Studies on the intramolecular oxa-Pictet-Spengler rearrangement of 5-aryl-1,3-dioxolanes to 4-hydroxy-isochromans

Article abstract of DOI:10.1016/j.tetlet.2003.10.143

The success and stereochemical outcome of the TiCl₄-promoted oxa-Pictet-Spengler cyclization of 5-aryl-1,3-dioxolanes to produce 1,3-disubstituted-4-hydroxy-isochromans, is influenced by the length and nature of the side chains bound to C-2 and C-4 of the dioxolane. Methyl groups yield a mixture of 4-hydroxy-isochromans in which the 1,3-trans diastereomer predominates, while bulkier substituents give 1,3-cis diastereomers. Functional groups in the C-2 side chain of the dioxolane ring may hinder cyclization by complexation with the promoter.

Full text of DOI:10.1016/j.tetlet.2003.10.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 411–415
Studies on the intramolecular oxa-Pictet–Spengler rearrangement
of 5-aryl-1,3-dioxolanes to 4-hydroxy-isochromans
*
ꢀ
Darıo A. Bianchi, Federico Rua and Teodoro S. Kaufman
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Instituto de Quımica Organica de Sıntesis (CONICET-UNR) and Facultad de Ciencias Bioquımicas yFarmac euticas,
Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
Received 21 September 2003; revised 21 October 2003; accepted 23 October 2003
ꢀ
Dedicated to Professor Edmundo A. Ruveda on the occasion of his 70th Birthday
Abstract—The success and stereochemical outcome of the TiCl4-promoted oxa-Pictet–Spengler cyclization of 5-aryl-1,3-dioxolanes
to produce 1,3-disubstituted-4-hydroxy-isochromans, is influenced by the length and nature of the side chains bound to C-2 and C-4
of the dioxolane. Methyl groups yield a mixture of 4-hydroxy-isochromans in which the 1,3-trans diastereomer predominates, while
bulkier substituents give 1,3-cis diastereomers. Functional groups in the C-2 side chain of the dioxolane ring may hinder cyclization
by complexation with the promoter.
ꢀ 2003Elsevier Ltd. All rights reserved.
Many interesting natural products are isochroman
derivatives, such as stephaoxocanine (1),1 glucoside B (2),
an aphid insect pigment derivative,2 the topoisomerase
II inhibitor CJ-12,373 (3),3 and the unnamed compound
4, isolated from softwood lignins.4 Synthetic isochro-
mans with activities as herbicides,5a dopamine receptor
ligands,5b and fragrances, such as the commercial musk
odorant galaxolideꢁ (5),5c have also been described.
matic ring substitution pattern.9 Interestingly, the effect
of the dioxolane substituents R1 and R2 on the stereo-
chemistry of C-1 in the product has not been evaluated,
since only 4-hydroxy-isochroman derivatives 7 bearing
methyl and acetate residues on C-3(sometimes c-lacto-
nized with the vicinal carbinol), and solely methyl groups
on C-1 have been synthesized to date.9;10
The oxa-Pictet–Spengler6 isomerization of aryl dioxo-
lanes 6 to 4-hydroxy-isochromans 7 (Scheme 1)7 has been
employed for the synthesis of natural products, but its
scope has been only partially studied. The overall yield of
the transformation was observed to be influenced by the
stereochemistry of the C-2 center of the dioxolane, the
reaction temperature, and the nature of the substituent
of the aromatic ring ortho to the dioxolane; however, the
factors, which determine the relative stereochemistry at
the newly generated C-1 center were found to be difficult
to understand,8 and ascribed to the 4,5-stereochemistry
of the substrate, steric elements, the characteristics of the
transition state, the reaction temperature, and the aro-
GlcO OH Me
OMe
OH
MeO
O
H
O
A
C
D
HO
O
Me
B
OH
N
1
2
OH
OH
HO2C
(CH2)6CH3
HO
OH
3
ArO
HO
O
O
MeO
Keywords: oxa-Pictet–Spengler; isochromans; rearrangement; dioxo-
lanes; isomerization.
OH
OH
OMe
* Corresponding author. Tel./fax: +54-341-4370477; e-mail: tkaufman@
fbioyf.unr.edu.ar
5
4
0040-4039/$ - see front matter ꢀ 2003Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.143

412
D. A. Bianchi et al. / Tetrahedron Letters 45 (2004) 411–415
ambiguously that C-4 is the more protected carbon
atom among the three, being C-3the most deprotected
one. Nuclear Overhauser effect (NOE) difference spec-
R3
R3
TiCl4, CH2Cl2
1
5
4
OH
R1
O
2
MeO
MeO
1
troscopy and H–1H decoupling experiments evidenced
R2
O
1
4
3
O
R1
R1= Me, CH2CO2Et
R2= Me
R3= Cl, OMe
that the small methyl substituents gave rise to a dia-
stereomeric mixture of 1,3-cis and 1,3-trans 4-hydroxy-
isochromans (entry 1), with the latter prevailing at )78,
)65, and )30 ꢂC, in agreement with previous observa-
tions made during the isomerization of related sub-
strates.8
R2
3
2
6
7
Scheme 1.
As part of our interest in the synthesis of stephaoxo-
canes,11 employing this dioxolane isomerization as key
transformation for the elaboration of the isochroman
AC-ring system embodied in these natural products12 we
investigated the structural requirements of the substi-
tuents R1 and R2 for the cyclization in precursors 6,
aiming to elaborate cis-1,3-disubstituted 4-hydroxy-
isochromans, conveniently x-functionalized in their side
chains.
Further analysis revealed that increase in bulkiness of
the Wittig (R1) and acetal (R2) derived side chains
promoted the stereoselective production of the all-cis
substituted heterocycles in those substrates undergoing
the rearrangement. This was clearly evidenced from
results of various NOE difference experiments; for exam-
ple, H-1 of 12d (entry 4) showed 2% signal enhancement
when H-3was irradiated and vice versa (5%); similarly,
12k (entry 11) demonstrated 6% signal enhancement of
H-1 upon irradiation of H-3and reciprocal irradiation
yielded 7% enhancement of the H-1 resonance. The
remaining NOE and decoupling experiments carried out
on all of the 4-hydroxy-isochromans gave results fully
consistent with the proposed stereochemistry in each
case.20
Dioxolanes 11a–k were prepared from 813 by olefin-
ation10 (Scheme 2), followed by alkene equilibration14 to
E-9, vicinal dihydroxylation, and PPTS assisted15 ace-
talization of the resulting diols 10 with aldehydes or
acetals. Superior yields were obtained when the acetal-
izations were carried out in a Soxhlet apparatus con-
ꢁ
taining 4 A MS in the thimble. Aldehydes and acetals
were accessed following literature procedures,16 while
Wittig reagents were prepared in 52–87% yield by
reaction of PPh3 with 4-chlorobutyronitrile, 4-bromo
butyric acid, 5-bromovaleric acid, and 4-benzyloxy-
bromobutane17 in refluxing xylene.18
In addition, the small vicinal coupling constant between
H-3and H-4 evidenced their respective pseudoaxial and
pseudoequatorial orientations and confirmed the exact
transfer of the stereochemical features of the dioxolanes
to the corresponding 4-hydroxy-isochromans.6;8 The
signals of C-4 were generally observed as broad dou-
blets, due to their coupling with the hydroxylic proton
(J ¼ 8:9–13:3Hz), which collapsed into broadened
singlets or doublets with J values smaller than 1.8 Hz
upon exchange with D2O. Furthermore, the diagnostic
signals of H-3, resonating around d 3.6, were also sup-
portive of the cis relationship between both side chains.8
The isomerization of the dioxolanes 11a–k was carried
19
out under the influence of TiCl4.
Stereochemical
assignments (Table 1) were made by H and 13C NMR
spectroscopies. In addition, unequivocal assignments for
C-1, C-3, and C-4 of this series of isochromans,7–10 were
obtained by analysis of two-dimensional C–H hetero-
nuclear correlation NMR spectra demonstrating un-
1
Noteworthy, in the camphorsulfonic acid (CSA)-medi-
ated rearrangement of aryldioxolanyl acetates to iso-
chroman-3-yl acetates, Giles et al. found a strong
dependence between the concentration of the promoter
and the epimeric ratio of the products.9a Changing the
CSA concentration from 5.7 · 10À3 mol LÀ1 (0.27 equiv)
to 8.6 · 10À2 mol LÀ1 (4 equiv), they were able to modify
the cis:trans products ratio from 6.8:1 to 0.28:1. In our
case, CSA was ineffective and, regardless of the final
concentration of TiCl4 employed (0.01–0.15 mol LÀ1),
1,3-trans diastereomers were not detected (except for
12a, where the dioxolane precursor bears two methyl
groups). This outcome may be attributed to the presence
of bulky side chains, which tend to minimize 1,3-diaxial
interactions in the cationic intermediate.21
Br
Br
a
MeO
MeO
CHO
MeO
MeO
R1
8
9
b
Br
O
O
Br
c
OH
OH
R2
R1
11
R1
10
The characteristics of the side chains, in terms of length
and nature of their functional groups also effect the
isomerization ability of the dioxolanes. The structure of
the R1 chain does not appear to have pronounced in-
fluence upon the feasibility of the rearrangement; how-
ever, a highly favored acid-catalyzed intramolecular
lactonization (entry 2) furnished the corresponding
Scheme 2. Reagents and conditions: (a) 1. R1CH2PPhþ3 XÀ (1.25 equiv,
X ¼ Cl, Br), KtBuO, PhMe, )30 ꢂC fi rt, overnight; 2. PhSH
(0.05 equiv), AIBN (cat.), PhMe, 80 ꢂC, 1 h (20 < E=Z > 36; 45–85%,
overall); (b) NMO, OsO4 (cat.), Me2CO–H2O (9:1), rt, overnight (80–
86%); (c) R2CHO or R2CH(OEt)2 (2 equiv), PhH, PPTS (0.1 equiv),
ꢁ
MS 4 A, reflux (68–93%). For the structural identities of R1 and R2, see
Table 1.

Table 1. TiCl4-promoted rearrangement of 5-aryl-1,3-dioxolanes carrying different substituents (synthesis of 1,3-disubstituted 4-hydroxy-isochromans)
Br
Br
TiCl4, CH2Cl2
Conditions
4
OH
O
O
MeO
MeO
R2
R2 1 O 3 R1
R1
2
Entry no Acetal no R1
R2
Temperature (ꢂC)
)78
Time (h)
0.5
Product
no
Yield (%)a
1H NMR
H-1
13C NMR
C-1 C-C4 -3
H-3H-4
1b
11a
Me
Me
12a
trans
5.08, q,
J ¼ 6:0
4.93, q,
4.11, dq
J ¼ 1:7, 6.4
3.69, dq,
4.44, dd
J ¼ 1:7, 8.9
4.49, dd,
67.01
68.44
66.20
68.33
50
cis
25c
70.83
71.98
J ¼ 6:2
J ¼ 1:2, 6.4
J ¼ 1:2, 9.6
2
3
11b
11c
(CH2)2CO2Et
(CH2)3CO2Et
CH2Br
CH2Br
)30
2
2
––d
47
)30 fi rt
12c
12d
12e
5.13, dd,
J ¼ 2:4, 2.6
5.21, dd,
3.55, dd,
J ¼ 4:1, 7.7
3.54, dd,
4.55, bd,
J ¼ 11:6
4.56, bd,
72.53
72.47
72.67
75.95
75.70
73.66
67.07
67.14
67.22
4
5
11d
11e
(CH2)3OBn
CH2CH2CN
CH2SPh
CH2SPh
)60 fi )3
)3
0
0
26
87
J ¼ 2:8, 3.2
5.30, dd,
J ¼ 2:3, 9.8
3.70, bdd,
J ¼ 13:3
4.58, bd,
2
J ¼ 2:8, 3.0
J ¼ 3:2, 11.1 J ¼ 11, 1
6
7
8
9
11f
11g
11h
11i
CH2CH2CN
CH2CH2CN
CH2CH2CN
CH2CH2CN
CH2CH@CH2
(CH2)2SPh
)78 ꢂC
)30 fi rt
)78 fi rt
)78
2
24
16
1.5
––e
––f
––g
59
(CH2)3SPh
(CH2)3SO2Ph
12i
4.84, dd,
J ¼ 1:5, 5.7
3.56, bdd,
J ¼ 3:5, 9.8
4.51, bs,
w1=2 ¼ 12
73.82
73.80
73.82
74.70
67.12
67.46
S
g
10
11
11j
CH2CH2CN
CH2CH2CN
)78 fi rt
)45
3––
4
S
11k
(CH2)3OTBDPS
12k
60
4.90, dd,
J ¼ 2:3, 6.6
3.63, bdd,
J ¼ 3:5, 8.7
4.54, bd,
J ¼ 10:7
a Isolated yields, after silica gel 60H flash column chromatography (eluent: hexane–EtOAc mixtures).
b According to IUPAC naming rules, the starting material is a 4-aryl-1,3-dioxolane.
c A 2:1 mixture, being the all-cis diastereomer the minor product.
d Converted into the five-membered ring lactone (mp 128–129 ꢂC)22a in isolated yield of 93%.
e The precursor diol 10 (R1 ¼ CH2CH2CN) was recovered almost quantitatively.
f The thioether side chain cyclized intramolecularly, furnishing 4-hydroxy-thiochroman22a (81%).
g No cyclization was observed at rt after 24 h of incubation with 2.2–6.3equiv of TiCl 4.

414
D. A. Bianchi et al. / Tetrahedron Letters 45 (2004) 411–415
c-butyrolactone22a and the benzyloxy-substituted sub-
strate 11d, was labile to the Lewis acid used and both,
starting material and product partially decomposed
during the reaction, diminishing the isolated yield of the
expected isochroman 12d (entry 4).
References and Notes
1. Kashiwaba, N.; Morooka, S.; Kimura, M.; Ono, M.;
Toda, J.; Suzuki, H.; Sano, T. J. Nat. Prod. 1996, 59, 803–
805.
2. Cameron, D. W.; Cromartie, R. I. T.; Kingston, D. G. I.;
Todd, A. R. J. Chem. Soc. 1964, 51–72.
On the contrary, length and terminal substitution of R2
seem to be key factors for success of the oxa-Pictet–
Spengler transformation. Comparative inspection of
acetals bearing a homologous series of phenyl thioethers
lead us to suspect that the coordination ability of these
substratesÕ side chain to the metal ion could be deter-
mining the success of the isomerization.
3. Inagaki, T.; Kaneda, K.; Suzuki, Y.; Hirai, H.; Nomura,
E.; Sakakibara, T.; Yamauchi, Y.; Huang, L. H.; Norcia,
M.; Wondrack, L. M.; Sutcliffe, J. A.; Kojima, N.
J. Antibiot. 1998, 51, 112–116.
4. Ralph, J.; Peng, J.; Lu, F. Tetrahedron Lett. 1998, 39,
4963–4964.
5. (a) Cutler, H. G.; Majetich, G.; Tian, X.; Spearing, P. U.S.
Patent 5,922,889, 1999; Chem. Abstr. 1999, 131, 73559; (b)
TenBrick, R. E.; Bergh, C. L.; Ducan, J. N.; Harris, D.
W.; Huff, R. M.; Lathi, R. A.; Lawson, C. F.; Lutzke, B.
S.; Martin, I. J.; Rees, S. A.; Schlachter, S. K.; Sih, J. S.;
Smith, M. W. J. Med. Chem. 1996, 39, 2435–2437; (c)
In fact, while the thioether 11e carrying the shortest chain
was capable of cyclizing in good yield (entry 5), its next
homolog (11g, entry 7) reacted through an alternative
path (probably involving an intramolecular Friedel
Crafts acylation) furnishing 4-hydroxy-thiochroman
(81%),22b and that bearing a four-carbon side chain (11h,
entry 8) was completely unreactive under various con-
ditions (2–4 equiv TiCl4). Our suspicion found additional
support when dithiane 11j, a three carbon side chain
analog of 11g, remained unreactive against TiCl4 (2.2–
6.3equiv), being found unchanged after 24 h at 0 ꢂC. In
neither of the last three cases production of 4-hydroxy-
isocromans could be detected. Furthermore, contrasting
with the unreactive thioether 11h, the related sulfone 11i
provided the corresponding 4-hydroxy-isochroman 12i
in 59% yield (entry 10) and the silyl ether 11k, a highly
hindered oxygen analog of 11h, furnished 60% of cyclized
product 12h (entry 11). Involvement of the heteroatoms
in the side chains leading to insoluble complexes may
have hindered the rearrangements of 11g and 11h; ana-
logously, the successful rearrangements of 11i and 11k
may be interpreted as being a consequence of difficulties
in titanium coordination to the heteroatoms in the side
chain (R2),23–25 probably due to unfavorable chain length
in the former case or to steric congestion surrounding the
oxygen atom of the side chain in the latter.
ꢀ
Frater, G.; Kraft, P. Helv. Chim. Acta 1999, 82, 1656–
1665.
6. Giles, R. G. F.; Green, I. R.; Knight, L. S.; Lee Son, V. R.;
Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Chem.
Commun. 1991, 1, 287–288.
7. Some representative examples: (a) Mohler, D. L.; Thomp-
son, D. W. Tetrahedron. Lett. 1987, 2567–2570; (b)
€
Wunsch, B.; Zott, M. Tetrahedron: Asymmetry 1993, 4,
2307–2310; (c) Xu, Y.-Ch.; Kohlman, D. T.; Liang, S. X.;
Erikkson, C. H. Org. Lett. 1999, 1, 1599–1602; (d) Guiso,
M.; Marra, C.; Cavarischia, C. Tetrahedron Lett. 2001, 42,
6531–6534.
8. Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S.
J. Chem. Soc., Perkin Trans. 1 1997, 3361–3370.
9. (a) Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S.
J. Chem. Soc., Perkin Trans. 1 1998, 3949–3956; (b) Giles,
R. G. F.; Rickards, R. W.; Senanayake, B. S. J. Chem.
Soc., Perkin Trans. 1 1996, 2241–2248.
10. Giles, R. G. F.; Green, I. R.; Knight, L. S.; Lee Son, V. R.;
Yorke, S. C. J. Chem. Soc., Perkin Trans. 1 1994, 865–874.
11. (a) Kaufman, T. S. Heterocycles 2001, 55, 323–330; (b)
Bianchi, D. A.; Kaufman, T. S. ARKIVOC 2003, X, 178–
188.
12. Kaufman, T. S.; Bernardi, C. R.; Cipulli, M.; Silveira,
C. C. Molecules 2000, 5, 493–494.
13. Fleming, I.; Woolias, M. J. Chem. Soc. (C) 1979, 829–837.
14. Schwarz, M.; Graminski, G. F.; Waters, R. M. J. Org.
Chem. 1986, 51, 260–263.
15. (a) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc.
1988, 110, 2248–2256; (b) Fuhry, M. A. M.; Holmes, A.
B.; Marshall, D. R. J. Chem. Soc., Perkin Trans. 1 1993,
2743–2746.
16. (a) Kritchevsky, D. J. Am. Chem. Soc. 1943, 65, 487; (b)
Crimmins, M.; Kirincich, S. J.; Wells, A. J.; Choy, A. L.
Synth. Commun. 1998, 2, 3675–3680; (c) Enders, D.;
In conclusion, it has been demonstrated that in the
TiCl4-assisted isomerization of 5-aryl-1,3-dioxolanes 11
derived from threo-diols 10, bulky substituents on C-2
and C-4 of the dioxolane ring produced exclusively the
1,3-cis 4-hydroxy-isochroman. The functional groups at
the end of the side chains of the starting dioxolane,
particularly those incorporated during the acetalization
step (R2), proved to have influence on the ability of the
substrates to undergo cyclization, probably through
complex formation with the catalyst. Application of the
above observations to the elaboration of tricyclic inter-
mediates toward the synthesis of natural stephaoxo-
canes is in progress.
€
Schafer, T.; Piva, O.; Zamponi, A. Tetrahedron 1994, 50,
3349–3362; (d) Seebach, D.; Corey, E. J. J. Org. Chem.
1975, 40, 231–237; (e) Priebe, W.; Grynkiewicz, G.
Tetrahedron Lett. 1991, 32, 7353–7356; (f) Freeman, F.;
Kim, D. S. H. L.; Rodriguez, E. J. Org. Chem. 1992, 57,
1722–1727.
17. Mp: 216–218 ꢂC; 244–246 ꢂC (lit.18b 241–243 ꢂC);
195–197 ꢂC (lit.18b 192–195 ꢂC) and 159–160 ꢂC, respec-
tively.
18. (a) Bestmann, H. J.; Koschatzky, K. H.; Stransky, W.;
Vostrowsky, O. Tetrahedron Lett. 1976, 353–356; (b)
Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A.
J. Am. Chem. Soc. 1985, 107, 217–226.
19. New compounds gave single spots on TLC employing
several solvent systems and were fully characterized.
Acknowledgements
The authors acknowledge the financial support provided
ꢀ
by SECyT-UNR, ANPCyT, Fundacion Antorchas and
CONICET. D.A.B. thanks CONICET for a fellowship.

D. A. Bianchi et al. / Tetrahedron Letters 45 (2004) 411–415
415
Inseparable mixtures of dioxolanes were characterized by
IR, 1H NMR, and 13C NMR spectroscopy. Assignment of
individual 13C resonances was supported by DEPT exper-
iments.
22. (a) 1H NMR (200 MHz, CDCl3): d 2.10–2.36 (m, 2H),
2.44–2.78 (m, 2H), 2.85 (bs, w1=2 ¼ 14 Hz, 1H), 3.79 (s,
3H), 4.70 (ddd, J ¼ 4:2, 5.0, 6.7 Hz, 1H), 5.11 (bd,
J ¼ 5:0 Hz, 1H), 6.74 (dd, J ¼ 3:1, 8.8 Hz, 1H), 7.10 (d,
J ¼ 3:1 Hz, 1H), and 7.42 (d, J ¼ 8:8 Hz, 1H); (b) 1H
NMR (200 MHz, CDCl3): d 1.77 (bs, 1H), 1.98–2.14 (m,
1H), 2.20–2.43 (m, 1H), 2.82–2.92 (m, 1H), 3.32 (ddd,
J ¼ 3:1, 12.1, 12.5 Hz, 1H), 4.80 (bt, 1H), and 7.02–7.35
(m, 4 H).
23. A coordinating group para to the MeO substituent
appears to favor good yields of products. The rearrange-
ment proceeds with similar stereoselectivity when acetals
having MeO or Cl groups8 instead of Br are employed;
however, rel-(2R,4S,5S)- and rel-(2S,4S,5S)-4-(30-meth-
oxyphenyl)-2,5-dimethyl-1,3-dioxolane gave less than
20% of rel-(1S,3S,4S)-1,3-dimethyl-4-hydroxy-6-meth-
oxy-isochroman.
24. Chemical shift changes have been observed in other
titanium complexes. See, for example: (a) Singh, D. K.;
Springer, J. B.; Goodson, P. A.; Corcoran, R. C. J. Org.
Chem. 1996, 61, 1436–1442; (b) Corcoran, R. C.; Ma, J.
J. Am. Chem. Soc. 1992, 114, 4536–4542.
25. Exposure of 11h in CDCl3 to 0.9 equiv of TiCl4 at )30 ꢂC
resulted in chemical shift changes (in ppm) of H-2 (0.25),
ortho-ArH (0.14), CH2SPh (0.09), and CH2CN (0.08).
20. The elaboration of 12k is representative. A freshly
prepared solution of TiCl4 (1.2 mmol) in CH2Cl2
(1.41 mL) was added dropwise to acetal 11k (303 mg,
0.5 mmol) in dry CH2Cl2 (10 mL), cooled to )45 ꢂC. After
stirring the mixture 4 h, the reaction was quenched with
saturated NH4Cl (5 mL), warmed to rt, and extracted with
EtOAc (3 · 30 mL). The organic extracts were washed with
brine (5 mL), dried (Na2SO4), and concentrated under
reduced pressure. Chromatography of the residue afforded
12k (183mg, 60%), as an oil; Rf ¼ 0.47 (hexanes–EtOAc,
7:3); IR (film): 3460, 2950, 2865, 1580, 1470, 1390, 1260,
1
1125, 1070, 930, 840, and 720 cmÀ1; H NMR (200 MHz,
CDCl3): d 1.04 (s, 9H), 1.60 (d, J ¼ 10:7 Hz, 1H), 1.75–
2.10 (m, 4H), 2.15–2.35 (m, 2H), 2.51 (d, J ¼ 6:5 Hz, 1H),
2.55 (d, J ¼ 6:1 Hz, 1H), 3.63 (bdd, J ¼ 3:5 and 8.7 Hz,
1H), 3.68 (dd, J ¼ 6:0 and 6.3 Hz, 2H), 3.75 (s, 3H), 4.54
(bd, J ¼ 10:7 Hz, 1H), 4.90 (dd, J ¼ 2:3and 6.6 Hz, 1H),
6.72 (d, J ¼ 8:8 Hz, 1H), 7.30–7.51 (m, 6H), 7.42 (d,
J ¼ 8:8 Hz, 1H), and 7.58–7.70 (m, 4H). 13C NMR
(50 MHz, CDCl3): d 13.45, 19.06, 26.70 (4C), 28.39,
31.01, 55.26, 63.71, 67.46, 73.80, 74.70, 111.78, 115.69,
119.34, 127.41 (4C), 129.19, 129.36 (2C), 131.30, 133.92
(2C), 135.39 (4C), 136.13, and 155.26. HRMS: Found Mþ
607.1750; C32H38BrNO4Si requires Mþ 607.1753.
Br
1
O
5H
H
21. (a) Melany, M. L.; Lock, G. A.; Thompson, D. W. J. Org.
Chem. 1985, 50, 3925–3927; (b) Miles, W. H.; Heinsohn, S.
K.; Brennan, M. K.; Swarr, D. T.; Eidam, P. M.; Gelato,
K. A. Synthesis 2002, 1, 1541–1545, and references cited
therein.
ortho
2
MeO
S
4
O
3
H
11h
CN