[3,3]-Sigmatropic rearrangements: Short, stereocontrolled syntheses of functionalized vitamin D3 side-chain units

Article abstract of DOI:10.1016/S0040-4039(02)00904-8

Enantiomerically pure C,D-ring allylic alcohol 4 stereospecifically undergoes five types of [3,4]-sigmatropic rearrangements to give C-23 functionalized 16-ene vitamin D₃ side-chain units with natural C-20(S) stereochemistry.

Full text of DOI:10.1016/S0040-4039(02)00904-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5009–5012
[3,3]-Sigmatropic rearrangements: short, stereocontrolled
syntheses of functionalized vitamin D3 side-chain units
Mark A. Hatcher* and Gary H. Posner*
The Johns Hopkins University, Department of Chemistry, Charles and 34th Streets, Baltimore, MD 21218, USA
Received 26 March 2002; accepted 2 May 2002
Abstract—Enantiomerically pure C,D-ring allylic alcohol 4 stereospecifically undergoes five types of [3,3]-sigmatropic rearrange-
ments to give C-23 functionalized 16-ene vitamin D3 side-chain units with natural C-20(S) stereochemistry. © 2002 Elsevier
Science Ltd. All rights reserved.
The natural hormone 1a,25-dihydroxyvitamin D3 (cal-
citriol, 1) and some synthetic analogs are currently being
(1)
evaluated
as
drug
candidates
for
cancer
chemoprevention1 and chemotherapy,2 as well as for
treatment of other human diseases such as osteoporosis
and skin and immunological disorders.3,4 Synthesis of
rationally designed analogs5 of calcitriol (1) often
requires attaching a C,D-ring unit to an A-ring unit via
a Horner–Wadsworth–Emmons (HWE) coupling to
form the conjugated triene system (Fig. 1).6
allylic carbamates to form 16-ene units carrying a specific
side-chain (Eq. (2)).8 Now we report that C,D-ring,
enantiomerically pure, allylic alcohol 4, easily prepared
from known C,D-ring chiron 2,9 stereoselectively under-
goes five types of [3,3]-sigmatropic rearrangements form-
ing 16-ene products with natural C-20(S) stereo-
chemistry. These rearrangements produce synthetically
versatile side-chain units with different C-23 carbonyl
groups: an aldehyde, an ester, a ketone, an a-phenyl-
thioketone as well as a 23 sulfone (Scheme 1).10 It is
noteworthy that 16-ene side-chain sulfone analogs of
calcitriol (1) have recently been shown to have pharma-
cologically desirable therapeutic potential.11
Pioneering research at Hoffmann–La Roche Inc. estab-
lished that the presence of a double bond between carbon
atoms 16 and 17 often produces analogs having especially
desirable pharmacological characteristics; introduction
of such D16,17 unsaturation usually is achieved via a Lewis
acid-catalyzed ene reaction of a 17-ethylidene unit with
an aldehyde (Eq. (1)).7 Recently, Mourin˜o and co-work-
ers reported an effective procedure involving stereocon-
trolled organocuprate SN2% reactions with C,D-ring
Figure 1.
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00904-8

5010
M. A. Hatcher, G. H. Posner / Tetrahedron Letters 43 (2002) 5009–5012
(2)
In developing a general method for preparing 16-ene
C,D-ring synthons with natural C-20(S) stereochem-
istry, we envisioned various allylic vinyl ethers undergo-
ing [3,3]-sigmatropic rearrangement on the a face of the
D-ring (Eq. (3)). D-ring allylic vinyl ethers of this type
have previously been shown to undergo rearrangement
in steroidal, but not vitamin D, systems.12,13 As seen in
Eq. (3), this rearrangement proceeds via a 6-membered
ring, chair-like transition state giving the natural abso-
lute stereochemistry at C-20. In order to achieve these
rearrangements, by either stepwise or in situ prepara-
tion of an appropriate allylic vinyl ether, we produced
Scheme 1.
(3)

M. A. Hatcher, G. H. Posner / Tetrahedron Letters 43 (2002) 5009–5012
5011
Acknowledgements
allylic alcohol 4 (Scheme 1). This allylic alcohol was
synthesized stereoselectively14 from known ethylidene
D-ring 3 via a selenium dioxide oxidation15 in 79%
yield. The ene-like SeO2 oxidation occurs exclusively on
the a face of the D-ring due to the steric hindrance of
both the b-C-18 methyl group and b-C-8 triethylsiloxy
group.16,17 With allylic alcohol 4 in hand, five different
We thank the NIH (CA 44530) for generous financial
support. We also thank Ge Gao (JHU) for her experi-
mental help.
[3,3]-sigmatropic
rearrangements
were
achieved
(Scheme 1).18
References
1. Guyton, K. Z.; Kensler, T. W.; Posner, G. H. Ann. Rev.
Pharm. Tox. 2001, 41, 421–442.
2. Konety, B. R.; Johnson, C. S.; Trump, D. L.; Getzen-
berg, R. H. In Seminars in Urologic Oncology; 1999; Vol.
17, pp. 77–84.
3. Feldman, D.; Glorieux, F. H.; Pike, J. W. Vitamin D;
Academic Press: San Diego, CA, 1997.
4. Holick, M. F. Vitamin D: Molecular Biology, Physiology,
and Clinical Applications; Humana Press: Totowa, NJ,
1999.
5. Bouillon, R.; Okamura, W. H.; Norman, A. W.
Endocrine Rev. 1995, 16, 200–257.
6. Dai, H.; Posner, G. H. Synthesis 1994, 1383–1398.
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Reddy, S. G.; Campbell, M. J.; Koeffler, H. P. Curr.
Pharm. Des. 1997, 3, 99–123.
8. de los Angeles Rey, M.; Mart´ınez-Pe´rez, J. A.; Ferna´n-
dez-Gacio, A.; Halkes, K.; Fall, Y.; Granja, J.; Mourin˜o,
A. J. Org. Chem. 1999, 64, 3196–3206.
9. Posner, G. H.; Lee, J. K.; Wang, Q.; Peleg, S.; Burke, M.;
Brem, H.; Dolan, P.; Kensler, T. W. J. Med. Chem. 1998,
41, 3008–3014.
10. All new compounds were characterized spectroscopically
(including 1H and 13C NMR) and by high resolution
mass spectroscopy.
11. Posner, G. H.; Wang, Q.; Han, G.; Lee, J. K.; Crawford,
K.; Zand, S.; Brem, H.; Peleg, S.; Dolan, P.; Kensler, T.
W. J. Med. Chem. 1999, 42, 3425–3435.
12. Kozikowski, A. P.; Ames, A. J. Am. Chem. Soc. 1980,
102, 862–863.
13. Mikami, K.; Kawamoto, K.; Nakai, T. Chem. Lett. 1985,
115–118.
14. The C-16(R) stereochemistry of allylic alcohol 4 was
determined by X-ray crystallography of the correspond-
ing C,D-ring 8,16-diol (recrystallized in hexane/EtOAc,
1/1). We thank Professor Arnold L. Rheingold and co-
workers at the University of Delaware for this X-ray
result.
Reaction of allylic alcohol 4 with ethyl vinyl ether and
mercury diacetate afforded the desired enol ether,
which underwent thermal rearrangement in situ to give
known aldehyde 5, isolated and purified in 97% yield,
1
with only one diastereomer detected by H NMR spec-
troscopy. This aldehyde 5 is a synthetically useful inter-
mediate for the formation of a number of vitamin D3
analogs.9,11,19 Aldehyde 5 has previously been prepared
from ethylidine 2 in five steps (37% overall yield);9 in
sharp contrast, however, only three steps (76% overall
yield) characterize the new methodology shown in
Scheme 1 for preparation of aldehyde 5. Obtaining the
single C-20(S) diastereomer of aldehyde 5 further sup-
ports the C-16(R) absolute stereochemistry of the start-
ing allylic alcohol 4. Next, a Johnson-orthoester Claisen
rearrangement20 was achieved by reaction of alcohol 4
with trimethyl orthoacetate in the presence of a cata-
lytic amount of 2,4,6-trimethylbenzoic acid. This reac-
tion afforded methyl ester 6 in 83% yield, as determined
1
by both H NMR and gas chromatography (GC) using
an internal standard; no other diastereomer was
detectable by GC. An anion-assisted Carroll reaction
was performed via the b-keto ester prepared in 94%
yield from the reaction of 4 with diketene (Scheme 1).
This b-keto-ester formed a dianionic intermediate upon
reaction with 2 equiv. of sodium hydride and then
smoothly underwent rearrangement and in situ decar-
boxylation at 140°C to give the 16-ene-23-methyl
ketone 7, isolated and purified in 96% yield. Synthesis
of a 16-ene-25-sulfide C,D-ring side chain was accom-
plished via a Claisen rearrangement of an allylic vinyl
ether containing the desired sulfide side chain (Scheme
1). Thus, converting allylic alcohol 4 into an a-sulfide
ester using (phenylthio)acetyl chloride proceeded in
95% yield. Using Tebbe’s reagent, this ester was then
methenylated to form the corresponding allylic vinyl
ether, which thermally rearranged into the b-keto
phenyl sulfide 8 in 89% yield.21 Finally, 23-sulfone 9
was prepared through a Carroll-like rearrangement22 of
an a-phenyl sulfone ester in 59% overall yield (Scheme
1).
15. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc.
1977, 99, 5526–5528.
16. Snider, B. B.; Shi, B. Tetrahedron 1999, 55, 14823–14828.
17. Schmuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48,
1404–1412.
In summary, we have shown that diversely functional-
ized 16-ene vitamin D3 side-chain units, with natural
C-20(S) stereochemistry, are easily accessible through a
number of different [3,3]-sigmatropic rearrangements
using enantiomerically pure allylic alcohol 4. These
rearrangements proceed in high yield and with high
stereocontrol, and they provide synthetically versatile
side-chain units useful for subsequent elaboration into
many different and pharmacologically desirable analogs
of calcitriol (1).
18. Characteristic data are as follows: (−)-4: mp 38–41°C;
1
[h]2D5 −20.9 (c 0.46, CHCl3); H NMR (400 MHz, CDCl3)
l 5.50 (dq, J=7.2, 1.2 Hz, 1H), 4.43 (d, J=6.4 Hz, 1H),
4.13 (d, J=2.8 Hz, 1H), 2.24 (dt, J=12.0, 3.2 Hz, 1H),
1.97 (ddd, J=13.2, 6.4, 0.8 Hz, 1H), 1.87 (dt, J=13.2, 4.0
Hz, 1H), 1.84–1.76 (m, 1H), 1.75–1.66 (m, 1H), 1.71 (dd,
J=7.2, 1.2 Hz, 3H), 1.61–1.53 (m, 1H), 1.51–1.40 (m,
4H), 1.08 (s, 3H), 0.94 (t, J=8.0 Hz, 9H), 0.55 (q, J=8.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) l 156.19, 118.17,
73.48, 69.33, 49.11, 44.39, 38.20, 34.76, 34.40, 20.18,

5012
M. A. Hatcher, G. H. Posner / Tetrahedron Letters 43 (2002) 5009–5012
17.79, 13.04, 6.88, 4.85; IR (CHCl3, cm−1) 3341, 2997,
CDCl3) l 7.31–7.23 (m, 4H), 7.17 (m, 1H), 5.23 (m, 1H),
4.07 (m, 1H), 3.62 (d, J=1.6 Hz, 2H), 2.81 (dd, J=15.6,
6.0 Hz, 1H), 2.64 (m, 1H), 2.57 (dd, J=16.0, 7.6 Hz, 1H),
2.15 (tt, J=13.2, 1.6 Hz, 1H), 1.91–1.77 (m, 2H), 1.72–
1.63 (m, 2H), 1.59–1.54 (m, 1H), 1.48–1.37 (m, 2H), 1.31
(dt, J=12.8, 3.6 Hz, 1H), 0.95 (d, J=7.2 Hz, 3H), 0.92 (s,
3H), 0.92 (t, J=8.0 Hz, 9H), 0.53 (q, J=8.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) l 204.70, 159.44, 134.91,
129.38, 129.04, 126.68, 120.60, 68.83, 54.94, 47.45, 46.89,
44.20, 35.83, 34.81, 30.68, 27.50, 21.82, 18.75, 18.02, 6.93,
4.89; HRMS m/z (M+) calcd 418.256695 for
C27H42O2SSiNa+ found 481.25422. (+)-9: [h]2D5 +18.6 (c
2876, 1379, 1107, 1019; HRMS m/z (M+) calcd 333.2220
for C18H34O2SiNa+ found 333.2233. (+)-5: [h]2D5 +38.8 (c
7.1, CHCl3); 1H NMR (400 MHz, CDCl3) l 9.63 (t,
J=2.4 Hz, 1H), 5.30 (t, J=1.6 Hz, 1H), 4.11 (m, 1H),
2.75–2.66 (m, 1H), 2.58 (dd, J=8.0, 2.8 Hz, 1H), 2.41
(dd, J=7.4, 2.0 Hz, 1H), 2.24 (tt, J=13.2, 1.2 Hz, 1H),
1.92–1.83 (m, 2H), 1.77–1.61 (m, 3H), 1.53–1.44 (m, 2H),
1.43–1.35 (m, 1H), 1.06 (d, 3H), 1.03 (s, 3H), 0.94 (t,
J=8.0 Hz, 9H), 0.55 (q, J=8.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) l 203.09, 158.68, 121.78, 68.79, 54.94,
49.93, 46.89, 35.90, 34.80, 30.75, 26.59, 22.00, 18.98,
1
18.02, 6.91, 4.88. (+)-6: [h]2D5 +34.8 (c 0.795, CHCl3); H
1
0.520, CHCl3); H NMR (400 MHz, CDCl3) l 7.91 (m,
NMR (400 MHz, CDCl3) l 5.31 (t, J=1.6 Hz, 1H), 4.11
(m, 1H), 3.64 (s, 3H), 2.62 (m, 1H), 2.51 (dd, J=14.8, 6.8
Hz, 1H), 2.36 (dd, J=14.8, 8 Hz, 1H), 2.23 (m, 1H),
1.95–1.83 (m, 2H), 1.75 (m, 1H), 1.67 (m, 1H), 1.61 (m,
1H), 1.50–1.33 (m, 4H), 1.02 (d, J=6.8, 3H), 1.00 (s, 3H),
0.94 (t, J=8.0 Hz, 9H), 0.55 (q, J=8.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) l 173.23, 159.09, 120.59, 68.86,
54.91, 51.35, 46.91, 41.49, 35.84, 34.86, 30.76, 28.68,
21.76, 18.63, 18.05, 6.92, 4.88. (+)-7: [h]2D5 +36.6 (c 0.635,
CHCl3); 1H NMR (400 MHz, CDCl3) l 5.28 (m, 1H),
4.11 (d, J=2.0 Hz, 1H), 2.69–2.60 (m, 2H), 2.48–2.41 (m,
1H), 2.27–2.19 (m, 1H), 2.11 (s, 3H), 1.91–1.83 (m, 2H),
1.78–1.74 (m, 1H), 1.69–1.58 (m, 2H), 1.50–1.42 (m, 1H),
1.42–1.33 (m, 1H), 1.01 (s, 3H), 0.99 (d, J=6.8 Hz, 3H),
0.94 (t, J=8.0 Hz, 9H), 0.55 (q, J=8.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) l 208.53, 159.58, 120.53, 68.85,
54.95, 50.78, 46.91, 35.91, 34.82, 30.71, 30.40, 27.59,
21.82, 18.84, 18.05, 6.92, 4.89; HRMS m/z (M+) calcd
373.253325 for C21H38O2SiNa+ found 373.25229. (+)-8:
[h]2D5 +28.6 (c 0.765, CHCl3); 1H NMR (400 MHz,
2H), 7.64 (m, 1H), 7.56 (m, 2H), 5.24 (m, 1H), 4.07 (m,
1H), 3.27 (dd, J=14.0, 3.6 Hz, 1H), 3.18 (dd, J=14.0, 9.2
Hz, 1H), 2.70 (m, 1H), 2.16 (t, J=13.2, 1H), 1.87–1.77
(m, 2H), 1.67–1.52 (m, 2H), 1.46–1.36 (m, 2H), 1.27 (m,
1H), 1.21 (d, J=7.2 Hz, 3H), 0.93 (t, J=8.0 Hz, 3H),
0.89 (s, 3H, 0.53 (q, J=8.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) l 158.18, 140.13, 133.48, 129.19, 127.89,
122.30, 68.69, 62.54, 54.74, 47.07, 35.51, 34.68, 30.75,
26.97, 21.67, 18.86, 17.90, 6.90, 4.86; HRMS m/z (M+)
calcd 471.235960 for C25H40O3SSiNa+ found 471.232612.
19. Posner, G. H.; Halford, B. A.; Peleg, S.; Dolan, P.;
Kensler, T. W. J. Med. Chem. 2002, 45, 1723–1730.
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