Synthesis of (-)-calicoferol B

Article abstract of DOI:10.1021/jo020103v

The first total synthesis of (-)-calicoferol B (III) is described. The cyclozirconation product I, prepared in enantiomerically pure form, was converted into the CD ring chiron II. This was coupled with the aromatic A-ring, and then the side chain was constructed with control of relative and absolute configuration to complete the total synthesis of III. The first total synthesis of (-)-calicoferol B (1) is described. The cyclozirconation product 8, prepared in enantiomerically pure form, was converted into the CD ring chiron 6. This was coupled with the aromatic A-ring, and then the side chain was constructed with control of relative and absolute configuration to complete the total synthesis of 1.

Full text of DOI:10.1021/jo020103v

Syn th esis of (-)-Ca licofer ol B
Douglass F. Taber,* Qin J iang, Bei Chen, Wei Zhang, and Carlton L. Campbell
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
taberdf@udel.edu
Received February 12, 2002
The first total synthesis of (-)-calicoferol B (III) is described. The cyclozirconation product I,
prepared in enantiomerically pure form, was converted into the CD ring chiron II. This was coupled
with the aromatic A-ring, and then the side chain was constructed with control of relative and
absolute configuration to complete the total synthesis of III. The first total synthesis of (-)-calicoferol
B (1) is described. The cyclozirconation product 8, prepared in enantiomerically pure form, was
converted into the CD ring chiron 6. This was coupled with the aromatic A-ring, and then the side
chain was constructed with control of relative and absolute configuration to complete the total
synthesis of 1.
In tr od u ction
vitamin D3 assays. Astrogorgiadiol (2) did, however, show
remarkable activity in one of them, clearly downregu-
lating the production of osteopontin at 30 nM concentra-
tion in cell culture.8 In contrast, 1R,25-dihydroxyvitamin
D3 (3) and its other known derivatives dramatically
upregulate osteopontin production.5
Osteopontin (OPN) is one of the major noncollagenous
bone matrix proteins produced by osteoblasts and osteo-
clasts.1 Substrate-bound OPN promotes attachment of
osteoclasts,2 whereas soluble OPN can alter calcium
levels in osteoclasts.3 These observations suggest that
OPN may play a key role both in cell attachment and in
controlling subsequent bone cell functions such as re-
sorption. Indeed, it has been observed that OPN knockout
mice are resistant to ovariectomy-induced bone resorption
compared with wild-type mice.4 This suggests that in-
duced downregulation of OPN may be an effective
strategy for the clinical treatment of osteoporosis.
We had been intrigued by the structural similarity
between calicoferol B (1), astrogorgiadiol (2), and 1R,25-
dihydroxyvitamin D3 (“calcitriol”, 3), the active hormonal
form of vitamin D.5 We recently completed the total
synthesis of astrogorgiadiol (2),6 a secosterol isolated from
a J apanese marine sponge of the genus Astrogorgia,7 and
submitted the synthetic material for screening. Astrogor-
giadiol (2) was inactive in most of the 1R,25-dihydroxy-
(1) (a) Butler, W. T.; Ridall, A. L.; McKee, M. D. Principles of Bone
Biology; Bilezikian, J . P., Raisz, L. G., Rodan, G. A., Eds.; 1997; pp
161-181. (b) Denhardt, D. T.; Noda, M. J . Cell Biochem. 1998, 31, 92.
(2) (a) Ross, F. P.; Chappel, J .; Alvarez, J . I.; Sander, D.; Butler, W.
T.; Farach-Carson, M. C.; Mintz, K. A.; Robey, P. G.; Teitelbaum, S.
L.; Cheresh, D. A. J . Biol. Chem. 1993, 268, 9901. (b) van Dijk, S.;
D′Errico, J .; Somerman, M. J .; Farach-Carson, M. C.; Butler, W. T. J .
Bone Miner. Res. 1993, 8, 1499.
(3) (a) Miyauchi, A.; Alvarez, J .; Greengield, E. M.; Teti, A.; Grano,
M.; Colucci, S.; Zambonin-Zallone, A.; Ross, F. P.; Teitelbaum, S. M.;
Cheresh, D.; et al. J . Biol. Chem. 1991, 266, 20369. (b) Zimolo, Z.;
Wesolowski, G.; Tanaka, H.; Hyman, J .; Hoyer, J . R.; Rodan, G. A.
Am. J . Physiol. 1994, 266, C376.
(4) Yoshitake, H.; Rittling, S. R.; Denhardt, D. T.; Noda, M. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 8156.
(5) For leading references to the physiological activity of 1R,25-
dihydroxyvitamin D3 and its derivatives, see: Manchand, P. S.;
Yiannikouros, G. P.; Belica, P. S.; Madan, P. J . Org. Chem. 1995, 60,
6574.
The synthetic route to astrogorgiadiol (2) that we had
established6 was efficient, but it was not flexible. We have
therefore developed an entirely new route (Scheme 1) to
this class of vitamin D-like materials. This triply con-
vergent approach allows ready modification of A-ring,
D-ring, and side-chain substitution. It was particularly
intriguing that semiempirical calculations suggested that
the two geometric isomers of 4 should be of approximately
equal energy. If this proved to be true, it would be
possible to prepare either relative configuration of the
side chain from the same precursor. We have taken as
our first objective the preparation of calicoferol B (1), a
(6) Taber, D. F.; Malcolm, S. C. J . Org. Chem. 2001, 66, 944.
(7) Fusetani, N.; Nagata, H.; Hirota, H.; Tsuyuki, T. Tetrahedron
Lett. 1989, 30, 7079.
(8) Xu, Y.; Farach-Carson, M. C. Personal communication.
10.1021/jo020103v CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002
J . Org. Chem. 2002, 67, 4821-4827
4821

Taber et al.
SCHEME 1
SCHEME 2a
a
The ratios were determined by 1H NMR.
Carrying out this same transformation at -100 °C gave
an even higher 10/7 ratio. In contrast, exposure of ketone
8 to diethyl carbonate in the presence of NaH and a
catalytic amount of ethanol in DME gave a 2:1 ratio of
the desired keto ester 7 to its regioisomer 10. The keto
esters 10 and 7 could be easily identified by their 1H
NMR spectra. The H(15) signal in keto ester 10 was a
doublet with an 13.0 Hz coupling constant at δ 3.04,
whereas the H(17) signal in keto ester 7 was a singlet at
δ 2.83. The undesired keto ester 10 could be efficiently
recycled to the tetracyclic ketone 8.13
Protection (Scheme 3) of the ketone carbonyl group in
the desired keto ester 7 with ethylene glycol in the
presence of triethyl orthoformate14 and a catalytic amount
of p-TsOH‚H2O produced the ketal 12, accompanied by
an uncharacterized mixture. This mixture was further
treated with p-TsOH‚H2O in EtOH to give an additional
portion of ketal 12 as well as the diol ketone 11. Further
protection then converted the diol ketone 11 to the
desired ketal 12. Selected benzenesulfonation of the
primary alcohol in 12 yielded the monobenzenesulfonate
13, which was reduced with DIBAL-H to furnish the
bicyclic chiron 6. The transformation of the ketone 8
(Scheme 2) to the monobenzenesulfonate 6 proceeded in
59% overall yield.
marine secosterol isolated from the gorgonian Calicogor-
gia sp. in 1991 that showed lethality to brine shrimp with
an LD50 of 2.3 ppm.9
Resu lts a n d Discu ssion
The key to this approach was the preparation of the
bicyclic chiron 6 (Scheme 1). We had already established
that cyclozirconation/carbonylation10,11 of the diene 9
proceeded smoothly to give the crystalline ketone 8.12 The
immediate task was to differentiate (Scheme 2) the two
methylenes flanking the ketone at C(16) (steroid num-
bering). We expected that the C(15) methylene, being
sterically less congested, would be kinetically more acidic
than the C(17) methylene. Indeed, exposure of ketone 8
to LDA at -78 °C followed by reaction with ethyl
chloroformate gave preponderantly the keto ester 10.
(9) Ochi, M.; Yamada, K.; Kotsuki, H.; Shibata, K. Chem. Lett. 1991,
427.
(10) For references to our previous work on intramolecular diene
cyclozirconation, see: (a) Nugent, W. A.; Taber, D. F. J . Am. Chem.
Soc. 1989, 111, 6435. (b) Taber, D. F.; Louey, J . P.; Wang, Y.; Nugent,
W. A.; Dixon, D. A.; Harlow, R. L. J . Am. Chem. Soc. 1994, 116, 9457.
(c) Taber, D. F.; Wang, Y. Tetrahedron Lett. 1995, 36, 6639.
(11) For leading references to work by others on intramolecular
diene cyclozirconation, see: (a) Rousset, C. J .; Swanson, D. R.; Lamaty,
F.; Negishi, E.-i. Tetrahedron Lett. 1989, 30, 5105. (b) Knight, K. S.;
Wang, D.; Waymouth, R. M.; Ziller, J . J . Am. Chem. Soc. 1994, 116,
1845. (c) Kim, S.; Kim, K. H. Tetrahedron Lett. 1995, 36, 3725. (d)
Mirza-Aghayan, M.; Boukherroub, R.; Etemad-Moghadam, G.; Manuel,
G.; Koenig, M. Tetrahedron Lett. 1996, 37, 3109. (e) Nishihara, Y.;
Aoyagi, K.; Hara, R.; Suzuki, N.; Takahashi, T. Inorg. Chim. Acta 1996,
252, 91. (f) Yamaura, Y.; Hyakutake, M.; Mori, M. J . Am. Chem. Soc.
1997, 119, 7615. (g) Martin, S.; Brintzinger, H. H. Inorg. Chim. Acta
1998, 280, 189. (h) Grepioni, F.; Grilli, S.; Martelli, G.; Savoia, D. J .
Org. Chem. 1999, 64, 3679. (i) Yamaura, Y.; Mori, M. Tetrahedron Lett.
1999, 40, 3221. (j) Campbell, A. D.; Raynham, T. M.; Taylor, R. J . K.
J . Chem. Soc., Perkin Trans. 1 2000, 3194. (k) Kasatkin, A. N.;
Checksfield, G.; Whitby, R. J . J . Org. Chem. 2000, 65, 3236.
(12) Taber, D. F.; Zhang, W.; Campbell, C. L.; Rheingold, A. L.;
Incarvito, C. D. J . Am. Chem. Soc. 2000, 122, 4813.
The aromatic A-ring synthon 5 was prepared from the
commercially available 3-methylanisole (14) (Scheme 4).
Thus, bromination and benzenesulfonylation of 14 fol-
lowing the procedure of Hoye15 gave the bromo sulfone
15. We had originally thought to prepare 5 by direct
methylation of 15, but CH3MgBr with Cu or Ni catalysts
returned only unreacted starting material. The alterna-
tive replacement of the bromine with copper(I) cyanide
(13) Krapcho, A. P.; Weimaster, J . F.; Eldridge, J . M.; J ahngen, E.
G. E., J r.; Lovey, A. J .; Stephens, W. P. J . Org. Chem. 1978, 43, 138.
(14) Koreeda, M.; Brown, L. J . Org. Chem. 1983, 48, 2122.
(15) Hoye, T. R.; Mi, L. J . Org. Chem. 1997, 62, 8586.
4822 J . Org. Chem., Vol. 67, No. 14, 2002

Synthesis of (-)-Calicoferol B
SCHEME 3
SCHEME 5
SCHEME 4
Based on the literature precedent,23 we expected that
conjugate addition of lithium dimethyl cuprate to enones
4 and 21 would proceed from the R-face. Thus, addition
to the desired enone 4 would give the (natural) C(20R)
methyl, while addition to the enone 21 would give the
epimeric C(20â) methyl. Indeed, conjugate addition of
lithium dimethyl cuprate to enone 4 (Scheme 6) gave the
dione 22. Reduction of the dione 22 with L-Selectride
afforded the diol 23, which was demethylated with
triethylsilane in the presence of a catalytic amount of tris-
(pentafluorophenyl)boron24 followed by desilylation with
TBAF to provide the target molecule, (-)-calicoferol B
proceeded efficiently, to yield the nitrile 16.16 Reduction
with DIBAL-H to the aldehyde 17 followed by Wolff-
Kishner reduction17 furnished the aromatic A-ring syn-
thon 5.
Coupling of the bicyclic chiron 6 with the aromatic
A-ring synthon 5 gave the sulfone 18 (Scheme 5). Desul-
fonylation of 18 with Na and ethanol in THF18 produced
the diol 19, which was oxidized with Dess-Martin
periodinane19 to afford the keto aldehyde 20. Addition of
isohexylmagnesium bromide20 followed by hydrolysis and
dehydration gave the easily separable enones 4 and 21
in the predicted 1:1 ratio.21 The two enones could readily
(21) Semiempirical calculations (MOPAC PM3) had shown that ii
is preferred over i by a 1.81 kcal/mol, so ii should be the predominant
product. In contrast, iii and iv had only a 0.01 kcal/mol difference,
suggesting a ∼1:1 ratio at equilibrium.
1
be identified by their H NMR spectra. The H(20) signal
of 4 appeared at δ 5.76, whereas the H(20) signal of 21
appeared at δ 6.53. Either enone could be equilibrated
efficiently to the ∼1:1 mixture by treatment with KI in
acetic acid.22
(16) Grootaert, W. M.; De Clercq, P. J . Tetrahedron Lett. 1986, 27,
1731.
(17) Paquette, L. A.; Schulze, M. M.; Bolin, D. G. J . Org. Chem. 1994,
59, 2043.
(18) Masaki, Y.; Serizawa, Y.; Nagata, K.; Kaji, K. Chem. Lett. 1984,
2105.
(19) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(20) For the preparation of isohexyl bromide, see: Crawforth, J . M.;
Fawcett, J .; Rawlings, B. J . J . Chem. Soc., Perkin Trans. 1 1998, 1721.
(22) Smith, A. B., III; Guaciaro, M. A.; Schow, S. R.; Wovkulich, P.
M.; Toder, B. H.; Hall, T. W. J . Am. Chem. Soc. 1981, 103, 219.
(23) (a) Schmuff, N. R.; Trost, B. M. J . Org. Chem. 1983, 48, 1404.
(b) Yu, W.; J in, Z. J . Am. Chem. Soc. 2001, 123, 3369.
(24) Gevorgyan, V.; Liu, J .-X.; Rubin, M.; Benson, S.; Yamamoto,
Y. Tetrahedron Lett. 1999, 40, 8919.
J . Org. Chem, Vol. 67, No. 14, 2002 4823

Taber et al.
SCHEME 6
synthetic strategy described here will offer a general
route to the naturally occurring A-ring aromatic B-seco
steroids.
Exp er im en ta l P r oced u r es
Gen er a l Meth od s. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were obtained as solutions in deuteriochloroform
(CDCl3) unless otherwise noted. 13C multiplicities were deter-
mined with the aid of a J VERT pulse sequence, differentiating
the signals for methyl and methine carbons as “down” from
methylene and quaternary carbons as “up”. The infrared (IR)
spectra were determined as neat oils. Optical rotations were
determined as solutions in chloroform unless otherwise noted.
Rf values indicated refer to thin-layer chromatography (TLC)
on 2.5 × 10 cm, 250 µm analytical plates coated with silica
gel GF and developed in the solvent system indicated. Silica
gel (60 Å) was used for flash column chromatography.25
Tetrahydrofuran (THF) and diethyl ether were distilled from
sodium metal/benzophenone ketyl under dry nitrogen. Dichlo-
romethane (CH2Cl2) and toluene were distilled from calcium
hydride under dry nitrogen. MTBE is methyl tert-butyl ether.
All reaction mixtures were stirred magnetically, unless oth-
erwise noted.
Keto Ester s 10 a n d 7. To a stirred suspension mixture of
diethyl carbonate (205 mg, 1.74 mmol) and NaH (60%, 104
mg, 2.60 mmol) in DME (2 mL) was added a solution of
tetracyclic ketone 8 (290 mg, 0.87 mmol) in DME (2.5 mL)
followed by EtOH (5 µL) at rt under N2. The reaction mixture
was heated to 90 °C and stirred at 90 °C for 4 h. The reaction
mixture was then partitioned between cooled 5% aqueous HCl
(10 mL) and MTBE. The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated. The
residue was chromatographed to produce the keto ester 10 (125
mg, 36% from 8) as a colorless oil: TLC Rf ) 0.78 (petroleum
ether/MTBE ) 7/3); IR (film) 2951, 2869, 1759, 1726, 1457,
1375, 1314, 1264, 1160, 1115, 1030, 925, 855 cm-1; 1H NMR δ
4.15-4.23 (m, 2H), 3.77 (t, J ) 11.1 Hz, 1H), 3.53-3.62 (m,
2H), 3.04 (d, J ) 13.0 Hz, 1H), 2.67-2.71 (m, 1H), 1.46-2.45
(m, 15H), 1.28 (t, J ) 7.1 Hz, 3H), 1.01 (s, 3H), 0.86-0.91 (m,
9H), 0.67 (t, J ) 12.8 Hz, 1H); 13C NMR δ up 210.3, 169.9,
101.3, 62.6, 61.7, 54.1, 37.9, 37.4, 35.6, 34.8, 27.7, 21.7; down
72.7, 55.5, 50.9, 47.7, 39.4, 29.0, 24.4, 23.7, 22.2, 19.5, 18.8,
14.1; HRMS calcd for C24H38O5Na (M + Na) 429.2617, found
429.2599. This was followed by the keto ester 7 (218 mg, 62%
from 7) as a colorless oil, TLC Rf ) 0.28 (petroleum ether/
MTBE ) 7/3): IR (film) 2950, 2868, 1764, 1725, 1458, 1370,
1313, 1268, 1181, 1145, 1115, 1031, 925, 854 cm-1; 1H NMR δ
4.16-4.24 (m, 2H), 3.77 (t, J ) 11.0 Hz, 1H), 3.67 (dd, J )
4.6, 11.0 Hz, 1H), 3.51-3.57 (m, 1H), 2.83 (s, 1H), 2.66-2.70
(m, 1H), 1.47-2.45 (m, 15H), 1.28 (t, J ) 7.1 Hz, 3H), 1.03 (s,
3H), 0.86-0.91 (m, 9H), 0.70 (t, J ) 12.8 Hz, 1H); 13C NMR δ
up 208.9, 167.8, 101.5, 63.1, 60.9, 43.8, 37.4, 35.8, 34.9, 31.7,
27.7, 21.9; down 73.0, 67.1, 51.1, 43.5, 38.8, 29.0, 24.5, 23.7,
22.2, 18.9, 14.9, 14.3; HRMS calcd for C24H38O5Na (M + Na)
429.2617, found 429.2603.
Keto Ester s 10 a n d 7 fr om Eth yl Ch lor ofor m a te a n d
LDA. To a stirred solution of the tetracyclic ketone 8 (45 mg,
0.14 mmol) in dry THF (0.7 mL) was added a 0.5 M lithium
diisopropylamide (LDA) solution in THF (0.7 mL, 0.35 mmol)
at -78 °C under N2. After an additional 1 h, ethyl chlorofor-
mate (30 mg, 0.28 mmol) was added. The cooling bath was
removed, and the reaction mixture was allowed to warm to
rt. After an additional 4 h at rt, the reaction mixture was
partitioned between cooled 5% aqueous HCl (5 mL) and MTBE.
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated. The residue was chromatographed
to give the keto ester 10 (13 mg, 51% from 8 based on 47%
conversion). This was followed by the tetracyclic ketone 8 (24
SCHEME 7
(1). The synthetic (-)-calicoferol B (1) was identical to
the natural product by H and 13C NMR and [R]D (obsd
1
[R]D -18.8, c 0.08, CHCl3; lit.9 [R]D -16.2°, c 0.09, CHCl3).
The C(20)-epi-calicoferol B (26) was prepared from the
enone 21 in the same manner as described for the
preparation of (-)-calicoferol B (1) (Scheme 7). The
synthetic (-)-calicoferol B (1) and its diastereomer 26
were separable on TLC and were not contaminated with
each other, demonstrating the stereochemical homogene-
ity of 22 and of 24. The identity of the synthetic 1 (and
not 26) with the natural product was established by 13C
NMR. The C(21) and C(22) signals of synthetic 1 ap-
peared at δ 18.9 (lit.9 δ 18.51) and δ 36.9 (lit.9 δ 36.59),
respectively, whereas the corresponding C(21) and C(22)
signals of 26 appeared at δ 19.3 and 35.5.
Con clu sion
The first total synthesis of (-)-calicoferol B (1) has been
accomplished. We believe that the triply convergent
(25) Still, W. C.; Kahn, M.; Mitra, A. J . J . Org. Chem. 1978, 43,
2923.
4824 J . Org. Chem., Vol. 67, No. 14, 2002

Synthesis of (-)-Calicoferol B
mg) and then the keto ester 7 (3.5 mg, 14% from 8 based on
47% conversion).
135.5, 116.1, 69.2, 65.7, 64.3, 59.8, 42.4, 40.3, 35.6, 30.4; down
133.8, 129.3, 127.8, 69.4, 63.5, 44.7, 42.5, 14.2, 13.1; HRMS
calcd for C22H30O8SNa (M + Na) 477.1559, found 477.1547.
This was followed by the diol ketal 12 (93 mg).
Tetr a cyclic Keton e 7 fr om Recyclin g th e Keto Ester
10. A stirred suspension mixture of keto ester 10 (25 mg, 0.062
mmol) and LiCl (13 mg, 0.31 mmol) in DMSO/H2O (0.6 mL,
DMSO/H2O ) 9/1, v/v) was heated to reflux for 30 min. After
the mixture was cooled to rt, the reaction solvent was removed
in vacuo. The residue was chromatographed to give the keto
diol (9.5 mg, 78% from 10) as a colorless oil.
To a stirred solution of the keto diol (219 mg, 1.11 mmol),
triethyl orthoformate (327 mg, 2.77 mmol), and (S)-(+)-
menthone (342 mg, 2.22 mmol) in dry THF (5 mL) was added
a catalytic amount of p-TsOH‚H2O (21 mg, 0.11 mmol) at rt.
After an additional 23 h, the reaction mixture was partitioned
between CH2Cl2 and, sequentially, saturated aqueous NaHCO3
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographed to yield
the tetracyclic ketone 8 (230 mg, 48% from 20).
Diol Ben zen esu lfon ate 6. To a stirred solution of monoben-
zenesulfonate 13 (144 mg, 0.32 mmol) in dry THF (10 mL) was
added a 1 M solution of DIBAL-H in hexanes (1.6 mL, 1.60
mmol) at -78 °C under N2. The reaction mixture was warmed
slowly to rt over 1 h. After an additional 1 h at rt, the reaction
mixture was partitioned between EtOAc and, sequentially, 5%
aqueous HCl, saturated aqueous NaHCO3, and brine. The
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to afford the diol benzene-
sulfonate 6 (116 mg, 89% from 13) as a colorless oil: TLC
Rf ) 0.11 (EtOAc/petroleum ether ) 4/1); IR (film) 3405, 2939,
1732, 1448, 1357, 1187, 1096, 1014, 920, 820, 732 cm-1 1H
;
NMR δ 7.85-7.97 (m, 2H), 7.66-7.72 (m, 1H), 7.56-7.60 (m,
2H), 4.34-4.48 (m, 1H), 3.44-3.98 (m, 8H), 1.25-2.71 (m,
11H), 0.78-0.87 (m, 3H); 13C NMR δ up 135.6, 116.8, 69.5,
64.8, 63.2, 58.8, 41.6, 38.9, 35.9, 30.6; down 133.8, 129.2, 127.8,
69.7, 59.9, 44.9, 42.5, 12.8; HRMS calcd for C20H28O7SNa
(M + Na) 435.1453, found 435.1443.
Diol Keton e 11 a n d Diol Keta l 12. To a stirred solution
of the keto ester 7 (336 mg, 0.83 mmol), triethyl orthoformate
(491 mg, 3.32 mmol), and ethylene glycol (555 mg, 8.28 mmol)
in dry CH2Cl2 (8.3 mL) was added a catalytic amount of
pTsOH‚H2O (16 mg, 0.084 mmol) at rt. After an additional 3
days, the reaction mixture was partitioned between EtOAc
and, sequentially, saturated aqueous NaHCO3 and brine. The
combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was chromatographed to afford an un-
known mixture as a colorless oil. This was followed by the diol
ketal 12 (146 mg, 52% from 6) as a colorless oil, TLC Rf )
0.17 (EtOAc/petroleum ether ) 4/1): IR (film) 3406, 2934,
Nitr ile 16. To a stirred solution of bromosulfone 15 (5.2 g,
15.6 mmol) in 1-methyl-2-pyrrolidinone (NMP) (120 mL) was
added CuCN (7.0 g, 77.8 mmol). The reaction mixture was
heated to reflux for 16 h and was then poured into 30%
aqueous NH4OH (300 mL) at 0 °C. After vigorous stirring for
3 h, the mixture was filtered, and the filter cake was
partitioned between CH2Cl2 and brine. The combined organic
extracts were dried (Na2SO4) and concentrated. The residue
was recrystallized (EtOAc/petroleum ether ) 20/1) to give the
nitrile 16 (3.35 g, 75% from 25) as a white solid: TLC Rf )
0.21 (MTBE/petroleum ether ) 1/1); mp 144-145 °C; IR (film)
2979, 2845, 2222, 1605, 1500 cm-1; 1H NMR δ 7.76 (d, J ) 7.3
Hz, 2H), 7.70 (t, J ) 8.8 Hz, 1H), 7.54 (t, J ) 7.8 Hz, 2H), 7.48
(d, J ) 8.8 Hz, 1H), 7.13 (d, J ) 2.5 Hz, 1H), 6.97 (dd, J ) 2.5
and 8.7 Hz, 1H), 4.56 (s, 2H), 3.90 (s, 3H); 13C NMR δ up 162.8,
137.6, 133.8, 117.2, 106.0, 60.7; down 134.50, 134.47, 129.5,
128.9, 117.5, 115.8, 56.0; HRMS calcd for C15H13O3NS 287.0616,
found 287.0611. Anal. Calcd for C15H13O3NS: C, 62.70; H, 4.56;
N, 4.87. Found: C, 62.60; H, 4.62; N, 4.98.
1733, 1458, 1370, 1296, 1178, 1081, 1032 cm-1 1H NMR δ
;
3.62-4.15 (m, 9H), 3.08 (brs, 1H), 2.79 (brs, 1H), 2.68 (s, 1H),
2.18-2.28 (m, 1H), 2.01 (dd, J ) 7.8 and 13.5 Hz, 1H), 1.69-
1.90 (m, 5H), 1.43-1.46 (m, 1H), 1.26 (t, J ) 7.1 Hz, 3H), 1.12
(s, 3H); 13C NMR δ up 169.6, 116.3, 65.7, 64.2, 59.9, 42.5, 40.5,
35.7, 30.4; down 63.5, 45.1, 43.3, 14.2, 13.4; HRMS calcd for
C
16H26O6Na (M + Na) 337.1627, found 337.1616.
To a stirred solution of the unknown mixture in EtOH (5
mL) was added p-TsOH‚H2O (5 mg, 0.026 mmol) at rt. After
an additional 2 days, the reaction mixture was partitioned
between EtOAc and, sequentially, saturated aqueous NaHCO3
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographed to give
the diol ketal 12 (51 mg, 20% from 7). This was followed by
the diol ketone 11 (40 mg, 18% from 7) as a colorless oil.
Diol Keta l 12 fr om Diol Keton e 11. To a stirred solution
of the diol ketone 11 (93 mg, 0.34 mmol), HC(OEt)3 (204 mg,
1.38 mmol), and HO(CH2)2OH (231 mg, 3.45 mmol) in dry CH2-
Cl2 (3.4 mL) was added a catalytic amount of p-TsOH‚H2O (6.5
mg, 0.034 mmol) at rt. After an additional 3 days, the reaction
mixture was partitioned between EtOAc and, sequentially,
saturated aqueous NaHCO3 and brine. The combined organic
extracts were dried (Na2SO4) and concentrated. The residue
was chromatographed to give the diol ketal 12 (93 mg, 86%
from 11).
Ald eh yd e 17. To a stirred solution of nitrile 16 (3.92 g,
13.66 mmol) in THF (120 mL) was added a 0.83 M solution of
DIBAL-H in hexanes (41.1 mL, 34.15 mmol) at -78 °C. The
reaction mixture was stirred and gradually warmed from -78
°C to rt over 2 h. The reaction mixture was quenched by
addition of saturated aqueous NH4Cl and 6 M aqueous HCl
(6:1, v/v) at 0 °C. The organic solvent was removed in vacuo,
and the residue was then partitioned between EtOAc and
brine. The combined organic extracts were dried (Na2SO4) and
concentrated. The crude residue was recrystallized (EtOAc/
petroleum ether ) 20/1) to give the aldehyde 17 (3.22 g, 81%
from 16) as a white solid: TLC Rf ) 0.17 (MTBE/petroleum
ether ) 1/1); mp 114-115 °C; IR (film) 2939, 2841, 1683, 1599,
1
1571, 1447 cm-1; H NMR δ 9.68 (s, 1H), 7.70-7.72 (m, 2H),
7.65 (d, J ) 8.5 Hz, 1H), 7.58-7.61 (m, 1H), 7.45 (t, J ) 7.7
Hz, 2H), 7.00 (dd, J ) 2.5 and 8.5 Hz, 1H), 6.92 (d, J ) 2.5
Hz, 1H), 5.05 (s, 2H), 3.85 (s, 3H); 13C NMR δ up 163.3, 138.2,
131.2, 127.9, 57.6; down 190.7, 137.2, 133.9, 128.9, 128.7, 119.4,
Mon oben zen esu lfon a te 13. To a stirred solution of the
diol ketal 12 (160 mg, 0.51 mmol) and pyridine (80 mg, 1.01
mmol) in dry CH2Cl2 (5.1 mL) was added benzenesulfonyl
chloride (BsCl) (72 mg, 0.41 mmol) at 0 °C under N2. The
reaction mixture was warmed to rt and then stirred for 12 h
at rt. The reaction mixture was partitioned between EtOAc
and, sequentially, 5% aqueous HCl, saturated aqueous NaH-
CO3, and brine. The combined organic extracts were dried (Na2-
SO4) and concentrated. The residue was chromatographed to
provide the monobenzenesulfonate 13 (83 mg, 86% from 12
based on 42% conversion) as a colorless oil: TLC Rf ) 0.68
(EtOAc/petroleum ether ) 4/1); IR (film) 3510, 2940, 1731,
114.4, 55.8; HRMS calcd for
C15H14O4S 290.0613, found
290.0605. Anal. Calcd for C15H14O4S: C, 73.43; H, 10.27.
Found: C, 73.24; H, 10.52.
Su lfon e 5. The aldehyde 17 (2.50 g, 8.62 mmol), hydrazine
monohydrate (50.7 g, 862.00 mmol), and K2CO3 (42.82 g,
310.32 mmol) were added into diethylene glycol (30 mL)
sequentially. The mixture was heated at 180 °C for 5 h and
then at 150 °C for another 16 h. The reaction mixture was
cooled to rt and then partitioned between EtOAc and brine.
The combined organic extracts were dried (Na2SO4) and
concentrated. The crude residue was recrystallized (CH2Cl2/
petroleum ether ) 20/1) to give the sulfone 5 (1.35 g, 57% from
17) as a white solid: TLC Rf ) 0.33 (MTBE/petroleum ether
1448, 1360, 1296, 1187, 1096, 1027, 926, 821, 757 cm-1 1H
;
NMR δ 7.86-7.96 (m, 2H), 7.64-7.70 (m, 1H), 7.55-7.60 (m,
2H), 4.40 (dd, J ) 3.4 and 9.9 Hz, 1H), 3.51-4.19 (m, 8H),
2.55 (s, 1H), 2.17 (brs, 1H), 1.41-1.97 (m, 7H), 1.25 (t, J ) 7.1
Hz, 3H), 1.19-1.29 (m, 1H), 1.09 (s, 3H); 13C NMR δ up 169.5,
J . Org. Chem, Vol. 67, No. 14, 2002 4825

Taber et al.
) 1/4); mp 86-87 °C; IR (film) 3062, 2935, 2836, 1612, 1580
neutralized by the addition of saturated aqueous NaHCO3, and
the solvent was removed in vacuo. The residue was partitioned
between EtOAc and H2O. The combined organic extracts were
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to yield the enone 4 (8 mg, 16% from 20) as a colorless
oil: TLC Rf ) 0.37 (petroleum ether/methylene chloride/
1
cm-1; H NMR δ 7.62-7.70 (m, 3H), 7.49 (t, J ) 7.8 Hz, 2H),
7.03 (d, J ) 8.4 Hz, 1H), 6.79 (dd, J ) 2.7 and 8.4 Hz, 1H),
6.56 (d, J ) 2.7 Hz, 1H), 4.36 (s, 2H), 3.68 (s, 3H), 2.04 (s,
3H); 13C NMR δ up 157.5, 138.3, 130.2, 127.3, 60.2; down 133.7,
131.4, 128.9, 128.7, 116.5, 115.2, 55.2, 18.3; HRMS calcd for
MTBE ) 7/2/1); [R]20 ) -61.7 (c ) 0.30, CH2Cl2); IR (film)
C
15H16O3SNa (M + Na) 299.0718, found 299.0720. Anal. Calcd
D
for C15H16O3S: C, 65.19; H, 5.84. Found: C, 65.16; H, 5.84.
2956, 2926, 2865, 1712, 1639, 1610, 1499, 1458, 1377, 1299,
1252, 1208, 1160, 1109, 1046 cm-1; 1H NMR δ 7.04 (d, J ) 8.2
Hz, 1H), 6.70 (d, J ) 2.7 Hz, 1H), 6.66 (dd, J ) 2.7, 8.2 Hz,
1H), 5.76 (t, J ) 7.5 Hz, 1H), 3.78 (s, 3H), 2.45-2.73 (m, 6H),
2.34 (dd, J ) 7.2, 17.3 Hz, 1H), 2.27 (s, 3H), 2.09-2.25 (m,
2H), 1.34-2.00 (m, 9H), 1.21 (s, 3H), 1.16-1.25 (m, 1H), 0.86
(d, J ) 6.6 Hz, 6H); 13C NMR δ up 210.4, 205.8, 157.8, 145.7,
141.6, 128.0, 43.1, 39.9, 38.51, 38.47, 35.5, 31.1, 27.83, 27.78,
27.1; down 138.1, 131.0, 114.5, 111.1, 55.2, 49.2, 46.9, 27.80,
22.57, 22.53, 19.4, 18.4; HRMS calcd for C27H38O3Na (M + Na)
433.2719, found 433.2704. This was followed by the enone 21
(8.5 mg, 17% from 20) as a colorless oil: TLC Rf ) 0.35
Keto Ald eh yd e 20. To a stirred solution of sulfone 5 (723
mg, 2.62 mmol) in dry THF (1 mL) was added a 2.5 M solution
of n-BuLi in hexanes (1.05 mL, 2.62 mmol) at -78 °C under
N2. The reaction mixture was stirred for 30 min, and a solution
of diol benzenesulfonate 6 (108 mg, 0.26 mmol) in dry THF
(1.6 mL) was then added. The reaction mixture was slowly
warmed to rt over 1.5 h and was then stirred at rt for another
6 h. The reaction mixture was partitioned between EtOAc and,
sequentially, saturated aqueous NH4Cl and brine. The com-
bined organic extracts were dried (Na2SO4) and concentrated.
The residue was chromatographed to afford the sulfone 18 (123
mg, 88% from 6) as a colorless oil: TLC Rf ) 0.11 (EtOAc/
petroleum ether ) 4/1).
(petroleum ether/methylene chloride/MTBE ) 7/2/1); [R]20
)
D
-41.7 (c ) 0.30, CH2Cl2); IR (film) 2954, 2921, 2865, 1710,
1644, 1608, 1503, 1455, 1377, 1299, 1252, 1204, 1160, 1102,
To a stirred solution of sulfone 18 (70 mg, 0.13 mmol) and
EtOH (122 mg, 2.65 mmol) in dry THF (3.5 mL) was added
Na (61 mg, 2.65 mmol) at -20 °C under N2. After an additional
2 h, the unreacted Na was quenched by careful addition of
MeOH, and the reaction mixture was then partitioned between
EtOAc and, sequentially, saturated aqueous NH4Cl and brine.
The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give the
diol 19 (43 mg, 74% from 6) as a colorless oil: TLC Rf ) 0.28
(EtOAc/methylene chloride/petroleum ether ) 80/15/5); IR
(film) 3406, 2934, 2890, 1733, 1609, 1579, 1503, 1456, 1286,
1
1046 cm-1; H NMR δ 7.04 (d, J ) 8.2 Hz, 1H), 6.70 (d, J )
2.7 Hz, 1H), 6.66 (dd, J ) 2.7, 8.2 Hz, 1H), 6.53 (t, J ) 7.8 Hz,
1H), 3.78 (s, 3H), 2.45-2.74 (m, 6H), 2.38 (dd, J ) 6.9, 17.0
Hz, 1H), 2.27 (s, 3H), 2.17-2.29 (m, 3H), 1.99-2.10 (m, 3H),
1.81-1.86 (m, 1H), 1.65-1.72 (m, 1H), 1.45-1.57 (m, 3H), 1.27
(s, 3H), 1.21-1.25 (m, 1H), 0.87 (d, J ) 6.6 Hz, 6H); 13C NMR
δ up 210.2, 204.4, 157.8, 145.0, 141.5, 128.0, 43.0, 38.74, 38.68,
38.3, 35.7, 31.0, 28.1, 27.0; down 137.0, 131.0, 114.6, 111.1,
55.2, 49.1, 47.3, 22.51, 22.49, 18.4, 17.8; HRMS calcd for
C
27H38O3Na (M + Na) 433.2719, found 433.2715.
1
1252, 1209, 1160, 1083, 1008, 910, 804, 732 cm-1; H NMR δ
En on e 4 fr om En on e 21. To a stirred solution of enone 22
(6 mg, 0.015 mmol) in HOAc (0.5 mL) was added KI (25 mg,
0.15 mmol) at rt. After an additional 2 days, the reaction
solvent was removed in vacuo. The residue was partitioned
between MTBE and, sequentially, saturated aqueous NaHCO3
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographed to give
the enone 4 (2.2 mg, 69% from 21 based on 53% conversion)
as a colorless oil. This was followed by the enone 21 (2.8 mg)
as a colorless oil.
7.04 (d, J ) 8.3 Hz, 1H), 6.64-6.71 (m, 2H), 3.78 (s, 3H), 3.45-
4.02 (m, 7H), 2.56-2.63 (m, 2H), 2.24 (S, 3H), 1.22-2.04 (m,
13H), 0.84-0.90 (m, 3H); 13C NMR δ up 157.7, 142.4, 127.8,
117.1, 64.9, 63.2, 59.0, 41.8, 39.9, 36.4, 31.6, 30.3, 30.0; down
130.8, 114.6, 110.4, 74.1, 60.2, 55.2, 48.4, 42.1, 18.4, 13.2;
HRMS calcd for
413.2307.
C23H34O5Na (M + Na) 413.2304, found
To a stirred solution of diol 19 (43 mg, 0.11 mmol) in CH2-
Cl2 (4 mL) was added Dess-Martin periodinane (139 mg, 0.33
mmol) at rt. The reaction mixture was stirred for 1.5 h and
was then concentrated in vacuo. The residue was chromato-
graphed to provide the keto aldehyde 20 (34 mg, 59% from 6)
as a colorless oil: TLC Rf ) 0.18 (petroleum ether/acetone )
9/1); IR (film) 2923, 2876, 1709, 1609, 1579, 1500, 1465, 1298,
Dion e 22. To a stirred suspension mixture of CuI (38 mg,
0.20 mmol) in dry Et2O (1.2 mL) was added a 2.2 M solution
of MeLi in Et2O (0.18 mL, 0.40 mmol) dropwise at -20 °C
under N2. After an additional 1 h, the reaction mixture was
added a solution of the enone 4 (8 mg, 0.020 mmol) in dry Et2O
(0.8 mL), and the reaction mixture was then stirred for another
1 h at -20 °C. The reaction mixture was partitioned between
CH2Cl2 and, sequentially, saturated aqueous NH4Cl and brine.
The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to provide the
dione 22 (5.5 mg, 66% from 4) as a colorless oil: TLC Rf )
0.40 (petroleum ether/methylene chloride/MTBE ) 7/2/1);
1
1252, 1159, 1084, 1035, 949, 862, 810 cm-1; H NMR δ 9.81
(d, J ) 1.9 Hz, 1H), 7.04 (d, J ) 8.2 Hz, 1H), 6.69 (d, J ) 2.7
Hz, 1H), 6.65 (dd, J ) 2.7, 8.2 Hz, 1H), 3.98-4.07 (m, 2H),
3.82-3.90 (m, 2H), 3.78 (s, 3H), 2.71 (ddd, J ) 4.9, 11.7, 13.3
Hz, 1H), 2.37-2.55 (m, 5H), 2.27 (s, 3H), 2.21 (ddd, J ) 1.9,
6.5, 13.2 Hz, 1H), 2.09 (dd, J ) 7.1, 13.1 Hz, 1H), 1.51-1.91
(m, 5H), 1.34 (s, 3H); 13C NMR δ up 210.5, 157.7, 141.8, 128.0,
116.6, 65.4, 64.2, 43.3, 41.3, 37.8, 37.1, 31.1, 27.7; down 202.0,
130.9, 114.6, 110.7, 68.6, 55.2, 50.3, 49.0, 18.3, 12.9; HRMS
calcd for C23H30O5Na (M + Na) 409.1991, found 409.2004.
[R]20 ) -85.7 (c ) 0.28, CH2Cl2); IR (film) 2954, 2921, 2865,
D
1738, 1709, 1608, 1500, 1464, 1383, 1299, 1252, 1209, 1160,
1104, 1046 cm-1; 1H NMR δ 7.04 (d, J ) 8.2 Hz, 1H), 6.70 (d,
J ) 2.7 Hz, 1H), 6.66 (dd, J ) 2.7, 8.2 Hz, 1H), 3.78 (s, 3H),
2.71 (ddd, J ) 4.8, 11.6, 13.2 Hz, 1H), 2.28-2.56 (m, 6H), 2.27
(s, 3H), 1.14-2.03 (m, 14H), 1.09 (s, 3H), 1.01 (d, J ) 6.4 Hz,
3H), 0.87 (d, J ) 6.6 Hz, 3H), 0.85 (d, J ) 6.6 Hz, 3H); 13C
NMR δ up 216.2, 210.4, 157.8, 141.6, 128.0, 43.2, 39.7, 39.1,
38.4, 35.8, 31.18, 28.01, 24.9; down 131.0, 114.6, 111.0, 67.7,
55.2, 49.1, 48.5, 31.16, 27.94, 22.7, 22.6, 18.7, 18.4, 13.2.
En on es 4 a n d 21. A stirred solution of keto aldehyde 20
(47.5 mg, 0.12 mmol) in dry THF (6 mL) was titrated with a
0.1 M solution of isohexylmagnesium bromide in THF (1.5 mL,
0.15 mmol) at 0 °C to disappearance of starting material
(monitored by TLC). The reaction mixture was then partitioned
between EtOAc and, sequentially, saturated aqueous NH4Cl
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was filtered through a short
pad of silica gel with MTBE. Concentration of the filtrate gave
a residue that was used in the next step without further
purification.
Diol 23. To a stirred solution of dione 22 (5.5 mg, 0.013
mmol) in dry THF (1 mL) was added a 1 M solution of
L-Selectride in THF (0.13 mL, 0.13 mmol) at -78 °C. The
reaction mixture was slowly warmed to rt over 1.5 h. After an
additional 0.5 h at rt, the reaction mixture was partitioned
between EtOAc and, sequentially, saturated aqueous NH4Cl
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographed to give
The residue obtained above was dissolved in THF (0.9 mL)
followed by the addition of MeOH (9 mL) and 3 M aqueous
HCl (1.2 mL). The reaction mixture was heated to reflux for
4.5 h and then cooled to rt. The reaction mixture was
4826 J . Org. Chem., Vol. 67, No. 14, 2002

Synthesis of (-)-Calicoferol B
the diol 23 (2.5 mg, 45% from 22) as a colorless oil: TLC Rf )
0.28 (petroleum ether/methylene chloride/MTBE ) 7/2/1);
dione 24 (2.7 mg, 37% from 21) as a colorless oil: TLC Rf )
0.40 (petroleum ether/methylene chloride/MTBE ) 7:2:1).
The reaction was performed with the dione 24 (2.7 mg,
0.0063 mmol), L-Selectride (1 M in THF, 0.13 mL, 0.13 mmol),
and dry THF (0.5 mL) in the same manner as described for
the preparation of diol 23 to give diol 25 (1.2 mg, 16% from
21) as a colorless oil: TLC Rf ) 0.20 (petroleum ether/
methylene chloride/MTBE ) 7:2:1); 1H NMR δ 7.04 (d, J )
8.2 Hz, 1H), 6.72 (d, J ) 2.7 Hz, 1H), 6.65 (dd, J ) 2.7, 8.2 Hz,
1H), 4.30-4.35 (m, 1H), 4.06 (brs, 1H), 3.78 (s, 3H), 2.70-
2.77 (m, 1H), 2.42-2.50 (m, 1H), 2.24 (s, 3H), 2.13-2.28 (m,
1H), 1.05-1.90 (m, 20H), 0.98 (d, J ) 6.4 Hz, 3H), 0.91 (s,
3H), 0.87 (d, J ) 6.6 Hz, 3H), 0.86 (d, J ) 6.5 Hz, 3H).
C(20)-epi-Ca licofer ol B (26). The reaction was performed
with the diol 25 (1.2 mg, 0.0028 mmol), Et3SiH (13 mg, 0.11
mmol), (C6F5)3B (0.3 mg, 0.00059 mmol), and dry CH2Cl2 (0.6
mL); Et3N (0.1 mL); TBAF (1 M in THF, 0.5 mL); in the same
manner as described for the preparation of calicoferol B (1) to
give C(20)-epi-calicoferol B (26) (0.8 mg, 69% from 25) as a
colorless oil: TLC Rf ) 0.40 (petroleum ether/MTBE ) 1:1);
[R]20D ) +52.8 (c ) 0.053, CH2Cl2); IR (film) 3380, 2925, 2858,
[R]20 ) -5.6 (c ) 0.13, CH2Cl2); IR (film) 3418, 2928, 2865,
D
1614, 1505, 1456, 1383, 1306, 1251, 1208, 1160, 1102, 1046
cm-1; 1H NMR δ 7.04 (d, J ) 8.2 Hz, 1H), 6.72 (d, J ) 2.7 Hz,
1H), 6.65 (dd, J ) 2.7, 8.2 Hz, 1H), 4.32-4.37 (m, 1H), 4.06
(d, J ) 1.3 Hz, 1H), 3.78 (s, 3H), 2.73 (ddd, J ) 4.5, 11.2, 13.2
Hz, 1H), 2.43-2.50 (m, 1H), 2.24 (s, 3H), 2.18-2.27 (m, 1H),
1.06-1.78 (m, 20H), 0.99 (d, J ) 6.6 Hz, 3H), 0.90 (s, 3H),
0.87 (d, J ) 6.6 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H); 13C NMR δ
up 157.8, 142.3, 127.8, 42.8, 39.5, 36.5, 36.2, 34.2, 31.1, 30.3,
29.9, 24.1; down 130.9, 114.5, 110.8, 71.9, 67.0, 61.3, 55.2, 45.4,
40.4, 29.7, 28.1, 22.8, 22.6, 18.3, 18.2, 12.1; HRMS calcd for
C
28H46O3Na (M + Na) 453.3345, found 453.3337.
Ca licofer ol B (1). To a stirred solution of diol 23 (2.3 mg,
0.0054 mmol) and Et3SiH (25 mg, 0.22 mmol) in dry CH2Cl2
(1 mL) was added a solution of (C6F5)3B (0.6 mg, 0.0012 mmol)
in dry CH2Cl2 (0.1 mL) at rt under N2. After an additional 1
h, Et3N (0.1 mL) was added, and the reaction mixture was
filtered through a short pad of silica gel. The filter cake was
washed with MTBE, and the filtrate was concentrated. The
residue was used in the next step without further purification.
The residue was dissolved in a 1 M solution of TBAF in THF
(0.8 mL) at rt. After an additional 24 h, the reaction mixture
was partitioned between EtOAc and, sequentially, saturated
aqueous NH4Cl and brine. The combined organic extracts were
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to produce the target molecule, (-)-calicoferol B (1)
(1.2 mg, 55% from 23), as a colorless oil: TLC Rf ) 0.52
1653, 1610, 1497, 1464, 1384, 1257, 1158, 1102, 1024 cm-1
;
1H NMR (C6D6) δ 6.94 (d, J ) 8.2 Hz, 1H), 6.61 (d, J ) 2.7 Hz,
1H), 6.44 (dd, J ) 2.7, 8.2 Hz, 1H), 3.96 (ddd, J ) 4.3, 7.6, 7.6
Hz, 1H), 3.71 (d, J ) 2.4 Hz, 1H), 2.68 (ddd, J ) 5.0, 12.8,
13.2 Hz, 1H), 2.34 (ddd, J ) 5.0, 11.7, 13.3 Hz, 1H), 2.23 (s,
3H), 1.93-2.11 (m, 2H), 1.15-1.70 (m, 19H), 1.07 (dd, J ) 4.2,
12.9 Hz, 1H), 0.97 (d, J ) 6.4 Hz, 3H), 0.93 (d, J ) 7.1 Hz,
6H), 0.92 (s, 3H); 13C NMR (C6D6) δ up 155.2, 143.3, 43.4, 40.2,
37.6, 35.5, 35.1, 31.6, 31.3, 30.8, 24.8; down 131.7, 116.4, 113.2,
72.3, 67.0, 62.0, 46.0, 41.2, 30.2, 28.9, 23.4, 23.2, 19.3, 18.9,
12.8; HRMS calcd for C27H44O3Na (M + Na) 439.3188, found
439.3176.
(petroleum ether/MTBE ) 1/1); [R]20 ) -18.8 (c ) 0.08,
D
CHCl3) (lit.9 [R]21 ) -16.2 (c ) 0.09, CHCl3)); IR (film) 3379,
D
2956, 2926, 2865, 1609, 1581, 1504, 1464, 1384, 1292, 1243,
1158, 1102, 1024, 869, 806 cm-1 1H NMR (C6D6) δ 6.95 (d,
;
J ) 8.2 Hz, 1H), 6.66 (d, J ) 2.6 Hz, 1H), 6.47 (dd, J ) 2.6,
8.2 Hz, 1H), 4.04 (ddd, J ) 4.4, 7.6, 7.6 Hz, 1H), 3.74 (d, J )
2.5 Hz, 1H), 2.68 (ddd, J ) 5.1, 11.9, 13.3 Hz, 1H), 2.35 (ddd,
J ) 5.3, 11.9, 14.3 Hz, 1H), 2.24 (s, 3H), 1.95-2.04 (m, 2H),
1.05-1.70 (m, 20H), 1.01 (d, J ) 6.7 Hz, 3H), 0.95 (d, J ) 6.6
Hz, 3H), 0.94 (d, J ) 6.6 Hz, 3H), 0.89 (s, 3H); 13C NMR (C6D6)
δ up 155.3, 143.3, 43.4, 40.3, 37.7, 36.9, 35.0, 31.6, 31.3, 30.7,
25.1; down 131.7, 116.5, 113.3, 71.9, 67.1, 62.1, 45.9, 41.1, 30.5,
28.8, 23.4, 23.2, 18.9, 18.8, 12.8; HRMS calcd for C27H44O3Na
(M + Na) 439.3188, found 439.3186.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM60287) for support for this work.
We also thank Dr. J ohn Dykins for high-resolution mass
spectra and Dr. Shi Bai for detailed NMR studies. This
work is dedicated to Barry Sharpless on the occasion of
his reception of the Nobel Prize in Chemistry.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Diol 25. The reaction was performed with the enone 21 (7
mg, 0.017 mmol), CuI (32.5 mg, 0.17 mmol), MeLi (2.2 M in
THF, 0.16 mL, 0.35 mmol), and dry Et2O (1.7 mL) in the same
manner as described for the preparation of dione 22 to give
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J . Org. Chem, Vol. 67, No. 14, 2002 4827