Enantioselective synthesis of the enyne a-ring synthon of the 1α- hydroxy vitamins D

Full text of DOI:10.1021/jo970957t

6692
J . Org. Chem. 1997, 62, 6692-6696
oxyphenol, rapidly equilibrates to the trans isomer (>20:1
En a n tioselective Syn th esis of th e En yn e
trans:cis).4 We surmised that a 2,4-dialkoxycyclohex-
anone (6) might also equilibrate to an isomer which was
almost exclusively trans. This thermodynamic prefer-
ence could then serve as the basis for the preparation of
one or more of the 1R,25-(OH)2D3 A-ring synthons
(Scheme 1). Alternatively, the trans-bromo compound 5
might be converted, by two consecutive SN2 reactions, to
trans-6.
A-Rin g Syn th on of th e 1r-Hyd r oxy
Vita m in s D
Kathlyn A. Parker* and Apostolos Dermatakis
Department of Chemistry, Brown University,
Providence, Rhode Island 02912
Received May 30, 1997
Sch em e 1. Gen er a l Ap p r oa ch
In tr od u ction
Vitamin D3 (1) and its metabolites and analogs exhibit
a multitude of biological activities. 1R,25-Dihydroxyvi-
tamin D3 (1R,25-(OH)2D3 or calcitriol, 2) is the active
hormone in bone homeostasis. Through synthesis, this
compound is now available as a prescription drug for the
management of hypocalcemia associated with renal
failure or with hypoparathyroidism. Other metabolites
have demonstrated roles in cell differentiation and im-
munomodulation, activities which suggest possible clini-
cal applications for these derivatives or for their analogs.1
Disp la cem en t/Ep im er iza tion a n d Dou ble
Disp la cem en t Stu d ies
For elaboration to intermediates 3 and/or 4b, the most
attractive candidate 6 was the bis-TBDMS ether cis-6a .
This compound was easily obtained in two steps (Scheme
2). First, bromo ketone trans-5 was treated with NaOH
under phase transfer conditions to give cis-2-hydroxy-4-
(tert-butyldimethylsiloxy)cyclohexanone (7).5 Then silyl-
ation afforded the desired equilibration substrate cis-6a .
Sch em e 2. Syn th esis of Ep im er iza tion
Su bstr a tesa
a
(a) NaOH, BuNHSO4, CH2Cl2/H2O, 85%; (b) TBDMSOTf, cat.
DMAP, Hunig’s base, -78 °C, CH2Cl2, 92%; (c) Ac2O, cat. DMAP,
Et3N, CH2Cl2, 0 °C to rt, 85%; (d) C6H5COCl, DMAP, Et3N, CH2Cl2,
0 °C to rt, 80%.
Two general strategies for the synthesis of vitamin D
metabolites have emerged. The first of these, initially
explored by Windaus and later extended by Barton, is
biomimetic and involves the photochemical opening of an
appropriately functionalized steroid precursor. The sec-
ond strategy, pioneered by Lythgoe, entails the coupling
of an appropriately fuctionalized A-ring precursor with
a trans-hydrindane. A number of A-ring equivalents
have been developed for this purpose, and the importance
of these targets has led to several clever syntheses of
intermediates 3 and 4.2,3
Epimerization of this bis-silyl ether with DBU was
sluggish. Hence, alternative substrates were examined.
Hydroxycyclohexanone 7 was derivatized as its acetate
(cis-6b) and as its benzoate (cis-6c). Unlike the bis-silyl
ether 6a , each of these compounds was easily epimerized
with DBU to an equilibrium mixture of stereoisomers.
The ratios of trans:cis-6b and -6c in several solvents are
reported in Table 1. However, in no case was total
conversion of cis-6b or -6c to its trans isomer observed,
and we considered the mixtures which were obtained to
be inappropriate for further development.
Gen er a l Ap p r oa ch
Ta ble 1. Equ ilibr iu m Ra tio of Tr a n s:Cis 6
The preparation of these functionalized trans-1,3-
cyclohexanediols is, in fact, not a trivial exercise. Our
own long-standing interest in this problem was rekindled
by the observation in our labs that a mixture of cis- and
tr a n s-2-br om o-4-(ter t-bu t yldim et h ylsiloxy)cycloh ex-
anone (5), readily obtained in three steps from 4-meth-
THF
DMF
CH3CN
1:1 DMF/formamidea
6b
6c
3
4
-
3
3
5
0.7
1
a
The solvent mixture was chosen for study because the
substrate 6 was insoluble in formamide.
A double displacement strategy might also exploit the
trans-stereochemistry of the 2-halo-4-alkoxycyclohex-
anones. In order to examine this possibility, we con-
verted hydroxycyclohexanone 7 to the corresponding
(1) Bouillon, R.; Okamura, W.; Norman, A. W. Endocrine Rev. 1995,
16, 200.
(2) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877.
(3) For more recent contributions, see: (a) Knolker, H.-J .; Ecker,
A.; Struwe, P.; Steinmeyer, A.; Muller, G.; Neef, G. Tetrahedron 1997,
53, 91. (b) Yokoyama, H.; Miyamoto, K.; Hirai, Y.; Takahashi, T. Synlett
1997, 187. (c) Posner, G. H.; Dai, H.; Bull, D. S.; Lee, J .-K.; Eydoux,
F.; Ishihara, U.; Welsh, W.; Pryor, N.; Petr, S., J r. J . Org. Chem. 1996,
61, 671. (d) Achmatowicz, B.; J ankowski, P.; Wicha, J . Tetrahedron
Lett. 1996, 37, 5589.
(4) Parker, K. A.; Kim, H.-J . J . Org. Chem. 1992, 57, 752.
(5) Alcohol
7 has been isolated from a cis/trans mixture; see
Majewski, M; Irvine, N. M.; McKinnon, J . Tetrahedron Asymmetry
1995, 6, 1837.
S0022-3263(97)00957-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 19, 1997 6693
Sch em e 4. In tr od u ction of th e C-1r Hyd r oxyl
mesylate and attempted SN2 displacement with sodium
hydroxide under the phase transfer conditions used above
(5 f 7). A mixture of R-hydroxy ketones 7 and 9 in a
ratio of 1:1.5 was obtained (Scheme 3). A second attempt
to effect efficient inversion of the center R to the ketone
in substrate 7 by a Mitsunobu procedure resulted in
recovery of the starting material.
Gr ou p a
Sch em e 3. Dou ble Disp la cem en t Exp er im en ta
a
(a) Ph3PCH3Br, tert-BuOK, THF, 93%; (b) SeO2, pyridine
N-oxide, dioxane, reflux, 60%; (c) TBDMSOTf, DMAP, (i-Pr2)NEt,
-78 °C, 95%; (d) K2CO3, MeOH, 94%.
a
(a) MsCl, cat. DMAP, Et3N, CH2Cl2, 0 °C, 75%; (b) NaOH,
Sch em e 5. Tr a p p in g of Un sta ble En ola te a n d
Acetylid e Cou p lin ga
Bu4NHSO4, CH2Cl2/H2O (1/1), 0 °C to rt, 65%.
Em p loyin g a cis-2,4-Dia lk oxycycloh exa n on e
Recognizing the difficulties associated with the clean
conversion of substrate 6 or 7 to the desired 9, we
resolved to take advantage of the stereospecific biases
inherent in the cis-2,4-dialkoxycyclohexanones. We an-
ticipated that these compounds (e.g. 6b) would undergo
Wittig reactions without epimerization and that the
resulting exocyclic olefins might be subject to axial
hydroxylation at the unsubstituted allylic position (Scheme
4). In this approach, the trans-diol arrangement would
be established by an indirect but nonetheless stereose-
lective route, and the previously positioned allylic alkoxy
group would remain to provide additional functionality
required for the target.
In fact, Wittig olefination of acetoxy ketone 6b gave
olefin 10 which underwent oxidation with SeO2 at the
unsubstituted allylic position6 to afford alcohol 11 as a
single stereoisomer. In such SeO2 oxidations, the new
stereocenter is derived from the transition state for 2,3-
sigmatropic rearrangement of the intermediate allylic
selenous acid.7 In our system and in closely related
systems,8 there is a useful preference for the transition
state which leads to introduction of an axial hydroxyl
group. Similar trends for axial placement of new func-
tionality have been noted for Claisen and oxy-Cope
rearrangements as well as for other (2,3)-sigmatropic
rearrangements.9
a
(a) Dess-Martin, CH2Cl2, 94%; (b) L-Selectride, PhNTf2, THF,
-78 °C to rt, 42%; (c) (Bu3Sn)CCTMS, Pd(PPh3)4, LiCl, THF,
reflux, 90%; (d) K2CO3, MeOH, 80%.
Wittig conditions with ethyl dimethylphosphonoacetate
(both standard10 and mild conditions11) led to decomposi-
tion of the enone.12 Alternative two-carbon reagents (the
lithium enolate of ethyl (trimethylsilyl)acetate, this eno-
late with cerium chloride additive, and lithium ethoxy-
acetylide, with or without cerium chloride additive)
afforded the enone elimination product in moderate
yields.
In light of these experiments, we turned to the conver-
sion of enone 14 to enyne 4b. This transformation might
be the result of a conjugate reduction of the enone system,
trapping of the enolate, and coupling of the resulting enol
derivative with an acetylene. While a route based on this
strategy appears troublesome at first sight, addition of
With alcohol 11 in hand, we focussed on the transfor-
mations required to convert it to one or both of the A-ring
precursors (3 and/or 4b). Enone 14 appeared to be a key
intermediate in either route and alcohol 13 presented
itself as the obvious precursor. Therefore, alcohol 11 was
silylated to give the bis-TBDMS ether 12 which was
deacylated to give the allylic alcohol 13. Finally, Dess-
Martin oxidation gave ketone 14 (Scheme 5).
13
L-Selectride to a THF solution of enone 14 and PhNTf2
led to in situ trapping of the unstable â-alkoxy enolate
and isolation of the vinyl triflate 15 in moderate yield.
Stille coupling of triflate 15 with (trimethylsilyl)(tribu-
tylstannyl)acetylene (TMSCCSnBu3)14 afforded the fully
protected enyne A-ring 16 in 90% yield.
Selective desilylation of the acetylene with K2CO3 in
methanol gave the desired enyne 4b. The spectroscopic
data of this compound were identical with those reported
in the literature, and it was further characterized as the
known fully desilylated 1,3-diol.
We first attempted to exploit this intermediate by
introducing the unsaturated two-carbon side chain of
intermediate 3. When applied to ketone 14, Horner-
(6) Paulmier, C. Selenium Reagents and Intermediates in Organic
Synthesis; Pergamon: New York, 1986; p 132.
(7) (a) Sharpless, K. B.; Lauer, R. F. J . Am. Chem. Soc. 1973, 95,
7917. (b) Sharpless, K. B.; Lauer, R. F. J . Am. Chem. Soc. 1972, 94,
7154.
(8) (a) Andrews, D. R.; Barton, D. H. R.; Cheng, K. P.; Finet, J .-P.;
Hesse, R. H.; J ohnson, G.; Pechet, M. M. J . Org. Chem. 1986, 51, 1637.
(b) Kiegiel, J .; Wovkulich, P. M.; Uskokovich, M. R. Tetrahedron Lett.
1991, 32, 6057.
(9) (a) Ireland, R. E.; Varney, M. D. J . Org. Chem. 1983, 48, 1829.
(b) Paquette, L. A.; Maynard, G. D.; J . Am. Chem. Soc. 1992, 114, 5018.
(c) Hoffmann, R. W.; Gerlach, R.; Goldmann, S. Tetrahedron Lett. 1978,
29, 2599. (d) Mander, L. N.; Turner, J . V. Aust. J . Chem. 1980, 33,
1559. (e) van Tamelen, E. E.; Taylor, E. G. J . Am. Chem. Soc. 1980,
102, 1202. (f) Mori, K.; Mori, H. Tetrahedron Lett. 1985, 41, 5487.
(10) (a) Wadsworth, W. S.; Emmons, W. D. J . Am. Chem. Soc. 1961,
83, 1733. (b) Boutagy, J .; Thomas, R. Chem. Rev. 1974, 74, 8.
(11) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(12) The poor behavior of this substrate in “alkylidenation” had
previously been alluded to: see Chen, C.; Crich, D. Tetrahedron 1993,
49, 7943.
(13) Crisp, G. T.; Scott, W. J . Synthesis 1985, 335.
(14) Logue, M. W.; Teng, K. J . Org. Chem. 1982, 47, 2549.

6694 J . Org. Chem., Vol. 62, No. 19, 1997
Notes
solution was extracted with CH2Cl2 (4 × 15 mL). The
combined organic solution was dried over Na2SO4 and con-
centrated to an oily residue. Silica gel chromatography with
a 15-40% EtOAc/hexanes gradient afforded 675 mg (85%) of
Sch em e 6. P r ep a r a tion of Ch ir a l Sta r tin g
Ma ter ia la
1
a colorless oil: IR (neat) 3478, 1725 cm-1. 250 MHz H NMR
(CDCl3) δ 0.22 (s, 6 H), 0.89 (s, 9 H), 1.60-1.86 (m, 3 H), 2.15
(m, 1 H), 2.38 (ddd, J ) 13.2, 6.3, 1.2 Hz, 1 H), 2.55 (m, 2 H),
4.13 (m, 2 H). 100.6 MHz 13C NMR (CDCl3) δ -4.8, 18.0, 25.7,
34.8, 35.3, 44.2, 67.3, 72.2, 210.1.
HRMS (CI) for C12H24O3Si (M+ + H): calcd, 245.1573; found,
245.1575.
a
(-)-cis-2-H yd r oxy-4-(ter t-b u t yld im et h ylsiloxy)cyclo-
h exa n on e ((-)-7). A 1.06 g sample of chiral trans-5 gave 650
mg (77% yield) of material with 80% ee according to the
(a) (R,R)-18, BuLi, THF, -95 °C, TMSCl, 93%; (b) 1.2 equiv
of NBS, 0.1 equiv of NaOAc, THF/H2O (1:1), 70%.
Mosher method. [R]24 ) -5.7° (CHCl3, c ) 0.47).
D
Ch ir a l Syn th esis
Keton e cis-6b. To a solution of 590 mg (0.24 mmol) of 7,
1.62 mL (1.23 g, 1.21 mmol) of Et3N, and a catalytic amount
of DMAP in 30 mL of CH2Cl2 was added 0.46 mL of Ac2O (495
mg, 0.49 mmol) at 0 °C. The reaction mixture was allowed to
warm to rt over 30 min. After 2 h, it was poured into H2O,
and the resulting mixture was extracted with CH2Cl2 (4 × 10
mL). The combined organic layer was extracted with several
portions of 1% aqueous citric acid (until the aqueous phase
showed an acidic pH) and then with aqueous saturated
NaHCO3 (2 × 5 mL). The combined organic solution was dried
over Na2SO4 and concentrated to an oily residue. Silica gel
chromatography with a 15-40% EtOAc/hexanes gradient gave
Synthetically useful chiral enyne would be available
if we could prepare chiral bromo ketone 5. Therefore,
with the intention of brominating the TMS ether 19, we
examined the enantioselective enolization of 4-(tert-
butyldimethylsiloxy)cyclohexanone (17).
Of the two methods we examined,15 the better asym-
metric induction was achieved when the lithium amide
of chiral base (R,R)-18 was employed for deprotonation
of ketone 17.16 The resulting enolate was trapped as the
TMS ether (-)-19 (Scheme 6). Treatment with NBS then
gave the desired halo ketone (-)-5, which was shown to
be of 80% ee.17
With bromoketone (-)-5, we followed the same reaction
sequence that was employed in the racemic series.18 The
optical purity of (-)-enyne 4b was verified as 80% by
integration of the 1H NMR spectrum of its bis-(S)-Mosher
ester derivative. Thus the stereospecific, asymmetric
synthesis of the enyne A-ring synthon of 1R-hydroxyvi-
tamin D3 from trans-2-bromo-4-(tert-butyldimethylsiloxy)-
cyclohexanone was completed.
590 mg (85%) of a colorless oil: IR (neat) 1754, 1733 cm-1
.
1
250 MHz H NMR δ 0.11 (s, 6 H), 0.90 (s, 9 H), 1.65-1.98 (m,
2 H), 2.13 (broad s, 4 H), 2.42 (m, 3 H), 4.19 (m, 1 H), 5.22
(dd, J ) 13.2, 6.4 Hz, 1 H). 100.6 MHz 13C NMR δ -4.8, -4.7,
18.0, 20.6, 25.7, 35.0, 35.8, 40.9, 67.7, 72.9, 169.9, 203.3.
HRMS (CI) for C14H26O4Si for (M+ + H): calcd, 287.1671;
found, 287.1646.
(-)-Keton e cis-6b. A 621 mg sample of chiral cis-7 gave
641 mg (88% yield) of material with [R]24 ) -33.2° (CHCl3, c
D
) 0.37).
Olefin 10. To a slurry of 360 mg (0.32 mmol) of tert-BuOK
and 1.08 g (0.32 mmol) of Ph3PCH3Br in 15 mL of THF under
Ar at 0 °C was added 430 mg (0.12 mmol) of ketone cis-6b in
THF (5 mL). After 5 min at 0 °C and 3 h at rt, the reaction
mixture was poured in H2O, and the resulting mixture was
extracted with Et2O (5 × 10 mL). The combined organic
solution was dried over Na2SO4 and concentrated to an oily
residue. Silica gel chromatography with 5% EtOAc/hexanes
afforded 568 mg (93%) of a colorless oil: IR (neat) 3100, 1743,
1658 cm-1. 400 MHz 1H NMR (CDCl3) δ 0.08 (s , 6 H), 0.89
(s, 9 H), 1.37 (m, 1 H), 1.49 (dt, J ) 11.5, 10.5 Hz, 1 H), 1.91
(m, 1 H), 2.03 (m, 1 H), 2.12 (s, 3 H), 2.19 (m, 1 H), 2.39 (ddd,
J ) 13.9, 7.7, 3.7 Hz, 1 H), 3.83 (m, 1 H), 4.78 (t, J ) 1.6 Hz,
2H), 5.18 (ddd, J ) 11.6, 4.6, 2.3 Hz, 1 H). 100.6 MHz 13C
NMR (CDCl3) δ -4.7, -4.6, 18.1, 21.1, 25.8, 30.0, 36.3, 42.3,
68.9, 71.2, 105.9, 145.0, 170.1. HRMS (CI) for C15H28O3Si (M+
+ H): calcd, 285.1878; found, 285.1899.
Exp er im en ta l Section
Gen er a l. High resolution mass spectra were obtained
under EI, CI, or FAB conditions. Thin layer chromatography
(TLC) was performed on precoated silica gel 60 F-254 glass-
supported plates 0.25 mm thick. Column chromatography was
performed with silica gel 60 (230-400 mesh). Ethyl ether,
THF, and benzene were distilled from sodium-benzophenone
ketyl. DMSO, DMF, pyridine, methylene chloride, methanol,
and toluene were distilled from calcium hydride. All reactions
were perfomed under argon unless otherwise stated.
cis-2-H yd r oxy-4-(ter t-b u t yld im et h ylsiloxy)cycloh ex-
a n on e (7). To 110 mg (0.3 mmol) of Bu4NHSO4 and 260 mg
(6.6 mmol) of NaOH in a mixture of 20 mL of CH2Cl2 and 20
mL of H2O at 0 °C was added 1.0 g (3.3 mmol) of trans-2-
bromo-4-(tert-butyldimethylsiloxy)cyclohexanone. The reac-
tion mixture was allowed to warm to rt over 30 min. After 4
h, the reaction mixture was partitioned, and the aqueous
(+)-Olefin 10. From 641 mg of chiral cis-6b was recovered
521 mg (82% yield) of olefin with [R]24 ) +8.0° (CHCl3, c )
D
0.80), 84% ee.18
Allylic Alcoh ol 11. To a solution of 524 mg (1.84 mmol)
of 10 and 700 mg (7.36 mmol) of pyridine N-oxide in 15 mL of
dioxane was added 247 mg (2.21 mmol) of SeO2. The reaction
mixture was stirred at 90 °C under argon for 2 h, cooled, and
poured into H2O. The aqueous layer was extracted with 5 ×
10 mL of EtOAc, and the combined organic solution was
washed with saturated aqueous NaHCO3 (1 × 5 mL), dried
over Na2SO4, and concentrated to a dark yellow-brown residue.
Silica gel chromatography with a 15-40% EtOAc/hexanes
gradient afforded 332 mg (60%) of a light yellow oil: IR (CHCl3)
(15) The asymmetrization of ketone 17 was initially attempted by
means of Yamamoto's TRIBAL-mediated opening of its (2R,4R)-2,4-
pentanediol acetal. The resulting enol ether was converted to R-hydroxy
ketone 7 (by way of the bromo ketone trans-5), the Mosher ester of
which indicated an optical purity that ranged from 38 to 44% ee. See
(a) Yamamoto, H.; Naruse, Y. Tetrahedron Lett. 1986, 27, 1363. (b)
Naruse, Y.; Yamamoto, H. Tetrahedron 1988, 44, 6029.
(16) Subsequent to the completion of our work, Majewski described
the enantioselective deprotonation of ketone 17 with a series of chiral
bases, obtaining the maximum ee of 90% with the chiral lithium amide
18 and LiCl as an additive; see ref 4 and also Majewski, M.; McKinnon,
J . Can. J . Chem. 1994, 72, 1699.
1
3446, 1734, 1653 cm-1. 250 MHz H NMR (CDCl3) δ 0.06 (s,
(17) Haloketone (-)-5 was converted to the R-hydroxy ketone (-)-7
by the procedure described above. Integration of the NMR spectrum
of the Mosher ester of (-)-7 indicated the enantiomeric excess.
(18) The allylic alcohol derived from the deacylation of (+)-10 as
well as compound (+)-13 were converted to their Mosher esters.
Integration of the NMR spectra of these derivatives showed enantio-
meric excesses of 82 ( 2%.
3 H), 0.09 (s, 3 H), 0.89 (s, 9 H), 1.62 (m, 3 H), 2.08 (m, 1 H),
2.13 (s, 3 H), 2.18 (m, 1H), 4.29 (m, 1 H), 4.56 (t, J ) 3.7 Hz,
1 H), 4.94 (t, J ) 1.5 Hz, 1 H), 5.02 (s, 1 H), 5.61 (m, 1 H).
100.6 MHz MHz 13C NMR (CDCl3) -4.8, -4.7, 18.0, 21.1, 25.8,
41.7, 42.8, 65.4, 69.8, 71.5, 108.6, 147.3, 170.1. HRMS (CI) for
C
15H28O4Si (M+-OH): calcd, 283.1722; found, 283.1723.

Notes
J . Org. Chem., Vol. 62, No. 19, 1997 6695
(+)-Allylic Alcoh ol 11. A 512 mg sample of chiral 10 gave
H), 2.58 (dd, J ) 17.5, 4.5 Hz, 1 H), 4.21 (m, 1 H), 4.32 (broad
t, J ) 3.9 Hz, 1 H). 100.6 MHz 13C NMR (CDCl3) δ -5.1, -4.9,
-4.8, -4.4, 13.8, 17.9, 18.0, 25.5, 25.6, 25.7, 25.7, 25.8, 37.6,
40.5, 64.3, 68.7, (113.6, 116.8, 119.9, 123.1; q, J ) 319.6 Hz),
128.3, 142.4. HRMS (CI) for C20H39F3O5SSi2 (M+ + H): calcd,
505.2087; found, 505.2079.
306 mg (57% yield) of material with [R]24 ) +32.4° (CHCl3, c
D
) 0.51).
Bis(silyloxy) Olefin 12. To a solution of 384 mg (1.28
mmol) of alcohol 11, 0.90 mL (660 mg, 5.12 mmol) of diiso-
propylethylamine, and a catalytic amount of DMAP in 15 mL
of CH2Cl2 at -78 °C, was added 500 µL (575 mg, 2.17 mmol)
of TBDMSOTf. After 40 min the reaction mixture was poured
into H2O and was extracted with CHCl3 (5 × 10 mL). The
combined organic solution was washed with 1% aqueous citric
acid and aqueous saturated NaHCO3, dried over Na2SO4, and
concentrated to an oily residue. Silica gel chromatography
with 5% EtOAc/hexanes yielded 504 mg (95%) of a colorless
(-)-Vin yl Tr ifla te 15. A 212 mg sample of chiral 14 gave
118 mg (41% yield) of material with [R]24 ) -22.9° (CHCl3, c
D
) 1.21).
Com p ou n d 16. To a solution of 37 mg (0.07 mmol) of vinyl
triflate 15, 16 mg (0.01 mmol) of Pd(PPh3)4, and 13 mg (0.29
mmol) of LiCl in 7 mL of THF was added 34 mg of (trimeth-
ylsilyl)(tributylstannyl)acetylene. The reaction mixture was
stirred at reflux for 11 h, cooled, and diluted with hexanes
(20 mL). The organic layer was washed with brine, dried over
Na2SO4, and concentrated to a dark yellow-brown residue.
Preparative TLC (silica gel, 1000 µm) with 15% EtOAc/hexanes
afforded 30 mg (90%) of a light yellow to colorless oil: IR
(CH2Cl2) 3090, 2140, 1260 cm-1. 250 MHz 1H NMR (CDCl3) δ
0.06 (s, 6 H), 0.09 (s, 6 H), 0.19 (s, 9 H), 0.88 (s, 18 H), 1.65
(ddd, J ) 14.6, 10.4, 4.2 Hz, 1 H), 1.83 (m, 1 H), 1.92 (broad s,
3 H), 2.07 (m, 1 H), 2.40 (dd, J ) 16.8, 4.4 Hz, 1 H), 4.08 (m,
1 H), 4.17 (t, J ) 3.8 Hz, 1 H). 100.6 MHz 13C NMR (CDCl3)
δ -4.8, -4.7, -4.6, -4.3, 0.1, 18.0, 18.1, 19.1, 25.8, 25.8, 25.9,
39.4, 41.2, 64.1, 69.8, 96.5, 105.4, 115.1, 143.1. HRMS (CI)
for C24H48O2Si3 (M+ + H): calcd, 453.3040; found, 453.3040.
oil: IR (neat) 3091, 1745, 1661 cm-1
.
250 MHz 1H NMR
(CDCl3) δ 0.04 (s, 3 H), 0.08 (s, 9 H), 0.86 (s, 18 H), 1.53 (m,
2H), 1.97 (m, 1 H), 2.09 (s, 3 H), 2.19 (m, 1 H), 4.28 (m, 1 H),
4.49 (m, 1 H), 4.88 (t, J ) 1.6 Hz, 1 H), 4.91 (s, 1 H), 5.57 (dd,
J ) 10.6, 4.9 Hz, 1 H). 100.6 MHz 13C NMR (CDCl3) δ -5.3,
-4.9, -4.8, -4.8, 18.0, 18.1, 21.1, 25.7, 25.8, 41.8, 44.5, 65.6,
69.9, 72.0, 107.1, 147.9, 169.8. HRMS (EI) for C21H42O4Si2 (M+
- C(CH3)3): calcd, 357.1917; found, 357.1908.
(+)-Bis(silyloxy) Olefin 12. A 295 mg sample of chiral
11 gave 373 mg (91% yield) of material with [R]24 ) +37.5°
D
(CHCl3, c ) 0.69).
Alcoh ol 13. To a solution of 271 mg (0.65 mmol) of olefin
12 in 15 mL of MeOH was added 90 mg (1.31 mmol) of K2CO3.
After 2 h the reaction mixture was poured into H2O, and the
resulting reaction mixture was extracted with EtOAc (6 × 10
mL). The organic solution was dried over Na2SO4 and
concentrated to an oily residue. Silica gel chromatography
with 5% EtOAc/hexanes afforded 230 mg (94%) of a white
(-)-Com p ou n d 16. A 70 mg-sample of chiral 15 gave 55
mg (87% yield) of material with [R]24 ) -48.9 (CHCl3, c )
D
0.64).
3,5-Bis(ter t-bu tyld im eth ylsiloxy)-1-eth yn yl-2-m eth yl-
cycloh exen e (4b). To a solution of 52 mg (0.11 mmol) of 16
in 3 mL of MeOH was added 33 mg (0.24 mmol) of K2CO3.
After 6 h the solvent was evaporated in vacuo at rt. The
addition of hexanes (10 mL) provided a slurry from which
solids were removed by filtration. The hexane solution was
concentrated to an oil which was subjected to preparative TLC
(silica gel, 1000 microns) with 15% EtOAc/hexanes to afford
34 mg (80%) of a light yellow oil: IR (CHCl3) 3312, 2145 (w),
solid: mp 69-71 °C. IR (CHCl3) 3480, 3015, 1256, 1218 cm-1
.
1
250 MHz H NMR (CDCl3) δ 0.08 (s, 6 H), 0.12 (s, 6 H), 0.92
(s, 18 H), 1.64 (m, 1 H), 1.81 (distorted dt, J ) 13.7, 3.3 Hz, 1
H), 1.98 (m, 2 H), 3.72 (d, J ) 8.7 Hz, 1 H), 4.36 (broad m, 1
H), 4.42 (m, 1 H), 4.80 (dd, J ) 9.7, 4.2 Hz, 1 H), 4.98 (s, 1 H),
5.04 (t, J ) 1.6 Hz, 1 H). 100.6 MHz 13C NMR (CDCl3) -5.2,
-5.1, -5.0, -4.9, 17.9, 18.2, 25.7, 25.8, 40.9, 44.6, 67.3, 69.4,
72.9, 107.0, 152.2. HRMS (CI) for C19H40O3Si2 (M+ - H2O):
calcd, 355.2478; found, 355.2489.
1
1472 cm-1. 250 MHz H NMR (CDCl3) δ 0.08 (s, 6 H), 0.11 (s,
6 H), 0.87 (s, 9H), 0.93 (s, 9 H), 1.68 (ddd, J ) 14.4, 10.0, 4.4
Hz, 1 H), 1.83 (m, 1 H), 1.93 (broad s, 3 H), 2.08 (dd, J ) 16.9,
8.2 Hz, 1 H), 2.43 (dd, J ) 17.1, 4.2 Hz, 1 H), 3.06 (s, 1 H),
4.10 (m, 1 H), 4.21 (broad t, J ) 3.9 Hz, 1 H). 100.6 MHz 13C
NMR (CDCl3) δ -4.8, -4.7, -4.7, -4.3, 18.0, 18.1, 18.9, 25.8,
25.8, 25.9, 39.4, 41.1, 64.1, 69.7, 79.5, 83.8, 114.1, 143.5. HRMS
(CI) for C21H40O2Si2 (M+ + H): calcd, 381.2645; found 381.2646.
(+)-Alcoh ol 13. A 373 mg sample of chiral 12 gave 320
mg (95% yield) of material with [R]24 ) +33.9° (CHCl3, c )
D
0.51), 82% ee.18
En on e 14. To a solution of 309 mg (0.83 mmol) of alcohol
13 in 15 mL of CH2Cl2 was added 936 mg (2.21 mmol) of Dess-
Martin reagent. After 1-1.5 h the reaction was quenched with
saturated aqueous NaHCO3. The aqueous phase was washed
with CH2Cl2 (3 × 15 mL), and the combined organic solution
was dried over Na2SO4 and concentrated to a milky residue.
Silica gel chromatography with a 5-15% EtOAc/hexanes
gradient gave 286 mg (94%) of product: IR (neat) 3018, 1697,
(-)-(3S,5R)-Bis(ter t-bu tyld im eth ylsiloxy)-1-eth yn yl-2-
m eth ylcycloh exen e (4b). A 30 mg sample of chiral 16 gave
19 mg (74% yield) of material with [R]24 ) -52.4o (CHCl3, c
D
) 0.36).
Silyl En ol Eth er (-)-19. To a solution of 1.54 g (6.83
mmol, 1.61 mL) of chiral amine 18 in 180 mL of anhydrous
THF at -95 °C was added 4.30 mL (6.83 mmol) of a 1.6 M
solution of BuLi in hexanes. The solution was allowed to warm
slowly to rt and then recooled to -95 °C. To this cold solution
was added 3.40 mL (2.91 g, 2.67 mmol) of TMSCl (previously
neutralized with Et3N). After 2-3 min, 1.30 mL (1.20 g, 5.26
mmol) of ketone 17 was added dropwise over a period of 40
min. After an additional 30-40 min, 15 mL of Et3N was
added, and the reaction mixture was poured into aqueous
saturated NaHCO3. The resulting mixture was extracted with
hexanes (5 × 60 mL), and the combined organic solution was
dried over Na2SO4 and concentrated to a light yellow liquid.
Silica gel chromatography with 5% EtOAc/hexanes and Kugel-
rohr distillation (160-164 °C, 0.8 mmHg) afforded 1.47 g (93%)
1
1624 cm-1. 250 MHz H NMR (CDCl3) δ 0.07 (s, 3 H), 0.09 (s,
6 H), 0.12 (s, 3 H), 0.88 (s, 9 H), 0.92 (s, 9 H), 1.92 (ddd, J )
12.5, 9.4, 2.4 Hz, 1H), 2.14 (m, 1 H), 2.55 (m, 2 H), 4.41 (broad
m, 1 H), 4.83 (m, 1 H), 5.42 (t, J ) 1.9 Hz, 1 H), 5.84 (t, J )
1.9 Hz, 1 H). 100.6 MHz 13C NMR (CDCl3) δ -5.0, -4.9, -4.9,
-4.8, 18.1, 25.7, 25.8, 42.0, 49.0, 65.8, 68.9, 118.7, 149.8, 200.6.
HRMS (EI) for C19H38O3Si2 (M+ - C(CH3)3): calcd, 313.1647;
found, 313.1676.
(-)-En on e 14. A 372 mg sample of chiral 13 gave 269 mg
(90% yield) of material with [R]24 ) -6.2° (CHCl3, c ) 0.66).
D
Vin yl Tr ifla te 15. A solution of 143 mg (0.38 mmol) of
enone 14 and 120 mg of Tf2NPh (0.43 mmol) in 12 mL of THF
was stirred at -78 °C during the addition of 425 µL (0.43
mmol) of a 1 M solution of L-Selectride in THF. The reaction
mixture was allowed to warm to rt overnight and then
quenched with brine. The resulting mixture was extracted
with CHCl3 (6 × 10 mL) and the combined organic solution
was concentrated. Preparative TLC (silica gel, 1000 µm) of
the residue with 15% EtOAc/hexanes afforded 80 mg (42%) of
a colorless oil: IR (CH2Cl2) 3054, 1700 (w), 1414 cm-1. 250
MHz 1H (CDCl3) δ 0.07 (s, 6 H), 0.11 (s, 6 H), 0.85 (s, 9 H),
0.92 (s, 9 H), 1.79 (broad s, 5 H), 2.32 (dd, J ) 15.4, 6.0 Hz, 1
of a colorless liquid: IR (neat) 3054, 3020, 1670 cm-1
. 250
1
MHz H NMR (CDCl3) δ 0.06 (s, 6 H), 0.18 (s, 9 H), 0.89 (s, 9
H), 1.74 (m, 2 H), 2.08 (m, 3H), 2.19 (m, 1H), 3.89 (m, 1 H),
4.71 (ddd, J ) 4.7, 3.2, 1.7 Hz, 1 H). 100.6 MHz 13C NMR
(CDCl3) δ -4.7, -4.6, 18.1, 25.9, 28.1, 31.7, 33.3, 67.3, 101.3,
149.7. HRMS (CI) for C15H32O2Si2 (M+ + H): calcd, 301.2019;
found 301.2010. [R]24 ) -28.8° (CHCl3, c ) 0.25).
D
(-)-5-tr a n s fr om (-)-19. To a solution of 1.05 g (5.89
mmol) of NBS and 41 mg (0.49 mmol) of NaOAc in 60 mL of
THF and H2O (50:50) at 0 °C was added dropwise 1.48 g (4.92

6696 J . Org. Chem., Vol. 62, No. 19, 1997
Notes
mmol) of enol ether (-)-19. The reaction mixture was allowed
slowly to warm to rt over 30 min. After stirring for 2-3 h at
rt, the reaction mixture was quenched with H2O, and the
resulting mixture was extracted with hexanes (5 × 15 mL).
The combined organic solution was dried over Na2SO4 and
concentrated. The residue was chromatographed on a silica
gel column with 5% EtOAc/hexanes to give 1.06 g (70%) of 80%
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of ketones cis-6a , cis-6c, 8, and
17, the deprotection of silyl ethers 16 and 4b to trans-5-
ethynyl-4-methylcyclohexene-1,3-diol; 1H NMR, 13C NMR, and
IR spectra for compounds 4b, 6-17 and (-)-19; 1H spectra for
the bis-(S)-Mosher ester of (-)-trans-5-ethynyl-4-methylcyclo-
hexene-1,3-diol, the (S)-Mosher ester derivatives of (-)-7 and
(+)-13, and the mixtures 6b (cis and trans), 6c (cis and trans),
and 7 and 9 (55 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
ee product (see text). [R]24 ) -21.8o (CHCl3, c ) 0.60).
D
Ack n ow led gm en t. Financial support from the Na-
tional Science Foundation (Grant No. CHE-95-21055)
and from Brown University is gratefully acknowledged.
J O970957T