A synthetic approach toward nitiol: Construction of two 1,22-dihydroxynitianes

Article abstract of DOI:10.1021/jo0604585

Synthetic work toward the total synthesis of nitiol has culminated in the construction of two epimeric hydroxylated derivatives, the 1,22- dihydroxynitianes. Key stereodefining steps in the construction of the A-ring fragment (13) were the use of a siloxy-epoxide rearrangement reaction, a Pauson-Khand reaction, a Norrish 1 photochemical cleavage reaction, and a highly regio- and stereoselective hydrostannylation reaction of an ynoate. The stereochemistry of the synthetically challenging C-ring fragment (20) was established using an Ireland-Claisen reaction and a Grubbs ring-closing metathesis process as key steps. The 12-membered B-ring of the nitiane skeleton was constructed using a copper-promoted Stille cross-coupling and a Kishi-Hiyama-Nozaki carbonyl addition reaction. Unfortunately, the carbonyl addition reaction produced hydroxyl functionality that could not be selectively removed. Consequently, a synthesis of epimeric 1,22-dihydroxynitianes, which are compounds that are structural hybrids of two natural products, nitiol and variculanol, was completed.

Full text of DOI:10.1021/jo0604585

A Synthetic Approach toward Nitiol: Construction of Two
1,22-Dihydroxynitianes
Michael S. Wilson, Jacqueline C. S. Woo, and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, B.C., Canada V6T 1Z1
gdake@chem.ubc.ca
ReceiVed March 2, 2006
Synthetic work toward the total synthesis of nitiol has culminated in the construction of two epimeric
hydroxylated derivatives, the 1,22-dihydroxynitianes. Key stereodefining steps in the construction of the
A-ring fragment (13) were the use of a siloxy-epoxide rearrangement reaction, a Pauson-Khand reaction,
a Norrish 1 photochemical cleavage reaction, and a highly regio- and stereoselective hydrostannylation
reaction of an ynoate. The stereochemistry of the synthetically challenging C-ring fragment (20) was
established using an Ireland-Claisen reaction and a Grubbs ring-closing metathesis process as key steps.
The 12-membered B-ring of the nitiane skeleton was constructed using a copper-promoted Stille cross-
coupling and a Kishi-Hiyama-Nozaki carbonyl addition reaction. Unfortunately, the carbonyl addition
reaction produced hydroxyl functionality that could not be selectively removed. Consequently, a synthesis
of epimeric 1,22-dihydroxynitianes, which are compounds that are structural hybrids of two natural
products, nitiol and variculanol, was completed.
Introduction
transcription are calcineurin inhibitors (cyclic polypeptides or
macrolides), 1 or its structural relatives are suggested to be
useful tools for the discovery of novel signal transduction
pathways guiding the transcription of the IL-2 gene.
Gentianella nitida (Gentianaceae), commonly known as
“Hercampuri” or “Hircampure”, is a biennial medicinal plant
from the Andes region of Peru. Aqueous extracts of the whole
plants are used in traditional Peruvian folk medicine. Chemical
investigations of G. nitida by Kawahara and co-workers led to
the discovery of the novel sesterterpenoids nitiol (1) and
nitidasin (Figure 1).1 The Kawahara group assessed the capabil-
ity of these terpenoids to modulate the gene expression of
interleukin-2 (IL-2) in Jurkat cells, a human T-cell line, using
a competitive PCR-based bioassay.2 After incubation for 6 h,
the IL-2 mRNA level in the cells treated with 1 was roughly
three times higher than that in the control cell line. Nitisadin
had no significant effect. Thus, 1 appears to be an enhancer of
IL-2 gene expression. As other known modulators of IL-2 gene
The structural complexity of 1 is characterized by a number
of features. Two five-membered rings are fused to a central 12-
membered macrocycle that contains two trisubstituted alkenes.
In addition, the isopropyl group at C18 in the A ring is cis to
the C23 methyl group at the ring junction. These structural
attributes are also observed in the presumably biosynthetically
related compound, variculanol, which was isolated in 1991.3
The structural complexity of 1, paired with its potential
biological activity, prompted us to initiate a program targeted
toward its synthesis.
Analysis of 1 suggested a bifurcative synthetic approach
(Scheme 1). Disconnection of the C1-C2 bond produced an
uncyclized precursor. In the synthetic direction, a number of
possibilities, including a carbonyl addition reaction, a transition-
(1) Nitiol: (a) Kawahara, N.; Nozawa, M.; Kurata, A.; Hakamatsuka,
T.; Sekita, S.; Satake, M. Chem. Pharm. Bull. 1999, 47, 1344. Nitidasin:
(b) Kawahara, N.; Nozawa, M.; Flores, D.; Bonilla, P.; Sekita, S.; Satake,
M. Kawai, K.-I. Chem. Pharm. Bull. 1997, 45, 1717.
(3) Singh, S. B.; Reamer, R. A.; Zink, D.; Schmatz, D.; Dombrowski,
(2) Hakamatsuka, T.; Tanaka, N. Bio. Pharm. Bull. 1997, 20, 464.
A.; Goetz, M. A. J. Org. Chem. 1991, 56, 5618.
10.1021/jo0604585 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/02/2006
J. Org. Chem. 2006, 71, 4237-4245
4237

Wilson et al.
FIGURE 1. Nitiol and structurally related compounds.
SCHEME 1. Analysis of 1
SCHEME 2. Analysis of the A-Ring Fragment
metal-catalyzed coupling process, or a tandem carbometalation-
SN2 displacement, were envisioned to connect this crucial ring-
forming bond. The necessary double bond geometry prior to
the ring-closing reaction would be generated by regio- and
stereoselective carbometalation of a terminal alkyne. Subsequent
disconnection of the C10-C11 bond generates two halves, A
and B. The construction of that bond was conceived to be
possible using standard palladium(0)-catalyzed cross-coupling
protocols.
Functionalized cyclopentane A, the “A-ring” of nitiol,
contains a cis stereochemical relationship between the C23
methyl group and isopropyl groups at C18 (nitiol numbering)
in addition to what will become the trans ring junction of the
A-B ring system. A key issue in any construction of nitiol is
the establishment of the configuration of the isopropyl moiety
on the cyclopentane A ring.4 A classic method for setting
stereochemistry is to use the bias of a cyclic system, after which
the ring is broken open. A trans-hydrindane ring system may
seem like an appropriate precursor to A. However, it is well
established that reactions generating trans-hydrindanes bearing
pendant methyl and isopropyl groups on the five-membering
ring almost exclusively result in a trans relationship between
the methyl and isopropyl groups.5 For this reason, the confor-
mational bias of a [3.3.0]bicyclooctane system was a key design
element in our synthetic approach to A. As envisioned, this
conformational bias would control the (relative) stereochemical
outcomes of reactions that established the stereogenic centers
at C17 and C18 (Scheme 2). A number of methods were
conceived to cleave the designated bond in the bicyclooctane,
including a Baeyer-Villiger reaction, a fragmentation proceed-
ing through an oxygen-based radical or a Norrish type 1 process.
The required bicyclooctane was thought to be obtainable using
a carbonylative cycloisomerization of an appropriate enynes
specifically the Pauson-Khand reaction.6,7 Of interest to us was
the question of diastereoselectivity in the Pauson-Khand process.
Earlier elegant studies had examined the stereoselectivity of
cyclizations of enynes containing substituents at the allylic or
propargylic positions. In general, the reaction path placed the
larger substituent on the exo face of the bicycle in the major
product.8 In this proposed application of the Pauson-Khand
reaction, would there be enough steric differentation between a
methyl group and a protected hydroxymethylene group to
achieve reasonable amounts of the desired diastereomer? As
this reaction would establish the necessary trans-ring junction
for the A-B ring fusion in 1, this consideration was an
important issue at the outset.
(6) Reviews dealing with the Pauson-Khand reaction: (a) Gibson, S.
E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022. (b) Gibson, S. E.;
Lewis, S. E.; Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873. (c) Blanco-
Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Dominguez, G.; Perez-Castells,
J. Chem. Soc. ReV. 2004, 33, 32. (d) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263. (e) Schore, N. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, p 1037. (f) Schore, N. E. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1991; Vol. 40, p 2. (g) An
interesting overview of other synthetic processes under the conditions of
the Pauson-Khand reaction: Bonaga, L. V. R.; Krafft, M. E. Tetrahedron
2004, 60, 9795.
(7) Examples of recent synthetic work using the Pauson-Khand reaction
as a critical step: (a) Winkler, J. D.; Lee, E. C. Y.; Nevels, L. I. Org. Lett.
2005, 7, 1489. (b) Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi,
T. Tetrahedron 2005, 61, 4053. (c) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.;
Deng, L.; Chen, J.; Yang, Z. Org. Lett. 2005, 7, 885. (d) Chan, J.; Jamison,
T. F. J. Am. Chem. Soc. 2004, 126, 10682.
(4) For synthetic sequences to produce structures related to that of the
nitiol A-ring, see: (a) Kato, N.; Wu, X.; Nishikawa, H.; Nakanishi, K.;
Takeshita, H. J. Chem. Soc., Perkin Trans. 1 1994, 1047. (b) Kato, N.;
Wu, X.; Nishikawa, H.; Takeshita, H. Synlett 1993, 293. (c) Mehta, G.;
Krishnamurthy, N.; Karra, S. R. J. Am. Chem. Soc. 1991, 113, 5765. (d)
Mehta, G. Pure Appl. Chem. 1990, 62, 1263. (e) Mehta, G.; Krishnamurthy,
N.; Karra, S. R. J. Chem. Soc., Chem. Commun. 1989, 1299. (f) Mehta, G.;
Krishnamurthy, N. Tetrahedron Lett. 1987, 28, 5945.
(5) See, for example, in retigeranic acid A-ring construction: (a) Corey,
E. J.; Desai, M. C.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339. (b)
Snider, B. B.; Rodini, D. J.; van Straten, J. J. Am. Chem. Soc. 1980, 102,
5872. (c) Attah-Poku, S. K.; Chau, F.; Yadav, V. K.; Fallis, A. G. J. Org.
Chem. 1985, 50, 3418.
(8) (a) Mukai, C.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M. Tetrahe-
dron Lett. 1995, 36, 5761. (b) Mukai, C.; Kim, J. S.; Uchiyama, M.;
Sakamoto, S.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1998, 2903. (c)
Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851. (d) Magnus,
P.; Becker, D. J. Am. Chem. Soc. 1987, 109, 7495 and references therein.
4238 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Approach toward Nitianes
SCHEME 3. Analysis of the C-Ring Fragment
set the stage for the siloxy-epoxide rearrangement reaction.
Following the procedures of Yamamoto, the treatment of 4
with methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide)
(MABR), a bulky aluminum-based Lewis acid, in CH2Cl2 from
-78 -40 °C generated aldehyde 5 in 95% yield (94% ee).16
As precedented, this rearrangement proceeded with rigorous
chirality transfer arising from antiperiplanar migration of the
siloxymethylene function to the epoxide moiety. This syntheti-
cally valuable transformation is highly recommended. The
spectral data for 5 produced in this manner was identical to
that of the previously prepared sample of racemic 5.11
The “C-ring” fragment B (X ) halogen, pseudohalogen, or
metal), which contains a protected hydroxyl function as a
synthetic precursor to an alkyne function, was believed to be
most directly derivable from a cis-2,3-disubstituted cyclopen-
tanone or a cis-4,5-disubstituted 2-cyclopentenone (Scheme 3).
There were a number of concerns, though. One was the known
sensitivity of compounds of these types to epimerization or
alkene migration processes. As those destructive pathways are
promoted by acidic, basic, or thermal conditions, care would
be necessary in the preparation, handling, and further reactions
of such a synthetic intermediate.9 In addition, although synthetic
protocols to generate such cis-disubstituted ketones have been
reported, these have limitations in terms of generality, and
importantly, most are not easily adaptable for the formation of
enantioenriched material.9,10 Therefore, our enantioselectiVe
synthetic route to B would have to incorporate mild conditions
to minimize destructive side reactions. It would be also be useful
for the synthetic community if this method could be generally
adaptable for the construction of structurally related cis-2,3-
disubstituted cyclopentanones. This report summarizes our
efforts toward that end.
With multigram quantities of enantioenriched 5 available,
efforts were focused on advancing this material to the fully
functionalized A-ring fragment. A standard Wittig olefination
reaction was used to convert 5 to enyne 6 (95%). A number of
conditions for the Pauson-Khand reaction were screened during
our earlier studies. The treatment of enyne 6 with Co2(CO)8,
powdered 4 Å molecular sieves, and NMO resulted in the
production of a 6:1 ratio of bicycles 7a and 7b in 86% yield.17
Separation of the diastereomers was readily performed using
column chromatography. The relative stereochemistry of each
diastereomer was supported through selective NOE experiments.
Treatment of 7a with lithium tri-sec-butylborohydride (L-
Selectride) in THF at -78 °C generated, in a site-selective
manner, the more substituted enolate which was subsequently
quenched with methyl iodide to yield 8 in 92% yield. The [3.3.0]
bicyclic framework ensured that the conjugate reduction oc-
curred to produce a cis-ring junction, thus establishing the
stereochemical identity for what would become the C18
isopropyl group in the nitiol A-ring. Although a number of
options to cleave the bicycle were entertained, the first process
we selected turned out to be most effective for our purposes
(Scheme 5). In an optimized, gram-scale experiment, ketone 8
was dissolved in dry methanol (to a 0.01 M solution) in a quartz
flask and subjected to UV light for roughly 24 h to produce
ester 9 in 82% yield (90% based on recovered starting material).
This Norrish type 1 fragmentation process is envisoned as
proceeding through an excited state that undergoes homolytic
cleavage of the more electron-rich R-bond.18 After intersystem
crossing of the resulting biradical, a hydrogen abstraction forms
a ketene intermediate that reacts with methanol, the solvent, to
produce 9. The Norrish type 1 fragmentation works exceedingly
well in the context of this synthetic route.19 The isopropyl group
of the A-ring is established in high yield without the need for
the removal of extra functional groups.
Results and Discussion
Enantioselective Synthesis of the A-Ring Fragment. The
preparation of an A-ring fragment in enantioenriched form was
patterned on our previously reported synthetic route to a racemic
A-ring fragment (Scheme 4).11 However, the establishment of
the quaternary stereogenic center in an enantiocontrolled manner
was required. To that end, we opted to use a siloxy-epoxide
rearrangement reaction to construct the quaternary center.12 Allyl
alcohol 2, which is readily available from geraniol,13 was
subjected to standard Sharpless epoxidation conditions to
produce epoxy alcohol 3 in 93% yield (94% ee).14,15 Protection
of the alcohol function of 3 as its tert-butyldimethylsilyl ether
As we had decided to prepare the A-ring fragment as the
organometallic component for a potential cross-coupling reac-
(9) Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008.
(10) (a) Mander, L. N.; Thomson, R. J. J. Org. Chem. 2005, 70, 1654.
(b) Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002, 67, 4346. (c)
Zanoni, G.; Porta, A.; Castronovo, F.; Vidari, G. J. Org. Chem. 2003, 68,
6005. (d) Crombie, L.; Mistry, K. M. J. Chem. Soc., Perkin Trans. 1 1991,
1981. (e) Helmchen, G.; Ernst, M. Angew. Chem., Int. Ed. 2002, 41, 4054.
(f) Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438. (g) Whitesell,
J. K.; Minton, M. J. Am. Chem. Soc. 1987, 109, 6403.
(14) (a) The Sharpless epoxidation of 2 has been reported previously:
Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990, 46,
7033. (b) Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 102, 5974.
(c) Gao, Y.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765.
(11) Wilson, M. S.; Dake, G. R. Org. Lett. 2001, 3, 2041.
(12) For syntheses of compounds that utilize a siloxy-epoxide rear-
rangement reaction as a key step, see: (a) Saito, T.; Suzuki, T.; Morimoto,
M.; Akiyama, C.; Ochiai, T.; Takeuchi, K.; Matsumoto, T.; Suzuki, K. J.
Am. Chem. Soc. 1998, 120, 11633. (b) Eom, K. D.; Raman, J. V.; Kim, H.;
Cha, J. K. J. Am. Chem. Soc. 2003, 125, 5415. (c) Kita, Y.; Kitagaki, S.;
Yoshida, Y.; Mihara, S.; Fang, D.-F.; Kondo, M.; Okamoto, S.; Imai, R.;
Akai, S.; Fujioka, H. J. Org. Chem. 1997, 62, 4991. (d) Jung, M. E.;
Marquez, R. Org. Lett. 2000, 2, 1669. (e) Fenster, M. D. B.; Dake, G. R.
Chem.sEur J. 2005, 11, 639.
(13) (a) Muto, S.-E.; Nishimuram Y.; Mori, K. Eur. J. Org. Chem. 1999,
2159. (b) Halcomb, R. L.; Mohr, P. J. J. Am. Chem. Soc. 2003, 125, 1712.
For an earlier synthesis of 2, see: (c) Abidi, S. L. J. Org. Chem. 1986, 51,
2687.
(15) The ee for this reaction was established by converting 3 to its (R)-
(-)-O-acetylmandelic ester. See the Supporting Information for details.
(16) (a) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989,
111, 6431. (b) Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamoto, H.
Tetrahedron 1991, 47, 6983.
(17) Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Perez-Castells,
J. Org. Lett. 1999, 1, 1187.
(18) Reviews: (a) Bohne, C. In CRC Handbook of Photochemistry and
Photobiology; Harspool, W. M., Song, P. S., Eds.; CRC Press: New York,
1995; Chapter 34, pp 416-422. (b) Bohne, C. In CRC Handbook of
Photochemistry and Photobiology; Harspool, W. M., Song, P. S., Eds.; CRC
Press: New York, 1995; Chapter 35, pp 423-436. (c) Horspool, W. M.
Photochemistry 1994, 25, 67.
J. Org. Chem, Vol. 71, No. 11, 2006 4239

Wilson et al.
SCHEME 4. Enantioselective Construction of the A-Ring Fragmenta
a Reaction conditions: (a) Ti(O-i-Pr)4, (-)-DIPT, t-BuOOH, 4 Å MS, CH2Cl2, -20 °C (93%, 94% ee); (b) TBSCl, imidazole, DMF, rt (97%); (c)
MABR, CH2Cl2, -78 to -40 °C (95%); (d) KHMDS, CH3PPh3Br, THF, -78 °C to rt (95%); (e) Co2(CO)8, 4 Å MS, NMO (9 equiv), CH2Cl2 (86%, 6.2:1
of 7a/7b); (f) (i) LiHB(s-Bu)3, THF, -78 °C, (ii) CH3I, -78 °C to rt (92%); (g) hν (>190 nm), quartz filter, 0.01 M in CH3OH, 28 h (90% brsm); (h)
DIBAL-H, CH2Cl2, -78 °C to rt (91%); (i) (COCl)2, DMSO, Et3N, CH2Cl2, -60 °C (92%); (j) Ohira-Bestmann phosphonate (10), K2CO3, CH3OH, 0 °C
to rt (94%); (k) LDA, ClCO2CH3, THF, -78 °C to rt (95%); (l) Bu3SnH, Pd(PPh3)4 (3 mol %), THF, rt (96%).
SCHEME 5. Norrish Fragmentation Reaction
Enantioselective Synthesis of the C-Ring Fragment. Allyl
alcohol 14, available by minor modification of the known kinetic
resolution of the racemic alcohol using a Sharpless epoxida-
tion,22 was esterified with 5-(p-methoxylbenzyl)oxypentanoic
acid23 using DCC and DMAP (Scheme 6). Conversion of this
ester to its (E)-ketene silyl acetal using literature conditions ((i)
NEt3, TMSCl, -78 °C; (ii) LDA, -78 °C) followed by heating
produced, after aqueous workup, carboxylic acid 16.24 The well-
accepted chair topology in the transition state of the Ireland-
Claisen reaction provided excellent transmission of stereochem-
ical information from the starting material to the desired product.
Conversion of the carboxylic acid to its corresponding Weinreb
amide proved to be quite difficult, and so specific conditions
were developed to circumvent this problem.25 To that end, the
reaction of 16 with methanesulfonyl chloride (1.1 equiv) and
triethylamine (3 equiv) followed by N,O-dimethylhydroxylamine
(1.5 equiv) produced the Weinreb amide in 80% yield. Its
conversion to enone 17 was smoothly carried out using
vinylmagnesium bromide. Ring-closing metathesis using a
second-generation Grubbs catalyst 18 in degassed dichlo-
romethane produced functionalized cyclopentanone 19 in 81%
yield.26,27 Interestingly, the remainder of the product mixture
tion, the stereocontrolled preparation of an appropriate vinyl-
stannane was a key problem. Further processing of 9 using
relatively standard synthetic manipulations (reduction, oxidation,
alkyne formation using the Ohira-Bestmann phosphonate 10,20
alkyne methoxycarbonylation) provided ynoate 12 in excellent
yield. Treatment of 12 with tri-n-butyltin hydride in the presence
of 3 mol % of tetrakis(triphenylphosphine)palladium(0) gener-
ated vinylstannane 13 in 96% yield in a regio- and stereocon-
trolled manner.21 Slow addition of the tin hydride over 45 min
to the reaction mixture was crucial to produce consistently
satisfactory results. This sequence enabled the preparation of
multigram quantities of 13, a suitable A-ring fragment.
(22) Wessel, T. A.; Berson, J. A. J. Am. Chem. Soc. 1994, 116, 495.
“Aging” of the reaction components at -20 °C rather than -40 °C for 30
min prior to the addition of oxidant was important to achieve high
selectivities. Our attempts to resolve this alcohol using enzyme catalysis
gave unsatisfactory results.
(23) This compound was generated from monoprotection of 1,5-
dihydroxypentane (NaH, PMBCl) followed by a Jones oxidation (CrO3,
sulfuric acid, acetone).
(24) (a) Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991,
56, 650. (b) Boeckman, R. K.; Napier, J. J.; Thomas, E. W.; Sato, R. I. J.
Org. Chem. 1983, 43, 4152. (c) Kurth, M. J.; Burns, D. H.; O’Brien, D. H.
J. Org. Chem. 1984, 49, 731. For a recent review of the Ireland-Claisen
rearrangement, see: (d) Chai, Y.; Hong, S.; Lindsay, H. A.; McFarland,
C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905.
(19) For examples of the use of Norrish 1 chemistry in synthesis, see:
(a) Nicolaou, K. C.; Gray, D.; Tae, J. S. Angew. Chem., Int. Ed. 2001, 40,
3675. (b) Muraoka, O.; Okumura, K.; Maeda, T.; Wang, L.; Tanabe, G.
Chem. Pharm. Bull. 1995, 43, 517. (c) Muraoka, O.; Okumura, K.; Maeda,
T.; Tanabe, G.; Momose, T. Tetrahedron: Asymmetry 1994, 5, 317. (d)
Hwu, J. R.; Gilbert, B. A.; Lin, L. C.; Liaw, B. R. J. Chem. Soc., Chem.
Commun. 1990, 161. (e) Morizur, J. P.; Tortajada, J. Bull. Chim. Soc. Fr.
1983, II-175. (f) Kossanyi, J.; Furth, B.; Morizur, J. P. Tetrahedron Lett.
1973, 36, 3459. (g) Bidan, G.; Kossanyi, J.; Meyer, V.; Morizur, J. P.
Tetrahedron 1977, 33, 2193.
(20) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mu¨ller, S.; Liepold,
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(25) Woo, J. C. S.; Fenster, E.; Dake, G. R. J. Org. Chem. 2004, 69,
8984.
(21) (a) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem.
2002, 67, 5167. (b) Rossi, R.; Carpita, A.; Cossi, P. Tetrahedron 1992, 48,
8801. (c) Bew, S. P.; Sweeney, J. B. Synlett 1991, 109. (d) Cochran, J. C.;
Terrence, K. M.; Phillips, H. K. Organometallics 1991, 10, 2411. (e)
Cochran, J. C.; Bronk, B. S.; Terrence, K. M.; Phillips, H. K. Tetrahedron
Lett. 1990, 31, 6621. (f) Cochran, J. C.; Williams, L. E.; Bronk, B. S.;
Calhoun, J. A.; Fassberg, J.; Clark, K. Organometallics 1989, 8, 804.
(26) (a) Chatterjee, A. K.; Morgan, J. P. Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3873. (b) Garber, S. B.; Kingsbury, J. S.; Gray,
B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. (c) Wilhelm, T.
E.; Belderrain, T. R.; Brown, S. N.; Grubbs, R. H. Organometallics 1997,
16, 3867. (d) Christ, M. L.; Sabo-Etienne, S.; Chaudret, B. Organometallics
1994, 13, 3800.
4240 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Approach toward Nitianes
SCHEME 6. Enantioselective Construction of the C-Ring Fragmenta
a Reaction conditions: (a) 5-(p-methoxybenzyl)oxypentanoic acid, DCC, DMAP, CH2Cl2, 0 °C to rt (85%); (b) (i) TMSCl, NEt3, THF, -78 °C, (ii) LDA,
-78 to +60 °C, (iii) 1 N HCl (91%); (c) (i) MsCl, NEt3, N,O-dimethylhydroxylamine, THF, 0 °C (80%); (d) vinylmagnesium bromide, THF, 0 °C to rt
(82%); (e) 18 (5 mol %), CH2Cl2, 40 °C (reflux) (81%); (f) (i) LiHB(s-Bu)3, THF, -78 °C, (ii) PhNTf2 (69%); (g) H2, Pd/C (88%); (h) LHMDS, PhNTf2,
THF, -78 °C to rt (43%).
SCHEME 7. Fragment Couplinga
from the metathesis reaction resulted from dimerization of 17
at the enone function. Reactions using the related benzylidene
catalyst from Aldrich resulted in lower yields (∼50-60%) of
19 due to increased cross-metathesis. The diastereomeric ratio
of 19 to its trans epimer (synthesized independently, see below)
after the metathesis reaction was 12:1, satisfactory for our
purposes.
Conversion of 19 to the substituted C-ring fragment could
be carried out by one of two methods. Catalytic hydrogenation
of 19 could subsequently be followed by kinetic enolization
(LHMDS, -78 °C) with subsequent reaction with N-phenyl-
triflimide to produce 20 with minimal epimerization. An
alternate route that was also explored was the reaction of enone
19 with L-Selectride followed by quenching with N-phenyltri-
flimide to produce 20 in 69% yield.28 Of the two protocols, the
latter proved to be more convenient. To ensure that minimal
epimerization occurred along this synthetic sequence, the trans-
disubstituted diastereomer of 20 (in racemic form) was con-
structed following this protocol in Scheme 6 using the (Z)-
diastereomer of 15 as the starting material.29 It could be
established that 20 was produced in a 10:1 diastereomeric ratio.
Fragment Coupling. The two fragments 13 and 20 were
combined using a Stille reaction modified by the addition of a
Cu(I) reagent (Scheme 7).30 This process proceeded efficiently
in 74% yield using 10 mol % of tetrakis(triphenylphosphine)-
palladium(0), CuCl (5 equiv), and LiCl (6 equiv) in DMSO at
a Reaction conditions: (a) Pd(PPh3)4 (10 mol %), CuCl (5 equiv), LiCl
(6 equiv), DMSO, rt to 60 °C (74%); (b) DIBAL-H, CH2Cl2, -78 °C (87%);
(c) TBDPSCl, imidazole, DMF, 0 °C to rt (93%); (d) catecholboron bromide
(3 equiv), 2,6-lutidine, 0 °C (91%); (e) Dess-Martin periodinane (5 equiv),
2,6-lutidine (87%); (f) phosphonate 10, K2CO3, CH3OH, 0 °C to rt (96%);
(g) (CH3CN)2PdCl2 (5 mol %), acetone/H2O, 75 °C (77%, 90% based on
recovered starting material).
60 °C. At this point, the ester functionality was reduced to an
alcohol and protected at its tert-butyldiphenyl silyl ether. The
p-methoxybenzyl ether proved to be quite resistant to depro-
tection without affecting the conjugated diene. Both DDQ and
CAN cleaved the benzyl ether, but each reagent also appeared
to isomerize the alkene within the C-ring to form a tetrasub-
stituted alkene. After significant experimentation, catecholboron
bromide in the presence of 2,6-lutidine was found to cleanly
deprotect the PMB ether in excellent yield (91%).31 Oxidation
of the alcohol function in 23 using Dess-Martin periodinane32
and reaction with the Ohira-Bestmann phosphonate20 furnished
the terminal alkyne 25 in 85% yield (over two steps). At this
point, deprotection of the tert-butyldimethylsilyl ether within
25 in the presence of the tert-butyldiphenyl silyl ether was
necessary. The reaction of 25 with 5 mol % of bis(acetonitrile)-
palladium chloride with water (5 equiv) in acetone at 75 °C,
(27) For pioneering examples of the use of Claisen and RCM reactions
in sequence to produce stereodefined cyclic compounds, see: (a) Miller, J.
F.; Termin, A.; Koch, K.; Piscopio, A. D. J. Org. Chem. 1998, 63, 3158.
(b) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org. Chem.
1998, 63, 3160. (c) Souers, A. J.; Ellman, J. A. J. Org. Chem. 2000, 65,
1222. (d) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.;
Braddock, D. C.; Procopiou, P. A.; White, A. J. P.; Williams, D. J. J. Org.
Chem. 2000, 65, 3716. (e) Francais, A.; Bedel, O.; Picoul, W.; Meddour,
A.; Courtieu, J.; Haudrechy, A. Tetrahedron: Asymmetry 2005, 16, 1141.
(f) Fujiwara, K.; Goto, A.; Sato, D.; Kawal, H.; Suzuki, T. Tetrahedron
Lett. 2005, 46, 3465.
(28) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335.
(29) Please refer to the Supporting Information for details.
(30) (a) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600. (b) Piers, E.; Yee, J. G. K.; Gladstone, P. L. Org. Lett. 2000, 2,
481. (c) Piers, E.; McEachern, E. J.; Romero, M. A.; Gladstone, P. L. Can.
J. Chem. 1997, 75, 694.
(31) Boeckman, R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.
(32) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
J. Org. Chem, Vol. 71, No. 11, 2006 4241

Wilson et al.
SCHEME 8. Macrocyclization by Carbonyl Additiona
a Reaction conditions: (a) (i) Al(CH3)3, Cp2ZrCl2, CH2Cl2, -20 °C to rt, (ii) I2, THF, -30 °C to rt (82%); (b) Dess-Martin periodinane, 2,6-lutidine,
CH2Cl2 (90%); (c) NiCl2 (1.3 equiv), CrCl2 (9 equiv), 3:1 DMSO-THF (70% of 29, 1:1 ratio of diastereomers; 21% of 30); (d) Dess-Martin periodinane,
2,6-lutidine, CH2Cl2, (∼80%).
conditions developed by Keay and Wilson, achieved this desired
tranformation effectively (77%, 90% based on recovered starting
material).33 With significant quantities of 26 in hand, our
attempts to construct the B-ring of 1 began.
I2, PPh3, imidazole, or DEAD, PPh3, ZnX2) failed to secure any
of the necessary alkyl halide products.36 Our attempts to convert
26 to its trifluoromethanesulfonate derivative were unsuccessfuls
the product (not fully characterized) that was obtained in these
attempts did not have a signal in its 19F NMR spectrum. This
setback forced us to consider alternative methods to close the
12-membered ring of 1.
Macrocyclization Strategy Using Cross-Coupling. The
initial, motivating retrosynthetic thinking regarding the construc-
tion of the macrocyclic B-ring centered on the use of a cross-
coupling reaction. Two options were generally considered (eq
1). Provided that a vinylmetal species could be selectively
generated from an alkyne in the presence of an alkyl halide, a
relatively unusual cross-coupling process between an sp2-
hybridized organometallic and a sp3-hybridized alkyl halide
could be used to form the final critical C-C bond (option 1).34
In the event that this reaction was not feasible, an alternative
idea was to take advantage of the known ability of elemental
zinc to selectively react with an alkyl halide bond in the presence
of an alkenyl halide (option 2).35 After the appropriate orga-
nometallic species was generated using either option, the
addition or presence of a group 10 catalyst system might enable
an intramolecular Negishi-type cross coupling reaction forming
a macrocycle.
Macrocyclization Strategy Using Carbonyl Addition. At
this point, there was some concern that the macrocycle could
be not formed under any conditions, and consequently, a more
deliberate approach was taken. The Kishi-Nozaki-Hiyama
(K-N-H) carbonyl addition reaction has excellent precedent
for the construction of large rings.37 Consequently, its application
toward the construction of 1 was investigated. The vinylorga-
nometallic species generated by the reaction of the alkyne
(33) Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918.
(34) At the project’s conception, this was an aggressive tactic. More
recent work demonstrates that this is conceptually achievable: (a) Giovan-
nini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186. (b) Netherton,
M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
10099. (c) Kirchhoff, K.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662. (d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc.
2003, 125, 12527. (e) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126,
1340. (f) Mentzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718. (g)
Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. (h) Frisch, A. C.;
Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 4056. (i)
Frisch, A. C.; Rataboul, F.; Zapf, A.; Beller, M. J. Organomet. Chem. 2003,
687, 403. (j) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297. (k)
Nakamura, M.; Matsuo, K.; Nakamura, E. J. Am. Chem. Soc. 2004, 126,
3686. (l) Martin, M.; Fu¨rtsner, A. Angew. Chem., Int. Ed. 2004, 43, 3955.
(35) Fenster, E. Ph.D. Thesis, University of British Columbia, February
2006.
Unfortunately, the investigations into such a bond-forming
event were completely stymied by our inability to convert
alcohol 26 to its corresponding alkyl halide (eq 2). Despite
reasonable precedent for this process within the literature and
in our research group using structurally related compounds, a
number of reaction conditions (e.g., Tf2O then NaI, solvent or
(36) (a) Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5544. (b)
Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am. Chem. Soc.
1988, 110, 5806. (c) Ho, P. T.; Davies, N. J. Org. Chem. 1984, 49, 3027.
4242 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Approach toward Nitianes
SCHEME 9. Synthesis of Metathesis Precursora
the recovery of 32 was 77% over the two steps. The conversion
of alcohol to allylic acetate 33 using standard conditions (Ac2O,
Et3N, DMAP, CH2Cl2, 86%) was followed by a palladium(0)-
catalyzed reduction.40 The reaction of 33 with triethylammonium
formate in the presence of 5 mol % of Pd2(dba)3 and tri-n-
butylphosphine in dioxane at 100 °C enabled the isolation of a
94% yield of the terminal alkene 34. Although this sequence
produced the requisite ring-closing metathesis precursor, the
limited quantities of 34 (from 30) did not permit an extensive
examination of possible metathesis reaction conditions. In most
instances, subjecting 34 to a second-generation Grubbs metath-
esis catalyst resulted in compound decomposition. Possible
macrocyclization products were not detected using GC-MS
analysis of the reaction mixture. At this point, it was evident
that the allyl alcohols 29 from the K-N-H cyclization would
have to serve as key synthetic intermediates if our route to nitiol
was to be successful.
Attempts to Deoxygenate 29. Our prior experience using
Pd(0)-catalyzed reduction to convert 33 to 34 suggested that
this protocol was particularly attractive for the C1 deoxygenation
of 29. Although the formation of alkene isomers was a
significant point of concern using this method, a limited number
of options at this point forced us to accept this possible outcome.
To that end, 29 was converted to its corresponding allylic
carbonate 35 using the method of Wuts and co-workers (N-
carboxymethylbenzotriazole, Et3N, DMAP, 80%).41 Quite sur-
prisingly, the submission of 35 to specific sets of conditions as
reported in the literature resulted in no reaction.42 Although
somewhat forcing conditions such as Pd(PPh3)4 (5 mol %) and
n-BuZnCl in THF at 70 °C resulted in reaction,43 the examina-
tion of the product mixture, after TBAF treatment to remove
the silyl protecting group, suggested that a diene mixture of
type 36 was produced (eq 3).44
a Reaction conditions: (a) (CH3O)2POCH2CO2CH3, NaH, THF; (b)
DIBAL-H, CH2Cl2, -78 °C to rt (77%, two steps); (c) Ac2O, Et3N, DMAP,
CH2Cl2 (86%); (d) Pd2(dba)3, P(n-Bu)3, Et3NHCO2H, 1,4-dioxane, 100 °C
(94%).
function within 26 with trimethylaluminum in the presence of
bis(cyclopentadienyl)zirconium chloride was quenched with
iodine using the conditions defined by Negishi to generate
alkenyl iodide 27 in 82% yield (Scheme 8).38 The aldehyde 28
was produced using the Dess-Martin protocol.32 Gratifyingly,
the treatment of 28 to K-N-H macrocyclization conditions as
used by the Pattenden laboratory produced a 70% yield of 29
as a 1:1 mixture of diastereomers.39 A small amount of aldehyde
30, an uncyclized byproduct, was recovered from the product
mixture as well. Alcohols 29a and 29b could be separated using
column chromatography. The relative configuration of each
epimer was established spectroscopically at a later stage (see
below). Oxidation of each diastereomeric alcohol gave macro-
cyclic ketone 31. As the feasibility of the macrocycle closure
had been convincingly demonstrated, we decided to examine a
third possibility for ring closure.
Macrocyclization Strategy Using Ring-Closing Metathesis.
The byproduct of the K-N-H cyclization, alkene 30, presented
an opportunity to examine a third method for the closure of the
macrocycle. A ring-closing metathesis strategy, if effective,
would generate the desired ring system of nitiol without
generating an extraneous functional group that requires removal.
Consequently, this synthetic route appeared to have clear
advantages over the K-N-H protocol. To test the metathesis
reaction, aldehyde 30 was elaborated to allyl alcohol 32 using
conventional conditions (Horner-Wadsworth-Emmons reac-
tion, DIBAL-H reduction) (Scheme 9). The isolated yield for
Concurrently with the experimental studies outlined in eq 3,
a simpler model system 37 was being used to survey potential
reduction conditions (Figure 2). The results of these studies were
particularly disappointing. Most of the tested conditions did not
(37) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.;
Nozaki, H. Tetrahedron Lett. 1983, 24, 5281. (c) Jin, H.; Uenishi, J.-I.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (d) Kishi, Y.
Pure Appl. Chem. 1992, 64, 343. (e) For an excellent review, see: Fu¨rstner,
A. Chem. ReV. 1999, 99, 991.
(38) (a) Okukado, E.; Negishi, E.-I. Tetrahedron Lett. 1978, 19, 2357.
(b) Van Horn, D. E.; Negishi, E.-I. J. Am. Chem. Soc. 1978, 100, 2252. (c)
Negishi, E.-I.; Van Horn, D. E.; King, A. O.; Okukado, N. Synthesis, 1979,
501. (d) Negishi, E.-I.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (e) Rand, C. L.; Van Horn, E.-I.; Moore, M. W.; Negishi,
E.-I. J. Org. Chem. 1981, 46, 4093. (f) Negishi, E.-I.; Van Horn, D. E.;
Yoshida, T. J. Am. Chem. Soc. 1985, 107, 6639.
(40) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623.
(41) Wuts, P. G. M.; Ashford, S. W.; Andherson, A. M.; Atkins, J. R.
Org. Lett. 2003, 5, 1483.
(42) (a) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (b) Tsuji, J. Pure Appl.
Chem. 1989, 61, 1673. (c) Tsuji, J. Tetrahedron 1985, 41, 4361. (d) Keinan,
E.; Greenspoon, N. J. Org. Chem. 1983, 48, 3545. (e) Hutchins, R. O.;
Learn, K. J. Org. Chem. 1982, 47, 4380. (f) Mohri, M.; Kinoshita, H.;
Inomata, K.; Kotake, H.; Takagaki, H.; Yamazaki, K. Chem. Lett. 1986,
1177.
(43) Matsushita, H.; Negishi, E.-I. J. Org. Chem. 1982, 47, 4161.
(44) (a) Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron
Lett. 1978, 19, 2075. (b) Trost, B. M.; Verhoeven, T. R.; Fortunak, J. M.
Tetrahedron Lett. 1979, 20, 2301.
(39) Goldring, W. P. D.; Pattenden, G. Chem. Commun. 2002, 1736.
J. Org. Chem, Vol. 71, No. 11, 2006 4243

Wilson et al.
As variculanol, a structural relative of nitiol, is oxidized at its
C-1 position, it is encouraging to speculate that one of these
two unnatural products may be isolated from Nature in the
future. Although the total synthesis of nitiol was not achieved,
a number of our initial synthetic objectives, specifically the
control of the relative stereochemistry within the A and C rings
of the natural product, was accomplished.
FIGURE 2. Model system for deoxygenation studies.
Conclusions
SCHEME 10. Deprotection to 1,22-Dihydroxynitianes
The synthesis of derivatives of nitiol containing a hydroxyl
function at the 1-position was completed in our laboratory.
Important synthetic operations within the sequence forming the
A-ring of nitiol included a siloxy-epoxide rearrangement
reaction, a diastereoselective Pauson-Khand reaction, and a
Norrish type 1 photofragmentation. The construction of the
C-ring fragment used the well-established Ireland-Claisen
reaction to establish stereochemistry and a ring-closing metath-
esis reaction to generate the necessary substituted cyclopenten-
one. This reaction sequence would likely be generally applicable
to the synthesis of a number of enantiomerically enriched 4,5-
cis-disubstituted 2-cyclopentenones. Formation of the macro-
cycle required a copper(I)-promoted Stille cross-coupling and
a Kishi-Nozaki-Hiyama carbonyl addition reaction. Unfortu-
nately, the latter reaction produced a synthetic intermediate that,
in our hands, could not be elaborated to the desired natural
product. The derivatives produced, however, are structural
hybrids of known related natural products.
ionize the allylic leaving group. The exception was the use of
a cationic rhodium(I) catalyst system that ultimately generated
mixtures of 1,3-dienes, similar to the results in eq 3.45
The allylic carbonate within 35 was problematic. A better
leaving group than carbonate was considered to be a potential
solution to this problem. Unfortunately, the reaction of alcohol
29 to standard mesylation conditions only produced eliminated
products (eq 4).
Experimental Section
Some representative experimental procedures for key transforma-
tions are supplied here. For a general experimental protocol and
complete experimental procedures and characterization data, please
refer to the Supporting Information.
Aldehyde 5. To a solution of 4-bromo-3,6-di-tert-butylphenol
(32.4 g, 114 mmol) in DCM (200 mL) was added trimethylalumi-
num (28.4 mL, 2 M in hexanes, 56.8 mmol). After 1 h of stirring
at rt, the solution was cooled to -78 °C and a solution of 4 (7.62
mg, 28.4 mmol) in DCM (60 mL) was added dropwise. The
resulting solution was stirred at -78 °C for 1 h then at -40 °C for
1 h before being poured into 1 N HCl. The aqueous layer was
separated and extracted with DCM (4 × 100 mL). The combined
extracts were washed with saturated aqueous sodium bicarbonate,
dried over magnesium sulfate, filtered, and concentrated by rotary
evaporation. The residue was purified by flash chromatography [15:
1 petroleum ether/ether)] to yield 7.33 g (95%) of 5 as a colorless
oil. IR (neat): 2931, 1729, 1472, 1362, 1256, 1099 cm-1. 1H NMR
(400 MHz, CDCl3): δ 9.56 (s, 1H), 3.61 (d, J ) 10.1 Hz, 2H),
3.57 (d, J ) 10.1 Hz, 2H), 2.12-2.03 (m, 2H), 1.87-1.80 (m,
1H), 1.68-1.61 (m, 1H), 1.70 (t, J ) 2.4 Hz, 3H), 1.00 (s, 3H),
0.83 (s, 9H), 0.00 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 206.1,
79.1, 67.2, 51.4, 32.4, 26.1, 18.5, 16.2, 14.2, 3.8, -5.3. LRMS (CI+
At this point, synthetic material was at a mininum. Conse-
quently, the separated allylic alcohols 29a and 29b were
deprotected using TBAF in the presence of 4 Å molecular sieves
to generate 1-hydroxynitiol derivatives (Scheme 10). These
compounds, the 1,22-dihydroxynitianes, were fully characterized
spectroscopically. Selective NOE NMR experiments were used
on each diastereomer 38a and 38b to support the assigned
relative stereochemical assignment.
(isobutane)): (M + 1)+ ) 269. [R]26.3 ) -2.63 (c ) 1.540,
D
CHCl3).
Although the end result was certainly frustrating to some
extent, the synthetic 1,22-dihydroxynitianes (1-hydroxynitiol)
can be viewed as a structural hybrid of nitiol and variculanol.
Ester 9. A 500 mL quartz round-bottom flask was charged with
a solution of 8 (1.29 g, 4.15 mmol) in anhydrous methanol (400
mL). The methanol solution was degassed (Ar sparge) for 45 min.
The degassed solution was subjected to hν (g190 nm) for 28.5 h.
The solvent was removed by rotary evaporation and the residue
was purified using flash chromatography [20:1 (hexanes/ethyl
acetate)] to yield 1.16 g of 9 (82%) and 122 mg of 8 (9.5%). IR
(neat): 2954, 2858, 1742, 1471, 1436, 1386, 1368, 1256 cm-1. 1H
NMR (400 MHz, CDCl3): δ 3.64 (s, 3H), 3.36 (d, J ) 9.5 Hz,
1H), 3.21 (d, J ) 9.5 Hz, 1H), 2.42 (ddd, J ) 3.4 Hz, 6.4 Hz, 10.1
Hz, 1H), 2.25 (dd, J ) 3.4 Hz, 16.2 Hz, 1H), 2.11 (dd, J ) 10.4
(45) Examples of conditions that were attempted. With formate 37a: Pd-
(PPh3)4; Pd2(dba)3, PPh3; Pd2(dba)3, PCy3; Pd2(dba)3, PBu3; Pd2(dba)3, PBu3
and PPh3; Pd2(dba)3, dppp; Pd2(dba)3, dppb; Pd2(dba)3, Xantphos; Rh(PPh3)3-
Cl, AgOTf; Ni(COD)2, PPh3; Ni(COD)2, PCy3; Ni(PPh3)2Cl2, 2 equiv of
MeLi; Ni(PPh3)2Cl2, 2 equiv of MeLi, PCy3. With carbonate 37b: Pd2-
(dba)3, PCy3, NaBH4; Pd2(dba)3, PCy3, Et3SiH.; Pd2(dba)3, PCy3, PHMS.;
Rh(PPh3)3Cl, AgOTf, Et3SiH.; Rh(PPh3)3Cl, AgOTf, PHMS.; Rh(PPh3)3-
Cl, AgOTf, NaBH4.
4244 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Approach toward Nitianes
Hz, 16.2 Hz, 1H), 1.73-1.64 (m, 2H), 1.51-1.14 (m, 4H), 0.89
(s, 9H), 0.88 (s, 3H), 0.86 (d, J ) 1.5 Hz, 3H), 0.85 (d, J ) 1.5
Hz, 3H), 0.01 (d, J ) 1.8 Hz, 6H). 13C NMR (75 MHz, CDCl3):
δ 175.0, 71.0, 51.5, 50.2, 47.6, 41.4, 33.4, 30.8, 29.5, 27.8, 25.9,
22.1, 21.7, 21.1, 18.2, -5.5. HRMS (CI+ (NH3+/isobutane)): calcd
29a. IR (neat): 3446, 3071, 1049, 2954, 2929, 2857, 1464, 1428,
1377, 1363, 1112, 1071, 1027 cm-1. 1H NMR (300 MHz, CDCl3):
δ 7.67 (d, J ) 6.55 Hz, 4H), 7.45-7.28 (m, 6H), 5.67 (dd, J ) 1.9
Hz, 7.7 Hz, 1H), 5.50 (s, diast), 5.45 (s, 1H), 5.37 (d, J ) 8.5 Hz,
1H), 5.28 (d, J ) 8.5 Hz, diast), 4.27 (q, J ) 11.2 Hz, 2H), 4.07
(d, J ) 8.1 Hz, 1H), 2.69 (t, J ) 6.9 Hz, 1H), 2.50-2.33 (m, 1H),
2.33-2.17 (m, 2H), 2.16-1.72 (m, 6H), 1.62 (s, 3H), 1.54-1.12
(m, 2H), 1.42 (s, 1H), 1.07 (d, J ) 6.9 Hz, 3H), 1.01 (s, 9H), 0.85
(dd, J ) 6.2 Hz, 10.4 Hz, 6H), 0.75 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 149.3, 140.7, 136.2, 135.8, 133.8, 131.5, 129.5, 127.5,
125.7, 122.9, 75.4, 60.7, 55.1, 51.5, 51.3, 41.2, 39.8, 39.3, 38.8,
37.5, 30.3, 28.2, 27.9, 26.8, 26.4, 24.4, 23.3, 22.3, 22.1, 19.3, 19.0,
for C19H38O3Si (M + 1)+ 343.26685, found 343.26615. [R]20.2
+5.31 (c ) 0.231, CHCl3).
)
D
Diene 21. A flame-dried 50 mL Schlenk flask was charged with
lithium chloride (660 mg, 15.6 mmol), copper(I) chloride (1.29 g,
13.0 mmol), and tetrakis(triphenylphosphine)palladium (300 mg,
0.26 mmol) in a glovebox. The mixture of solids was degassed
four times. A solution of 20 (1.04 g, 2.55 mmol) in degassed DMSO
(11 mL) was added dropwise. Then, a solution of 13 (1.87 g, 2.85
mmol) in degassed DMSO (11 mL) was added. The resulting
mixture was degassed using the freeze-pump-thaw method. The
mixture was stirred in a foil-wrapped flask for 1 h at rt before being
heated to 60 °C for 37 h. The reaction was cooled to rt, diluted
with Et2O (300 mL), and washed with a mixture of brine (400 mL)
and 5% NH4OH (80 mL) resulting in a bright blue aqueous layer.
The aqueous layer was separated and extracted with Et2O (3 ×
150 mL). The combined organic layers were washed with water (3
× 75 mL) and brine (3 × 75 mL), dried over magnesium sulfate,
filtered, and concentrated by rotary evaporation. The residue was
purified using flash chromatography [10:1 (petroleum ether/ether)]
to yield 1.18 g (74%) of 21. IR (neat): 2953, 2924, 2857, 1730,
14.9. LRMS (EI): (M)+ ) 610. [R]21.7 ) -30.54 (c ) 0.497,
D
CH2Cl2).
29b. IR (neat): 3420, 3071, 2954, 2927, 2856, 1718, 1636, 1465,
1430, 1387, 1262, 1112, 1072, 1007, 822, 740, 702, 610, 518 cm-1
.
1H NMR (300 MHz, CDCl3): δ 7.67 (d, J ) 6.2 Hz, 4H), 7.45-
7.28 (m, 6H), 5.50 (s, diast), 5.44 (s, 1H), 5.39-5.27 (m, 2H), 4.28
(dd, J ) 11.2 Hz, 30.4 Hz, 2H), 4.06 Hz, d, J ) 9.6 Hz, 1H),
2.45-2.12 (m, 3H), 2.12-1.89 (m, 3H), 1.85 (s, 3H), 1.75-1.36
(m, 9H), 1.42 (s, 1H), 1.33-1.16 (m, 3H), 1.05 (dd, J ) 6.2 Hz,
35.1 Hz, 3H), 1.02 (s, 9H), 0.84 (dd, J ) 6.2 Hz, 18.5 Hz, 6H),
0.82 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 149.3, 138.6, 136.4,
135.8, 133.9, 133.8, 130.8, 129.5, 127.5, 126.9, 122.9, 60.5, 53.4,
50.5, 46.9, 46.6, 41.1, 39.0, 37.9, 36.6, 30.3, 29.7, 28.1, 28.9, 26.9,
1614, 1514, 1466, 1433, 1383, 1362, 1302, 1249, 1200, 1175 cm-1
.
26.2, 24.4, 22.4, 22.1, 20.7, 19.3, 16.9, 14.6. LRMS (EI): (M)+
)
1H NMR (400 MHz, CDCl3): δ 7.23 (d, J ) 8.6 Hz, 2H), 6.83 (d,
J ) 8.6 Hz, 2H), 5.79 (dd, J ) 6.4 Hz, 11.0 Hz, 1H), 5.57 (s, 1H),
4.37 (s, 2H), 3.78 (s, 3H), 3.75 (d, J ) 2.1 Hz, 3H), 3.35 (t, J )
6.7 Hz, 2H), 3.34 (d, J ) 9.5 Hz, 1H), 3.11 (d, J ) 9.5 Hz, 1H),
2.75-2.66 (m, 1H), 2.48-2.39 (m, 1H), 2.39-2.31 (m, 1H), 2.27-
2.20 (m, 1H), 2.20-2.10 (m, 1H), 2.06-1.95 (m, 1H), 1.95-1.88
(m, 1H), 1.74-1.56 (m, 3H), 1.56-1.43 (m, 3H), 1.39-1.16 (m,
4H), 1.03 (dd, J ) 2.4 Hz, 7.0 Hz, 3H), 0.93 (s, 3H), 0.87 (s, 9H),
0.83 (dt, J ) 1.8 Hz, 6.1 Hz, 6H), 0.00 (s, 6H). 13C NMR (75
MHz, CDCl3): δ 169.2, 159.0, 144.4, 137.6, 130.9, 130.4, 129.1,
127.8, 113.7, 72.4, 71.2, 70.7, 55.2, 51.4, 50.8, 47.8, 46.6, 44.6,
39.7, 37.2, 34.0, 29.2, 27.8, 25.9, 25.7, 24.5, 22.3, 22.1, 22.0, 18.3,
15.3, -4.0. Anal. Calcd for C38H62O5Si: C, 72.79; H, 9.97.
610. [R]22.1 ) +43.05 (c ) 0.428, CH2Cl2).
D
30. IR (neat): 3071, 3046, 2957, 2931, 2867, 1728, 1648, 1471,
1459, 1428, 1388, 1374, 1365, 1112, 1069, 886, 823, 742, 702,
1
612 cm-1. H NMR (300 MHz, CDCl3): δ 9.34 (s, 1H), 7.67 (d,
J ) 7.3 Hz, 4H), 7.46-7.31 (m, 6H), 5.67 (s, 1H), 5.56 (s, diast.),
5.47 (t, J ) 6.6 Hz, 1H), 4.62 (s, 1H), 4.60 (s, 1H), 4.35 (dt, J )
11.2 Hz, 16.2 Hz, 2H), 2.77-2.65 (m, 1H), 2.51-2.25 (m, 2H),
2.14-1.82 (m, 7H), 1.76-1.13 (m, 3H), 1.66 (s, 3H), 1.10 (d, J )
6.9 Hz, 3H), 1.03 (s, 9H), 0.95 (t, J ) 11.2 Hz, 3H), 0.78 (d, J )
6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 205.4, 147.3, 146.6,
135.7, 134.0, 133.7, 131.0, 129.6, 127.6, 125.7, 109.2, 77.2, 65.8,
60.3, 58.1, 51.7, 46.1, 44.5, 40.0, 37.6, 30.0, 29.2, 27.3, 26.8, 26.5,
22.8, 22.7, 22.0, 21.7, 19.3, 17.9, 15.4. Anal. Calcd for C41H58O2-
Si: C, 74.19; H, 10.43. Found: C, 74.24; H, 10.58. [R]22.0D ) +9.67
(c ) 1.18, CH2Cl2).
Found: C, 72.59; H, 10.08. [R]27.1 ) +1.09 (c ) 1.024, CH2Cl2).
D
Cyclization of 28 to 29 and 30. A flame-dried 25 mL round-
bottom flask was charged with chromium(II) chloride (63 mg, 0.513
mmol) and nickel chloride (13 mg, 0.103 mmol) in the glovebox.
A 3:1 mixture of degassed DMSO/THF (7 mL) was added, and
the suspension was stirred in the dark for 10 min. A solution of 28
(41 mg, 0.056 mmol) in 3:1 DMSO/THF (12 mL) was added
dropwise. The reaction mixture was stirred in the dark for 42 h.
The reaction was quenched with basic NH4Cl (pH ) 8 buffer) and
extracted with Et2O (4 × 25 mL). The combined organic layers
were washed with brine (3 × 10 mL), dried over magnesium sulfate,
filtered, and concentrated by rotary evaporation. The residue was
purified using flash chromatography [gradient: (1) (30:1 petroleum
ether/ether), (2) (8:1 petroleum ether/ether), (3) (5:1 petroleum ether/
ether)] to yield 7.2 mg (21%) of 30, 11.7 mg (35%) of 29a and
12.1 mg (35%) of 29b (70% total).
Acknowledgment. We thank the University of British
Columbia, Merck-Frosst, for unrestricted research support, the
Natural Sciences and Engineering Research Council (NSERC)
of Canada (CRD and Discovery grant programs), and Glaxo-
Smith Kline for the financial support of our programs. G.R.D.
thanks Prof. Viresh Rawal and Prof. Edward Piers for stimulat-
ing discussions and Prof. John Scheffer for the use of photo-
chemistry equipment.
Supporting Information Available: Experimental procedures
and characterization data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0604585
J. Org. Chem, Vol. 71, No. 11, 2006 4245