleum ether/EtOAc) to give the desired product 13 as a colorless
solid (224 mg, 75%). Mp 100-101 °C; 1H NMR (250 MHz, CDCl3)
δ 7.74-7.55 (4H, m), 7.50-7.32 (6H, m), 5.01 (1H, br), 4.86 (1H,
br), 4.07 (2H, br), 3.48 (2H, d, J ) 2.0 Hz), 2.45 (1H, br), 2.22-
1.98 (2H, m), 1.84-1.48 (3H, m), 1.17 (3H, s), 1.08 (9H, s); 13C
NMR (100 MHz, CDCl3) δ 149.3, 135.7, 133.1, 130.0, 127.9, 109.3,
72.8, 70.9, 66.2, 36.5 (2C), 27.0, 23.3, 19.5; FTIR (CH2Cl2, νmax
cm-1) 3345 (br), 3071 (w), 3050 (w), 2931 (s), 2858 (s), 1651 (w),
1589 (w), 1742 (m), 1428 (s), 1391 (m), 1362 (m), 1307 (w), 1188
(w), 1112 (s), 1030 (m), 1008 (m), 931 (m), 905 (m), 822 (s), 740
(s), 702 (s), 614 (s), 504 (s), 490 (s); HRMS (ES) m/z [M + Na]+
calcd for C24H34O3NaSi 421.2175, found 421.2177.
catalyzed hydroboration methodology was moderately diaster-
oselective, but was found to favor the cis-diastereomer.22
Surprisingly, however, the use of 9-BBN successfully over-
turned the diastereoselectivity to favor the desired trans-28 in
high yield.23 Conversion of trans-28 to the iodide 29 proceeded
in excellent yield and allowed us to separate the trans/cis-
diastereomers. At this stage, we took the opportunity to examine
the hydrozirconation of alkene 27 as a direct means to obtain
iodide 29. Treatment of 27 with Schwartz’s reagent followed
by addition of iodine provided a 2.5:1 mixture of diastereomers
in favor of the cis-iodide (Scheme 8). While this approach
predominantly generated the wrong diastereomer for the syn-
thesis of rhopaloic acid A, it provides a more direct means for
accessing rhopaloic acid B by this strategy.10
We next opted to install the farnesyl chain by alkylation of
iodide 29 with sulfone 30. This reaction proceeded efficiently;
however, sulfone 31 was found to be contaminated by some
unreacted 30 and so the crude material was subjected to Pd-
catalyzed reduction to provide 32 in good overall yield. Finally,
conversion of the protected 2-hydroxyethyl chain to the required
R,â-unsaturated acid was carried out by cleavage of the silyl
ether with TBAF followed by Swern oxidation, Mannich
methylenation, and Pinnick oxidation.
cis- and trans-4-tert-Butyl-1-(3-(hydroxymethyl)but-3-enyl)-
cyclohexanol (15a and 15b). To a solution of Grignard 4 (15 mL,
0.10 M, 1.5 mmol) was added a solution of epoxide 14 (168 mg,
1.0 mmol) in THF (10 mL) via cannula at rt and the reaction was
stirred for 2 h. The crude residue was purified by flash chroma-
tography to give compounds 15a/b as separable colorless solids,
15a (160 mg, 66%) and 15b (50 mg, 21%). 15a: Mp 92-94 °C;
1H NMR (250 MHz, CDCl3) δ 4.98 (1H, br), 4.85 (1H, br), 4.06
(2H, br), 2.23-2.09 (2H, m), 1.76-1.64 (2H, m), 1.64-1.46
(4H, m), 1.39-1.19 (4H, m), 1.00-0.75 (1H, m), 0.84 (9H, s);
13C NMR (62.9 MHz, CDCl3) δ 149.7, 109.6, 70.8, 66.0, 48.1,
42.0, 37.5, 32.5, 27.7, 26.5, 22.5; FTIR (CH2Cl2, νmax cm-1) 3307
(br), 2932 (s), 2040 (m), 1435 (m), 1360 (w), 1292 (w), 1234 (w),
1148 (w), 1068 (w), 1012 (s), 925 (m), 901 (w), 887 (w), 616 (w);
[M]+ calcd for C15H28O2 240.2089, found 240.2093. Anal. Calcd
for C15H28O2: C, 74.95; H, 11.74. Found: C, 74.77; H, 11.60.
Conclusion
We have developed a stepwise annelation route to pyrans
from epoxides that employs addition of a readily prepared
Grignard reagent 4 and a Pd-catalyzed cyclodehydration reac-
tion. The potential of this process to be employed in natural
product synthesis has been exemplified by its use in the
preparation of rhopaloic acid A.
1
15b: Mp 108-110 °C; H NMR (250 MHz, CDCl3) δ 5.02 (1H,
br), 4.91 (1H, br), 4.11 (2H, br), 2.21-2.08 (2H, m), 1.90-1.78
(2H, m), 1.75-1.61 (4H, m), 1.45-1.23 (2H, m), 1.17-0.96
(3H, m), 0.85 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ 149.7, 109.7,
72.4, 66.2, 47.8, 39.0, 34.4, 32.4, 27.8, 26.3, 24.6; FTIR (CH2Cl2,
νmax cm-1) 3201 (br), 2935 (s), 2860 (m), 1452 (s), 1364 (s),
1289 (w), 1265 (w), 1197 (w), 1131 (w), 1089 (m), 1070 (m),
1034 (m), 1019 (s), 990 (w), 928 (w), 890 (m), 734 (m); HRMS
(ES) m/z [M]+ calcd for C15H28O2 240.2089, found 240.2100.
Anal. Calcd for C15H28O2: C, 74.95; H, 11.74. Found: C, 74.87;
H, 11.45.
(22) This result was obtained with use of aged catalyst. The employment
of freshly prepared Wilkinson’s catalyst resulted in a significantly slower
reaction, albeit with better levels of selectivity. For a mechanistic study
and lead references see: Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am.
Chem. Soc. 1992, 114, 6679.
(23) Complementary diastereofacial selectivities in catalyzed and non-
catalyzed alkene hydroboration reactions are well documented. For a
discussion see: Burgess, K.; van der Donk, W. A.; Jarstfer, M. B.;
Ohlmeyer, M. J. J. Am. Chem. Soc. 1991, 113, 6139.
Representative Procedure for the Pd-Catalyzed Cyclodehy-
dration. tert-Butyl-(2-methyl-5-methylenetetrahydropyran-2-yl-
1950 J. Org. Chem., Vol. 73, No. 5, 2008

Organomagnesium-Based [3 + 3] Annelation to Pyrans
1
methoxy)diphenylsilane (19). A round-bottomed flask containing
molecular sieves 4 Å (46 mg) was flame dried under vacuum and
cooled under a nitrogen atmosphere. To this was added palladium
acetate (3.5 mg, 0.016 mmol), triphenylphosphine (16.45 mg, 0.063
mmol), and anhydrous toluene (1 mL). The suspension was stirred
for 10 min, and a solution of allylic alcohol 13 (125 mg, 0.31 mmol)
in anhydrous toluene (2 mL) was transferred via cannula to the
reaction mixture. Titanium isopropoxide (24 µL, 0.078 mmol) was
added and the reaction mixture was heated at reflux for 1.5 h. After
cooling to rt, direct purification by chromatography on silica gel
(gradient starting with petroleum ether and ending with 98:2
petroleum ether/EtOAc) provided the pyran 19 as a clear oil (45
ether/EtOAc) to give 22 as a clear oil (45 mg, 76%); H NMR
(250 MHz, CDCl3) δ 7.40-7.21 (5H, m), 5.01 (1H, br), 4.95 (1H,
br), 4.50 (4H, s), 3.88-3.77 (1H, m), 3.76-3.58 (2H, m), 3.04
(1H, br), 2.34-2.00 (2H, m), 2.06 (3H, s), 1.80-1.68 (2H, m),
1.67-1.54 (2H, m); 13C NMR (62.9 MHz, CDCl3) δ 170.9, 143.9,
138.0, 128.6, 127.9, 127.8, 112.4, 73.5, 71.1, 69.3, 67.0, 36.5, 35.3,
29.3, 21.0; IR (film, cm-1) 3460 (s), 3089 (m), 3031 (m), 2939
(s), 2863 (s), 1739 (s), 1654 (m), 1496 (w), 1452 (s), 1373 (s),
1235 (s), 1029 (s), 909 (m), 739 (m), 699 (m), 607 (w); HRMS
(EI) m/z [M]+ calcd for C17H24O4 292.1675, found 292.1681.
6-(tert-Butyldiphenylsilyloxy)-5-hydroxy-5-methyl-2-methyl-
enehexyl Acetate (23). Following the representative procedure,
allylic alcohol 13 (100 mg, 0.250 mmol) in anhydrous CH2Cl2 (3.5
mL) was treated with triethylamine (70 µL, 0.502 mmol), DMAP
(1.5 mg), and acetic anhydride (35 µL, 0.376 mmol). The crude
residue was purified by flash chromatography (60:40; petroleum
1
mg, 38%); H NMR (250 MHz, CDCl3) δ 7.73-7.62 (4H, m),
7.48-7.33 (6H, m), 4.87-4.61 (2H, m), 4.13 (1H, d, J ) 13.0
Hz), 4.00 (1H, d, J ) 13.0 Hz), 3.61 (1H, d, J ) 9.5 Hz), 3.54
(1H, d, J ) 9.5 Hz), 2.43-2.15 (2H, m), 1.85-1.63 (2H, m), 1.32
(3H, s), 1.08 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ 144.6, 135.8,
133.7, 129.8, 127.8, 108.4, 74.0, 69.7, 66.2, 33.4, 27.7, 27.0, 20.9,
19.5; FTIR (CH2Cl2, νmax cm-1) 3071 (s), 3050 (s), 2931 (s), 2857
(s), 1656 (m), 1589 (m), 1472 (s), 1428 (s), 1390 (m), 1362 (m),
1278 (w), 1270 (w), 1221 (m), 1189 (m), 1112 (s), 1062 (s), 1000
(m), 998 (m), 939 (w), 898 (m), 862 (m), 824 (m), 740 (m), 701
(m), 624 (m), 504 (m); HRMS (EI) m/z [M]+ calcd for C24H32O2Si
380.2171, found 380.2167.
1
ether/EtOAc) to give 23 as a clear oil (102 mg, 93%); H NMR
(250 MHz, CDCl3) δ 7.76-7.61 (4H, m), 7.52-7.32 (6H, m), 5.03
(1H, br), 4.95 (1H, br), 4.53 (2H, br), 3.50 (2H, br), 2.46 (1H, br),
2.22-1.99 (2H, m), 2.07 (3H, s), 1.82-1.54 (2H, m), 1.18 (3H,
s), 1.10 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ 170.7, 144.2,
135.7, 133.1, 130.0, 127.9, 112.0, 72.5, 70.9, 67.0, 36.4, 27.2, 27.0,
23.3, 21.0, 19.4; FTIR (CH2Cl2, νmax cm-1) 3482 (m), 3072 (m),
3050 (m), 2933 (s), 2859 (s), 1745 (s), 1655 (m), 1590 (w), 1472
(m), 1428 (m), 1375 (m), 1238 (m), 1113 (m), 1030 (m), 909 (m),
822 (m); HRMS (EI) m/z [M + Na]+ calcd for C26H36O4NaSi
463.2281, found 463.2273.
cis-4-(4-tert-Butyl-1-hydroxycyclohexyl)-2-methylenebutyl Ac-
etate (24). Following the representative procedure, allylic alcohol
15a (84 mg, 0.354 mmol) in anhydrous CH2Cl2 (5 mL) was treated
with triethylamine (98 µL, 0.707 mmol), DMAP (2 mg), and acetic
anhydride (50 µL, 0.530 mmol). The crude residue was purified
by flash chromatography (80:20; petroleum ether/EtOAc) to give
cis-9-tert-Butyl-3-methylene-1-oxaspiro[5.5]undecane (20). Fol-
lowing the representative procedure, a solution of allylic alcohol
15a (100 mg, 0.42 mmol) in anhydrous toluene (3.5 mL) was
transferred via cannula to a suspension of molecular sieves 4 Å
(65 mg), Pd(OAc)2 (4.7 mg, 0.021 mmol), PPh3 (22.0 mg, 0.084
mmol), and anhydrous toluene (1.0 mL). Titanium isopropoxide
(32 µL, 0.10 mmol) was added and the reaction mixture was heated
at reflux for 1.5 h. Pyran 20 was isolated as a clear oil (22 mg,
23%). 1H NMR (250 MHz, CDCl3) δ 4.77-4.69 (2H, m), 4.0 (2H,
s), 2.37-2.27 (2H, m), 2.12-2.00 (2H, m), 1.58-1.45 (4H, m),
1.40-0.90 (5H, m), 0.85 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ
145.0, 108.3, 71.0, 65.3, 48.5, 38.5, 34.5, 32.6, 27.9, 27.8, 22.1;
FTIR (CH2Cl2, νmax cm-1) 2939 (s), 2867 (s), 2838 (s), 1477 (m),
1442 (m), 1364 (m), 1284 (w), 1212 (w), 1158 (w), 1140 (w), 1090
(m), 1063 (s), 1038 (m), 1012 (w), 982 (w), 926 (w), 895 (m), 876
(m), 810 (w); HRMS (EI) m/z [M]+ calcd for C15H26O 222.1984,
found 222.1990.
1
24 as a clear oil (92 mg, 92%); H NMR (250 MHz, CDCl3) δ
4.98 (1H, br), 4.92 (1H, br), 4.51 (2H, s), 2.18-2.08 (2H, m), 2.06
(3H, s), 1.73-1.62 (2H, m), 1.61-1.48 (4H, m), 1.36-1.23 (5H,
m), 0.87-0.87 (1H, m), 0.83 (9H, s); 13C NMR (62.9 MHz, CDCl3)
δ 170.9, 144.5, 112.1, 70.5, 67.0, 48.0, 42.0, 37.5, 32.5, 27.6, 26.8,
22.5, 21.0; FTIR (CH2Cl2, νmax cm-1) 3480 (s), 2941 (s), 2868 (s),
2844 (s), 1744 (s), 1653 (m), 1478 (m), 1445 (m), 1392 (m), 1366
(s), 1315 (w), 1235 (s), 1143 (w), 1095 (w), 1029 (m), 988 (w),
960 (w), 926 (m), 914 (m); HRMS (EI) m/z [M]+ calcd for C17H30O3
282.2195, found 282.2193.
trans-9-tert-Butyl-3-methylene-1-oxaspiro[5.5]undecane (21).
Following the representative procedure, a solution of allylic alcohol
15b (80 mg, 0.33 mmol) in anhydrous toluene (3.0 mL) was
transferred via cannula to a suspension of molecular sieves 4 Å
(50 mg), Pd(OAc)2 (3.7 mg, 0.016 mmol), PPh3 (17.3 mg, 0.066
mmol), and anhydrous toluene (1.0 mL). Titanium isopropoxide
(25 µL, 0.08 mmol) was added and the reaction mixture was heated
at reflux for 1.5 h. Pyran 21 was isolated as a clear oil (25 mg,
trans-4-(4-tert-Butyl-1-hydroxycyclohexyl)-2-methylenebu-
tyl Acetate (25). Following the representative procedure, allylic
alcohol 15b (150 mg, 0.624 mmol) in anhydrous CH2Cl2 (9 mL)
was treated with triethylamine (173 µL, 1.25 mmol), DMAP (4
mg), and acetic anhydride (88 µL, 0.94 mmol). The crude residue
was purified by flash chromatography (80:20; petroleum ether/
1
1
34%). H NMR (250 MHz, CDCl3) δ 4.78-4.69 (2H, m), 4.10
EtOAc) to give 25 as a clear oil (150 mg, 85%); H NMR (250
(2H, s), 2.33-2.23 (2H, m), 2.11-1.98 (2H, m), 1.80-1.60 (4H,
m), 1.40-1.23 (2H, m), 1.15-0.98 (3H, m), 0.85 (9H, s); 13C NMR
(62.9 MHz, CDCl3) δ 145.0, 108.2, 73.0, 65.8, 48.1, 35.5 (2C),
32.4, 32.0, 27.7, 24.0; FTIR (CH2Cl2, νmax cm-1) 2939 (s), 2867
(s), 2838 (s), 1477 (m), 1442 (m), 1364 (m), 1284 (w), 1212 (w),
1158 (w), 1140 (w), 1090 (m), 1063 (s), 1038 (m), 1012 (w), 982
(w), 926 (w), 895 (m), 876 (m), 810 (w); HRMS (EI) m/z [M]+
calcd for C15H26O 222.1984, found 222.1980.
Representative Procedure for Allylic Alcohol Acetylation:
7-(Benzyloxy)-5-hydroxy-2-methyleneheptyl Acetate (22). In a
flame-dried flask was dissolved allylic alcohol 9 (50 mg, 0.20
mmol) in anhydrous CH2Cl2 (4 mL). The solution was cooled to 0
°C and triethylamine (56 µL, 0.40 mmol), DMAP (1.5 mg), and
acetic anhydride (19 µL, 0.20 mmol) were added sequentially. The
cool bath was removed and the reaction stirred at rt for 1 h. The
reaction was quenched with aqueous HCl solution (1 M) and
extracted with CH2Cl2. The combined organic extracts were washed
with brine, dried over MgSO4, and concentrated in vacuo. The crude
residue was purified by flash chromatography (60:40; petroleum
MHz, CDCl3) δ 4.98 (1H, br), 4.93 (1H, br), 4.51 (2H, s), 2.15-
1.96 (2H, m), 2.04 (3H, s), 1.85-1.50 (6H, m), 1.42-1.21 (2H,
m), 1.09-0.87 (4H, m), 0.80 (9H, s); 13C NMR (62.9 MHz, CDCl3)
δ 170.8, 144.5, 112.1, 71.9, 67.0, 47.6, 38.8, 34.3, 32.3, 27.7, 26.5,
24.5, 20.9; FTIR (CH2Cl2, νmax cm-1) 3436 (s), 2941 (s), 2867 (s),
1743 (s), 1653 (m), 1458 (m), 1392 (m), 1366 (s), 1233 (s), 1126
(w), 1084 (w), 1032 (m), 984 (w), 960 (w), 926 (m), 916 (m);
HRMS (ES) m/z [M + Na]+ calcd for C17H30O3Na 305.2093, found
305.2098.
Representative Procedure for Pd-Catalyzed Allylic Acetate
Cyclization: tert-Butyl(2-methyl-5-methylenetetrahydropyran-
2-ylmethoxy)diphenylsilane (19). In a flame-dried flask was
dissolved Pd(OAc)2 (2.6 mg, 0.011 mmol) and PPh3 (11.5 mg, 0.044
mmol) in anhydrous toluene (0.8 mL) and the solution was stirred
for 10 min at rt. A solution of allylic acetate 29 (88 mg, 0.20 mmol)
in anhydrous toluene (1.2 mL) was transferred via cannula to the
suspension. Titanium isopropoxide (15 µL, 0.035 mmol) was added
and the reaction mixture was heated at reflux for 1.5 h. After cooling
to rt, direct purification by chromatography on silica gel provided
J. Org. Chem, Vol. 73, No. 5, 2008 1951

Brioche et al.
the desired product 26 as a clear oil (69 mg, 90%). The product
showed identical spectroscopic data to that outlined earlier.
cis-9-tert-Butyl-3-methylene-1-oxaspiro[5.5]undecane (20). Fol-
lowing the representative procedure, a mixture of Pd(OAc)2 (3.2
mg, 0.014 mmol) and PPh3 (14.9 mg, 0.057 mmol) in anhydrous
toluene (1.0 mL) was treated with a solution of 30 (80 mg,
0.28 mmol) in anhydrous toluene (1.9 mL) and titanium isopro-
poxide (21 µL, 0.07 mmol). Purification by chromatography on
silica gel provided the desired product 27 as a clear oil (42 mg,
67%). The product showed identical spectroscopic data to that
outlined earlier.
trans-9-tert-Butyl-3-methylene-1-oxaspiro[5.5]undecane (21).
Following the representative procedure, a mixture of Pd(OAc)2 (5.0
mg, 0.022 mmol) and PPh3 (23.1 mg, 0.088 mmol) in anhydrous
toluene (1.5 mL) was treated with a solution of 31 (125 mg, 0.44
mmol) in anhydrous toluene (3.5 mL) and titanium isopropoxide
(32.5 µL, 0.11 mmol). Purification by chromatography on silica
gel provided the desired product 27 as a clear oil (74 mg, 75%).
The product showed identical spectroscopic data to that outlined
earlier.
7-(tert-Butyldiphenylsilyloxy)-2-methyleneheptane-1,5-diol. To
a solution of Grignard 4 (10 mL, 0.14 M, 1.4 mmol) was added a
solution of epoxide 26 (304 mg, 0.93 mmol) in THF (4 mL) via
cannula at rt and the reaction was stirred for 2 h. The crude residue
was purified by flash chromatography (60:40 petroleum ether/ethyl
acetate) to give the title compound as a clear oil (293 mg, 79%);
1H NMR (250 MHz, CDCl3) δ 7.70-7.63 (4H, m), 7.48-7.33 (6H,
m), 5.06-5.01 (1H, m), 4.92-4.88 (1H, m), 4.09 (2H, br), 3.99-
3.78 (3H, m), 3.50 (1H, br), 2.33-1.94 (3H, m), 1.84-1.54 (4H,
m), 1.04 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ 149.0, 135.7,
133.1, 133.0, 130.0, 127.9, 109.7, 71.5, 66.1, 63.6, 38.5, 35.7, 29.0,
26.9, 19.1; FTIR (CH2Cl2, νmax cm-1) 3354 (br), 3071 (w), 3050
(w), 2932 (s), 2858 (s), 1652 (w), 1472 (m), 1428 (s), 1390 (m),
1361 (m), 1112 (s), 1085 (s), 1029 (m), 900 (m), 823 (m), 737
(m), 702 (s), 688 (m), 614 (m), 504 (s); HRMS (ES) m/z [M +
H]+ calcd for C24H35O3Si 399.2355, found 399.2371.
1.04 mmol) in anhydrous THF (3.5 mL) was added via cannula at
0 °C to the reaction mixture. The reaction was then warmed to rt
over 1 h, diluted with 70 mL of EtOAc, and washed with saturated
Na2S2O3, saturated NaHCO3, and brine. The organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The crude residue
was purified by flash chromatography (99:1; petroleum ether/
EtOAc) to give the desired products as yellow oils trans-29 (31
mg, 23%) and cis-29 (78 mg, 58%). Satisfactory spectroscopic data
were obtained for these compounds.10
tert-Butyldiphenyl(2-((2R*,5S*)-5-((3E,7E)-4,8,12-trimethyl-
trideca-3,7,11-trienyl)tetrahydro-2H-pyran-2-yl)ethoxy)silane (32).
Farnesyl sulfone 30 (62 mg, 0.18 mmol) was dissolved in anhydrous
THF (550 µL) and DMPU (200 µL) and cooled to -78 °C. A 330
µL sample of a freshly prepared LDA solution (from 200 µL of
DIPA, 710 µL of 1.9 M nBuLi in 1.45 mL of THF) was added to
the sulfone and the resulting bright orange solution was stirred for
1 h at -78 °C. A solution of trans-29 (105 mg, 0.20 mmol) in
anhydrous THF (350 µL) was added dropwise. The reaction was
stirred an additional 1 h at -78 °C, and then the cold bath was
removed and the reaction stirred for another 3-4 h. The reaction
mixture was then quenched with a saturated aqueous NH4Cl
solution. The aqueous solution was extracted three times with ether,
dried over MgSO4, and concentrated in vacuo. The resulting oil
residue was purified via flash chromatography on silica gel (90:
10; petroleum ether/EtOAc) to give an inseparable mixture (105
mg) of the desired product 31 and farnesyl sulfone.
The obtained mixture (105 mg) was dissolved in anhydrous THF
(1.6 mL) and PdCl2(dppf) (13.2 mg, 0.018 mmol) was added. Super
Hydride (1 M in THF, 540 µL, 0.54 mmol) was added dropwise at
10 °C to the orange solution, the cold bath removed, and the reaction
stirred at rt for 6 h. The reaction was quenched carefully at 0 °C
with saturated aqueous NH4Cl solution. The resulting aqueous layer
was extracted with ether three times. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The resulting oily residue was purified by flash
chromatography on silica gel (98:2; petroleum ether/EtOAc) to give
the desired product 32 as a yellow oil (74 mg, 70% over two steps).
1H NMR (250 MHz, CDCl3) δ 7.73-7.63 (4H, m), 7.45-7.34 (6H,
m), 5.18-5.04 (3H, m), 3.91 (1H, ddd, J ) 11.0, 4.0, 2.0 Hz),
3.86-3.69 (2H, m), 3.50-3.37 (1H, m), 3.00 (1H, t, J ) 11.0 Hz),
2.15-1.85 (11H, m), 1.76-1.69 (4H, m), 1.66-1.55 (10H, m),
1.30-1.10 (6H, m), 1.06 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ
135.7, 135.3, 135.1, 134. 3, 134.1, 131.3, 129.9, 127.7, 124.5, 124.4,
124.3, 74.6, 73.6, 60.6, 39.8, 39.4, 35.7, 32.8, 32.1, 30.7, 29.8, 27.0,
26.9, 26.7, 25.8, 25.1, 19.4, 17.8, 16.1 (2C); FTIR (CH2Cl2, νmax
cm-1) 3174 (w), 3049 (w), 2928 (s), 2855 (s), 1472 (m), 1446 (m),
1428 (m), 1384 (m) 1361 (w), 1261 (w), 1213 (w), 1188 (w), 1112
(s), 1088 (s), 1007 (w), 940 (w), 823 (m), 736 (m), 701 (s), 613
(m), 504 (s); HRMS (ES) m/z [M]+ calcd for C39H58O2Si 586.4206,
found 586.4194.
Preparation of cis- and trans-(6-(2-(tert-Butyldiphenylsily-
loxy)ethyl)tetrahydro-2H-pyran-3-yl)methanol (28). In a round-
bottomed flask under a nitrogen atmosphere was dissolved 27 (650
mg, 1.7 mmol) in anhydrous THF (2 mL). To this solution was
added dropwise, at rt, 9-BBN (0.5 M in THF, 4.40 mL, 2.20 mmol).
The reaction was stirred at rt for 18 h, cooled to 0 °C, and quenched
with NaOH (1 M, 3.4 mL, 3.4 mmol) and H2O2 (1 M, 0.4 mL, 3.4
mmol). The reaction was then stirred for 3 h at rt, and after this
time saturated aqueous NH4Cl solution was added to the solution
and the product extracted with EtOAc. The combined organic
extracts were washed with brine, dried over MgSO4 and concen-
trated in vacuo. The crude residue was purified by flash chroma-
tography (60:40; petroleum ether/EtOAc) to give a mixture of cis:
trans 28 as a yellow oil (608 mg, 90%, 3:1 trans/cis ratio). 1H NMR
(250 MHz, CDCl3) δ 7.80-7.57 (4H, m, trans/cis-isomers), 7.52-
7.28 (6H, m, trans/cis-isomers), 4.06 (0.75 H, ddd, J ) 11.0, 4.0,
2.5 Hz, trans-isomer), 3.95 (0.25 H, d, J ) 12.0 Hz, cis-isomer),
3.89-3.33 (5.25 H, m, trans/cis-isomers), 3.13 (0.75H, t, J ) 11.0
Hz, trans-isomer), 1.91-1.19 (8H, m, trans/cis-isomers), 1.06 (9H,
s, trans/cis-isomers); 13C NMR (62.9 MHz, CDCl3) δ 135.7, 134.2,
134.1, 129.6, 127.7, 74.8, 74.7, 71.0, 68.5, 65.1, 63.4, 60.5, 60.3,
39.2, 39.0, 36.0, 31.5, 27.9, 27.0, 26.8, 24.6, 19.4; FTIR (CH2Cl2,
2-((2R*,5R*)-Tetrahydro-5-((3E,7E)-4,8,12-trimethyltrideca-
3,7,11-trienyl)-2H-pyran-2-yl)ethanol (33). To a solution of 32
(135 mg, 0.23 mmol) in anhydrous THF (2.5 mL) was added
dropwise TBAF (1 M in THF, 350 µL, 0.36 mmol). The reaction
was stirred at rt for 20 h and quenched with H2O. The aqueous
layer was extracted two times with EtOAc. The combined organic
extracts were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The crude residue was purified by flash chroma-
tography (80:20; petroleum ether/EtOAc) to give the desired product
ν
max cm-1) 3377 (br), 3071 (m), 2930 (s), 2857 (s), 1472 (m), 1428
1
(s), 1389 (m), 1361 (m), 1212 (w), 1186 (w), 1112 (s), 1088 (s),
1007 (m), 974 (w), 940 (w), 910 (w), 863 (w), 823 (m), 788 (w),
736 (s), 702 (s), 613 (m), 505 (s); HRMS (ES) m/z [M + Na]+
calcd for C24H34O3NaSi 421.2175, found 421.2177.
33 as yellow oil (78 mg, 98%). H NMR (250 MHz, CDCl3) δ
5.15-5.02 (3H, m), 3.93 (1H, ddd, J ) 11.0, 4.0, 2.0 Hz), 3.77
(2H, t, J ) 5.0 Hz), 3.52-3.39 (1H, m), 3.03 (1H, t, J ) 11.0 Hz),
2.94-2.76 (1H, br), 2.13-1.80 (10H, m), 1.77-1.04 (21H, m);
13C NMR (62.9 MHz, CDCl3) δ 135.4, 135.0, 131.3, 124.5, 124.3
(2C), 78.4, 73.6, 61.6, 39.8 (2C), 38.1, 35.4, 32.7, 31.9, 30.3, 26.8,
26.7, 25.8, 25.0, 17.8, 16.1 (2C); FTIR (CH2Cl2, νmax cm-1) 3391
(br), 2919 (s), 2850 (s), 1448 (m), 1382 (m), 1223 (w), 1092 (s),
1059 (m), 890 (w), 853 (w); HRMS (ES) m/z [M]+ calcd for
C23H40O2 348.3028, found 348.3033.
Hydrozirconation Route to trans/cis-tert-Butyl(2-(5-(iodo-
methyl)tetrahydro-2H-pyran-2-yl)ethoxy)diphenylsilane (29). To
a solution of pyran 27 (100 mg, 0.26 mmol) in anhydrous THF
(2.2 mL) under nitrogen atmosphere was added in one portion Cp2-
Zr(H)Cl (203 mg, 0.79 mmol). The reaction was stirred at room
temperature for 20 h. After this time, a solution of I2 (264 mg,
1952 J. Org. Chem., Vol. 73, No. 5, 2008

Organomagnesium-Based [3 + 3] Annelation to Pyrans
2-((2R*,5R*)-Tetrahydro-5-((3E,7E)-4,8,12-trimethyltrideca-
3,7,11-trienyl)-2H-pyran-2-yl)acrylaldehyde (34). To a solution
of oxalyl chloride (23 µL, 0.26 mmol) in anhydrous CH2Cl2 (380
µL) was added dropwise at -78 °C a solution of DMSO (37 µL,
0.52 mmol) in CH2Cl2 (380 µL). The reaction was stirred at -78
°C for 20 min. A solution of 33 (45 mg, 0.13 mmol) in CH2Cl2
(330 µL) was added dropwise at -78 °C for 15 min and the reaction
mixture was stirred for 1 h at -78 °C. Et3N (128 µL, 0.91 mmol)
was added dropwise and the reaction was stirred for a further hour.
The reaction was quenched with brine and the aqueous layer was
extracted two times with CH2Cl2. The combined organic extracts
were washed with brine, dried over Na2SO4, and concentrated in
vacuo to give the corresponding aldehyde as a yellow oil. The crude
residue (37 mg, 83% crude) was dissolved in anhydrous CH2Cl2
(1.8 mL) and Eschenmoser’s salt (98 mg, 0.53 mmol) and Et3N
(300 µL, 2.13 mmol) were added. The reaction was stirred at rt for
20 h. The reaction was quenched with a solution of NaHCO3 and
the aqueous layer was extracted three times with CH2Cl2. The
combined organic extracts were washed with brine, dried over Na2-
SO4, and concentrated in vacuo. The crude residue was purified
by flash chromatography (99:9:1 petroleum ether/EtOAc/Et3N) to
give the desired product 34 as a yellow oil (30 mg, 66% over two
steps). 1H NMR (250 MHz, CDCl3) δ 9.53 (1H, s), 6.55-6.51 (1H,
m), 6.05 (1H, s), 5.14-5.04 (3H, m), 4.13 (1H, d, J ) 9.5 Hz),
4.02 (1H, ddd, J ) 11.0, 4.0, 2.0 Hz), 3.13 (1H, t, J ) 11.0 Hz),
2.15-1.78 (12H, m), 1.67 (3H, s), 1.62-1.55 (1H, m), 1.60 (9H,
s), 1.30-1.04 (4H, m); 13C NMR (62.9 MHz, CDCl3) δ 193.4,
151.7, 135.4, 135.1, 133.8 (2C), 124.5, 124.3 (2C), 74.0, 73.8, 39.8
(2C), 35.5, 32.6, 32.2, 30.4, 26.9, 26.8, 25.8, 25.0, 17.8, 16.1 (2C);
FTIR (CH2Cl2, νmax cm-1) 2919 (s), 2850 (s), 1694 (s), 1448 (m),
1378 (m), 1352 (w), 1292 (w), 1250 (w), 1094 (s), 1049 (w), 951
(w), 902 (w), 840 (w), 668 (w), 665 (w), 550 (w); HRMS (ES) m/z
[M]+ calcd for C24H38O2 358.2871, found 358.2888.
Rhopaloic A (35). To a solution of aldehyde 35 (29 mg, 0.08
mmol) in tBuOH/H2O (5:1, 4.0 mL) was added 2-methyl-2-butene
(2M in THF, 2.5 mL, 4.85 mmol), NaH2PO4 (58.2 mg, 0.48 mmol),
and NaClO2 (80%, 55 mg, 0.485 mmol). The reaction was stirred
at rt for 2 h, brine was added, and the reaction mixture was extracted
three times with EtOAc. The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo. The crude residue was
purified by flash chromatography (gradient starting with 100:0 and
ending with 60:40 petroleum ether/EtOAc) to give the desired
product as a yellow oil (24 mg, 80%). The compound showed
satisfactory spectral data:16a 1H NMR (250 MHz, CDCl3) δ 6.38
(1H, br), 5.91 (1H, br), 5.12-5.07 (3H, m), 4.12 (1H, d, J ) 11.0
Hz), 4.06 (1H, ddd, J ) 11.0 4.0, 1.5 Hz), 3.17 (1H, t, J ) 11.0
Hz), 2.11-1.91 (12H, m), 1.68 (3H, d, J ) 1.0 Hz), 1.64-1.57
(1H, m), 1.60 (9H, s), 1.38-1.30 (1H, m), 1.27-1.12 (3H, m);
13C NMR (62.9 MHz, CDCl3) δ 169.8, 141.0, 135.6, 135.1, 131.4,
127.1, 124.5, 124.3, 124.2, 76.2, 74.1, 39.9, 39.8, 35.3, 32.6, 32.1,
30.4, 26.9, 26.7, 25.8, 25.0, 17.8, 16.2 (2C); HRMS (ES) m/z [M]+
calcd for C24H38O3 374.2820, found 374.2807.
Acknowledgment. We are grateful to GlaxoSmithKline and
the University of Sheffield for financial support.
Supporting Information Available: 1H and 13C NMR spectra
for selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO702620E
J. Org. Chem, Vol. 73, No. 5, 2008 1953